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Does infliximab prevent Crohn 's disease recurrence after ileal resection? | Crohn's disease commonly recurs after intestinal resection. We evaluated whether the administration of infliximab after resective intestinal surgery for Crohn's disease reduces postoperative recurrence. We randomly assigned 24 patients with Crohn's disease who had undergone ileocolonic resection to receive intravenous infliximab (5 mg/kg), administered within 4 weeks of surgery and continued for 1 year, or placebo. The primary end point was the proportion of patients with endoscopic recurrence at 1 year. Secondary end points were clinical recurrence and remission and histologic recurrence. The rate of endoscopic recurrence at 1 year was significantly lower in the infliximab group (1 of 11 patients; 9.1%) compared with the placebo group (11 of 13 patients; 84.6%) (P = .0006). There was a nonsignificant higher proportion of patients in clinical remission in the infliximab group (8 of 10; 80.0%) compared with the placebo group (7 of 13; 53.8%) (P = .38). The histologic recurrence rate at 1 year was significantly lower in the infliximab group (3 of 11 patients; 27.3%) compared with the placebo group (11 of 13 patients; 84.6%) (P = .01). The occurrence of adverse events was similar between the placebo and infliximab groups, and none occurred in the immediate postoperative period. | The non-neuronal acetylcholine system (NNAS) in endothelial cells participates in modulating endothelial function, vascular tone, angiogenesis and inflammation, thus plays a critical role in cardiovascular diseases. In this study, we used a proteomic approach to study potential downstream receptor-effectors of NNAS that were involved in regulating cellular function in endothelial cells. Human umbilical vein endothelial cells were incubated in the presence of acetylcholine, oxotremorine, pilocarpine or nicotine at the concentration of 10 μmol/L for 12 h, and the expressed proteins in the cells were separated and identified with two-dimensional electrophoresis (2-DE) and LC-MS. The protein spots with the largest changes were identified by LC-MS. Biowork software was used for database search of the peptide mass fingerprints. Over 1200 polypeptides were reproducibly detected in 2-DE with a pH range of 3-10. Acetylcholine, oxotremorine, pilocarpine and nicotine treatment caused 16, 9, 8 and 9 protein spots, respectively, expressed differentially. Four protein spots were identified as destrin, FK506 binding protein 1A (FKBP1A), macrophage migration inhibitory factor (MIF) and profilin-1. Western blotting analyses showed that treatment of the cells with cholinergic agonists significantly decreased the expression of destrin, FKBP1A and MIF, and increased the expression of profilin-1. |
Does resveratrol inhibit fatty acid and triacylglycerol synthesis in rat hepatocytes? | The putative role of resveratrol, a polyphenol present in grapes and other plants, in modulating dislypidemia, thus preventing cardiovascular diseases, is generally based on proliferating cell lines and in vivo studies in different pathological conditions. The aim of the present study was to investigate whether resveratrol plays a role on lipid biosynthesis in rat hepatocytes. The effect of resveratrol on total rate of fatty acid, cholesterol and complex lipid synthesis, assayed by the incorporation of [1-(14)C]acetate into these lipid fractions, was investigated in rat hepatocyte suspensions. Enzyme activities of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) as well as 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA-R), pace-setting steps of de novo fatty acid and cholesterol synthesis, respectively, were in situ measured in digitonin-permeabilized hepatocytes. Resveratrol-treated hepatocytes exhibited a short-term (30 min) inhibition (IC(50) approximately 25 microm) of total fatty acid synthesis from [1-(14)C]acetate. Among neosynthesized fatty acids, palmitic acid formation was mainly reduced, thus suggesting that enzymatic step(s) of de novo fatty acid synthesis was affected by resveratrol. In digitonin-permeabilized hepatocytes, only ACC activity was noticeably reduced, while no change in FAS activity was observed. A noticeable resveratrol-induced reduction of label incorporation into triacylglycerols was also detected. Conversely, cholesterol synthesis and HMG-CoA-R activity were unaffected by resveratrol. | Von Willebrand factor antigen (vWF-Ag) is a marker of pulmonary and systemic endothelial activation and injury. Adult studies indicate that patients with plasma vWF-Ag levels > or = 450% of control early in the course of acute lung injury (ALI) have an increased risk of death. The objective of this study was to evaluate whether vWF-Ag is elevated in the early phase of ALI in children and whether the magnitude of the increase was predictive of two important outcomes: mortality or duration of mechanical ventilation. Two-center, prospective observational study. Two pediatric intensive care units: one in an academic university setting and one in a major community children's hospital. After appropriate consent, plasma was collected from 48 pediatric patients on day 1 of ALI, 45 patients on day 2 of ALI, and four intubated controls. None. Mean PaO2/FiO2 at the onset of ALI was 140 +/- 70, and mortality rate was 17%. vWF-Ag levels on day 1 of ALI were higher in patients compared with controls (287 +/- 183 vs. 87 +/- 84% of control [mean +/- SD], p < .05). Patients with vWF-Ag levels > or = 450% of control on day 1 of ALI had a markedly greater risk of death (odds ratio, 7.0; confidence interval, 1.31, 37.30; p < .05). Multivariate analysis revealed that elevated vWF-Ag level and either presence of multiple organ system failure or Pediatric Risk of Mortality III score independently predict increased risk of death. vWF-Ag levels on day 2 of ALI were significantly higher in patients who required prolonged mechanical ventilation (316 +/- 173 vs. 191 +/- 89% of control, p < .05). |
Have the increased utilisation of dopamine agonists and the introduction of COMT inhibitors reduced levodopa consumption -- a nation-wide perspective in Sweden? | To study the impact of the new pharmacological treatment strategies in Parkinson's disease by analysis of the sales of dopaminergic drugs in Sweden 1990-2001. Invoice statistics and statistics on prescription sales of dopaminergic drugs 1990-2001 were obtained from the 906 public pharmacies and the 89 hospital pharmacies in Sweden. The Swedish Diagnosis and therapy survey was used to study the diagnosis the drugs were prescribed for. During the period the sales expressed in DDD/1000 inhabitants and day increased from 1.75 to 1.86 (6%) for levodopa and from 0.04 to 0.27 (575%) for dopamine agonists. The increase in sales of dopamine agonists occurred after 1997 and consisted entirely of the sales of the new agonists, cabergoline, pramipexole and ropinirole. In Swedish crowns the total sales of dopaminergic drugs increased with 126% during the period. The cost for the dopamine agonists was 8% of the total cost for dopaminergic drugs in 1990 and 23% in 2001. The prescription sales figures of levodopa and dopamine agonists for the different Swedish counties in 2001 varied between 1.52 and 2.44 and 0.13 and 0.74 DDD/1000 inhabitants and day, respectively. There was no correlation, whether positive or negative, between the sales of dopamine agonists, levodopa and COMT inhibitors or between the sales and the densities of neurologists. | Cell signaling pathways underlying wound repair are under extensive investigation; however, there is still a poor understanding of the mechanisms orchestrating these processes. Hox genes, which are a subgroup of homeobox genes, encode for a family of transcription factors that play a critical role in tissue migration and cell differentiation during embryogenesis and may also serve as master regulatory genes of postnatal wound repair. We have developed a fetal excisional wound healing model whereby mid-gestational wounds heal in a regenerative manner while late-gestational wounds display scar formation. We theorize that Hoxd3 and Hoxd8 will be differentially expressed in mid- and late-gestational wounds compared with normal skin. Pregnant FVB mice underwent hysterotomy at mid (E15)- or late (E18)-gestational time points, and 3-mm excisional wounds were made on the dorsum of each fetus. Wound samples (w) were collected at the site of injury as well as near wound normal skin (nwc) on the same fetus. Control (c) skin samples were also obtained from unwounded adjacent fetuses. Samples were harvested at 3 and 6 h and real-time polymerase chain reaction was performed for Hoxd3 and Hoxd8 and normalized to glyceraldehyde-3-phosphate dehydrogenase. Data were analyzed by analysis of variance with statistical significance of P < 0.05. Hoxd3 levels were increased in all of the mid-gestational groups, with a significant increase at 3 h compared with late-gestational control groups. In the 3-h time group, Hoxd8 is increased in mid-gestational wounds compared with late-gestational control skin. This is repeated in the 6-h time group, where Hoxd8 is increased in mid-gestational wounds compared with all groups. Also, Hoxd8 in the mid-gestational near wound controls is significantly greater than that in the late-gestational near wound control and control groups. |
Does a common polymorphism within MSLN affect miR-611 binding site and soluble mesothelin levels in healthy people? | Soluble mesothelin related peptide (SMRP) was proposed as a promising diagnostic marker for malignant pleural mesothelioma (MPM). In a previous study, we found that rs1057147 within the 3' untranslated region of MSLN gene was associated with SMRP levels. Thus, we aimed to (1) confirm the previous association on a large series of volunteers and (2) test the hypothesis that the SNP could affect microRNA binding sites. The association analysis was verified in 759 subjects. Then, in silico predictions highlighted miR-611 and miR-887 as candidate miRNAs binding to the polymorphic site. Thus, chimeric constructs bearing the alternative alleles (G > A) were assayed alone or in cotransfection with the miRNA mimics, with dual luciferase reporter assay in non-MPM Met-5A cells. The miRNAs were also assayed by western blot analysis for their ability to down-regulate endogenous mesothelin in the MPM Mero-14 cell line. We confirmed that, among non-MPM volunteers, GG homozygotes have the lowest SMRP levels. When the genotype is taken into account, the specificity of SMRP as biomarker improves from 79.7% to 85.3%. Dual-luciferase assays showed a significantly lower reporter activity when the vector harbored the G allele as compared to A allele. miR-887 mimic caused a reduced reporter activity of vectors harboring A or G alleles, while miR-611 was effective only on the vector harboring the G allele. Transfection of these miRNAs into Mero-14 cells significantly reduced endogenous MSLN protein. | Physiological data suggest that autumn leaf colours of deciduous trees are adaptations to environmental stress. Recently, the evolution of autumn colouration has been linked to tree condition and defence. Most current hypotheses presume that autumn colours vary between tree individuals. This study was designed to test if within-tree variation should be taken into account in experimental and theoretical research on autumn colouration. Distribution of red autumn leaf colours was compared between partially dead and vigorous specimens of Norway maple (Acer platanoides) in a 3-year study. In August, the amount of reddish foliage was estimated in pairs of partially dead and control trees. Within-tree variation in the distribution of reddish leaves was evaluated. Leaf nitrogen and carbon concentrations were analysed. Reddish leaf colours were more frequent in partially dead trees than in control trees. Reddish leaves were evenly distributed in control trees, while patchiness of red leaf pigments was pronounced in partially dead trees. Large patches of red leaves were found beneath or next to dead tree parts. These patches reoccurred every year. Leaf nitrogen concentration was lower in reddish than in green leaves but the phenomenon seemed similar in both partially dead and control trees. |
Does cPAP therapy of obstructive sleep apnea in type 2 diabetics improve glycemic control during sleep? | Type 2 diabetes and obstructive sleep apnea (OSA) are frequently comorbid conditions. OSA is associated with increased insulin resistance, but studies of continuous positive airway pressure (CPAP) have shown inconsistent effects on glycemic control. However, endpoints such as hemoglobin A1c and insulin sensitivity might not reflect short-term changes in glycemic control during sleep. We used a continuous glucose-monitoring system to measure interstitial glucose every 5 minutes during polysomnography in 20 patients with type 2 diabetes and newly diagnosed OSA. The measurements were repeated after an average of 41 days of CPAP (range 26-96 days). All patients were on a stable diet and medications. Each 30-second epoch of the polysomnogram was matched with a continuous glucose-monitoring system reading, and the sleeping glucose level was calculated as the average for all epochs scored as sleeping. The mean sleeping glucose decreased from untreated (122.0 +/- 61.7 mg/dL) to treated (102.9 +/- 39.4 mg/dL; p = 0.03 by Wilcoxon paired rank test). The sleeping glucose was more stable after treatment, with the median SD decreasing from 20.0 to 13.0 mg/dL (p = 0.005) and the mean difference between maximum and minimum values decreasing from 88 to 57 mg/dL (p= 0.003). The change in the mean hemoglobin A1c from 7.1% to 7.2% was not significant. | In HCV-related graft hepatitis, immunosuppression has been implicated in rapid progression to cirrhosis, a serious clinical issue. We investigated the effects of cyclosporine or tacrolimus on cell growth and collagen production by hepatic stellate cells (HSC), which play a role in hepatic fibrosis. Cultured rat HSCs and human HSC-derived TWNT-4 cells were evaluated for proliferation, type I collagen, phosphorylation states of mitogen-activated protein kinases extracellular signal-regulated kinase 1/2; [MAPKs Erk1/2], c-Jun N-terminal kinase (JNK, p38), as well as the expression of collagen, matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) genes. Cyclosporine suppressed cell growth and collagen production in a concentration-dependent manner. At clinically relevant concentrations of 0.125 micromol (150 ng/mL) cyclosporine significantly reduced collagen production per cell by more than 50%. Similarly, tacrolimus also reduced both collagen concentration and cell number; however, tacrolimus at a clinically relevant concentration of 12.5 nmol (10 ng/mL) did not significantly reduce collagen production. Treatment with cyclosporine reduced type I collagen and TIMP-1 expression and enhanced MMP-1 expression. Cyclosporine also inhibited phosphorylation strongly for JNK and p38, and weakly inhibited for Erk1/2. |
Does novel individual metabolic profile characterize the protein kinase B-alpha ( pkbα-/- ) in vivo model? | Type 2 diabetes and associated co-morbidities run epidemic waves worldwide. Since pathophysiological constellations are individual and display a wide spread of dysmetabolic profiles personalized health care assessments start to emerge. Therefore, we established a specific in silico assessment tool targeting metabolic characterizations individually. Values obtained from oral glucose and intraperitoneal insulin tolerance tests performed on pkbα(-/-) mice (KO) as well as age- and gender-matched controls (WT) were analysed using our established in silico model. Generally, male pkbα(-/-) mice (KO) presented significantly increased insulin sensitivity at an age of 6 months compared with age-matched WTs (p = 0.036). Female KO and WT groups displayed improved glucose sensitivities compared with age-matched males (for WT p ≤ 0.011). | Biofilm formation in otopathogenic of Pseudomonas aeruginosa (OPPA) strains is inhibited by ethylenediaminetetraacetic acid (EDTA). EDTA, a widely used chelating agent, has been shown to inhibit biofilm formation in a number of bacteria. Because EDTA may be a well-tolerated reagent to inhibit biofilm formation in cases of suppurative otitis media, we asked if it might be effective in all OPPA strains isolated from chronically infected cholesteatomas. OPPA strains were isolated from patients with infected cholesteatomas. These strains were grown into log phase then were placed in minimal media with varying concentrations of EDTA and incubated for varying periods. Biofilm production was measured colorimetrically by staining with crystal violet. Without added EDTA, most otopathogenic PA exhibited a distinct, but varying, time course of biofilm formation and dissolution with peak production at 12 to 18 hours. Addition of 1 mM EDTA resulted in a delay in the time to peak biofilm formation for most strains, although the amount of biofilm was not decreased. In contrast, some strains showed greater biofilm production with 1 mM EDTA compared with the untreated bacteria. Addition of 10 mM EDTA resulted in a similar effect. Some strains increased biofilm production over controls. Moreover, EDTA inhibited planktonic growth of all OPPA strains at the concentrations studied. |
Does prolonged right ventricular ejection delay identify high risk patients and gender differences in Brugada syndrome? | Right ventricular (RV) conduction delay has been suggested as an underlying pathophysiological mechanism in Brugada syndrome (BS). In this cross-sectional study we non-invasively assessed the value of echocardiographic markers reflecting ventricular ejection delay to further assess electromechanical abnormalities in BS and to identify patients at risk for life-threatening arrhythmic events. Furthermore, we sought to assess differences in ejection delays between genders because male BS patients demonstrate a more malignant clinical phenotype. 124 BS patients (57.3% males) and 62 controls (CTR) (48.4% males) were included. Using Tissue Velocity Imaging, the ejection delay, determined as the time from QRS onset to the onset of the sustained systolic contraction, was measured for both RV free wall (RVED) and lateral LV wall (LVED). From these parameters, the interventricular ejection delay between both walls (IVED) was calculated. BS patients had longer RVEDs and IVEDs compared to the CTR. BS patients with a previous history of syncope or spontaneous ventricular arrhythmia showed the longest RVEDs and IVEDs. Male BS patients demonstrated longer RVEDs and IVEDs than females. Male BS patients with malignant events had the longest delays. No significant differences regarding LVED were observed between BS patients and CTR. | Ulcerative colitis (UC) is a chronic inflammatory intestinal disease. It is necessary to find out new effective drugs for UC. In our study epicatechin extracted from grape seed by our institute for the first time could treat UC effectively. Then anti-UC mechanisms of epicatechin were elucidated in vivo and in vitro. Dextran sulfate sodium (DSS)-induced acute UC mice model was used to evaluate the activity of epicatechin and its properties against UC. Then its anti-inflammatory and antioxidant effects were evaluated as follows: the concentrations of TNF-α and IL-6 in the colon supernatants were determined by ELISA. NO and MPO were assayed by Griess method and commercial kit respectively. NF-κB were determined by NF-κB-Dependent Reporter Gene Expression Assay and Western Blotting respectively. Antioxidant factors such as SOD, MDA, GSH-Px and CAT were also measured in colon tissues and cell supernatant stimulated by LPS respectively. In C57BL/6J mice model with DSS-induced UC, epicatechin was able to decrease the disease activity index and colon macroscopic damage index scores, reduce body weight loss, and significantly relieve colon contracture and crypt damage. TNF-α, IL-6, NO, MPO and MDA were reduced in the mice administered epicatechin, whereas antioxidant enzymes showed increased activity in epicatechin-treated mice and cell line respectively. Furthermore, inhibition effect on NF-κB activation by epicatechin were demonstrated in vivo and in vitro. |
Are arterial stiffness and pulse wave reflection increased in patients suffering from severe periodontitis? | This single blind cross-sectional study compared the vascular health of subjects suffering from severe chronic periodontitis, severe aggressive periodontitis and periodontal healthy controls by evaluating pulse wave velocity (PWV), augmentation index (AIx) and pulse pressure amplification (PPA). In a total of 158 subjects, 92 suffering from severe periodontitis and 66 matched periodontal healthy controls, PWV, AIx, central and peripheral blood pressure were recorded using an oscillometric device (Arteriograph). Subjects suffering from severe chronic or aggressive periodontitis exhibited significantly higher PWV (p = 0.00004), higher AIx (p = 0.0049) and lower PPA (p = 0.028) than matched periodontal healthy controls. | Lafora disease (LD) is a fatal autosomal recessive neurodegenerative disease. A hallmark of LD is cytoplasmic accumulation of insoluble glucans, called Lafora bodies (LBs). Mutations in the gene encoding the phosphatase laforin account for approximately 50% of LD cases, and this gene is conserved in all vertebrates. We recently demonstrated that laforin is the founding member of a unique class of phosphatases that dephosphorylate glucans. Herein, we identify laforin orthologs in a protist and two invertebrate genomes, and report that laforin is absent in the vast majority of protozoan genomes and it is lacking in all other invertebrate genomes sequenced to date. We biochemically characterized recombinant proteins from the sea anemone Nematostella vectensis and the amphioxus Branchiostoma floridae to demonstrate that they are laforin orthologs. We demonstrate that the laforin gene has a unique evolutionary lineage; it is conserved in all vertebrates, a subclass of protists that metabolize insoluble glucans resembling LBs, and two invertebrates. We analyzed the intron-exon boundaries of the laforin genes in each organism and determine, based on recently published reports describing rates of molecular evolution in Branchiostoma and Nematostella, that the conservation of laforin is linked to the molecular rate of evolution and the glucan metabolism of an organism. |
Is influence of parafascicular thalamic input on neuronal activity within the nucleus accumbens mediated by nitric oxide - an in vivo study? | Thalamostriatal fibers are involved in cognitive tasks such as acquisition, learning, processing of sensory events, and behavioral flexibility and might play a role in Parkinson's disease. The aim of the present study was the in vivo electrochemical characterization of the projection from the lateral aspect of the parafascicular thalamus (Pfl) to the dorsolateral aspect of the nucleus accumbens (dNAc). Since nitric oxide (NO) plays a crucial role in striatal synaptic transmission, its implication in Pfl-evoked signaling within the dNAc was investigated. The Pfl was electrically stimulated utilizing paired pulses and extracellular potentials were recorded within the dNAc. Simultaneously, the dNAc was superfused using the push-pull superfusion technique for local application of compounds and for assessing the influence of NO on release of glutamate, aspartate and GABA. Stimulation of the Pfl evoked a negative-going component at 9-14 ms followed by a positive-going component at 39-48 ms. The early response was current-dependent and diminished by superfusion of the dNAc with tetrodotoxin, kynurenic acid or N(G)-nitro-l-arginine methyl ester (L-NAME), while 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (PAPA/NO) increased this evoked potential. Transmitter release was inhibited by L-NAME and facilitated by PAPA/NO. | Incidence of renal cell carcinoma (RCC) is higher in Black patients with disease-specific and overall survival being lower compared with White patients even though renal tumors among Black patients are more likely to be localized. These disparities have been attributed to higher rates of obesity and hypertension, lower rates of nephrectomy, and a lack of access to quality health care. With scant genomic evidence to account for these disparities, the present study sought to compare BAP1 expression between Black and White patients with clear cell RCC (ccRCC); a gene that inhibits tumor progression when overexpressed and results in poor clinical outcomes when silenced. The cancer genome atlas dataset was used to identify 58 (9.9%) Black and 529 (90.9%) White patients with ccRCC with an initial pathologic diagnosis from 1998 to 2013. BAP1 expression was compared using a Mann-Whitney U test. The association between BAP1 expression and pathologic stage, American Joint Committee on Cancer (AJCC) stage, and Fuhrman grade was assessed for the overall cohort and stratified by race. The association between BAP1 expression and overall survival was assessed using Cox proportion hazards models adjusting for Fuhrman grade, pathologic stage, and the presence of pathologic metastases for the overall cohort and stratified by race. The level of BAP1 expression was significantly higher in Black vs. White patients with ccRCC (10.5 vs. 10.3; P<.001). For the overall cohort, increasing BAP1 expression was associated with decreasing pathologic stage (β =-0.25, P = .004) and decreasing AJCC stage (β =-0.029, P = .006). For Black patients, increasing BAP1 expression was associated with decreasing AJCC stage (β =-0.79, P = .016), decreasing Fuhrman grade (β =-0.55, P = .011), and a decreased risk of pathologic metastases (odds ratio [OR] = 0.83, P = .038). For White patients, increasing BAP1 expression was associated with decreasing pathologic stage (β =-0.20, P = .026). |
Does shilajit attenuate behavioral symptoms of chronic fatigue syndrome by modulating the hypothalamic-pituitary-adrenal axis and mitochondrial bioenergetics in rats? | Shilajit has been used as a rejuvenator for ages in Indian ancient traditional medicine and has been validated for a number of pharmacological activities. The effect of processed shilajit which was standardized to dibenzo-α-pyrones (DBPs;0.43% w/w), DBP-chromoproteins (DCPs; 20.45% w/w) and fulvic acids (56.75% w/w) was evaluated in a rat model of chronic fatigue syndrome (CFS). The mitochondrial bioenergetics and the activity of hypothalamus-pituitary-adrenal (HPA) axis were evaluated for the plausible mechanism of action of shilajit. CFS was induced by forcing the rats to swim for 15mins for 21 consecutive days. The rats were treated with shilajit (25, 50 and 100mg/kg) for 21 days before exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility and the climbing period. The post-CFS anxiety level was assessed by elevated plus maze (EPM) test. Plasma corticosterone and adrenal gland weight were estimated as indices of HPA axis activity. Analysis of mitochondrial complex chain enzymes (Complex I, II, IV and V) and mitochondrial membrane potential (MMP) in prefrontal cortex (PFC) were performed to evaluate the mitochondrial bioenergetics and integrity respectively. Shilajit reversed the CFS-induced increase in immobility period and decrease in climbing behavior as well as attenuated anxiety in the EPM test. Shilajit reversed CFS-induced decrease in plasma corticosterone level and loss of adrenal gland weight indicating modulation of HPA axis. Shilajit prevented CFS-induced mitochondrial dysfunction by stabilizing the complex enzyme activities and the loss of MMP. Shilajit reversed CFS-induced mitochondrial oxidative stress in terms of NO concentration and, LPO, SOD and catalase activities. | Conflicting evidence has been reported on the association of prostate-specific antigen velocity (PSAV) with Gleason score in prostate needle biopsy specimens. The Gleason score is an important prognostic indicator for men with prostate cancer, and, in modern practice, it frequently affects treatment decisions. To our knowledge, the relationship between preoperative PSAV and Gleason score in the radical prostatectomy specimen has not been formally demonstrated. A total of 1049 men treated with radical prostatectomy had data on PSAV and Gleason score. Statistical analysis was performed to examine the relationship between the preoperative PSAV and the prostatectomy Gleason score and other adverse tumor features. The median preoperative PSAV was 0.84, 0.97, and 1.39 ng/mL/y in men with a Gleason score of 6, 7, and 8-10, respectively (P = .05). A PSAV greater than 2 ng/mL/y was significantly associated with a prostatectomy Gleason score of 7 or greater on univariate and multivariate analysis. In addition, the preoperative PSAV was significantly lower in men with organ-confined disease (0.82 vs 1.17 ng/mL/y, respectively, P = .002). |
Do t cells expressing the gamma delta T cell receptor induce apoptosis in cardiac myocytes? | Enterovirus infections are major etiological factors in myocarditis and dilated cardiomyopathy. Using an experimental murine model of this disease, previous studies have shown that myocarditis susceptibility depends upon activation of T lymphocytes expressing the gamma delta T cell receptor (TcR), and that only mouse strains which accumulate gamma delta T cells in the myocardium show apoptosis of myocytes or evidence of dilated cardiomyopathy-like disease. The objective of the present studies is to demonstrate that gamma delta T cells directly induce greater Fas-dependent apoptosis of cultured myocytes than T cells expressing the alpha beta TcR. Bl.Tg.E alpha mice were infected for 7 days with coxsackievirus B3 (CVB3). Hearts were removed and were either formalin-fixed, sectioned and stained with hematoxylin and eosin for inflammation, and using TdT-TUNEL for apoptosis, or were minced and collagenase digested for isolation of gamma delta+ and alpha beta+ T cells using immunomagnetic bead separation. Neonatal cultures of cardiac myocytes were isolated from mice less than 2 days old by collagenase and pancreatin digestion, and were either untreated or infected with virus. Levels of Fas (CD95) were measured using FITC-conjugated hamster anti-mouse Fas monoclonal antibody and flow cytometry. Susceptibility of myocytes to Fas-dependent killing was measured by 51Cr-release by labeled myocytes incubated for 4 h on either 3T3-mock or 3T3-FasL transfected cell monolayers. Killing by T cells was also measured in a 4 h 51Cr-release assay. Fas-dependent and perforin-dependent cytotoxicity was determined by specific blocking using either Fas-Fc or concanamycin A. Virally infected myocyte cultures showed significantly enhanced Fas expression compared to uninfected cells, with maximal upregulation of Fas occurring 18-24 h after virus infection. Both infected and uninfected myocytes were selectively killed by FasL-transfected 3T3 cells but not by mock control cells. Approximately 38% of CD3+ lymphocytes isolated from the heart express the gamma delta TcR with the remainder expressing the alpha beta TcR. Both gamma delta+ and alpha beta+ T cells lysed myocyte targets. Blocking studies indicate that gamma delta+ T cells induced predominantly Fas-mediated killing, while alpha beta+ cell produced more perforin-mediated death, although these effectors were capable of Fas-dependent killing as well. | Knowledge about supportive care needs in patients with cutaneous invasive melanoma is scarce. We examined the unmet needs of melanoma patients treated with surgery and factors associated with these needs to assist health professionals identify areas needing clinical attention. Cross-sectional multisite survey of UK patients ascertained 3 months to 5 years after complete resection of stage I-III cutaneous melanoma. Participants completed the following validated questionnaires: Supportive Care Needs Survey (SCNS-SF34 with melanoma module), Hospital Anxiety and Depression Scale and 51-item Functional Assessment of Cancer Therapy-Melanoma quality-of-life scale. A total of 472 participants were recruited [319 (67%) clinical stage I-II). Mean age was 60 years (standard deviation = 14) and 255 (54%) were female. One hundred and twenty-three (27%) participants reported at least one unmet need (mostly 'low' level). The most frequently reported unmet needs were fears of cancer returning (n = 138, 29%), uncertainty about the future (n = 119, 25%), lack of information about risk of recurrence (n = 112, 24%) and about possible outcomes if melanoma were to spread (n = 91, 20%). One hundred and thirty-eight (29%) participants reported anxiety and 51 (11%) depression at clinical or subclinical levels. Patients with nodal disease had a significantly higher level of unmet supportive care needs (P < 0.001) as did patients with anxiety or depression (P < 0.001). Key correlates of the total SCNS-SF34 score for unmet supportive care needs were younger age (odds ratio, OR = 2.23, P < 0.001) and leaving school early (OR = 4.85, P < 0.001), while better emotional (OR = 0.89, P < 0.001) and social well-being (OR = 0.91, P < 0.001) were linked with fewer unmet needs. Neither patients' sex nor tumour thickness was associated with unmet needs. |
Does constitutive CXCL12 expression induce anoikis in colorectal carcinoma cells? | CXCL12 and CXCR4 signaling plays critical roles in development, homeostasis, and tumor metastasis. Previously, we have shown that epigenetic silencing of CXCL12 in colorectal and mammary carcinomas promotes metastasis. Anoikis is an essential process of colonic epithelial turnover and limits the metastatic progression of carcinoma. We sought to determine the role for anoikis in limiting tumor metastasis following reexpression of CXCL12 in human colorectal carcinoma cells. Tumor formation and metastasis of colonic carcinoma cells was monitored using in vivo bioluminescence imaging. Anoikis was defined by using caspase-3/7, focal adhesion kinase (FAK) and p130Cas cleavage, DNA fragmentation, and cell survival assays. Phosphorylation of extracellular-regulated kinase-1/2 (ERK1/2) was monitored by immunoblot and immunohistochemistry, and activity was inhibited by using U0126. Constitutive expression of CXCL12 in human colorectal carcinoma cells reduced orthotopic tumor formation and inhibited metastasis in severe combined immunodeficient mice. Further, CXCL12 expression induced apoptosis specifically in nonadherent colorectal carcinoma cells. Apoptotic cell death was preceded by hypophosphorylation and cleavage of FAK and p130Cas, leading to increased cellular detachment in culture, and depended on alterations in the extracellular matrix. Similar to in vivo colonic epithelium, CXCL12-induced anoikis of carcinoma cells depended on basal ERK1/2 activation. | The purpose of this study was to investigate time delays, adherence to guidelines, and their impact on outcomes in patients with warfarin-associated intracerebral hemorrhage transferred from community emergency departments to a comprehensive stroke center. We collected demographic, clinical, transfer time, treatment, and outcome data for patients transferred to our institution with warfarin-associated intracerebral hemorrhage from community emergency departments. Among 928 patients with intracerebral hemorrhage, 56 (6%) with warfarin-associated intracerebral hemorrhage (median international normalized ratio, 2.55) were transferred to the comprehensive stroke center. Twenty patients received no acute reversal therapy before transfer, only 4 of whom had international normalized ratios ≤1.4 in the community emergency department. Median time of emergency department stay was 3.66 hours and median time to initiation of acute reversal therapy was 4.48 hours. Those who received ≥3 U of fresh-frozen plasma or recombinant activated Factor VIIa (11 patients) before transfer had lower repeat international normalized ratios and better discharge dispositions than those treated less aggressively. |
Does salidroside alleviate cachexia symptoms in mouse models of cancer cachexia via activating mTOR signalling? | Cachexia has a devastating impact on survival and quality of life for many cancer patients and contributes to nearly one-third of all cancer deaths; also, it is associated with poor responses to chemotherapy and survival. A better understanding of the underlying mechanisms of cancer-associated cachexia (CAC), coupled with effective therapeutic approaches, will improve management of progressive functional impairment in cancer patients. Salidroside, a phenylpropanoid glycoside in Rhodiola rosea L, has been reported to possess potential anti-fatigue, anti-ageing, and anti-Alzheimer's disease properties. It is widely consumed as a nutritional supplement, but its effects on CAC and the possible mechanism remain a mystery. In the murine models of cachexia induced by CT-26 and Lewis lung carcinoma (LLC) tumour, respectively, main features of CAC were determined after treatment of salidroside or chemotherapy. In vitro experiments were performed using murine C2C12 myotubes, which were treated by tumour necrosis factor-α. Levels of several critical muscle-related signal proteins such as mammalian target of rapamycin (mTOR), p-mTOR, and myosin heavy chain (MyHC) were examined using western blot both in vitro and in vivo. In the present study, we showed the exciting effect of salidroside on the treatment of CAC. In CT-26 and LLC models, respectively, salidroside treatment could effectively preserve the tumour-free body weight, decrease loss of adipose and gastrocnemius muscles, alleviate tumour burden, and prolong their survival time. Additionally, in combined chemotherapy, salidroside could synergistically enhance the anti-tumour activity of cisplatin, especially decreased or eliminated chemotherapy-induced cachexia. Further analysis demonstrated that salidroside could significantly increase expression of mTOR, p-mTOR, and MyHC in gastrocnemius muscle. Also, results in vitro showed that salidroside could not only obviously increase mTOR, p-mTOR, and MyHC expression in C2C12 myotubes but also effectively rescue their down-regulation induced by tumour necrosis factor-α. | Violence-exposed youth rarely receive mental health services, even though exposure increases risk for academic and psychosocial problems. This study examines the association between violence exposure and mental health service contact. The 4 forms of violence exposure were peer, family, sexual, and witnessing. Data are from 1534 Boston public high school students who participated in a 2008 self-report survey of violence exposure and its correlates. Multivariate logistic regressions estimated associations between each form of violence with service contact, then examined whether associations persisted when controlling for suicidality and self-injurious behaviors. In unadjusted models, violence-exposed students more often reported service contact than their peers. However, in multivariate models, only exposure to family (odds ratio [OR] = 1.69, 95% confidence interval [CI] = 1.23-2.31) and sexual violence (OR = 2.34, 95% CI = 1.29-4.20) were associated with service contact. Associations attenuated when controlling for suicidality and self-injurious behaviors, indicating they were largely explained by self-harm. Sexual violence alone remained associated with mental health service contact in fully adjusted models, but only for girls (OR=3.32, 95% CI=1.30-8.45), suggesting sex-specific pathways. |
Are adipocytokines associated with radiographic joint damage in rheumatoid arthritis? | Obesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and radiographic joint damage in animal models. The purpose of this study was to examine the hypothesis that adipocytokines modulate inflammation and radiographic joint damage in patients with RA. We compared serum concentrations of leptin, resistin, adiponectin, and visfatin in 167 RA patients and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNFalpha]), and radiographic joint damage (Larsen score; n = 93 patients) was examined in RA patients by multivariable regression analysis first controlling for age, race, and sex, and then for obesity (BMI) and inflammation (TNFalpha, IL-6, and CRP). Concentrations of all adipocytokines were significantly higher in RA patients than in controls; for visfatin and adiponectin, this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen scores, and this association remained significant after adjustment for age, race, sex, disease duration, BMI, and inflammation (odds ratio [OR] 2.38 [95% confidence interval (95% CI) 1.32-4.29], P = 0.004). Leptin concentrations showed a positive association with the BMI (rho = 0.58, P < 0.01) and showed a negative association with the Larsen score after adjustment for inflammation (OR 0.32 [95% CI 0.17-0.61], P < 0.001), but not after adjustment for BMI (OR 0.86 [95% CI 0.42-1.73], P = 0.67). | Cellular transcriptional regulatory factor YY1 represses the activity of the early promoter P97 of HPV 16, but the regulatory activity to early promoter P105 of HPV 18 depends on a switch region which locates at the upstream sequences of YY1 binding sites. This study is to find out whether within the HPV 16 LCR there is such motif. DNA sequences of the whole HPV 16 LCR region were analyzed. Two similar switch structures were found. Different CAT reporter plasmids, one containing HPV 16 reference and the other mutated LCRs, both starting at the end of L1 and from the beginning of the enhancer, were generated and transfected in HeLa cells transiently. CAT assays showed there is no change of regulation pattern of YY1 on P97, when the two switch-similar structures were deleted. Sequences analysis also showed that no switch region like motif could be demonstrated in enhancer region, in promoter proximal segment, and even in E6/E7 area. |
Is waist-to-hip ratio associated with pulmonary gas exchange in the morbidly obese? | Morbidly obese individuals (ie, body mass index [BMI], > or = 40 kg/m2) may have a pulmonary gas exchange impairment due to the large fat mass surrounding their abdomen. To examine the effect of the waist-to-hip (W/H) ratio on pulmonary gas exchange in the morbidly obese. Twenty-five morbidly obese individuals (mean [+/- SD] age, 39 +/- 10 years; mean BMI, 49 +/- 7 kg/m2; mean body fat, 50 +/- 6%; mean waist circumference, 135 +/- 15 cm; mean W/H ratio, 0.97 +/- 0.11) scheduled for bariatric surgery were recruited. Arterial blood was sampled in duplicate after 5 min of rest sitting upright. The mean PaO2 at rest was 88 +/- 7 mm Hg (range, 72 to 108 mm Hg), the alveolar-arterial oxygen pressure difference (P[A-a]O2) was 19 +/- 9 mm Hg (range, 1 to 37 mm Hg), and the PacO2 was 38 +/- 3 mm Hg (range, 32 to 44 mm Hg). Linear regression showed that 32% and 36%, respectively, of the variance in the P(A-a)O2 and PaO2 were explained by the W/H ratio (p < 0.004 for both). As well, 20% of the variance in PacO2 was explained by the W/H ratio (p = 0.02). Men had larger W/H ratios (p < 0.01) and poorer gas exchange (p = 0.06) compared to women (mean difference: PaO2, -7 mm Hg; P[A-a]O2, 6 mm Hg). | To explore the therapeutic effectivity and the possible mechanism of triptolide (Tri) on experimental autoimmune encephalomyelitis (EAE). All female C57BL/6 mice were randomly divided into EAE group (28), Tri treated group (20) and adjuvant group (18). Mice in EAE and treated groups were immunized with myelin oligodendrocyte glycoprotein peptides 35-55 (MOG(35-55);), adjuvant group was injected at the same time, but instead of MOG(35-55); with normal saline. Tri was intraperitoneally injected in the dosage of 100 microg/(kg.d) in treated group on day 5 post-immunization (p.i.), and mice in EAE and adjuvant group injected with normal saline as control. The clinical feature and pathological changes were observed and the splenic lymphocytes were prepared on days 18-20 p.i. The cell cultures were divided into the control group (only 200 microL of cell suspension) and the experimental group (cell suspension in the presence of 10 mg/L MOG(35-55);). Then all of them were inoculated in 96-well flat-bottom plates under 37 degrees Celsius, 50 mL/L CO(2);. After 48 h, the proliferation assay was determined by MTT, and the supernatants were harvested for the detection of INF-gamma, IL-17, IL-10 and IL-4 by ELISA. Tri treatment showed an significantly protective action on EAE. After the intervention of Tri, the levels of IL-10 were increased (P<0.05), but the secretion of INF-gamma and proliferation response of splenic lymphocytes induced by MOG(35-55); were statistically significantly inhibited(P<0.05 and P<0.01, respectively). There were no influences on the amount of IL-17 and IL-4 by Tri. |
Does tezosentan normalize hepatomesenteric perfusion in a porcine model of cardiac tamponade? | To investigate endothelin-1 (ET-1)-dependent hepatic and mesenteric vasoconstriction, and oxygen and lactate fluxes in an acute, fixed low cardiac output (CO) state. Sixteen anesthetized, mechanically ventilated pigs were studied. Cardiac tamponade was established to reduce portal venous blood flow (Q(PV)) to 2/3 of the baseline value. CO, hepatic artery blood flow (Q(HA)), Q(PV), hepatic laser-Doppler flow (LDF), hepatic venous and portal pressure, and hepatic and mesenteric oxygen and lactate fluxes were measured. Hepatic arterial (R(HA)), portal (R(HP)) and mesenteric (R(mes)) vascular resistances were calculated. The combined ET(A)-ET(B) receptor antagonist tezosentan (RO 61-0612) or normal saline vehicle was infused in the low CO state. Measurements were made at baseline, after 30, 60, 90 min of tamponade, and 30, 60, 90 min following the infusion of tesozentan at 1 mg/kg/h. Tamponade decreased CO, Q(PV), Q(HA), LDF, hepatic and mesenteric oxygen delivery, while hepatic and mesenteric oxygen extraction and lactate release increased. R(HA), R(HP) and R(mes) all increased. Ninety minutes after tesozentan, Q(PV), LDF and hepatic and mesenteric oxygen delivery and extraction increased approaching baseline values, but no effect was seen on CO or Q(HA). Hepatic and mesenteric handling of lactate converted to extraction. R(HA), R(HP) and R(mes) returned to baseline values. No changes were observed in these variables among control animals not receiving tesozentan. | Advanced glycation end products (AGE) are involved in the progression of diabetic complications. Although our previous reports show that AGE increased dental pulp calcification, AGE accumulation is also associated with inflammation. This study examined AGE effect on the expression of inflammation factors using rat dental pulp tissues and cell cultures. Receptor for AGE (RAGE), S100A8, S100A9, and interleukin (IL)-1β were selected as inflammation parameters. Rat dental pulp cells were cultured and treated with AGE, and the effects were determined by real-time PCR. An anti-RAGE antibody or MAPK pathway inhibitors (PD98059, SB203580, and SP60012) were used to investigate AGE signaling pathway. The mRNA levels of RAGE, S100A8, S100A9, and IL-1β were higher in diabetic pulp tissues. AGE increased mRNA expressions of S100A8, S100A9, and IL-1β in cultured dental pulp cells. In the presence of anti-RAGE antibody, AGE did not increase in S100A8 or S100A9 expressions. The AGE-induced increases in S100A8 and S100A9 were inhibited by PD98059 and SB203580, respectively. |
Is arecoline cytotoxic for human endothelial cells? | Oral submucous fibrosis is a pre-malignant fibrotic condition caused by areca nut use and involves reduced mucosal vascularity. Arecoline is the principal areca nut alkaloid and is cytotoxic for epithelium and fibroblasts. Endothelial cell cycle arrest is reported on exposure to arecoline, as is cytotoxicity for endothelial-lung carcinoma hybrid cells. We here describe cytotoxicity for primary human endothelial cultures from seven separate donors. Human umbilical vein endothelial cells were exposed to increasing concentrations of arecoline and examined by: phase-contrast microscopy, haemocytometer counts, transmission electron microscopy, lactate dehydrogenase release and the methyl-thiazol-tetrazolium assay. Vacuolation and detachment of endothelium were observed at and above arecoline concentrations of 333 μg/ml or more. Ultrastructural features of cellular stress were seen after 24-h treatment with 111 μg/ml arecoline and included reduced ribosomal studding of endoplasmic reticulum, increased autophagolysosomal structures, increased vacuolation and reduced mitochondrial cristae with slight swelling. Similar changes were seen at 4 h with arecoline at 333 μg/ml or above, but with more severe mitochondrial changes including increased electron density of mitochondrial matrix and greater cristal swelling, while by 24 h, these cells were frankly necrotic. Haemocytometer counts were paralleled by both lactate dehydrogenase release and the methyl-thiazol-tetrazolium assays. | A retrospective study on patients with chronic nonspecific low back pain (NSLBP). To describe the gait stride characteristics of patients with chronic NSLBP, and to examine the effect of a novel biomechanical device on the gait stride characteristics of these patients. Patient with NSLBP alters their gait patterns. This is considered a protective mechanism as patients try to avoid extensive hip and spine ranges of motion and minimize forces and moments acting on the body. In addition, there are changes in the neuromuscular control system in patients with LBP that could possibly be attributed to the effects of pain on motor control. Nineteen patients underwent a gait test, using an electronic walkway, at baseline and after 12 weeks of treatment. Spatiotemporal parameters were used to identify changes in gait pattern. A novel biomechanical device comprised of 4 modular elements attached to foot-worn platforms was used in the study. The modules are 2 convex shaped biomechanical elements attached to each foot, one is located under the hindfoot region and the other is located under the forefoot region. The device was individually calibrated to each patient. The patients were instructed to walk with the calibrated biomechanical device on a daily basis for a period of 12 weeks. Significant differences were found at baseline and after 12 weeks in normalized velocity (P = 0.03), cadence (P < 0.01), left normalized step length (P = 0.02), right normalized step length (P = 0.02), right swing (P < 0.01), right stance (P < 0.01), left single limb support (P = 0.01), left double limb support (P = 0.02), and right double limb support (P = 0.02). |
Do skin dendritic cells induce follicular helper T cells and protective humoral immune responses? | The contribution of individual subsets of dendritic cells (DCs) to generation of adaptive immunity is central to understanding immune homeostasis and protective immune responses. We sought to define functions for steady-state skin DCs. We present an approach in which we restrict antigen presentation to individual DC subsets in the skin and monitor the effects on endogenous antigen-specific CD4(+) T- and B-cell responses. Presentation of foreign antigen by Langerhans cells (LC) in the absence of exogenous adjuvant led to a large expansion of T follicular helper (TFH) cells. This was accompanied by B-cell activation, germinal center formation, and protective antibody responses against influenza. The expansion of TFH cells and antibody responses could be elicited by both systemic and topical skin immunization. TFH cell induction was not restricted to LCs and occurred in response to antigen presentation by CD103(+) dermal DCs. CD103(+) DCs, despite inducing similar TFH responses as LCs, were less efficient in induction of germinal center B cells and humoral immune responses. We also found that skin DCs are sufficient to expand CXCR5(+) TFH cells through an IL-6- and IFN-α/β receptor-independent mechanism, but B cells were required for sustained Bcl-6(+) expression. | Triptolide treatment leads to an improvement in Diabetic Cardiomyopathy (DCM) in streptozotocin-induced diabetic rat model. DCM is characterized by abnormal cardiac energy metabolism. We hypothesized that triptolide ameliorated cardiac metabolic abnormalities in DCM. We proposed (31)P nuclear magnetic resonance ((31)P NMR) spectrometry method for assessing cardiac energy metabolism in vivo and evaluating the effect of triptolide treatment in DCM rats. Six weeks triptolide treatment was conducted on streptozotocin-induced diabetic rats with dose of 100, 200 or 400 μg/kg/day respectively. Sex- and age-matched non-diabetic rats were used as control group. Cardiac chamber dimension and function were determined with echocardiography. Whole heart preparations were perfused with Krebs-Henseleit buffer and (31)P NMR spectroscopy was performed. Cardiac p38 Mitogen Activating Protein Kinase (MAPK) was measured using real time PCR and western blot analysis. In diabetic rats, cardiac mass index was significantly higher, where as cardiac EF was lower than control group. (31)P NMR spectroscopy showed that ATP and pCr concentrations in diabetic groups were also remarkably lower than control group. Compared to non-treated diabetic rats, triptolide-treated diabetic groups showed remarkable lower cardiac mass index and higher EF, ATP, pCr concentrations, and P38 MAPK expressions. Best improvement was seen in group treated with Triptolide with dose 200 μg/kg/day. |
Does dexmedetomidine reduce atrial fibrillation after lung cancer surgery? | To evaluate whether the use of intraoperative dexmedetomidine (DEX) during lung cancer surgery may reduce the incidence of postoperative atrial fibrillation (POAF). A retrospective study. Academic hospital. Seven hundred three adult patients with non-small-cell lung cancer. Patients younger than 18 years of age with a history of atrial fibrillation were excluded. Episodes of atrial fibrillation were identified from electronic medical records and consisted of cardiology consultations, electrocardiogram records, and use of anti-arrhythmic medications within the postoperative admission time. The Wilcoxon rank sum test was used to evaluate the difference in a continuous variable between patient groups. Fisher's exact test or the chi-square test was used to evaluate the association between 2 categorical variables. Logistic regression models were used for multivariate analysis. Overall POAF incidence was 136 of 703 (19.35%), with a mean onset of 3.01±2.03 days after surgery. Among patients, 204 (29.02%) received DEX intraoperatively. Male gender and age were strong predictors of POAF. POAF incidence was comparable between patients who were (n=93, 21.1%) and were not (n=43, 18.6%) treated with DEX (p=0.46). The mean onset time of arrhythmia was similar in both groups (DEX users: 2.93±2.49 days; non-DEX users: 3.05±1.79 days; p=0.146). | Neisseria meningitidis are common colonizers of the human nasopharynx. In some circumstances, N. meningitidis becomes an opportunistic pathogen that invades tissues and causes meningitis. While a vaccine against a number of serogroups has been in effective use for many years, a vaccine against N. meningitidis group B has not yet been universally adopted. Bacterial heat shock protein complex (HSPC) vaccines comprise bacterial HSPs, purified with their chaperoned protein cargo. HSPC vaccines use the intrinsic adjuvant activity of their HSP, thought to act via Toll-like receptors (TLR), to induce an immune response against their cargo antigens. This study evaluated HSPC vaccines from N. meningitidis and the closely related commensal N. lactamica. The protein composition of N. lactamica and N. meningitidis HSPCs were similar. Using human HEK293 cells we found that both HSPCs can induce an innate immune response via activation of TLR2. However, stimulation of TLR2 or TLR4 deficient murine splenocytes revealed that HSPCs can activate an innate immune response via multiple receptors. Vaccination of wildtype mice with the Neisseria HSPC induced a strong antibody response and a Th1-restricted T helper response. However, vaccination of mice deficient in the major TLR adaptor protein, MyD88, revealed that while the Th1 response to Neisseria HSPC requires MyD88, these vaccines unexpectedly induced an antigen-specific antibody response via a MyD88-independent mechanism. |
Is fSHB promoter polymorphism within evolutionary conserved element associated with serum FSH level in men? | No polymorphisms affecting serum FSH levels have been described in the human FSHB gene. We have identified a potential regulatory single nucleotide polymorphism (SNP, rs10835638; G/T) 211 bp upstream from the FSHB mRNA transcription start-site, located within a highly conserved region among placental mammals. We aimed to determine the correlation of carrier status of rs10835638 alternative alleles with serum FSH level in men, and testicular and hormonal parameters. A quantitative genetic association study using a cohort of healthy men (n = 554; age 19.2 +/- 1.7 years) visiting the Centre of Andrology, Tartu University Hospital, Estonia. Rs10835638 (allele frequencies: G 87.6%, T 12.4%) was significantly associated with serum FSH level (analysis of variance: F = 13.0, P = 0.0016, df = 1; regression testing for a linear trend: P = 0.0003). Subjects with the GG genotype exhibited higher FSH levels (3.37 +/- 1.79 IU/l, n = 423) compared with heterozygotes (2.84 +/- 1.54 IU/l, n = 125) (P = 0.0005), the group of T-allele carriers (GT+TT, 2.78 +/- 1.51 IU/l, n = 131) (P = 0.0005) and TT-homozygotes (2.02 +/- 0.81 IU/L, n = 6) (P = 0.031). Rs10835638 was also associated with significant (P < 0.05) reduction in free testosterone index and testes volume, but increased semen volume, sex hormone-binding globulin, serum testosterone and estradiol. LH and inhibin-B levels did not differ significantly between groups. | Caudal block is a common technique for paediatric analgesia but with the disadvantage of short duration of action after single injection. Caudal dexmedetomidine and clonidine could offer significant analgesic benefits. We compared the analgesic effects and side-effects of dexmedetomidine and clonidine added to bupivacaine in paediatric patients undergoing lower abdominal surgeries. Sixty patients (6 months to 6 yr) were evenly and randomly assigned into three groups in a double-blinded manner. After sevoflurane in oxygen anaesthesia, each patient received a single caudal dose of bupivacaine 0.25% (1 ml kg(-1)) combined with either dexmedetomidine 2 microg kg(-1) in normal saline 1 ml, clonidine 2 microg kg(-1) in normal saline 1 ml, or corresponding volume of normal saline according to group assignment. Haemodynamic variables, end-tidal sevoflurane, and emergence time were monitored. Postoperative analgesia, use of analgesics, and side-effects were assessed during the first 24 h. Addition of dexmedetomidine or clonidine to caudal bupivacaine significantly promoted analgesia time [median (95% confidence interval, CI): 16 (14-18) and 12 (3-21) h, respectively] than the use of bupivacaine alone [median (95% CI): 5 (4-6) h] with P<0.001. However, there was no statistically significant difference between dexmedetomidine and clonidine as regards the analgesia time (P=0.796). No significant difference was observed in incidence of haemodynamic changes or side-effects. |
Does stress affect carers before patient 's first visit to a memory clinic? | To measure and compare the burden on spousal carers of patients with and without dementia who were consulting a memory clinic for the first time. We included 413 dyads of patients and their spousal carers consulting a memory clinic for the first time. Of them 276 had a diagnosis of Cognitive Impairment No Dementia (CIND) and 137 had a dementia diagnosis. The burden of care was measured with the Relative Stress Scale (RSS). The gender of patients and their spouses was recorded and measures of cognition, depression and functional capacity of the patients were included in the analysis. Of all carers, 27.6% had a score on the RSS of above 23, indicating a moderate to severe burden. The corresponding score for carers of patients with CIND was 20.3%, compared to 42.2% for those with dementia. However, in a linear regression analysis with RSS as the dependent variable, the dementia diagnosis variable was not significant. Three variables were significant (p < 0.05) and has explained 34% of the variance of the score on the RSS, impaired function in activities of daily living (ADL) was the most important variable (beta 0.56), followed by female gender of carers (beta 0.19) and the extent of the symptoms of depression observed in the patients (beta 0.10). | We have recently reported that recombinant human soluble thrombomodulin (rTM) counteracted capillary leakage associated with engraftment, as well as sinusoidal obstructive syndrome after hematopoietic stem cell transplantation. These observations prompted us to explore whether rTM possessed cytoprotective effects on endothelial cells. Exposure of human umbilical vein endothelial cells to rTM induced expression of antiapoptotic protein myeloid leukemia cell-1 through the activation of extracellular signal-regulated kinase in these cells. Additional studies found that exposure of human umbilical vein endothelial cells to cyclosporine A and FK506, an immunosuppressant used for the individuals receiving hematopoietic stem cell transplantation, induced apoptosis, which was attenuated when human umbilical vein endothelial cells were exposed to these agents in the presence of rTM. Further studies using deletion mutants of thrombomodulin (TM) identified that the epidermal growth factor domain of TM possessed cytoprotective effects. A single nucleotide substitution at codon 376 or 424 of TM, which impairs the ability of TM to produce activated protein C or bind to thrombin, respectively, did not hamper the cytoprotective effects of TM, which suggested that cytoprotective effects of rTM were distinctive from those of activated protein C. |
Does graft shape affect midfoot correction and forefoot loading mechanics in lateral column lengthening osteotomies? | Adult acquired flatfoot deformity is characterized by midfoot abduction and collapse of the medial longitudinal arch. Lateral column lengthening osteotomies primarily correct the abduction deformity, but the effects of graft shape on deformity correction and forefoot loading are unclear. Therefore, the purpose of this study was to demonstrate the effect of graft shape and taper on deformity correction and forefoot loading mechanics in a cadaveric flatfoot model. Flatfoot deformity was simulated in 18 cadaveric specimens. A lateral column lengthening osteotomy was performed using a triangular, trapezoidal, and rectangular graft for each specimen. During each testing condition, talonavicular joint angles and forefoot plantar pressures were measured. Each graft shape corrected abduction and dorsiflexion deformity at the talonavicular joint. Coronal plane correction was affected by graft shape, and the less tapered trapezoidal and rectangular grafts overloaded the lateral forefoot compared to the intact condition. The more tapered triangular graft did not cause a lateral shift in forefoot pressures. Forefoot plantar pressures were strongly correlated with talonavicular abduction correction (R (2) = .473, P < .001). | Natalizumab blocks α4-integrins and is a prototypic agent for a series of anti-inflammatory drugs that impair trafficking of immune cells into the CNS. However, modulation of the access of immune cells to the CNS is associated with impaired immune surveillance and detrimental viral infections of the CNS. Here, we explored the potency of cellular immune responses within the CNS to protect against viral encephalitis in mice with T cell conditional disruption of VLA-4 integrin (α4β1) expression. While VLA-4 expression in virus specific Th1 cells is non-redundant for their ability to access the CNS, α4-integrin deficient Th17 cells enter the CNS compartment and generate an inflammatory milieu upon intrathecal vaccinia virus (VV) infection. However, in contrast to Th1 cells that can adopt direct cytotoxic properties, Th17 cells fail to clear the virus due to insufficient Eomes induced perforin-1 expression. |
Do extracellular IgC2 constant domains of CEACAMs mediate PI3K sensitivity during uptake of pathogens? | Several pathogenic bacteria utilize receptors of the CEACAM family to attach to human cells. Binding to different members of this receptor family can result in uptake of the bacteria. Uptake of Neisseria gonorrhoeae, a gram-negative human pathogen, via CEACAMs found on epithelial cells, such as CEACAM1, CEA or CEACAM6, differs mechanistically from phagocytosis mediated by CEACAM3, a CEACAM family member expressed selectively by human granulocytes. We find that CEACAM1- as well as CEACAM3-mediated bacterial internalization are accompanied by a rapid increase in phosphatidylinositol-3,4,5 phosphate (PI(3,4,5)P) at the site of bacterial entry. However, pharmacological inhibition of phosphatidylinositol-3' kinase (PI3K) selectively affects CEACAM1-mediated uptake of Neisseria gonorrhoeae. Accordingly, overexpression of the PI(3,4,5)P phosphatase SHIP diminishes and expression of a constitutive active PI3K increases CEACAM1-mediated internalization of gonococci, without influencing uptake by CEACAM3. Furthermore, bacterial uptake by GPI-linked members of the CEACAM family (CEA and CEACAM6) and CEACAM1-mediated internalization of N. meningitidis by endothelial cells require PI3K activity. Sensitivity of CEACAM1-mediated uptake toward PI3K inhibition is independent of receptor localization in cholesterol-rich membrane microdomains and does not require the cytoplasmic or the transmembrane domain of CEACAM1. However, PI3K inhibitor sensitivity requires the Ig(C2)-like domains of CEACAM1, which are also present in CEA and CEACAM6, but which are absent from CEACAM3. Accordingly, overexpression of CEACAM1 Ig(C2) domains blocks CEACAM1-mediated internalization. | Morbidly obese patients usually present vitamin D deficiency or secondary hyperparathyroidism. Low vitamin D levels have been recently related to non-alcoholic fatty liver disease (NAFLD). The aim of this study was to analyse the relationship between vitamin D, bone turnover markers and non-alcoholic fatty liver disease and metabolic syndrome in severely obese patients. One hundred and ten patients who underwent bariatric surgery were included. Liver biopsy was taken during surgery. Two univariate analyses were carried out in order to i) analyse the relationship between liver histology and vitamin D-bone turnover markers (intact parathyroid hormone (PTH), osteocalcin and Carboxy-terminal collagen crosslinks) and ii) establish the association between metabolic syndrome components-insulin resistance (HOMA) and vitamin D-bone turnover markers. 70% of the patients had lower levels of vitamin D or secondary hyperparathyroidism. None of the components of liver histology were associated with levels of vitamin D or with bone turnover parameters. Patients with metabolic syndrome showed lower levels of PTH and osteocalcin (72,42 (29,47) vs 61.25(19.59) p-Value: 0.022; 19.79 (10.43) vs 16.87(10.25) p-Value: 0,028, respectively). HOMA was not related to Vitamin D or bone turnover markers. |
Is risk of primary sclerosing cholangitis associated with nonsmoking behavior? | Seventy percent of patients with primary sclerosing cholangitis (PSC) have concomitant ulcerative colitis. Smoking and previous appendectomy may protect against ulcerative colitis. The aim of this study was to examine these factors in patients with PSC. Fifty-nine patients with PSC, 130 patients with ulcerative colitis and normal liver biochemistry, and 197 control subjects were interviewed about smoking behavior and history of appendectomy. There were less current smokers in the PSC and ulcerative colitis groups than in the control group (19%, 12%, and 38%, respectively). The resulting odds ratio for current smoking was 0.37 (95% confidence interval, (0.18-0.76) in the PSC group and 0.23 (95% confidence interval, 0.13-0.41) in the ulcerative colitis group. Percentage of persons who ever smoked was also significantly less in the PSC group (41% vs. 56% in the control group). Frequency of previous appendectomy in the PSC and ulcerative colitis groups was not significantly different from that of controls (19%, 9%, and 14%, respectively). | The important functions of the meniscus are shock absorption, passive stabilization and load transmission of the knee. Because of the avascularity of two-thirds of the meniscal center region, the treatment of tears in this area is hard. Recently, microRNAs have been proven to play an important role in the pathogenesis of diseases. We focused on microRNA (miR)-210, which plays a wide spectrum of roles comprising mitochondrial metabolism, angiogenesis, DNA repair and cell survival. This study aimed to investigate the effect of intra-articular injection of synthetic miR-210 on the injured meniscus in the avascular zone. The middle segments of the medial meniscus of Spraque Dawley rats were incised longitudinally with a scalpel. An intra-articular injection of double-stranded (ds) miR-210 (for control group using control dsRNA) with atelocollagen was administered immediately after injury. Four weeks and 12 weeks after the injection, we conducted a histologic evaluation, immunohistochemical evaluation and Real-time PCR analysis. In vitro, the inner meniscus and synovial cells were isolated from rat knee joint, and were transfected with ds miR-210 or control dsRNA. Real-time PCR and immunohistochemical evaluations were performed. Twenty-four hours after the injection, FAM (Fluorescein amidite) labeled miR-210 was observed in the cells around the injured site. Four weeks after the injection, the injured site of the miR-210 group was filled with repaired tissue while that of the control was not repaired. In gene expression analysis of the meniscus, the expression of miR-210, Collagen type 2 alpha 1 (Col2a1), Vascular endothelial growth factor (VEGF), and Fibroblast growth factor-2 (FGF2) in the miR-210 group was significantly higher than that in the control. At 12 weeks, the intra-articular injection of miR-210 had healed the injured site of the meniscus and had prevented articular cartilage degeneration. In vitro, miR-210 upregulated Col2a1 expression in the meniscus cells and VEGF and FGF2 expression in the synovial cells. |
Is use of modern contraception by the poor falling behind? | The widespread increase in the use of contraception, due to multiple factors including improved access to modern contraception, is one of the most dramatic social transformations of the past fifty years. This study explores whether the global progress in the use of modern contraceptives has also benefited the poorest. Demographic and Health Surveys from 55 developing countries were analyzed using wealth indices that allow the identification of the absolute poor within each country. This article explores the macro level determinants of the differences in the use of modern contraceptives between the poor and the national averages of several countries. Despite increases in national averages, use of modern contraception by the absolute poor remains low. South and Southeast Asia have relatively high rates of modern contraception in the absolute poor, on average 17% higher than in Latin America. Over time the gaps in use persist and are increasing. Latin America exhibits significantly larger gaps in use between the poor and the averages, while gaps in sub-Saharan Africa are on average smaller by 15.8% and in Southeast Asia by 11.6%. | Airway epithelium integrity is essential to maintain its role of mechanical and functional barrier. Recurrent epithelial injuries require a complex mechanism of repair to restore its integrity. In chronic obstructive pulmonary disease (COPD), an abnormal airway epithelial repair may participate in airway remodeling. The objective was to determine if airway epithelial wound repair of airway epithelium is abnormal in COPD. Patients scheduled for lung resection were prospectively recruited. Demographic, clinical data and pulmonary function tests results were recorded. Emphysema was visually scored and histological remodeling features were noted. Primary bronchial epithelial cells (BEC) were extracted and cultured for wound closure assay. We determined the mean speed of wound closure (MSWC) and cell proliferation index, matrix metalloprotease (MMP)-2, MMP-9 and cytokines levels in supernatants of BEC 18 hours after cell wounding. In a subset of patients, bronchiolar epithelial cells were also cultured for wound closure assay for MSWC analyze. 13 COPD and 7 non COPD patients were included. The severity of airflow obstruction and the severity of emphysema were associated with a lower MSWC in BEC (p = 0.01, 95% CI [0.15-0.80]; p = 0.04, 95% CI [-0.77;-0.03] respectively). Cell proliferation index was decreased in COPD patients (19 ± 6% in COPD vs 27 ± 3% in non COPD, p = 0.04). The severity of COPD was associated with a lower level of MMP-2 (7.8 ± 2 10(5) AU in COPD GOLD D vs 12.8 ± 0.13 10(5) AU in COPD GOLD A, p = 0.04) and a lower level of IL-4 (p = 0.03, 95% CI [0.09;0.87]). Moreover, higher levels of IL-4 and IL-2 were associated with a higher MSWC (p = 0.01, 95% CI [0.17;0.89] and p = 0.02, 95% CI [0.09;0.87] respectively). Clinical characteristics and smoking history were not associated with MSWC, cell proliferation index or MMP and cytokines levels. Finally, we showed an association of the MSWC of bronchial and corresponding bronchiolar epithelial cells obtained from the same patients (p = 0.02, 95% CI [0.12;0.89]). |
Are brief alcohol intervention trials conducted by higher prestige authors and published in higher impact factor journals cited more frequently? | To examine the relationships between study quality, author prestige, journal impact factors, and citation rates of trials and to examine whether journal impact factors mediated the relationships between study quality and author prestige on citation rates. We used bibliometric data from 128 controlled trials included in a recent meta-analysis on brief alcohol interventions for adolescents and young adults. We obtained the number of citations from ISI Web of Knowledge and Google Scholar; journal impact factors were obtained from ISI Web of Knowledge. Linear regression models were used to examine the direct and indirect effects of interest. The results indicated that studies were published in journals with higher impact factors when first authors had higher h-indices and studies were funded, but this was largely because those studies were of higher quality. Studies were cited more frequently when first authors had higher h-indices and studies were funded, even after adjusting for study quality proxies. The observed associations between study quality and author prestige on citation rates were also partly mediated through journal impact factors. | To discriminate non-proliferative diabetic retinopathy (NPDR) patients from healthy controls by fluorescence lifetime imaging ophthalmoscopy (FLIO). A prototype FLIO (Heidelberg-Engineering, Heidelberg, Germany) was used to examine the retina of 33 patients and 28 controls. As increased fluorescence of the diabetic lens is known, the lenses of 34 patients and 24 controls were investigated as well. Time-resolved decay was detected in two spectral channels (ch1: 498-560 nm, ch2: 560-720 nm) and approximated by a series of three exponential functions yielding in lifetimes (τ Significant differences between patients and controls were found for all fundus lifetime components (τ |
Does 24-Hour colonic manometry in pediatric slow transit constipation show significant reductions in antegrade propagation? | The physiological basis of slow transit constipation (STC) in children remains poorly understood. We wished to examine pan-colonic motility in a group of children with severe chronic constipation refractory to conservative therapy. We performed 24 h pan-colonic manometry in 18 children (13 boys, 11.6 +/- 0.9 yr, range 6.6-18.7 yr) with scintigraphically proven STC. A water-perfused, balloon tipped, 8-channel, silicone catheter with a 7.5 cm intersidehole distance was introduced through a previously formed appendicostomy. Comparison data were obtained from nasocolonic motility studies in 16 healthy young adult controls and per-appendicostomy motility studies in eight constipated children with anorectal retention and/or normal transit on scintigraphy (non-STC). Antegrade propagating sequences (PS) were significantly less frequent (P < 0.01) in subjects with STC (29 +/- 4 per 24 h) compared to adult (53 +/- 4 per 24 h) and non-STC (70 +/- 14 per 24 h) subjects. High amplitude propagating sequences (HAPS) were of a normal frequency in STC subjects. Retrograde propagating sequences were significantly more frequent (P < 0.05) in non-STC subjects compared to STC and adult subjects. High amplitude retrograde propagating sequences were only identified in the STC and non-STC pediatric groups. The normal increase in motility index associated with waking and ingestion of a meal was absent in STC subjects. | We have previously shown the prognostic importance of tumor-infiltrating lymphocytes (TILs) in newly diagnosed triple-negative breast cancer (TNBC) using tumor samples from a large clinical trial cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+). A prospective-retrospective study was conducted using samples from the FinHER adjuvant, phase III trial that enrolled 1010 early-stage BC patients, 778 of whom were HER2-nonamplified. Those with HER2+ disease (n = 232) were randomized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy. Two pathologists independently quantified stromal TILs in 935 (92.6%) available slides. The primary end point of distant disease-free survival (DDFS) and interactions with trastuzumab were studied in Cox regression models. Confirming our previous findings, in TNBC (n = 134) each 10% increase in TILs was significantly associated with decreased distant recurrence in TNBC; for DDFS the hazard ratio adjusted for clinicopathological factors: 0.77; 95% confidence interval (CI) 0.61-0.98, P = 0.02. In HER2+ BC (n = 209), each 10% increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients randomized to the trastuzumab arm (DDFS P interaction = 0.025). |
Is epithelial-to-mesenchymal transition ( EMT ) in intraductal papillary mucinous neoplasm ( IPMN ) associated with high tumor grade and adverse outcomes? | Epithelial-to-mesenchymal transition (EMT) is generally associated with increased tumor aggressiveness and poor prognosis. We evaluated EMT characteristics in intraductal papillary mucinous neoplasm (IPMN) tumor specimens and their potential role as biomarkers for malignancy, metastasis, and adverse patient outcomes. IPMN surgical specimens were identified and reviewed by two gastrointestinal pathologists. Immunohistochemical analysis of E-cadherin, vimentin, and ZEB-1 was performed. Samples were linked to clinicopathologic and outcome data for these patients. Western blot test was used to evaluate ZEB-1 expression in IPMN samples; 846 human miRNAs were profiled, and EMT-related differentially expressed miRNAs were validated using quantitative real-time polymerase chain reaction. Fifty-eight IPMN specimens and five normal pancreatic tissue samples were immunohistochemically stained and scored. E-cadherin expression was significantly lower in malignant versus low-grade IPMN (p < 0.05). Vimentin expression was increased in malignant IPMN tumor samples (p < 0.05). EMT was associated with increased lymph node metastasis and decreased survival of malignant IPMN patients (p < 0.05). ZEB-1, an imperative EMT regulator, was exclusively expressed by malignant IPMN tumors. miRNA hierarchical clustering demonstrated grouping of two main IPMN subgroups: low-grade IPMN versus high-grade IPMN and carcinoma. Twenty-four miRNAs were differentially expressed (14 up-regulated, 10 down-regulated). The EMT-regulatory miRNAs, miR-200c and miR-141, were down-regulated (twofold and 1.8-fold decrease, respectively) in malignant versus low-grade IPMN (p < 0.05). | Stepping response may be considered the most important postural reaction to prevent a fall because it is the inability to respond effectively to a loss of balance that ultimately determines whether a fall occurs. However, very little has been studied on the effect of exercising on step execution behavior in the elderly. To explore whether older persons who exercise regularly have faster voluntary stepping times than sedentary elderly persons. Additionally, we investigated the association between step execution behavior, self-reported physical function, and balance performance. Case-control study of 48 elderly adults aged 65-91 years who live independently in retirement homes. Participants were classified as 24 exercisers (reporting >2 exercise training activities/week) and 24 age- and gender-matched inactive elderly individuals (who do not exercise regularly). The Voluntary Step Execution Test was performed as a reaction time task while standing on a force platform under single-task and dual-task conditions. Step initiation phase, foot off time, foot contact time, preparatory, and swing phases were extracted from center of pressure and ground reaction force data. Self-reported function was examined using Late-Life Function and Disability Instrument; Berg Balance Test was also performed. Exercisers had significantly faster voluntary step times in single-task condition (959 vs. 1,158 ms) but not during dual-task condition (1,170 vs. 1,303 ms). Exercisers had a significantly higher Berg Balance Test (53.7 +/-3.6 vs. 49.8 +/-5.3), consumed less medication (3.3 +/-2.3 vs. 5.6 +/-2.9), and their lower extremity function scores were higher (88.61 +/-2.3 vs. 73.1 +/-2.7) than those of inactive subjects. |
Does sucralfate reduce the risk of acid aspiration pneumonitis? | To study the pulmonary effects of aspirating a mixture of sucralfate in water and sucralfate in hydrochloric acid in an animal model of aspiration pneumonia. Prospective, randomized, controlled study with repeated measures. University research laboratory. Thirty-two in situ, isolated, blood perfused porcine lung preparations. Five control preparations received no aspiration. Twenty-seven preparations received a standard aspiration of 1.5 mL/kg body of a) distilled water (n = 5), b) sucralfate in distilled water (n = 8), c) 1/10 normal hydrochloric acid (n = 6), and d) mixture of sucralfate in distilled water and hydrochloric acid (n = 8). The pH measurements were made of all aspirates. Lung weight, airway pressures, and pulmonary artery pressures were continuously monitored before and for 4 hrs after aspiration. Lung wet/dry weight ratio was measured at the completion of the study. The pH of sucralfate mixed with distilled water was 4.9, pH of 1/10 normal hydrochloric acid was 1.0, and pH of equal volumes of a sucralfate-water suspension mixed with hydrochloric acid was 1.5. Airway pressures and pulmonary arterial pressures increased in all aspirate groups over time compared with those values of control lungs. Control lungs gained 18 +/- 3 (SEM) g over 4 hrs and the wet/dry ratio was 4.951 +/- 0.310. Lungs aspirating distilled water gained 147 +/- 49 g and the wet/dry ratio was 5.198 +/- 0.120. Lungs aspirating sucralfate and distilled water increased their weight by 109 +/- 30 g and the wet/dry ratio was 5.380 +/- 0.076. Lungs aspirating a suspension of sucralfate and water and hydrochloric acid were similar to lungs aspirating hydrochloric acid alone with weight increases of 265 +/- 30 g and 346 +/- 81 g, and the wet/dry ratio of 7.011 +/- 0.273 and 7.230 +/- 0.390, respectively. | PIK3CA is the most frequent somatic mutated oncogene in estrogen receptor (ER) positive breast cancer. We previously observed an association between PIK3CA genotype and aromatase inhibitors (AI) treatment outcome. This study now evaluates whether expression of mRNAs and miRs are linked to PIK3CA genotype and are independently related to AI therapy response in order to define potential expressed biomarkers for treatment outcome. The miR and mRNA expression levels were evaluated for their relationship with the PIK3CA genotype in two breast tumor datasets, i.e. 286 luminal cancers from the TCGA consortium and our set of 84 ER positive primary tumors of metastatic breast cancer patients who received first line AI. BRB Array tools class comparison was performed to define miRs and mRNAs whose expression associate with PIK3CA exon 9 and 20 status. Spearman correlations established miR-mRNA pairs and mRNAs with related expression. Next, a third dataset of 25 breast cancer patients receiving neo-adjuvant letrozole was evaluated, to compare expression levels of identified miRs and mRNAs in biopsies before and after treatment. Finally, to identify potential biomarkers miR and mRNA levels were related with overall survival (OS) and progression free survival (PFS) after first-line AI therapy. Expression of 3 miRs (miR-449a, miR-205-5p, miR-301a-3p) and 9 mRNAs (CCNO, FAM81B, LRG1, NEK10, PLCL1, PGR, SERPINA3, SORBS2, VTCN1) was related to the PIK3CA status in both datasets. All except miR-301a-3p had an increased expression in tumors with PIK3CA mutations. Validation in a publicly available dataset showed that LRG1, PGR, and SERPINA3 levels were decreased after neo-adjuvant AI-treatment. Six miR-mRNA pairs correlated significantly and stepdown analysis of all 12 factors revealed 3 mRNAs (PLCL1, LRG1, FAM81B) related to PFS. Further analyses showed LRG1 and PLCL1 expression to be unrelated with luminal subtype and to associate with OS and with PFS, the latter independent from traditional predictive factors. |
Is hepatic growth hormone resistance during sepsis associated with increased suppressors of cytokine signaling expression and impaired growth hormone signaling? | During sepsis, a two- to four-fold increase in circulating growth hormone (GH) is seen with 40-50% reductions in plasma insulin-like growth factor (IGF)-I. The suppressors of cytokine signaling (SOCS), inhibitors of cytokine, and growth factor signaling via the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway have been implicated in the development of hepatic GH resistance. In this study we examine the effects of sepsis on GH-induced IGF-I expression and potential mechanisms for GH resistance. Prospective experimental study. University research laboratory. Male Sprague-Dawley rats. Rats were randomized to laparotomy alone (control) or implantation of fecal agar pellets inoculated with Escherichia coli and Bacteroides fragilis (sepsis). GH was injected intravenously to assess hepatic IGF-I synthesis and GH signaling. Plasma IGF-I was measured in both groups at baseline (4 hrs postoperatively) and then again at 12 hrs and 24 hrs after GH administration. Basal IGF-I levels were similar in both groups, but controls had a 35% increase in IGF-I at 12 hrs, whereas septic rats demonstrated reductions in circulating IGF-I at 12 and 24 hrs after GH. Hepatic expression of SOCS-1, -2, -3, and cytokine-inducible SH2-containing protein (CIS) were determined at 1, 4, 8, and 24 hrs in septic and control rats by Northern blot. SOCS-1, SOCS-3, and CIS messenger RNA in liver were increased from 4 to 8 hrs after the induction of sepsis (p < .05 for SOCS-1 and -3). Total GH receptor (GHR), JAK2, and STAT5 signaling proteins and the time course of STAT5 activation were also measured in liver after recombinant human GH administration by immunoblot and electrophoretic mobility shift analysis. Levels of total GHR, JAK2, and STAT5 were unaltered in liver from septic rats. However, phosphorylated STAT5 and STAT5 DNA binding were significantly reduced 30 mins after GH administration in liver from septic rats. | There is controversy as to whether migraine is associated with white matter abnormalities (WMAs) on magnetic resonance images. These abnormalities may be important as a risk factor for future stroke. Further, it is controversial whether any increased risk of WMAs is attributable to comorbidities such as vascular disease. A meta-analysis of published case-control studies was undertaken to address the relationship between migraine and magnetic resonance imaging WMAs. Seven studies were identified. Data from studies reporting the incidence of magnetic resonance imaging WMAs in those with migraine and appropriate control populations were used to calculate odds ratios for WMAs in migraine for each study. A stratified meta-analysis was performed using studies that did and did not exclude subjects with disease comorbidities. The summary odds ratio shows that those with migraine are at increased risk for WMAs (odds ratio, 3.9 [95% confidence interval, 2.26-6.72]). The risk does not differ between studies that included subjects with comorbidities and those that did not. |
Does notch signaling enhance osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells? | The Notch signaling pathway has been shown to play a role in bone marrow-derived stromal cell differentiation, however, the precise outcome of Notch activation remains controversial. The aim of this study was to evaluate the effect of Notch signaling in primary human bone marrow-derived stromal cells (hBMSCs). hBMSCs were transduced to >90% with lentiviral vectors containing either human notch1 intracellular domain (NICD), jagged1, or dominant negative mastermind1. Cells were exposed to adipogenic and osteogenic differentiation stimuli and differentiation was quantified by oil red or alizarin red staining, alkaline phosphatase liver/bone/kidney (ALPL) activity and expression of adipogenic or osteogenic marker genes. NICD and jagged1 transgene-expressing hBMSCs demonstrated enhanced mineralization, nodule formation, and ALPL activity in osteogenic differentiation media. These findings correlated with increased gene expression of bone morphogenetic protein 2 and ALPL. In contrast, NICD or jagged1 transgene expression strongly inhibited adipocyte formation and reduced peroxisome proliferator-activated receptor-gamma, fatty acid binding protein 4, and adiponectin precursor gene expression. Co-overexpression of dominant negative mastermind1 and NICD or jagged1 led to a partial rescue of the differentiation phenotypes. In addition, high endogenous jagged1 expression levels were observed in hBMSCs samples with strong ALPL activity compared to a group of samples with low ALPL activity. | The diagnosis of cytomegalovirus encephalitis (CMV-E) in AIDS patients is challenging as other illnesses may obscure the symptoms. Here, we characterize the clinical symptoms of CMV-E and link them to post-mortem findings. Patients and methods In 254 homosexual men with AIDS, followed from HIV diagnosis to death before the antiretroviral combination therapy era, CMV-E was suspected in 93 cases. All were CMV-positive in blood. Neurological examination, including cognitive testing was performed in 34 of them within 6 months before death. CMV-E was diagnosed by CMV-PCR in cerebrospinal fluid (n = 24) or by post-mortem (n = 24). The majority complained of forgetfulness (91%), balance difficulties (85%) and impotence (85%). Impaired short-term memory was present in 29 patients. It was extreme in 17, justifying the diagnosis of Korsakoff's syndrome. This was often associated with infectious CMV in blood (P = 0.01). Brainstem symptoms were found in 19 patients. Post-mortem examination often revealed ventriculoencephalitis. CMV was found primarily around the ventricles and in other structures, described in Korsakoff's syndrome. |
Is increased Neutrophil to Lymphocyte Ratio Associated with In-Hospital Mortality in Patients with Aortic Dissection? | i ne prognostic relevance of hematological parameters in cardiovascular diseases has been well demonstrated. The purpose of the present study is to investigate the association between the hematological parameters, particularly neutrophil to lymphocyte ratio (NLR), and outcomes of aortic dissection (AD). Two hundred patients diagnosed with AD were retrospectively recruited and compared with 76 subjects with ascending aortic dilatation (AAD) and 92 subjects with normal aortic diameters. The independent relation between hematological parameters and in-hospital mortality was analyzed by regression analysis. The NLR was significantly higher in the AD group compared to the AAD and control groups (median 8.83 [8.13] vs. median 1.95 [1.10] vs. median 1.71 [0.77], respectively; p = 0.01). The NLR was higher in the deceased (n = 57) compared to the surviving patients (n = 143) (median 10.37 [10.86] vs. median 7.84 [8.17]; p = 0.01). Receiver operating curve (ROC) analysis revealed that a NLR measurement higher than > 8.78 predicted in-hospital mortality for patients with acute aortic dissection with a sensitivity of 67.4% and a specificity of 57.2% (AUC: 0.672; p = 0.01). In multivariate logistic regression analysis, increased aortic diameter, acute dissection, and increased levels of NLR remained as the independent markers of in-hospital mortality within the study population. | Topiramate, an anticonvulsant, has been reported to increase the number of abstinent days and decrease craving in alcohol-dependent individuals. However, the neurobiological basis for topiramate's effect is unknown. To assess topiramate's effect on ethanol's rewarding and conditioning rewarding effects, the present experiments examined the effects of topiramate on the acquisition and expression of ethanol-induced conditioned place preference (CPP) in DBA/2J and C57BL/6J mice. A biased apparatus and subject assignment were used. Mice received ethanol (2 g/kg) or saline paired with an initially nonpreferred floor (CS+) and saline paired with an initially preferred floor (CS-) for 5-minute conditioning trials. During the acquisition experiments, mice received a pretreatment of topiramate (0, 5, 10, 20, 50, or 100 mg/kg) 1 hour before the CS+ trials. On intervening CS- trials, mice received a pretreatment of saline. For the preference test, all mice received saline injections and were placed on a split floor for a 30-minute test. During the expression experiments, mice received no drug pretreatment on conditioning trials, but were pretreated with topiramate (0, 10, 50, or 100 mg/kg) 1 hour before the test session. Ethanol-induced CPP was observed in both strains, but topiramate did not affect the acquisition or expression of ethanol-induced CPP in either strain. Despite its failure to alter CPP, topiramate produced dose-dependent locomotor activating effects in both strains. These effects were observed both in the presence and in the absence of ethanol. |
Does gestational diabetes mellitus alter apoptotic and inflammatory gene expression of trophobasts from human term placenta? | Increased placental growth secondary to reduced apoptosis may contribute to the development of macrosomia in GDM pregnancies. We hypothesize that reduced apoptosis in GDM placentas is caused by dysregulation of apoptosis related genes from death receptors or mitochondrial pathway or both to enhance placental growth in GDM pregnancies. Newborn and placental weights from women with no pregnancy complications (controls; N=5), or with GDM (N=5) were recorded. Placental villi from both groups were either fixed for TUNEL assay, or snap frozen for gene expression analysis by apoptosis PCR microarrays and qPCR. Maternal, placental and newborn weights were significantly higher in the GDM group vs. Controls. Apoptotic index of placentas from the GDM group was markedly lower than the Controls. At a significant threshold of 1.5, seven genes (BCL10, BIRC6, BIRC7, CASP5, CASP8P2, CFLAR, and FAS) were down regulated, and 13 genes (BCL2, BCL2L1, BCL2L11, CASP4, DAPK1, IκBκE, MCL1, NFκBIZ, NOD1, PEA15, TNF, TNFRSF25, and XIAP) were unregulated in the GDM placentas. qPCR confirmed the consistency of the PCR microarray. Using Western blotting we found significantly decreased placental pro-apoptotic FAS receptor and FAS ligand (FASL), and increased mitochondrial anti-apoptotic BCL2 post GDM insult. Notably, caspase-3, which plays a central role in the execution-phase of apoptosis, and its substrate poly (ADP-ribose) polymerase (PARP) were significantly down regulated in GDM placentas, as compared to non-diabetic Control placentas. | Nonoperative management of hemodynamically stable patients with blunt hepatic injuries has become the standard of care over the past decade. However, controversy regarding the role of in-hospital follow-up computed tomographic (CT) scans as a part of this nonoperative management scheme is ongoing. Although many institutions, including our own, have advocated routine in-hospital follow-up scans, others have suggested a more selective policy. Over time, we have perceived a low yield from follow-up studies. The hypothesis for this study is that routine follow-up imaging of asymptomatic patients is unnecessary. All patients selected for nonoperative management of blunt hepatic injury were evaluated for utility of follow-up CT scans over a 4-year period. There were 530 stable patients with hepatic injury on admission CT scans in which follow-up scans were obtained within a week of admission. All injuries were classified according to the revised American Association for the Surgery of Trauma Organ Injury Scale: 102 (19.2%) grade I, 181 (34.1%) grade II, 158 (29.8%) grade III, 74 (13.9%) grade IV, and 15 (2.8%) grade V. Follow-up scans showed that most injuries were either unchanged (51%) or improved (34.7%). Only three patients underwent intervention based on their follow-up scans: two patients had arteriography (one with therapeutic embolization) and one had percutaneous drainage. Each of those patients had clinical signs or symptoms that were indicative of ongoing hepatic abnormality. |
Does the bisphosphonate olpadronate inhibit skeletal prostate cancer progression in a green fluorescent protein nude mouse model? | Metastatic bone disease is one of the major causes of morbidity and mortality in prostate cancer patients. Bisphosphonates are currently used to inhibit bone resorption and reduce tumor-induced skeletal complications. More effective bisphosphonates would enhance their clinical value. We tested several bisphosphonates in a green fluorescent protein (GFP)-expressing human prostate cancer nude mouse model. The in vivo effects of four bisphosphonates, including pamidronate, etidronic acid, and olpadronate, on bone tumor burden in mice intratibially inoculated with PC-3-GFP human prostate cancer cells were visualized by whole-body fluorescence imaging and X-ray. The PC-3-GFP cells produced extensive bone lesions when injected into the tibia of immunocompromised mice. The skeletal progression of the PC-3-GFP cell growth was monitored by GFP fluorescence and the bone destruction was evaluated by X-ray. We showed that 3,3-dimethylaminopropane-1-hydroxy-1,1-diphosphonic acid (olpadronate) was the most effective bisphosphonate treatment in reducing tumor burden as assessed by GFP imaging and radiography. The GFP tumor area and X-ray score significantly correlated. Reduced tumor growth in the bone was accompanied by reduced serum calcium, parathyroid hormone-related protein, and osteoprotegerin. | Heme oxygenase (HO) is considered to be an antioxidant enzyme that catabolizes heme to produce carbon monoxide (CO) and biliverdin. Three isoforms of HO have been discovered. Recently, HO-1 has been found to be upregulated after allergic inflammations of the lower airway. The objective of this study was to address the expression of HO isoenzymes 1 and 2 in the nasal mucosa of patients with allergic rhinitis as well as normal control subjects. Nasal mucosa from 30 patients with persistent allergic rhinitis as well as from 10 normal volunteers was used in this study. We used immunofluorescent technique, Western blotting, and real-time quantitative polymerase chain reaction to localize and quantify the expression of these isoenzymes in normal and allergic human nasal tissues. We found that HO-1 is expressed in the epithelial cells of seromucinous glands and macrophages with significant upregulation of its glandular expression in allergic rhinitis but with no difference in its macrophage expression between the study groups in contrast to HO-2 that is expressed in the vascular endothelial lining cells as well as macrophages with no marked difference between the study groups. |
Are botulinum toxin injections for chronic sialorrhoea in children effective regardless of the degree of neurological dysfunction : A single tertiary institution experience? | To determine the effectiveness of submandibular salivary gland Botulinum Toxin Type-A (BTX-A) injection in the treatment of drooling in children with varying degrees of neurological dysfunction. A retrospective review of pre- and post-procedure drooling frequency and severity scores of patients receiving BTX-A between January 2008 and January 2013. Stratification to different subgroups of neurological impairment was performed according to Gross Motor Function Classification System (GMFCS) score. Drooling severity was assessed using Thomas-Stonell and Greenberg symptom questionnaires administered at time of initial consultation and 3 months after treatment. 48 sets of BTX-A injections in 26 patients with an average age of 9.45 years (range 7 months-18 years) were included in the study. Marked improvement in drooling was seen in 60.4% of patients, a marginal or brief improvement was seen in 20.8% and there was no improvement in 18.8%. No adverse events were reported following any of the BTX-A injections. BTX-A was safe and effective in the eight patients with pre-existing swallowing dysfunction. Subsequent drooling surgery was performed in 15 (57.7%) of the cohort, all 15 patients responded to BTX-A injections. In patients with Cerebral Palsy, there was no correlation between the severity of the neurological dysfunction as measured by the Gross Motor Function Classification System (GMFCS) score and the response to BTX-A treatment. | Recent reviews of reproductive isolation (RI) in plants propose that boundaries between closely related species are maintained predominantly through prezygotic mechanisms. However, few experimental studies have explored how boundaries are maintained in long-lived species. Hawaiian Cyrtandra presents an intriguing challenge to our understanding of RI, as it comprises 60 shrub or small tree species that are almost exclusively restricted to wet forests, where sympatry of multiple species is common. We assessed the relative strengths of pre- and postzygotic barriers among four species of Cyrtandra occurring at the extremes of the main Hawaiian Island's natural island-age gradient, Kaua'i (4.7 Myr) and Hawai'i Island (0.6 Myr), to contrast the strengths and stages of reproductive isolation among species at different stages of divergence. A combination of F1 seed germination, F1 seedling survival, and F1 seedling growth isolated (61-91%) three of the species from sympatric relatives. In contrast, the fourth species was isolated (59%) from its sympatric relative through phenological differences alone. Significant postzygotic barriers in between-island crosses were also observed in one species. |
Do microleakage and bond strength of sealant to primary enamel comparing air abrasion and acid etch techniques? | The objective of this study was to compare the effect of air abrasion (KCP 2000), acid etching (37% phosphoric acid), and the combination of both procedures on the shear bond strength and microleakage of a light-cured pit-and-fissure sealant to the enamel of human primary molar teeth. Noncarious extracted human primary molars were randomly divided into 4 groups in preparation for enamel bonding. The enamel surface was treated as follows for each group: (1) group 1 (control group); (2) group 2 (acid etch group); (3) group 3 (KCP [Kinetic Cavity Preparation System] group); and (4) group 4 (KCP and acid etch group). Delton, a light-cured pit-and-fissure sealant, was then applied to the occlusal surface after conditioning. The bonded specimens were maintained in distilled water at 37 degrees C+/-2 degrees C for 7 days, after which they were subjected to thermocycling followed by shear bond testing. Microleakage was determined by immersing the prepared teeth in 50% silver nitrate dye followed by sectioning and calculation of dye penetration. The mean shear bond strength of the KCP+acid etch group exhibited nearly 50% higher bond strength than the acid etch group (P<.01). In addition, specimens bonded to enamel conditioned only with acid etch exhibited bond strengths that were nearly twice that of those conditioned with the KCP system alone. No significant difference was noted between the air abrasion and control groups. | POEMS syndrome is a plasma cell disorder manifested by Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes. Pulmonary morbidity includes restriction, decreased diffusing capacity for carbon monoxide (DLCO), respiratory muscle weakness, abnormal imaging, and pulmonary hypertension. Autologous peripheral blood stem cell transplantation (aPBSCT) is an effective treatment for POEMS syndrome. It is unknown if aPBSCT improves pulmonary morbidity. We hypothesize pulmonary morbidity will improve following aPBSCT. Retrospective cohort study of POEMS syndrome aPBSCT recipients from 2000 to 2010. Demographic, pulmonary function test (PFT), echocardiogram, cytokine, and imaging data at baseline and after aPBSCT were abstracted. Pre- and post-transplant data were compared using Wilcoxon signed-rank and McNemar's tests. 53 patients met criteria. Median improvements in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and total lung capacity (TLC) after transplant were 180, 315 and 350 ml respectively (median follow-up of 1.1 years). DLCO, maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) improved by a median of 11, 12.5 and 10% predicted respectively. RVSP and chest imaging also improved. Vascular endothelial growth factor and IL-6 decreased by a median of 334 and 2 pg/ml respectively. All comparisons were statistically significant. Longitudinal data demonstrated stability in FEV1, MEP, and TLC and continued improvement in FVC, MIP and DLCO on subsequent PFTs (median follow-up 26.5 months). |
Does interference microscopy delineate cellular proliferations on flat mounted internal limiting membrane specimens? | To demonstrate that interference microscopy of flat mounted internal limiting membrane specimens clearly delineates cellular proliferations at the vitreomacular interface. ILM specimens harvested during vitrectomy were fixed in glutaraldehyde 0.05% and paraformaldehyde 2% for 24 h (pH 7.4). In addition to interference microscopy, immunocytochemistry using antibodies against glial fibrillar acidic protein (GFAP) and neurofilament (NF) was performed. After washing in phosphate-buffered saline 0.1 M, the specimens were flat-mounted on glass slides without sectioning, embedding or any other technique of conventional light microscopy. A cover slide and 4',6-diamidino-2-phenylindole (DAPI) medium were added to stain the cell nuclei. Interference microscopy clearly delineates cellular proliferations at the ILM. DAPI stained the cell nuclei. Areas of cellular proliferation can be easily distinguished from ILM areas without cells. Immunocytochemistry can be performed without changing the protocols used in conventional microscopy. | Inflammation plays a major role in the development and progression of atherosclerosis and coronary artery disease (CAD). Inflammation markers, including white blood cell (WBC) count, C-reactive protein (CRP) and interleukin-6 (IL-6), are widely used for cardiovascular risk prediction. The aim of the study was to establish factors associated with WBC, CRP and IL-6 in patients with CAD. Two functional polymorphisms in genes encoding enzymes participating in adenosine metabolism were analyzed (C34T AMPD1, G22A ADA). Plasma concentrations of IL-6 were measured using high-sensitivity ELISA kits, and the nephelometric method was used for high-sensitivity CRP (hs-CRP) measurement in 167 CAD patients. Presence of metabolic syndrome (MS) and its components, presence of heart failure, severity of CAD symptoms, severe past ventricular arrhythmia (sustained ventricular tachycardia [sVT] or ventricular fibrillation [VF]), lower left ventricle ejection fraction, higher left ventricle mass index, higher end-diastolic volume and higher number of smoking pack-years were significantly associated with higher WBC, CRP and IL-6. Strong associations with arrhythmia were observed for IL-6 (median 3.90 vs 1.89 pg/mL, p<0.00001) and CRP concentration (6.32 vs 1.47 mg/L, p=0.00009), while MS was associated most strongly with IL-6. CRP and IL-6 were independent markers discriminating patients with sVT or VF. There were no associations between AMPD1 or ADA genotypes and inflammation markers. |
Are brain white matter hyperintensities associated with carotid intraplaque hemorrhage? | To retrospectively assess the relationship between carotid intraplaque hemorrhage (IPH), which indicates plaque instability, and brain white matter hyperintense lesions (WMHLs) by using a within-patient design. All patients gave written informed consent for the initial magnetic resonance (MR) studies, and the institutional review board and local research ethics committee waived initial informed consent for the pooled analysis. A total of 190 patients with symptomatic carotid artery disease underwent fluid-attenuated inversion-recovery imaging of the brain and fat-suppressed black-blood T1-weighted MR imaging of the carotid arteries. The volumes of periventricular lesions, subcortical lesions, and total WMHLs were calculated and compared between hemispheres in relation to symptoms and IPH, and their interaction was calculated and compared by using repeated measures three-factorial multivariate analysis. After exclusion of 12 patients, 178 patients (116 men, 62 women; mean age, 70.2 years +/- 8.6 [standard deviation]) remained. There was no significant difference in WMHL volume between the symptomatic and asymptomatic hemispheres, and WMHL volume was not related to the degree of carotid stenosis. The presence of carotid IPH significantly interacted with the interhemispheric WMHL difference (Wilks lambda test, F = 9.95; df = 3; P < .001). Univariate analysis showed larger total and periventricular WMHL volumes (P < .05) in patients with ipsilateral IPH. | Genes essential for bacterial growth are of particular scientific interest. Many putative essential genes have been identified or predicted in several species, however, little is known about gene expression requirement stringency, which may be an important aspect of bacterial physiology and likely a determining factor in drug target development. Working from the premise that essential genes differ in absolute requirement for growth, we describe silencing of putative essential genes in E. coli to obtain a titration of declining growth rates and transcript levels by using antisense peptide nucleic acids (PNA) and expressed antisense RNA. The relationship between mRNA decline and growth rate decline reflects the degree of essentiality, or stringency, of an essential gene, which is here defined by the minimum transcript level for a 50% reduction in growth rate (MTL(50)). When applied to four growth essential genes, both RNA silencing methods resulted in MTL(50) values that reveal acpP as the most stringently required of the four genes examined, with ftsZ the next most stringently required. The established antibacterial targets murA and fabI were less stringently required. |
Is dACT1 involved in human placenta development by promoting Wnt signaling? | The aim of this study was to evaluate the expression of DACT1 in human placenta tissue and the relationship between DACT1 and target genes of the Wnt signaling pathway. Real-time PCR and western blotting were used to detect the expression of DACT1 and the target genes of Wnt signaling pathway in human placenta tissue. And the relationship between them was analyzed using SPSS 19. Real-time PCR results showed that DACT1 expression was significantly higher in 49- to 71-day placenta tissues (mean value = 0.020) than that in 39- to 48-day (the mean value = 0.009). The mRNA expressions of the Wnt signaling pathway target genes, CCND1, CCND2, FOSL1, DAB2 and JUN, were also increased expressed in human placenta tissues. Significant positive associations between DACT1 and CCND1, CCND2, FOSL1, DAB2 and JUN were observed. Western blotting analysis showed that the protein expression of DACT1, CCND1, CCND2, FOSL1, DAB2 and JUN displayed the increasing trend in 43-, 49- and 71-day placenta samples. | While some studies have shown that physicians with healthy personal habits are especially likely to discuss prevention with their patients, to our knowledge no one has published information testing whether physician credibility and patient motivation to adopt healthier habits are enhanced by physician's disclosures of their own healthy behaviors. Two brief health education videos about improving diet and exercise were produced and shown to subjects (n1 = 66, n2 = 65) in an Emory University general medical clinic waiting room in Atlanta, Ga. In one video, the physician revealed an additional half minute of information about her personal healthy dietary and exercise practices and had a bike helmet and an apple visible on her desk (physician-disclosure video). In the other video, discussion of personal practices and the apple and bike helmet were not included (control video). Viewers of the physician-disclosure video considered the physician to be generally healthier, some-what more believable, and more motivating than did viewers of the control video. They also rated this physician to be specifically more believable and motivating regarding exercise and diet (P < or = .001). |
Are serum levels of fibroblast growth factor-21 increased in chronic and acute renal dysfunction? | Fibroblast growth factor (FGF)-21 has recently been introduced as a circulating adipokine which reverses insulin resistance and obesity in rodents. In this study, regulation of FGF-21 in renal dysfunction was elucidated in both chronic kidney disease (CKD) and acute kidney dysfunction (AKD). Serum concentrations of total FGF-21 were quantified by enzyme-linked immunosorbent assay in 499 patients with CKD stages 1-5 (study population 1). Furthermore, total FGF-21 was determined before and within 30 h after unilateral nephrectomy, a model of AKD, in 32 patients (study population 2). FGF-21 levels were correlated to anthropometric and biochemical parameters of renal function, glucose and lipid metabolism, as well as inflammation, in both studies. In study population 1, median [interquartile range] circulating FGF-21 adjusted for age, gender and body mass index was significantly different between CKD stages with highest values detectable in stage 5 (stage 1: 86·4 [132·9]; 2: 206·4 [223·1]; 3: 289·8 [409·3]; 4: 591·3 [789·0]; 5: 1918·1 [4157·0] ng/l). Furthermore, estimated glomerular filtration rate remained a strong independent and negative predictor of FGF-21. In study population 2, FGF-21 increased significantly postsurgically (325·0 [984·0] ng/l) as compared to presurgical values (255·5 [243·0] ng/l). Furthermore, relative changes of FGF-21 were independently and positively predicted by relative changes of creatinine. | The aim of the study was to calculate benchmark dose for chromosomal damage and reduced white blood cell (WBC) associated with exposure to benzene (BZ). A group of 317 exposed workers and 102 controls were examined for WBC count and genotoxicity by micronucleus (MN) frequency. The cumulative exposure concentration of BZ was calculated by ambient air BZ concentration at worksites in conjunction with job type and associated service duration. MN frequency (P < 0.01) was higher and WBC count was lower (P < 0.01) in exposed workers on average than in the controls. MN frequency was a more sensitive than WBC; workers older than 30 were more susceptible to abnormal MN frequency and WBC count reduction than those younger than 30. |
Is the diagnostic value of provocative clinical tests in ulnar neuropathy at the elbow marginal? | Provocative clinical tests are often performed in the diagnosis of ulnar neuropathy at the elbow (UNE) although the evidence for the usefulness of these tests is limited. The aim of this study was to determine the diagnostic value of provocative clinical tests in the diagnosis of UNE in a relevant spectrum of patients and controls. A prospective cohort study was performed in consecutive patients clinically suspected of having UNE. All patients underwent a neurological examination and four commonly used provocative clinical tests (Tinel's test, flexion compression test, palpating for local ulnar nerve tenderness and nerve thickening). Subsequently, in all patients a reference standard test comprising electrophysiological studies and neurosonography was independently assessed. 192 eligible patients completed the study protocol. UNE was diagnosed in 137 and an alternative diagnosis was made in 55 patients. The sensitivity, specificity, and positive and negative predictive values were as follows: Tinel's test 62%, 53%, 77% and 30%; flexion compression test 61%, 40%, 72% and 29%; palpating for nerve thickening 28%, 87%, 84% and 33%; and palpating for nerve tenderness 32%, 80%, 80% and 32%. Logistic regression and receiver operating characteristic curves showed that the added value of one or more provocative tests over routine clinical examination is minimal. | The G-protein-coupled receptor kinase interacting protein-1 (GIT1) is a multidomain scaffold protein that participates in many cellular functions including receptor internalization, focal adhesion remodeling, and signaling by both G-protein-coupled receptors and tyrosine kinase receptors. However, there have been no in vivo studies of GIT1 function to date. To determine essential functions of GIT1 in vivo, we generated a traditional GIT1 knockout mouse. GIT1 knockout mice exhibited approximately 60% perinatal mortality. Pathological examination showed that the major abnormality in GIT1 knockout mice was impaired lung development characterized by markedly reduced numbers of pulmonary blood vessels and increased alveolar spaces. Given that vascular endothelial growth factor (VEGF) is essential for pulmonary vascular development, we investigated the role of GIT1 in VEGF signaling in the lung and cultured endothelial cells. Because activation of phospholipase-Cgamma (PLCgamma) and extracellular signal-regulated kinases 1/2 (ERK1/2) by angiotensin II requires GIT1, we hypothesized that GIT1 mediates VEGF-dependent pulmonary angiogenesis by modulating PLCgamma and ERK1/2 activity in endothelial cells. In cultured endothelial cells, knockdown of GIT1 decreased VEGF-mediated phosphorylation of PLCgamma and ERK1/2. PLCgamma and ERK1/2 activity in lungs from GIT1 knockout mice was reduced postnatally. |
Does treatment of obstructive sleep apnoea lead to improved microvascular endothelial function in the systemic circulation? | Obstructive sleep apnoea (OSA) is a common and potentially reversible cause of systemic hypertension. The mechanisms whereby OSA leads to hypertension and the effects of treatment on arterial function, however, are not well established. Microvascular arterial endothelial and smooth muscle function was assessed in subjects with OSA before and after treatment with continuous positive airways pressure (CPAP). Ten subjects of mean (SE) age 49 (8) years with at least moderately severe OSA had detailed forearm vascular reactivity studies before and after 3 months of CPAP treatment. The systemic circulation was assessed by measuring brachial artery pressure, flow and resistance responses to intra-arterial infusions of acetylcholine (ACh; an endothelium dependent vasodilator), sodium nitroprusside (SNP; an endothelium independent vasodilator), L-NMMA (a nitric oxide (NO) antagonist), and L-arginine (the substrate for NO). Before CPAP, ACh and SNP infusions increased forearm blood flow in a dose dependent manner (p<0.01). After CPAP, endothelium dependent dilation to ACh was significantly increased (434 (23)% of baseline after CPAP v 278 (20)% before CPAP, p<0.001), whereas SNP induced dilation was unchanged. Resting NO production was higher after CPAP, evidenced by a significantly greater reduction in basal flow by L-NMMA (p=0.05). L-Arginine reversed the effect of L-NMMA in all cases. | RECQ helicase family members act as guardians of the genome to assure proper DNA metabolism in response to genotoxic stress. Hematological malignancies are characterized by genomic instability that is possibly related to underlying defects in DNA repair of genomic stability maintenance. We have investigated the expression of RECQ helicases in different hematological malignancies and in their normal counterparts using publicly available gene expression data. Furthermore, we explored whether RECQ helicases expression could be associated with tumor progression and prognosis. Expression of at least one RECQ helicase family member was found significantly deregulated in all hematological malignancies investigated when compared to their normal counterparts. In addition, RECQ helicase expression was associated with a prognostic value in acute myeloid leukemia, chronic lymphocytic leukemia, lymphoma and multiple myeloma. |
Are lower urinary tract symptoms and erectile dysfunction highly prevalent in ageing men? | To evaluate a possible correlation between the International Prostate Symptom Score (IPSS) and the Sexual Health Inventory for Men (SHIM) in an unselected population of men presenting to a clinic, as lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are highly prevalent in ageing men, and recent largely community-based epidemiological studies reported a close association between ED and LUTS. This was a cross-sectional study in an unselected consecutive sample of 118 men aged >40 years attending a urology clinic; the reason for consulting was not ascertained. While in the waiting room the men were asked to participate in the study and on agreement were given the IPSS and the SHIM to complete. The mean (range) age of the participants was 61.7 (45-82) years. Overall, 19 (16%) and 47 (40%) of the men reported having moderate or severe LUTS, respectively. Erectile problems were also common, the prevalence of moderate ED was 11% and complete ED 29%. The Pearson correlation coefficient between the IPSS and the SHIM was - 0.32 (P < 0.001). | The volatile anesthetic isoflurane protects the heart from hypoxia/reperfusion (H/R) injury. However, it is still incompletely understood whether isoflurane exerts its protective role through preventing mitochondrial permeability transition pore (MPTP) opening. Primary cultured cardiocytes were exposed to H/R in the absence or presence of isoflurane. Cell cytotoxicity and apoptosis were detected by MTT assay and TUNEL staining, respectively. MPTP function was monitored by confocal imaging after reoxygenation. ROS production and activation of caspase-3 were determined by fluorescent reader and western blot, respectively. As compared to the control group, H/R led to significant cell cytotoxicity and apoptosis, while application of isoflurane markedly reversed the effects. Furthermore, isoflurane significantly inhibits the formation of H/R-induced excess ROS production. Finally, isoflurane attenuated the onset of mitochondrial permeability transition pore (MPTP) occurred during hypoxia/reoxygenation, and in turn inhibited activation of caspase-3. |
Is variation in catechol-O-methyltransferase associated with duloxetine response in a clinical trial for major depressive disorder? | The study objective was to evaluate variations in genes implicated in antidepressant mechanism of action for association with response to duloxetine treatment in major depressive disorder (MDD). We assessed response over 6 weeks in 250 duloxetine-treated Caucasian patients in a randomized, double-blind study of patients with MDD. Single nucleotide polymorphisms (SNPs) were genotyped in 19 candidate genes selected based on evidence for involvement in antidepressant mechanism of action. Primary analysis examined baseline to end point reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score, using a set-based test for association for each gene. Follow-up analyses examined individual SNPs within any significant gene for association with reduction in HAMD17 and 30-item Inventory of Depressive Symptomatology-Clinician Rated (IDS-C-30). After correction for multiple comparisons, only COMT was associated with change in HAMD17 (experiment wide p = .018). Peak association was detected with rs165599 (p = .006), which accounted for approximately 3% of variance in HAMD17 change and >4% of variance in IDS-C-30 change (p = .001). The least-squared mean change (SE) in HAMD17 score by rs165599 genotype was -10.8 (1.2), -8.7 (.6), and -6.5 (.7) for patients with GG, GA, and AA genotypes, respectively. For SNPs in serotonin 2A receptor (HTR2A) previously associated with citalopram response, including rs7997012, no significant evidence of association with duloxetine response was identified. | To examine the hypothesis that induction of heat shock proteins in human endothelial cells (ECs) by either heat shock or sodium arsenite could prevent subsequent EC necrosis induced by activated human polymorphonuclear neutrophil leukocytes (PMNs). Cultures of ECs were exposed to heat shock (42 degrees C, 30 to 60 minutes) or sodium arsenite (40 to 320 mumol/L) for 6 hours to induce the expression of a heat shock protein of 72-kd molecular weight (HSP-72). Activated PMNs were subsequently added to these ECs for 24 hours to evaluate the ability of HSP-72 to prevent activated PMN-mediated EC necrosis. Neither EC necrosis nor apoptosis was induced by heat shock. Sodium arsenite (40 to 80 mumol/L) did not induce EC necrosis, although 320-mumol/L sodium arsenite caused a significant increase in EC necrosis. Sodium arsenite (80 to 320 mumol/L) also induced dose-dependent EC apoptosis. Endothelial cells exposed to heat shock and sodium arsenite (40 and 80 mumol/L) significantly attenuated subsequent EC necrosis induced by activated PMNs. However, sodium arsenite at 320 mumol/L aggravated activated PMN-mediated EC necrosis. Expression of HSP-72 was detected after ECs were treated both with heat shock and sodium arsenite (40 to 320 mumol/L) for 6 hours. |
Do myofibroblast matrix metalloproteinases activate the neutrophil chemoattractant CXCL7 from intestinal epithelial cells? | The up-regulation of matrix metalloproteinases (MMPs) in the inflamed gut has mainly been associated with mucosal degradation and ulceration. However, their in vitro capacity to specifically cleave inflammatory mediators indicates that MMPs may have a profound immunoregulatory impact. We hypothesized that MMPs proteolytically modify intestinal epithelial chemokine signaling. Interleukin-1beta-stimulated Caco-2 cells were exposed basolaterally to nanomolar concentrations of activated MMP-3 or cocultured with interleukin-1beta-stimulated, MMP-producing, colonic myofibroblasts (CCD-18co). The conditioned media were subjected to chemotaxis assays. In addition, epithelial cells from patients with colitis were examined by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. MMP-3 dose-dependently induced the neutrophil (up to 5-fold) but not monocyte chemoattractant capacity of Caco-2 cells. A similar Caco-2 chemotactic response was obtained in the Caco-2/CCD-18co cocultures. The principal mediator of these protease-related effects was identified as the potent neutrophil chemokine CXCL7 (neutrophil activating peptide 2), a proteolytic cleavage product of chemotactically inert platelet basic protein (PBP), not previously identified in the intestine. Antibodies against CXCL7 inhibited the MMP-induced chemotactic response by 84%, and PBP mRNA and protein were detected in stimulated Caco-2 but not in CCD-18co cells. Furthermore, PBP transcript and protein levels were low in the mucosa and in isolated epithelial cells from patients with Crohn's disease and from normal intestine but increased up to 13-fold in patients with ulcerative colitis. | We compared the results of laboratory examinations, echocardiography, arterial stiffness, central blood pressure (BP) and ambulatory BP monitoring (ABPM) between treatment-naïve patients with low normal thyroid-stimulating hormone (TSH) and those with high normal TSH levels. A total of 285 consecutively-eligible patients with both treatment-naïve hypertension and euthyroid were divided into two groups: those with low-normal TSH (0.40-1.99 μIU/mL, group 1) and high-normal TSH (2.00-4.50 μIU/mL, group 2) and compared according to group and gender. Males were divided into group 1 (n = 113, 68.9%) and group 2 (n = 51, 31.1%) and females were divided into group 1 (n = 71, 58.7%) and group 2 (n = 50, 41.3%). Multivariate analyses revealed that the augmentation index (71.0 [adjusted mean] ± 1.7 [standard error] vs. 78.8 ± 2.5%, P = 0.045), central systolic BP (SBP) (143.3 ± 2.1 vs. 153.0 ± 3.2 mmHg, P = 0.013), systemic vascular resistance (SVR, 21.4 ± 0.6 vs. 23.9 ± 0.9 mmHg/L/min, P = 0.027), SBP during daytime (144.1 ± 1.4 vs. 151.6 ± 2.1 mmHg, P=0.004) and nighttime (130.4 ± 1.6 vs. 138.5 ± 2.5 mmHg, P=0.008), and nighttime pulse pressure (PP, 47.2 ± 0.9 vs. 51.7 ± 1.4 mmHg, P = 0.010) were significantly higher while cardiac output (5.4 ± 0.1 vs. 4.8 ± 0.2L/min, P = 0.043) and PP amplification (1.02 ± 0.02 vs. 0.94 ± 0.03, P = 0.039) were significantly lower in the male group 2 than in the male group 1. However, there were no significant differences between the two groups in females. |
Is a trabecular plate-like phenotype overrepresented in Chinese-American versus Caucasian women? | This study used extreme phenotype selection to define two trabecular bone phenotypes in a cohort of Chinese-American and Caucasian women. A trabecular plate-predominant phenotype is more common in Chinese-Americans while the rod-predominant phenotype is more typical of Caucasians. The robustness of these phenotypic associations with respect to lifestyle factors suggests that this trait may have a genetic basis and that these phenotypes can be utilized in future genetic studies. Compared to Caucasians, Chinese-Americans have more plate-like trabecular bone when measured by individual trabecula segmentation (ITS). These findings suggest a phenotypic difference between the races, which may be amenable to genetic analysis. We sought to identify a single ITS plate trait to pursue in genetic studies by conducting an extreme phenotype selection strategy to numerically define two distinct phenotypes-plate-like and rod-like-and determine whether the selected phenotypic associations were independent of lifestyle factors in order to conduct future genetic studies. A previously described cohort of 146 Chinese-American and Caucasian women with high-resolution peripheral quantitative computed tomography imaging and ITS analyses were studied with logistic regression and receiver operator characteristic analyses. The tibial plate-to-rod (TPR) ratio was the best ITS discriminator of race. Using extreme phenotypic selection, two TPR ratio phenotypes were defined numerically: plate-like as a TPR ratio value in the highest quartile (≥1.336) and rod-like as a TPR ratio value in the lowest quartile (≤0.621). Women with a plate-like phenotype were 25.7 times more likely (95 % CI 7.3-90.1) to be Chinese-American than women with rod-like morphology. After controlling for constitutional and lifestyle covariates, women in the highest vs. lowest TPR ratio quartile were 85.0 times more likely (95 % CI 12.7-568.0) to be Chinese-American. | To develop a specific SARS virus-targeted antibody preparation for emergent prophylaxis and treatment of SARS virus infection. By using phage display technology, we constructed a naive antibody library from convalescent SARS patient lymphocytes. To obtain the neutralizing antibody to SARS virus surface proteins, the library panning procedure was performed on purified SARS virions and the specific Fab antibody clones were enriched by four rounds of repeated panning procedure and screened by highthroughput selection. The selected Fab antibodies expressed in the periplasma of E. coli were soluble and further purified and tested for their binding properties and antiviral function to SARS virus. The functional Fab antibodies were converted to full human IgG antibodies with recombinant baculovirus/insect cell systems and their neutralizing activities were further determined. After four rounds of the panning, a number of SARS-CoV virus-targeted human recombinant Fab antibodies were isolated from the SARS patient antibody library. Most of these were identified to recognize both natural and recombinant SARS spike (S) proteins, two Fab antibodies were specific for the virus membrane (M) protein, only one bound to SARS-CoV nucleocapsid protein. The SARS-CoV S and M protein-targeted Fab or IgG antibodies showed significant neutralizing activities in cytopathic effect (CPE) inhibition neutralization test, these antibodies were able to completely neutralize the SARS virus and protect the Vero cells from CPE after virus infection. However, the N protein-targeted Fab or IgG antibodies failed to neutralize the virus. In addition, the SARS N protein-targeted human Fab antibody reacted with the denatured N proteins, whereas none of the S and M protein specific neutralizing antibodies did. These results suggested that the S and M protein-specific neutralizing antibodies could recognize conformational epitopes which might be involved in the binding of virions to cellular receptors and the fusion activity of the virus. |
Do deficits in visuospatial processing contribute to quantitative measures of freezing of gait in Parkinson 's disease? | The aim of this study was to investigate whether an objective measure of freezing of gait (FOG) using a validated alternating stepping in place (SIP) task, is related to executive and/or visuospatial cognitive impairment in Parkinson's disease (PD). We studied prospectively 30 PD subjects with the Unified Parkinson's Disease Rating Scale (UPDRS) III, the FOGq, Trail Making Test Part B (TMTB), Wisconsin Card Sorting, Initiation/Perseveration, Matrix Reasoning (MR) and Block Design (BD). PD subjects performed three, 100s trials of alternative SIP while standing on two force platforms to assess the number and duration of freezing episodes (FE), SIP rhythmicity and symmetry. Freezers had larger cycle asymmetry and arrhythmicity than non-freezers (P<0.05). Performance on BD and MR tests differentiated freezers from non-freezers (P<0.04; P=0.001, respectively). BD performance negatively correlated with the FOGq total (P<0.05), the number and duration of FE (P<0.01), SIP arrhythmicity and asymmetry (P=0.01, P<0.05). MR performance negatively correlated with all FOGq #3 and total as well as SIP FE metrics (P≤0.01), except for SIP asymmetry. | Surfactant protein A (SP-A) is a C-type lectin involved in surfactant homeostasis as well as host defense in the lung. We have recently demonstrated that SP-A enhances the killing of bacillus Calmette-Guerin (BCG) by rat macrophages through a nitric oxide-dependent pathway. In the current study we have investigated the role of tyrosine kinases and the downstream mitogen-activated protein kinase (MAPK) family, and the transcription factor NFkappaB in mediating the enhanced signaling in response to BCG in the presence of SP-A. Human SP-A was prepared from alveolar proteinosis fluid, and primary macrophages were obtained by maturation of cells from whole rat bone marrow. BCG-SP-A complexes were routinely prepared by incubation of a ratio of 20 microg of SP-A to 5 x 105 BCG for 30 min at 37 degrees C. Cells were incubated with PBS, SP-A, BCG, or SP-A-BCG complexes for the times indicated. BCG killing was assessed using a 3H-uracil incorporation assay. Phosphorylated protein levels, enzyme assays, and secreted mediator assays were conducted using standard immunoblot and biochemical methods as outlined. Involvement of tyrosine kinases was demonstrated by herbimycin A-mediated inhibition of the SP-A-enhanced nitric oxide production and BCG killing. Following infection of macrophages with BCG, the MAPK family members ERK1 and ERK2 were activated as evidence by increased tyrosine phosphorylation and enzymatic activity, and this activation was enhanced when the BCG were opsonized with SP-A. An inhibitor of upstream kinases required for ERK activation inhibited BCG- and SP-A-BCG-enhanced production of nitric oxide by approximately 35%. Macrophages isolated from transgenic mice expressing a NFkappaB-responsive luciferase gene showed increased luciferase activity following infection with BCG, and this activity was enhanced two-fold in the presence of SP-A. Finally, lactacystin, an inhibitor of IkappaB degradation, reduced BCG- and SP-A-BCG-induced nitric oxide production by 60% and 80% respectively. |
Does bRCAness predict resistance to taxane-containing regimens in triple negative breast cancer during neoadjuvant chemotherapy? | To provide optimal treatment of heterogeneous triple negative breast cancer (TNBC), we need biomarkers that can predict the chemotherapy response. We retrospectively investigated BRCAness in 73 patients with breast cancer who had been treated with taxane- and/or anthracycline-based neoadjuvant chemotherapy (NAC). Using multiplex, ligation-dependent probe amplification on formalin-fixed core needle biopsy (CNB) specimens before NAC and surgical specimens after NAC. BRCAness status was assessed with the assessor unaware of the clinical information. We obtained 45 CNB and 60 surgical specimens from the 73 patients. Of the 45 CNB specimens, 17 had BRCAness (38.6% of all subtypes). Of the 23 TNBC CNB specimens, 14 had BRCAness (61% of TNBC cases). The clinical response rates were significantly lower for BRCAness than for non-BRCAness tumors, both for all tumors (58.8% vs. 89.3%, P = .03) and for TNBC (50% vs. 100%, P = .02). All tumors that progressed with taxane therapy had BRCAness. Of the patients with TNBC, those with non-BRCAness cancer had pathologic complete responses significantly more often than did those with BRCAness tumors (77.8% vs. 14.3%, P = .007). After NAC, the clinical response rates were significant lower for BRCAness than for non-BRCAness tumors in all subtypes (P = .002) and in TNBC cases (P = .008). After a median follow-up of 26.4 months, 6 patients-all with BRCAness-had developed recurrence. Patients with BRCAness had shorter progression-free survival than did those with non- BRCAness (P = .049). | Children involved with child welfare systems are at high risk for emotional and behavioral problems. Many children with identified mental health problems do not receive care, especially ethnic/minority children. To examine how patterns of specialty mental health service use among children involved with child welfare vary as a function of the degree of coordination between local child welfare and mental health agencies. Specialty mental health service use for 1 year after contact with child welfare was examined in a nationally representative cohort of children aged 2 to 14 years. Predictors of service use were modeled at the child/family and agency/county levels. Child- and agency-level data were collected between October 15, 1999, and April 30, 2001. Ninety-seven US counties. A total of 2823 child welfare cases (multiple informants) from the National Survey of Child and Adolescent Well-being and agency-level key informants from the participating counties. Specialty mental health service use during the year after contact with the child welfare system. Only 28.3% of children received specialty mental health services during the year, although 42.4% had clinical-level Child Behavior Checklist scores. Out-of-home placement, age, and race/ethnicity were strong predictors of service use rates, even after controlling for Child Behavior Checklist scores. Increased coordination between local child welfare and mental health agencies was associated with stronger relationships between Child Behavior Checklist scores and service use and decreased differences in rates of service use between white and African American children. |
Does naloxone combined with epinephrine decrease cerebral injury in cardiopulmonary resuscitation? | Cardiopulmonary arrest is a serious disease that claims many lives every day; 30% of the patients suffer irreversible central nervous system injury after restoration of systemic circulation (ROSC). Naloxone combined with epinephrine was tested in a cardiac arrest rat model in which asphyxia was induced to determine if this drug combination could increase the resuscitation rate (survival) and decrease the cerebral damage. Twenty-four male Wistar rats were randomly assigned to one of three groups: the group treated with 1 mL saline (SA group; n = 8), the group treated with only epinephrine 5 microg/100 g (EP group; n = 8), or the group treated with epinephrine 5 microg/100 g combined with naloxone 1 mg/kg (NA group; n = 8). Eight minutes after arrest, cardiopulmonary resuscitation was initiated and the different drugs were administered to the rats in their respective groups at the same time. Mean arterial pressure (MAP), heart rate (HR), and neurodeficit score (NDS) were measured. The HR in the NA group (414 +/- 45 beats/min) was faster than in the EP group (343 +/- 29 beats/min) at the 5-min time point (P < 0.01). The HR in the NA group was 392 +/- 44 beats/min and 416 +/- 19 beats/min at the 60-min and 180-min time points, respectively. There were no statistically significant differences in MAP before or after ROSC. The rates of ROSC were 2 of 8, 6 of 8, and 7 of 8 animals in the SA group, EP group, and NA group, respectively. Three days later, the rates decreased to 1, 3, and 5 in the SA group, EP group, and NA group, respectively. The average resuscitation time in the NA group was significantly shorter than in the other two groups. The NDS in the NA group was 57 +/- 13, higher than in the EP group (45 +/- 13) and SA group (38). | Excess adipose tissue is a source of inflammation. Polycystic ovary syndrome (PCOS) is a proinflammatory state and is often associated with excess abdominal adiposity (AA) alone and/or frank obesity. To determine the effect of glucose ingestion on cytokine release from mononuclear cells (MNC) in women with PCOS with and without excess AA and/or obesity. A cross-sectional study. Academic medical center. Twenty-three women with PCOS (seven normal weight with normal AA, eight normal weight with excess AA, eight obese) and 24 ovulatory controls (eight normal weight with normal AA, eight normal weight with excess AA, eight obese). Three-hour 75-g oral glucose tolerance test (OGTT). Body composition was measured by dual energy x-ray absorptiometry. Insulin sensitivity was derived from the OGTT (ISOGTT). TNFα, IL-6, and IL-1β release was measured in supernatants of cultured MNC isolated from blood samples drawn while fasting and 2 hours after glucose ingestion. Insulin sensitivity was lower in obese subjects regardless of PCOS status and in normal-weight women with PCOS compared with normal-weight controls regardless of body composition status. In response to glucose ingestion, MNC-derived TNFα, IL-6, and IL-1β release decreased in both normal-weight control groups but failed to suppress in either normal-weight PCOS group and in obese women regardless of PCOS status. For the combined groups, the cytokine responses were negatively correlated with insulin sensitivity and positively correlated with abdominal fat and androgens. |
Is 24-week oral ganciclovir prophylaxis in kidney recipients associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course? | Cytomegalovirus (CMV) infection is associated with reduced graft and patient survival among kidney recipients. The highest risk of CMV infection occurs in CMV-naive recipients of kidneys from seropositive donors (D+/R-). Optimal CMV prophylaxis is not established. This prospective cohort study compared the safety and efficacy of prophylaxis with 12 versus 24 weeks of oral ganciclovir. We prospectively administered 24 weeks ganciclovir to 31 D+/R- recipients. The control group comprised 39 patients transplanted in the immediately preceding era who received a 12-week course of prophylaxis. All patients received cytolytic therapy within the first month, as well as a tacrolimus-based maintenance regimen. A logistic regression model was fit to examine the relationship between 24 weeks ganciclovir prophylaxis and the odds of developing CMV infection by one year. Groups were matched, though the 12-week cohort had more delayed graft function than their 24-week counterparts (45% vs. 29%, P=0.04). CMV infection occurred in 31% and 7% patients in the 12-week and 24-week groups, respectively (P<or=0.01). Mean time to development of CMV infection was 17.5+/-2.2 weeks in the 12-week, and 22.0+/-10.0 weeks in the 24-week, groups (P=0.79). Both 24 weeks ganciclovir prophylaxis (O.R. 0.15, 95% C.I. 0.03-0.91, P=0.04) and delayed graft function (O.R. 4.49, 95% C.I. 1.67-36.56, P<0.01) were associated with CMV infection. | Prooxidant effects of fish oil supplementation could unfavorably affect the cardiovascular benefits of fish oil. We tested the effects of 8 wk vitamin E cosupplementation with fish oil on antioxidant defenses at rest and in response to exhaustive exercise in rats. Rats (N = 80) were divided into fish oil, fish oil and vitamin E (FOVE), soy oil, and soy oil and vitamin E (SOVE) supplemented groups. For the vitamin E supplemented rats, corresponding groups (FOVE-Ex and SOVE-Ex) performed an acute bout of exhaustive exercise after the supplementation period. Fish oil supplementation increased the activity of catalase, glutathione peroxidase, and glutathione-S-transferase in the liver and red gastrocnemius (RG) muscle. Fish oil decreased liver total glutathione (TGSH) levels. Vitamin E supplementation decreased antioxidant enzyme activities to levels at or near those in SOVE in a tissue specific pattern. Vitamin E increased TGSH in liver, heart, and RG. Regression analysis showed TGSH to be a negative determinant of protein oxidative damage as measured by protein carbonyl levels in both liver and RG. Catalase activity was associated with liver lipid peroxidation as measured by thiobarbituric acid-reacting substances. The exercise-induced decrease in hepatic TGSH tended to be less in FOVE versus SOVE. Exhaustive exercise also modulated tissue antioxidant enzymes. |
Does rectocele repair improve evacuation and prolapse complaints independent of anorectal function and colonic transit time? | Evacuation disorders associated with a rectocele can be improved by rectocele repair. This study investigated whether anorectal function tests results change after rectocele repair. Fourteen patients with 2nd or 3rd degree rectocele and evacuation disorder were treated by posterior colporrhaphy and evaluated pre- and postoperatively (after 8 months, range 3-14) using questionnaires, anal manometry and endosonography, rectal barostat testing, and colonic transit time measurement with radio-opaque markers. Results from female controls were used for comparison. Preoperatively, rectocele patients had high maximal basal sphincter pressures, large sphincter lengths, and low maximal squeeze pressures, with an anal sphincter defect in seven and lower visceral sensitivity scores than in controls. Postprandial rectal responses (more than 10% decrease in postprandial volume after 1 h) were found in 3 of 14 patients compared to 2 of 11 parous and 9 of 11 nulliparous controls. After repair, a rectocele of 2nd degree was found in four patients. Questionnaire scores were significantly decreased for straining, evacuation disorder, manual support, and protrusion. Overall patient satisfaction with the operation scored 8.25 (range 3-10). Defecation frequencies and stool consistencies were unaltered. Anal pressures, rectal compliance-curves, visceral sensitivity, and colonic transit times were unaltered after the rectocele repair. | As the primary immune cells of the central nervous system, microglia contribute to development, homeostasis, and plasticity of the central nervous system, in addition to their well characterized roles in the foreign body and inflammatory responses. Increasingly, inappropriate activation of microglia is being reported as a component of inflammation in neurodegenerative and neuropsychiatric disorders. The statin class of cholesterol-lowering drugs have been observed to have anti-inflammatory and protective effects in both neurodegenerative diseases and ischemic stroke, and are suggested to act by attenuating microglial activity. We sought to investigate the effects of simvastatin treatment on the secretory profile and phagocytic activity of primary cultured rat microglia, and to dissect the mechanism of action of simvastatin on microglial activity. Simvastatin treatment altered the release of cytokines and trophic factors from microglia, including interleukin-1-β, tumour necrosis factor-α, and brain derived neurotrophic factor in a cholesterol-dependent manner. Conversely, simvastatin inhibited phagocytosis in microglia in a cholesterol-independent manner. |
Are low 2-methoxyestradiol levels at the first trimester of pregnancy associated with the development of pre-eclampsia? | To determine whether maternal plasma levels of 2-methoxyestradiol (2-ME) are decreased early in pregnancies that subsequently develop pre-eclampsia (PE) and whether this difference could be attributed to the presence of Val158Met catechol-O-methyltransferase (COMT) polymorphism in the placenta. Clinical characteristics and plasma samples were collected at 11 to 14 weeks prospectively in a cohort of patients. From them, 13 PE and 72 control pregnant women were chosen. Plasma soluble fms-like tyrosine kinase1 and placental growth factor levels were measured by electrochemiluminescence and 2-ME was measured by high-performance liquid chromatography with mass spectrometry/mass spectrometry detection. At delivery, placental tissue was collected and the Val158Met COMT polymorphism was determined by restriction fragment length polymorphism-PCR. At 11 to 14 weeks, patients who would develop PE have significantly lower plasma levels of 2-ME than controls [1.9 ± 2 standard error of the mean (SEM) vs 61.7 ± 27 pg/mL, P < 0.05]. The Val158Met polymorphism was more frequent in controls than in PE patients and the placental presence of COMT polymorphism was associated with a decreased risk of developing PE [PE: 23.1% vs control: 66.6%; χ(2) = 10.9, p = 0.0041]. | To observe the effects of Sanhuangyinchi decoction (SHYCD) pretreatment on acute hepatic failure (AHF) induced by D-galactosamine and lipopolysaccharide (LPS) in rats and explore the possible mechanisms involving antioxidant stress and cell apoptosis-related protein expression. Forty-eight SD rats were randomized equally into control group, AHF model group, high-, medium- and low-dose SHYCD groups, and Bicyclol group. Five days after administration of the corresponding drugs, the rats were challenged with peritoneal D-galactosamine (700 mg/kg) plus LPS (10 ug/kg) injections to induce AHF acute hepatic failure except for those in the control group. At 48 h after the injections, blood samples were collected from the rats to detect the levels of ALT, AST, TBIL, PT, INR and FIB, and pathological changes and superoxide dismutase (SOD) and malondialdehyde (MDA) contents in the liver were examined; immunohistochemistry and western blotting were used to detect caspase-3 protein expression in the liver. The levels of ALT, AST, TBIL, TP and INR in the 3 SHYCD groups and Bicyclol group significantly decreased (P<0.05) while FIB significantly increased in comparison with those in the model group. SHYCD obviously ameliorated the pathological changes, enhanced SOD activity (P<0.05), and decreased MDA levels (P<0.05) and caspase-3 expression (P<0.05) in the liver tissue. SHYCD at the medium dose produced similar effects to Bicyclol (P>0.05) and showed better effects at the high dose than Bicyclol (P<0.05). |
Does iNKT/CD1d-antitumor immunotherapy significantly increase the efficacy of therapeutic CpG/peptide-based cancer vaccine? | Therapeutic cancer vaccines aim to boost the natural immunity against transformed cancer cells, and a series of adjuvants and co-stimulatory molecules have been proposed to enhance the immune response against weak self-antigens expressed on cancer cells. For instance, a peptide/CpG-based cancer vaccine has been evaluated in several clinical trials and was shown in pre-clinical studies to favor the expansion of effector T versus Tregs cells, resulting in a potent antitumor activity, as compared to other TLR ligands. Alternatively, the adjuvant activity of CD1d-restricted invariant NKT cells (iNKT) on the innate and adaptive immunity is well demonstrated, and several CD1d glycolipid ligands are under pre-clinical and clinical evaluation. Importantly, additive or even synergistic effects have been shown upon combined CD1d/NKT agonists and TLR ligands. The aim of the present study is to combine the activation and tumor targeting of activated iNKT, NK and T cells. Activation and tumor targeting of iNKT cells via recombinant α-galactosylceramide (αGC)-loaded CD1d-anti-HER2 fusion protein (CD1d-antitumor) is combined or not with OVA peptide/CpG vaccine. Circulating and intratumoral NK and H-2Kb/OVA-specific CD8 responses are monitored, as well as the state of activation of dendritic cells (DC) with regard to activation markers and IL-12 secretion. The resulting antitumor therapy is tested against established tumor grafts of B16 melanoma cells expressing human HER2 and ovalbumin. The combined CD1d/iNKT antitumor therapy and CpG/peptide-based immunization leads to optimized expansion of NK and OVA-specific CD8 T cells (CTLs), likely resulting from the maturation of highly pro-inflammatory DCs as seen by a synergistic increase in serum IL-12. The enhanced innate and adaptive immune responses result in higher tumor inhibition that correlates with increased numbers of OVA-specific CTLs at the tumor site. Antibody-mediated depletion experiments further demonstrate that in this context, CTLs rather than NK cells are essential for the enhanced tumor inhibition. | Uncontrolled blood pressure (BP), among patients diagnosed and treated for the condition, remains an important clinical challenge; aspects of clinical operations could potentially be adjusted if they were associated with better outcomes. To assess clinical operations factors' effects on normalization of uncontrolled BP. Observational cohort study. Patients diagnosed with hypertension from a large urban clinical practice (2005-2009). We obtained clinical data on BP, organized by person-month, and administrative data on primary care provider (PCP) staffing. We assessed the resolution of an episode of uncontrolled BP as a function of time-varying covariates including practice-level appointment volume, individual clinicians' appointment volume, overall practice-level PCP staffing, and number of unique PCPs. Among the 7409 unique patients representing 50,403 person-months, normalization was less likely for the patients in whom the episode starts during months when the number of unique PCPs were high [the top quintile of unique PCPs was associated with a 9 percentage point lower probability of normalization (P<0.01) than the lowest quintile]. Practice appointment volume negatively affected the likelihood of normalization [episodes starting in months with the most appointments were associated with a 6 percentage point reduction in the probability of normalization (P=0.01)]. Neither clinician appointment volume nor practice clinician staffing levels were significantly associated with the probability of normalization. |
Is chronic cerebrospinal venous insufficiency associated with chronic venous disorders : A case-control study? | To evaluate the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and the presence of a Chronic Venous Disorder (CVD). We included 55 subjects with CCSVI aged >18 years, and 186 controls without CCSVI. Each subject was evaluated with color Doppler sonography in accordance with Zamboni's five criteria, examined by two neurologists and interviewed with an ad-hoc designed form. The neurologists and the sonographers were mutually blinded. CVD were classified according to CEAP. Mean age was 42 years (SD = 9) in cases and 43 years (10) in controls (p = ns). The odds ratios in subjects CCSVI were 0.6 (0.2-2.2) for CEAP 1, 0.9 (0.2-4.5) for CEAP 2, and 1.0 (0.6-1.9) for family history of varicose veins. The prevalence of CVD and, family history of varicose veins, was similar between cases and controls for each Zamboni criterion. | The aim of the current study was to test the impact of dentin powder on the antimicrobial efficacy of bioactive glass S53P4 (BAG). BAG was suspended (preincubated) in saline at 37 degrees C for different time periods with or without human dentin powder, hydroxylapatite, or decalcified dentin. Subsequently, Enterococcus faecalis ATCC 29212 cells were added to these suspensions and bacterial recovery measured with and without the use of gentle sonication. Furthermore, survival of bacteria in test and control suspensions was assessed over time. Supernatants of suspensions were analyzed for their element contents using atomic absorption spectrophotometry. The effects of pH, silica, and osmolarity on E faecalis viability were assessed using specifically prepared solutions. BAG preincubated with dentin powder caused a significant (P < .05) decrease in viability compared to pure BAG suspensions. This was not based on adherence of bacteria to solid particles or agglutination of the cells, because sonication did not increase bacterial yields. Hydroxylapatite and decalcified dentin did not increase BAG killing efficacy. The additive effect of BAG + dentin powder was dose dependent, occurred only with solids in suspension, and increased with suspension time. An augmented dissolution of glass components, especially silicon, was measured in BAG + dentin powder compared to pure BAG suspensions or counterparts containing hydroxylapatite or decalcified dentin. High osmolarity per se did not affect E faecalis viability, whereas high pH and silica levels did. |
Does n2 extenuate experimental ischemic stroke through platelet aggregation inhibition? | Thromboxane A2 (TXA2) can induce the platelet aggregation and lead to thrombosis. This will cause the low-reflow phenomenon after ischemic stroke and aggravate the damage of brain issues. Therefore, it is potential to develop the drugs inhibiting TXA2 pathway to treat cerebral ischemia. This study aims to prove the protective effect of N2 (4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoic acid) on focal cerebral ischemia and reperfusion injury through platelet aggregation inhibition. Middle cerebral artery occlusion/reperfusion (MCAO/R) is used as the animal model. Neurological deficit score, Morris water maze, postural reflex test, Limb-use asymmetry test, infarct volume, and water content were performed to evaluate the protective effect of N2 in MCAO/R rats. 9, 11-dieoxy-11α, 9α-methanoepoxyprostaglandin F2α (U46619) or adenosine diphosphate (ADP) was used as the inducer of platelet aggregation. | The present study evaluated whether the poorer baseline performance of cochlear implant (CI) users or the technical and/or physiological properties of CI stimulation are responsible for the absence of masking release. This study measured speech reception thresholds (SRTs) in continuous and modulated noise as a function of signal to noise ratio (SNR). A total of 24 subjects participated: 12 normal-hearing (NH) listeners and 12 subjects provided with recent MED-EL CI systems. The mean SRT of CI users in continuous noise was -3.0 ± 1.5 dB SNR (mean ± SEM), while the normal-hearing group reached -5.9 ± 0.8 dB SNR. In modulated noise, the difference across groups increased considerably. For CI users, the mean SRT worsened to -1.4 ± 2.3 dB SNR, while it improved for normal-hearing listeners to -18.9 ± 3.8 dB SNR. |
Does gene expression profiling reveal potential prognostic biomarkers associated with the progression of heart failure? | Heart failure (HF) is the most common cause of morbidity and mortality in developed countries. Here, we identify biologically relevant transcripts that are significantly altered in the early phase of myocardial infarction and are associated with the development of post-myocardial infarction HF. We collected peripheral blood samples from patients with ST-segment elevation myocardial infarction (STEMI): n = 111 and n = 41 patients from the study and validation groups, respectively. Control groups comprised patients with a stable coronary artery disease and without a history of myocardial infarction. Based on plasma NT-proBNP level and left ventricular ejection fraction parameters the STEMI patients were divided into HF and non-HF groups. Microarrays were used to analyze mRNA levels in peripheral blood mononuclear cells (PBMCs) isolated from the study group at four time points and control group. Microarray results were validated by RT-qPCR using whole blood RNA from the validation group. Samples from the first three time points (admission, discharge, and 1 month after AMI) were compared with the samples from the same patients collected 6 months after AMI (stable phase) and with the control group. The greatest differences in transcriptional profiles were observed on admission and they gradually stabilized during the follow-up. We have also identified a set of genes the expression of which on the first day of STEMI differed significantly between patients who developed HF after 6 months of observation and those who did not. RNASE1, FMN1, and JDP2 were selected for further analysis and their early up-regulation was confirmed in HF patients from both the study and validation groups. Significant correlations were found between expression levels of these biomarkers and clinical parameters. The receiver operating characteristic (ROC) curves indicated a good prognostic value of the genes chosen. | It has been shown that vitamin A supplementation has different effects on skeletal health and the antioxidant system. Deficiency or excess of this vitamin can lead to health problems. Vitamin A can work as either an antioxidant or prooxidant depending on its concentration. The present study was conducted to investigate the effects of different doses of vitamin A supplementation on the antioxidant system in rats. Forty Spargue-Dawley male rats were divided into four groups according to the dose of vitamin A received: 0 (A0), 4,000 (A1), 8,000 (A2), and 20,000 (A3) IU retinyl palmitate/kg diet. After a feeding period of 4 wks, lipid peroxide levels, glutathione concentration, antioxidant enzyme activities, and vitamins A and E concentrations were measured. Histopathological changes were observed in rat liver tissue using an optical microscope and transmission electron microscope. Lipid peroxide levels in plasma were significantly decreased in the A1 and A2 groups compared to the A0 rats. Erythrocyte catalase and hepatic superoxide dismutase activities of the A2 group were significantly higher than those of the A0 group. Hepatic glutathione peroxidase activity was significantly lower in the A3 group compared to the other groups. Total glutathione concentrations were significantly higher in the A1 and A2 groups than in the A0 group. Histological examination of liver tissue showed that excessive supplementation of vitamin A might lead to lipid droplet accumulation and nuclear membrane deformation. |
Does β-Catenin regulate deiodinase levels and thyroid hormone signaling in colon cancer cells? | Activation of the β-catenin/T-cell factor (TCF) complex occurs in most colon tumors, and its actions correlate with the neoplastic phenotype of intestinal epithelial cells. Type 3 deiodinase (D3), the selenoenzyme that inactivates thyroid hormone (3,5,3' triiodothyronine [T3]), is frequently expressed by tumor cells, but little is known about its role in the regulation of T3 signaling in cancer cells. We measured D3 expression in 6 colon cancer cell lines and human tumors and correlated it with the activity of the β-catenin/TCF complex. We also determined the effects of D3 loss on local thyroid hormone signaling and colon tumorigenesis. We show that D3 is a direct transcriptional target of the β-catenin/TCF complex; its expression was higher in human intestinal adenomas and carcinomas than in healthy intestinal tissue. Experimental attenuation of β-catenin reduced D3 levels and induced type 2 deiodinase (the D3 antagonist that converts 3,5,3',5' tetraiodothyronine into active T3) thereby increasing T3-dependent transcription. In the absence of D3, excess T3 reduced cell proliferation and promoted differentiation in cultured cells and in xenograft mouse models. This occurred via induction of E-cadherin, which sequestered β-catenin at the plasma membrane and promoted cell differentiation. | The presence of silent cerebral infarction (SCI) increases the risk of transient ischaemia attack, symptomatic stroke, cardiovascular disease and dementia. Mean platelet volume (MPV) is a surrogate marker of activated platelets and is considered a link between inflammation and thrombosis. In addition, MPV is a risk predictor for cardiovascular disease, stroke and overall vascular mortality. The purpose of the study was to assess the MPV levels in SCI patients. A cross-sectional study was conducted to evaluate the association between MPV and SCI in 2215 subjects (1385 men and 830 women). The participants with SCI had higher MPV levels than those without SCI (10.4 ± 1.3 fL vs. 9.2 ± 1.2 fL; P < 0.001). Moreover, the subjects with a high MPV had a higher prevalence of SCI. Multivariate logistic regression analyses revealed that the odds ratios and 95% confidence intervals for SCI according to MPV quartiles were 1.000, 2.131 (1.319-3.444), 3.015 (1.896-4.794), 7.822 (4.874-12.554) respectively (P < 0.001). |
Does pneumonia Pathogen Characterization be an Independent Determinant of Hospital Readmission? | Hospital readmissions for pneumonia occur often and are difficult to predict. For fiscal year 2013, the Centers for Medicare & Medicaid Services readmission penalties have been applied to acute myocardial infarction, heart failure, and pneumonia. However, the overall impact of pneumonia pathogen characterization on hospital readmission is undefined. This was a retrospective 6-year cohort study (August 2007 to September 2013). We evaluated 9,624 patients with a discharge diagnosis of pneumonia. Among these patients, 4,432 (46.1%) were classified as having culture-negative pneumonia, 1,940 (20.2%) as having pneumonia caused by antibiotic-susceptible bacteria, 2,991 (31.1%) as having pneumonia caused by potentially antibiotic-resistant bacteria, and 261 (2.7%) as having viral pneumonia. The 90-day hospital readmission rate for survivors (n = 7,637, 79.4%) was greatest for patients with pneumonia attributed to potentially antibiotic-resistant bacteria (11.4%) followed by viral pneumonia (8.3%), pneumonia attributed to antibiotic-susceptible bacteria (6.6%), and culture-negative pneumonia (5.8%) (P < .001). Multiple logistic regression analysis identified pneumonia attributed to potentially antibiotic-resistant bacteria to be independently associated with 90-day readmission (OR, 1.75; 95% CI, 1.56-1.97; P < .001). Other independent predictors of 90-day readmission were Charlson comorbidity score > 4, cirrhosis, and chronic kidney disease. Culture-negative pneumonia was independently associated with lower risk for 90-day readmission. | To establish the mouse model of Gly374Arg mutation in fibroblast growth factor receptor 3(Fgfr3) and to analyze the phenotype of the mutant mice. The double PCR was used to introduce Gly374Arg point mutation into mouse Fgfr3. The electroporation of embryonic stem(ES) cells was carried out with targeting vector. The targeted ES cells were screened by Positive-Negative Selection of G418 and Ganciclovir, and Southern blot. The correct targeted ES cells were microinjected into blastula. Finally, mutant mice were obtained by crossing between EIIa-Cre transgenic mice and mice carrying recombined mutant Fgfr3 allele. The mice were genotyped by PCR, and phenotype was observed by skeleton staining, histology, etc. Fgfr3-Gly374Arg mutant mice exhibited small size, short tail, macrocephaly and had dome-shaped heads, the epiphyseal growth plates of mutant mice were narrower, and the hypertrophic chondrocyte zone was also obviously decreased. Meanwhile, the majority of female mice were infertile, and the uterus, ovary and mammal gland in mutant female mice were also smaller and underdeveloped. |
Does the sinus of Valsalva relieve abnormal stress on aortic valve leaflets by facilitating smooth closure? | Recently, various modifications have been made to aortic root replacement procedures to include the pseudosinus in the synthetic graft, but its effect on valve function still remains to be elucidated. The purpose of this study was to compare the flow dynamics and its influence on the stress/strain in the valve leaflet in two types of aortic root, either with or without the pseudosinus, with a simulation model. The proximal portions of the ascending aorta and aortic valves were modeled with blood flowing inside. Blood flow and the motion of aortic valve leaflets were studied while applying a physiologic pressure waveform using fluid-structure interaction finite element analysis. Waveforms were varied to simulate the change in cardiac contractility. In the aorta without the sinus, the time during which the valve was open was longer and the rapid valve closing velocity was faster under all conditions studied. In the pseudosinus model, we could clearly observe vortex formation from the early phase of ejection, which seemed to facilitate the gradual but smooth closure of the valve. Valve leaflets without the sinus were subject to greater stress and underwent bending deformation in the longitudinal direction. | The proteasome is a major cellular proteinase. Its activity is modulated by cellular oxidants. Hepatitis C core protein and ethanol exposure both cause enhanced oxidant generation. The aim was to investigate whether core protein, by its ability to generate oxidants, alters proteasome activity and whether these alterations are further affected by ethanol exposure. These interactions were examined in Huh-7 cell lines that expressed inducible HCV core protein and/or constitutive cytochrome P450 2E1 (CYP2E1) and as purified components in a cell-free system. Chymotrypsin-like proteasome activity was measured fluorometrically. Proteasome activity in core-positive 191-20 cells was 20% higher than that in core-negative cells and was enhanced 3-fold in CYP2E1-expressing L14 cells. Exposure of core-positive cells to glutathione ethyl ester, catalase, or the CYP2E1 inhibitor diallyl sulfide partially reversed the elevation of proteasome activity in core-positive cells, whereas ethanol exposure suppressed proteasome activity. The results indicate that proteasome activity was up-regulated by low levels of core-induced oxidative stress but down-regulated by high levels of ethanol-elicited stress. These findings were partially mimicked in a cell-free system. Addition of core protein enhanced the peptidase activity of purified 20S proteasome containing the proteasome activator PA28 and was further potentiated by addition of liver mitochondrial and/or microsome fractions. However, proteasome activation was significantly attenuated when fractions were obtained from ethanol-fed animals. |
Is upregulation of miR-650 correlated with down-regulation of ING4 and progression of hepatocellular carcinoma? | In the last decade, studies in hepatocellular carcinoma (HCC) demonstrate dysregulation of miRNAs expression. For instance, miR-650 has been implicated in gastric and colorectal cancer tumorigenicity; however, the role of miR-650 remains unknown in HCC. In this study, we performed a comprehensive analysis to examine the miR-650 expression level in 248 HCC and 120 paracarcinomatous liver (PCL) tissues. The correlations between miR-650 expression level and the clinicopathological characteristics (HCC tumorigenicity) were evaluated. The role of miR-650 played in HCC was investigated by Q-PCR, western blot, and MTT. We found that miR-650 expression was significantly increased in HCC patients and significantly associated with the patients' age (P = 0.0019), differentiation capability (P = 0.0108), and also tumor stage (P = 0.0069). Moreover, we compared the expression level of both ING4 and miR-650 in 122 HCC patients by western blot and real-time PCR. Statistical result showed a significant negative correlation between them (r(s) = -0.2011, P = 0.0264). Transfection and MTT test suggested that miR-650 decreased the expression of ING4 and stimulate liver cells proliferation significantly. | To determine whether the ingestion of a herbal supplement called Rhodiola-Gingko Capsule (RGC) would enhance the endurance performance of healthy volunteers and change relevant hormones in a favorable manner. Seventy healthy male volunteers (age ranges from 18 to 22 years old) were randomly assigned to RGC group (35 cases, each capsule containing 270 mg herbal extracts, 4 capsules per day) or placebo group (35 cases, equivalent placebo preparation) for 7 weeks using computer produced digital random method. The endurance performance, serum testosterone and cortisol levels were measured at the baseline and the endpoint. Sixty-seven subjects (34 in the RGC group and 33 in the placebo group) completed a 7-week treatment. The RGC group displayed a significantly greater baseline-to endpoint increase in maximal oxygen uptake (VO(2max)) than placebo group in both absolute (P=0.020) and relative values (P=0.023). At the endpoint, the serum cortisol level was unchanged in the RGC group compared with the baseline, but it was significantly elevated in the placebo group (P<0.05). The endpoint ratio of testosterone to cortisol, a surrogate for overtraining and fatigue in endurance exercises, was also indifferent compared with the baseline in the RGC group, but significantly decreased in the placebo group (P<0.05). |
Do flowers of the early-branching papilionoid legume Petaladenium urceoliferum display unique morphological and ontogenetic features? | Floral development can help to shed light on puzzling features across flowering plants. The enigmatic Amazonian monospecific genus Petaladenium of the legume family (Leguminosae) had rarely been collected and only recently became available for ontogenetic studies. The fimbriate-glandular wing petals of P. urceoliferum are unique among the more than 19000 legume species. Ontogenetic data illuminate the systematic position of the genus and foster our understanding on floral evolution during the early diversification of the papilionoid legumes. Flower buds were collected in the field, fixed in 70% ethanol, and investigated using scanning electron microscopy (SEM). Results were compared with existing material from early-diverging papilionoid legumes. Formation of sepals and petals shows bidirectional tendencies. Stamens arise in two whorls, and the single carpel arises concomitantly with the outer stamen whorl. Gland formation starts early on the edges of the wing petals. The carpel reopens for a short time when the initiation of ovules is visible. Stomata at the base of the hypanthium indicate that the flower functions like other standard flag blossoms. | Neutralizing antibodies (NAbs) appearing during treatment with Interferon-beta (IFN-beta) reduce or abolish bioactivity and therapeutic efficacy. Initial combination therapy with methylprednisolone (MP) may reduce the frequency of NAb positive patients. We hypothesized that MP treatment might also reduce NAb levels and re-establish IFN-beta bioactivity in patients already NAb+, who discontinue IFN-beta therapy. In a 6-month open-label trial, we compared monthly high-dose pulsed MP treatment in 38 Nab positive patients with 35 NAb+, MP-untreated control patients discontinuing any therapy or switching to glatiramer acetate. All patients were NAb+ with an absent in vivo response to IFN-beta. NAbs were measured using a cytopathic effect assay and expressed as neutralizing capacity (NC) in percentage of added IFN-beta. Bioactivity was expressed as in vivo Myxovirus Resistance Protein A (MxA) mRNA induction in whole blood using real time PCR. At the end of study, median NAb NC was 92% in both groups. Eight patients (21%) in the MP group and four patients (11%) in the control group had regained an in vivo MxA response to IFN-beta (P = 0.35). |
Does granulocyte colony-stimulating factor mobilize functional endothelial progenitor cells in patients with coronary artery disease? | Endothelial progenitor cells (EPCs) that may repair vascular injury are reduced in patients with coronary artery disease (CAD). We reasoned that EPC number and function may be increased by granulocyte colony-stimulating factor (G-CSF) used to mobilize hematopoietic progenitor cells in healthy donors. Sixteen CAD patients had reduced CD34(+)/CD133(+) (0.0224+/-0.0063% versus 0.121+/-0.038% mononuclear cells [MNCs], P<0.01) and CD133(+)/VEGFR-2(+) cells, consistent with EPC phenotype (0.00033+/-0.00015% versus 0.0017+/-0.0006% MNCs, P<0.01), compared with 7 healthy controls. Patients also had fewer clusters of cells in culture, with out-growth consistent with mature endothelial phenotype (2+/-1/well) compared with 16 healthy subjects at high risk (13+/-4/well, P<0.05) or 14 at low risk (22+/-3/well, P<0.001) for CAD. G-CSF 10 microg/kg per day for 5 days increased CD34(+)/CD133(+) cells from 0.5+/-0.2/microL to 59.5+/-10.6/microL and CD133(+)/ VEGFR-2(+) cells from 0.007+/-0.004/microL to 1.9+/-0.6/microL (both P<0.001). Also increased were CD133(+) cells that coexpressed the homing receptor CXCR4 (30.4+/-8.3/microL, P<0.05). Endothelial cell-forming clusters in 10 patients increased to 27+/-9/well after treatment (P<0.05), with a decline to 9+/-4/well at 2 weeks (P=0.06). | Protein hydrolysate accelerates gastrointestinal transit (GIT) and feeding advancement in preterm infants compared to native protein. In rat pups, opioid receptor agonists released from casein during digestion such as beta-casomorphins slow down GIT. We hypothesized that hydrolysis of casein reduces the opioid activity released during digestion thereby accelerating GIT compared to native casein. The aim of the present study was to investigate whether casein hydrolysate accelerates GIT compared to native casein and whether pretreatment with naloxone, an opioid receptor blocker, abolishes this difference in rat pups. In a randomized controlled trial following a 2 x 2 factorial design, 216 female Wistar rat pups were fed with pellets based on hydrolyzed or native casein. After pretreatment with naloxone or normal saline, carmine red was administered by oro-gastric gavage as a tracer for GIT velocity measurement. Four hours later the animals were sacrificed, their intestine was removed and the length of the colon from the cecocolonic junction to the anus was measured. GIT was recorded as percentage of the total colonic length (percentage of colonic transit) passed by carmine red. Data were given as mean +/- SD. GIT was significantly higher with hydrolyzed casein compared to native casein formula (77.4 +/- 17 and 51.2 +/- 20%), but there was no difference after naloxone pretreatment (77.1 +/- 16 and 76.5 +/- 17%). |
Do mast cells play a partial role in allergen-induced subepithelial fibrosis in a murine model of allergic asthma? | Role of mast cells in the development of allergen-induced airway remodelling has not been fully investigated in vivo. To clarify the possible role of mast cells in the development of allergen-induced airway remodelling, we compared their responses of genetically mast cell-deficient mice, WBB6F1-W/Wv (c-kit mutant) and Sl/Sld (c-kit ligand mutant) mice with those of congenic normal mice in a murine model of allergic asthma. Mice were sensitized to ovalbumin (OA) with alum, and exposed daily for 3 weeks to aerosolized OA. Twenty-four hours after the last inhalation, bronchial responsiveness to acetylcholine (Ach) was measured, and bronchoalveolar lavage (BAL), and biochemical and histological examinations were performed. In both sensitized mast cell-deficient mice, the degree of bronchial hyper-responsiveness to Ach, the number of inflammatory cells and the level of transforming growth factor-beta1 in BAL fluid, IgE response and goblet cell hyperplasia in the epithelium after repeated allergen provocation were not significantly different from those of congenic mice. In contrast, subepithelial fibrosis, evaluated in the fibrotic area around the airways, observed in congenic mice after repeated allergen challenge was partially attenuated in both mast cell-deficient mice. In addition, the amount of hydroxyproline in the lung of mast cell-deficient mice was significantly lower than that of congenic mice. Furthermore, the decreased fibrotic area and amount of hydroxyproline in W/Wv mice was completely recovered by reconstitution of tissue mast cells with bone marrow-derived mast cells of congenic mice. | To evaluate the prognostic performance of tumour-free distance (TFD) compared with depth of invasion (DOI) and percentage of myometrial invasion (MI). Retrospective cohort study. Regional gynaecological oncology centre. All women identified with stage I-III endometrioid endometrial carcinoma from January 2000 to December 2007, who had surgery at the Northern Gynaecological Oncology Centre (NGOC). Surgicopathological, follow-up and survival data were collected. Univariate and multivariate analyses were performed comparing TFD, DOI and MI with known prognostic factors. The prognostic accuracy of TFD was assessed by receiver operating characteristic (ROC) curve analyses, and an optimum cut-off was proposed. Death from disease, recurrence and pelvic lymph node involvement. A total of 288 women were identified. The median follow-up time was 67 months, with 40 recurrences and 32 disease-related deaths. When TFD, DOI and MI were separately examined in multivariate analyses with other covariates, TFD was an independent predictor of death from disease (HR 1.22; 95% CI 1.00-1.48; P = 0.05). In multivariate analyses including all three measures together (TFD, DOI and MI), TFD was an independent predictor of death from disease (HR 1.49; 95% CI 1.03-2.16; P = 0.04) and recurrence (HR 1.39; 95% CI 1.01-1.91; P = 0.05). TFD was also an independent predictor of lymph node involvement when examined separately (OR 0.74; 95% CI 0.56-0.96; P = 0.03), and together with DOI and MI (OR 0.67; 95% CI 0.49-0.92; P = 0.01), in women who had pelvic lymphadenectomy (n = 86). A TFD cut-off of 1.75 mm showed good prognostic performance. |
Do comparative clinical results after implant placement in the posterior maxilla with and without sinus augmentation? | The objective was to compare implants in the posterior maxilla with or without sinus floor augmentation. A retrospective study was conducted of patients who received implants in the posterior maxilla. All patients received solitary, implant-retained fixed partial dentures or crowns. A standardized form for implant treatment was used to document the follow-up examination. The different parameters were initially analyzed descriptively by frequency distribution, measure of central tendency, and statistical spread. A 95% level of significance was set for all tests. A total of 76 patients with 141 dental implants in the posterior region of the maxilla were evaluated. Fifty-one patients with 71 implants received prior no augmentation (sinus floor elevation) and composed the control group. Twenty-five patients with 70 implants received an additional bone transfer prior to implant placement. The mean age of the patients at time of the follow-up examination was 49.7 years in the overall group, 52.6 years for men and 46.7 years for women. The implants inserted in an augmented area had similar implant stability and implant loss results after a mean functional observation period of 1.6 years (range, 0.5 to 4.7 years) compared to those inserted without augmentation. Augmented implants exhibited less peri-implant bone resorption. | Stathmin is a ubiquitous cytosolic regulatory phosphoprotein and is overexpressed in different human malignancies. The main physiological function of stathmin is to interfere with microtubule dynamics by promoting depolymerization of microtubules or by preventing polymerization of tubulin heterodimers. Stathmin plays important roles in regulating many cellular functions as a result of its microtubule-destabilizing activity. Currently, the critical roles of stathmin in cancer cells, as well as in lymphocytes have been valued. This review discusses stathmin and microtubule dynamics in cancer development, and hypothesizes their possible relationship with epithelial-mesenchymal transition (EMT). A PubMed search using such terms as "stathmin", "microtubule dynamics", "epithelial-mesenchymal transition", "EMT", "malignant potential" and "cancer" was performed to identify relevant studies published in English. More than 100 related articles were reviewed. The literature clearly documented the relationship between stathmin and its microtubule-destabilizing activity of cancer development. However, the particular mechanism is poorly understood. Microtubule disruption is essential for EMT, which is a crucial process during cancer development. As a microtubule-destabilizing protein, stathmin may promote malignant potential in cancer cells by initiating EMT. |
Is a Fixed Flow More Effective than Titrated Flow during Bubble Nasal CPAP for Respiratory Distress in Preterm Neonates? | The clinical effects of a pre-fixed flow of air-oxygen versus a flow titrated according to visible bubbling are not well understood. To compare the effects of a fixed flow (5 L/min) and titrated flow (flow just enough to ensure bubbling) at different set pressures on delivered intra-prong pressure, gas exchange and clinical parameters in preterm infants on bubble CPAP for respiratory distress. Preterm infants <35 weeks gestational age on bubble CPAP and <96 h of age were enrolled in this crossover study. They were subjected to 30-min periods of titrated flow and fixed flow. At the end of both epochs, gas flow rate, set pressure, FiO2, SpO2, Silverman retraction score, respiratory rate, abdominal girth, and blood gases were recorded. The delivered intra-prong pressure was measured by an electronic manometer. 69 recordings were made in 54 infants. For each of the set CPAP pressures (4, 5, and 6 cm H2O), the mean delivered pressure with a fixed flow of 5 L/min was higher than that delivered by the titrated flow. During the fixed flow epoch, the delivered pressure was closer to and higher than the set pressure resulting in higher PaO2 and lower PaCO2 as compared to titrated flow epoch. In the titrated flow period, the delivered pressure was consistently lower than the set pressure. | It has been demonstrated that the interplay of adhesion molecule CD44 and its ligands can regulate cancer cell proliferation, migration and invasion, as well as tumor-associated angiogenesis and is related to breast cancer patient survival. In this two-stage, case control study, we determined whether common functional tagSNPs (single nucleotide polymorphisms) are associated with breast cancer risk and prognosis. Five tagSNPs of CD44 (rs10836347C>T, rs13347C>T, rs1425802A>G, rs11821102G>A, rs713330T>C) were selected and genotyped in 1,853 breast cancer patients and 1,992 healthy control subjects in Eastern and Southern populations. Potential function of rs13347C>T and association between this variation and breast cancer were further studied. Compared with the most common rs13347CC genotype, variant genotypes (CT and TT) increased an individual's susceptibility to breast cancer, especially in estrogen receptor (ER) negative patients (odds ratio (OR) = 1.37, 95%CI = 1.17 to 1.59 for ER positive patients; OR = 2.37, 95% CI = 2.00 to 2.80 for ER negative patients). We also found that rs13347CT+ TT genotypes predicts lower five-year survival rate (hazard ratio (HR) = 1.85, 95% CI = 1.09 to 3.15, P = 0.023), with the lowest survival probability in ER negative T allele carriers. Furthermore, our reporter assay findings, although preliminary and rather modest, showed that miR-509-3p may suppress CD44 expression more strongly in C allele carriers than T allele carriers (P < 0.01). Similarly, rs13347 variant genotypes (CT and TT) carriers were shown to have more CD44 expression than CC carriers in both immunohistochemistry (P < 0.001) and western blotting (P = 0.001) results. |
Are mitochondrial and oxidative stress genes differentially expressed in neutrophils of sJIA patients treated with tocilizumab : a pilot microarray study? | Various pathways involved in the pathogenesis of sJIA have been identified through gene expression profiling in peripheral blood mononuclear cells (PBMC), but not in neutrophils. Since neutrophils are important in tissue damage during inflammation, and are elevated as part of the acute phase response, we hypothesised that neutrophil pathways could also be important in the pathogenesis of sJIA. We therefore studied the gene profile in both PBMC and neutrophils of sJIA patients treated with tocilizumab. We studied the transcriptomes of peripheral blood mononuclear cells (PBMC) and neutrophils from eight paired samples obtained from 4 sJIA patients taken before and after treatment, selected on the basis that they achieved ACR90 responses within 12 weeks of therapy initiation with tocilizumab. RNA was extracted and gene expression profiling was performed using Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray platform. A longitudinal analysis using paired t-test (p < 0.05 and FC ≥ 1.5) was applied to identify differentially expressed genes (DEGs) between the two time points followed by ingenuity pathway analysis. Gene Set Enrichment Analysis (GSEA) and quantitative real-time PCR were then performed to verify the microarray results. Gene ontology analysis in neutrophils revealed that response to tocilizumab significantly altered genes regulating mitochondrial dysfunction and oxidative stress (p = 4.6E-05). This was independently verified with GSEA, by identifying a set of oxidative genes whose expression correlated with response to tocilizumab. In PBMC, treatment of sJIA with tocilizumab appeared to affect genes in Oncostatin M signalling and B cell pathways. | The objective of this study was to investigate the long-term effect of intraoperative application of steroid suspension and coating of the electrode contacts with a thin film of iridium oxide on the intracochlear impedance development after cochlear implantation and on the impedance difference before and after stimulation. Time-dependent development of intracochlear impedances was investigated in 4 different groups of adult patients up to 4 years after implantation. Additionally, during rehabilitation period just after first fitting, impedances before and after stimulation were measured as to investigate the influence of electrical stimulation on the impedances. Results from standard Nucleus 24 Contour (control), standard Nucleus 24 Contour with intraoperative application of steroids, iridium-coated Nucleus 24 Contour, and iridium-coated Nucleus 24 Contour with intraoperative application of steroids were compared. Steroid application reduced impedances significantly throughout the observation period of up to 4 years after implantation. Iridium oxide coating had no effect. Differences between the groups were mainly found on the basal and middle parts of the cochlea, but not close to the tip of the array, also indicating that postoperative fibrous tissue growth is stronger in the basal region of the cochlea. Group mean values of the stimulation effect were not influenced by the different treatments. Nevertheless, only in both steroid-treated groups a correlation between the impedance before stimulation and the stimulation effect was found. |
Is the induction of CXCR4 expression in human osteoblast-like cells ( MG63 ) by CoCr particles regulated by the PLC-DAG-PKC pathway? | Osteolysis which leads to aseptic loosening of implants is a fundamental problem in joint replacement surgery (arthroplasty) and the leading cause for implant failure and revision surgery. Metal (CoCr) particles separated from implants by wear cause osteolysis and the failure of orthopedic implants, but the molecular mechanism is not clear. The chemokine receptor CXCR4 has been shown to play a pivotal role in periprosthetic osteolysis. The aim of this study was to determine which signal transduction pathway (PLC-DAG-PKC or MAPK/ERK) induces CXCR4 expression in osteoblast-like cells (MG63) cells. MG63 and Jurkat cells were stimulated with different amounts of particles (10 Real-time PCR data showed that CXCR4 mRNA expression in MG63 cells induced by CoCr particles was significantly diminished by the PKC-specific inhibitor chelerythrine. This effect was not observed with the MAPK/ERK inhibitor PD98059. The involvement of PKC was also confirmed by an intensified phosphorylation pattern after stimulation with CoCr particles. In Jurkat cells, none of the inhibitors exhibited any effect. | In the 1990s, US welfare reform legislation imposed a 5-year lifetime limit on financial support for low-income families with young children (younger than 18 years). With increasing numbers of single mothers and their children reaching the end of their welfare eligibility, there is concern about potentially high rates of untreated psychiatric and substance use disorders in this population. To determine the prevalence, correlates, and likelihood of treatment for mental and substance use disorders in a population of urban single mothers receiving Temporary Assistance for Needy Families (TANF). In-person diagnostic assessments were conducted from November 1, 2003, to October 31, 2004. Cook County, Illinois. Female TANF recipients and residents of Cook County (N = 333) who were randomly sampled during the final 24 months of their eligibility for TANF. Prevalence rates of DSM-IV mental and substance use disorders using the World Health Organization's Composite International Diagnostic Interview. Lifetime prevalence of Composite International Diagnostic Interview disorders was 61.0% (95% confidence interval [CI], 55.7%-66.3%); 12-month prevalence was 46.8% (41.5%-52.2%). Lifetime prevalence of mental disorders was 53.2% (95% CI, 47.8%-58.5%); 12-month prevalence was 44.1% (38.8%-49.5%). Lifetime prevalence of substance use disorders was 29.1% (95% CI, 23.9%-33.8%); 12-month prevalence was 9.0% (6.8%-12.0%). Lifetime prevalence of comorbid mental/substance use disorders was 21.3% (95% CI, 16.9%-25.7%); 12-month prevalence was 6.3% (3.7%-8.9%). Only 21.7% (95% CI, 14.8%-28.5%) of participants with 12-month mental disorders received treatment for mental disorders; 41.4% (22.3%-60.4%) of participants with 12-month substance abuse disorders received treatment for substance use disorders. |
Do hair concentrations of antiretrovirals predict viral suppression in HIV-infected pregnant and breastfeeding Ugandan women? | Hair concentrations are a noninvasive measure of cumulative antiretroviral exposure and the strongest predictor of viral suppression in large cohorts of nonpregnant patients. We examined hair concentrations of antiretrovirals in relation to virologic outcomes in pregnant and breastfeeding women for the first time. The Prevention of Malaria and HIV Disease in Tororo trial (NCT00993031) enrolled HIV-infected pregnant Ugandan women at 12-28 weeks gestation who were randomized to lopinavir or efavirenz-based antiretroviral therapy (ART). Small hair samples were collected at 30-34 weeks gestation and 10-25 weeks postpartum. Efavirenz and lopinavir hair concentrations were measured via liquid chromatography/tandem mass spectrometry. Multivariate logistic regression models examined predictors of viral suppression (HIV-1 RNA ≤400 copies/ml) at delivery and 24 weeks postpartum. Among 325 women, median CD4 cell count was 366 cells/μl (interquartile range 270-488) at ART initiation. Mean self-reported 3-day adherence was greater than 97% in each arm. Viral suppression was achieved by 98.0% (efavirenz) and 87.4% (lopinavir) at delivery. At 24 weeks postpartum, 92.5% (efavirenz) and 90.6% (lopinavir) achieved viral suppression; 88% of women were breastfeeding. In multivariate models including self-reported adherence and pretreatment HIV-1 RNA, antiretroviral hair concentrations were the strongest predictor of viral suppression at delivery [efavirenz: adjusted odds ratio (aOR) 1.86 per doubling in concentration, 95% confidence interval (CI) 1.14-3.1, P = 0.013; lopinavir: aOR 1.90, 95% CI 1.33-2.7, P = 0.0004] and 24 weeks postpartum (efavirenz: aOR 1.81, 95% CI 1.22-2.7, P = 0.003; lopinavir: aOR 1.53, 95% CI 1.05-2.2, P = 0.026). | This study tested the premise that immunoreactivity representing the p75 neurotrophin receptor (p75(NTR)) appears in plasma of diabetic rats in association with the early stages of neuronal dysfunction or damage. We also examined whether treatment beneficial to neuropathy might reduce the p75(NTR) immunoreactivity. Plasma proteins were fractionated by SDS-PAGE and immunoblots exposed to p75(NTR) antibody, using receptor protein from cultured PC12 cells as an external standard. Rats were made diabetic with streptozotocin for various periods and exsanguinated. Plasma glucose, HbA(1)c and plasma proteins were determined. We also studied plasma samples from diabetic mice lacking the gene coding for p75(NTR), as well as the effect of sciatic nerve crush on healthy male Wistar rats. Plasma p75(NTR) immunoreactivity began to exceed normal levels at 8 weeks after induction of diabetes, and was significantly raised at 10 (p<0.05) and 12 weeks (p<0.001). Treatment between 8 and 12 weeks with insulin, fidarestat (an aldose reductase inhibitor), nerve growth factor and neurotrophin 3 all normalised the plasma p75(NTR) immunoreactivity. Plasma from p75(NTR) (-/-) mice contained no such immunoreactivity, though it was present in plasma from wild-type mice. Following nerve crush, p75(NTR) immunoreactivity appeared in plasma of non-diabetic mice, indicating that this can be a result of nerve trauma. |
Does arteriovenous-shunt-mediated increase in venous return cause apparent right coronary arterial autoregulation? | Reports of autoregulation in the right coronary vasculature have varied from non-existent to almost perfect. At least some of this discrepancy may be due to failure to account for changes in myocardial metabolism secondary to the method used to vary perfusion pressure. The aim of this study was to determine if the potent autoregulation reported when right coronary perfusion pressure was lowered by opening a large arteriovenous shunt was due to increased right ventricular myocardial oxygen consumption (MVO2) induced by augmented preload and afterload. Two protocols were used to produce right coronary perfusion pressures of 100, 80, and 60 mm Hg in anaesthetised dogs. In both protocols the right coronary artery was cannulated and supplied with blood from a pressurised chamber. In protocol 1, right coronary perfusion pressure was decreased independently of aortic pressure, and in protocol 2, aortic pressure was decreased in parallel with right coronary perfusion pressure by opening a large arteriovenous shunt. Right coronary blood flow, central venous pressure, and pulmonary arterial pressure were measured, and right ventricular oxygen extraction and MVO2. Central venous pressure (right ventricular preload) and pulmonary arterial pressure (right ventricular afterload) did not change. In protocol 2, opening the arteriovenous shunt increased venous return, as shown by increased central venous pressure and pulmonary arterial pressure. This increased right ventricular MVO2 at the lower right coronary perfusion pressures and maintained right coronary blood flow at the level recorded when right coronary perfusion pressure was 100 mm Hg. | Endometrial cancer is a common gynecologic cancer whose incidence is increasing annually worldwide. Current methods to detect endometrial cancer are unreliable and biomarkers are unsatisfactory for screening. Cervical scrapings were reported as a potential source of material for molecular testing. DNA methylation is a promising cancer biomarker, but limited use for detecting endometrial cancer. We analyzed two methylomics databases of endometrioid-type endometrial cancer. Using nonnegative matrix factorization algorithm clustered the methylation pattern and reduced the candidate genes. We verified in pools DNA from endometrial cancer tissues and cervical scrapings, and validated in 146 cervical scrapings from patients with endometrioid-type endometrial cancer (n = 50), uterine myoma (n = 40), and healthy controls (n = 56) using quantitative methylation-specific PCR (QMSP). The logistic regression was used to evaluate the performance of methylation signal and gene combination. We filtered out 180 methylated genes, which constituted four consensus clusters. Serial testing of tissues and cervical scrapings detected 14 genes that are hypermethylated in endometrial cancer. Three genes, BHLHE22, CDO1, and CELF4, had the best performance. Individual genes were sensitivity of 83.7%-96.0% and specificity of 78.7%-96.0%. A panel comprising any two of the three hypermethylated genes reached a sensitivity of 91.8%, specificity of 95.5%, and odds ratio of 236.3 (95% confidence interval, 56.4-989.6). These markers were also applied to cervical scrapings of type II endometrial cancer patients, and detected in 13 of 14 patients. |
Does elimination of laboratory ozone lead to a dramatic improvement in the reproducibility of microarray gene expression measurements? | Environmental ozone can rapidly degrade cyanine 5 (Cy5), a fluorescent dye commonly used in microarray gene expression studies. Cyanine 3 (Cy3) is much less affected by atmospheric ozone. Degradation of the Cy5 signal relative to the Cy3 signal in 2-color microarrays will adversely reduce the Cy5/Cy3 ratio resulting in unreliable microarray data. Ozone in central Arkansas typically ranges between approximately 22 ppb to approximately 46 ppb and can be as high as 60-100 ppb depending upon season, meteorological conditions, and time of day. These levels of ozone are common in many areas of the country during the summer. A carbon filter was installed in the laboratory air handling system to reduce ozone levels in the microarray laboratory. In addition, the airflow was balanced to prevent non-filtered air from entering the laboratory. These modifications reduced the ozone within the microarray laboratory to approximately 2-4 ppb. Data presented here document reductions in Cy5 signal on both in-house produced microarrays and commercial microarrays as a result of exposure to unfiltered air. Comparisons of identically hybridized microarrays exposed to either carbon-filtered or unfiltered air demonstrated the protective effect of carbon-filtration on microarray data as indicated by Cy5 and Cy3 intensities. LOWESS normalization of the data was not able to completely overcome the effect of ozone-induced reduction of Cy5 signal. Experiments were also conducted to examine the effects of high humidity on microarray quality. Modest, but significant, increases in Cy5 and Cy3 signal intensities were observed after 2 or 4 hours at 98-99% humidity compared to 42% humidity. | Our objective was to investigate how postprandial processing of intact proinsulin is influenced by different pharmacological strategies in type 2 diabetes mellitus (T2DM). This exploratory, nonrandomized, cross-sectional study recruited T2DM patients and healthy subjects. Upon recruitment, eligible T2DM patients had been treated for ≥6 months with insulin glargine (GLA) plus metformin (MET), sulfonylureas (SU) plus MET, or dipeptidyl-peptidase-4 inhibitors (DPP-4-I) plus MET. Blood samples were drawn from study participants after an 8 h fast and at regular intervals for up to 5 h after consumption of a standardized meal. Study endpoints included postprandial intact proinsulin and insulin levels and the insulin/proinsulin ratio. As expected, postprandial secretion of proinsulin was greater in all T2DM treatment groups than in healthy subjects (p < .01 for all comparisons). Postprandial release of proinsulin was significantly greater in T2DM patients treated with SU plus MET than in those treated with GLA plus MET (p = .003). Treatment with DPP-4-I plus MET was associated with reduced proinsulin secretion versus SU plus MET and an increased insulin/proinsulin ratio versus the other T2DM groups. |
Does myocardial deformation imaging unmask subtle left ventricular systolic dysfunction in asymptomatic and treatment-naïve HIV patients? | Patients infected by the human immunodeficiency virus (HIV) and receiving highly active antiretroviral therapy have a higher incidence of cardiovascular disease than healthy subjects, but little is known about cardiac function in asymptomatic and treatment-naïve patients. We sought to study cardiac function in asymptomatic HIV-infected, treatment-naïve patients. We studied 41 HIV-infected and treatment-naïve patients and 20 age- and sex-matched healthy controls. Patients with cardiac symptoms, history of cardiac disease or NT-proBNP >100 pg/mL were excluded. We addressed cardiac function using standard echocardiography along with tissue Doppler (TDI) measurements, including strain/strain rate assessment. Standard echocardiographic parameters did not differ between groups, except for transmitral E wave velocity (64.8 ± 14 cm/s in HIV vs 76.1 ± 10 cm/s in controls, p = 0.002). In contrast, TDI mitral and tricuspid annulus s velocity and all strain/strain rate measurements were significantly lower in HIV patients: s lateral, 10.2 ± 2.4/11.3 ± 0.7, p = 0.011; s septal, 8.1 ± 1.6/8.7 ± 0.8, p = 0.045; s tricuspid, 13.4 ± 2.3/14.9 ± 1.3, p = 0.002; strain/strain rate, septal (strain/strain rate, 15.1 ± 5.7/-0.9 ± 0.3, 25.3 ± 1.7/-1.9 ± 0.2, p < 0.001), anterior (16.7 ± 3/-1.0 ± 0.1, 26.7 ± 1.7/-1.9 ± 0.2, p < 0.001), lateral (16.0 ± 6/-1.0 ± 0.1, 27.5 ± 1.8/-2.2 ± 0.3, p < 0.001) and posterior (15.2 ± 5.8/-1.0 ± 0.2, 26.2 ± 1.8/-2.2 ± 0.3, p < 0.001) left ventricular wall. | This study was carried out to examine decoy receptor 3 (DcR3) expression and investigate its clinical and prognostic significance in patients with pancreatic head carcinoma. Tissue samples were obtained from 50 patients with pancreatic head carcinoma. DcR3 protein expression in tissues and sera was assessed by immunohistochemistry and ELISA. Correlations between DcR3 and clinicopathologic features and prognoses were analyzed statistically. Serum DcR3 levels were significantly elevated in patients with pancreatic head carcinoma compared with patients with cystadenoma and healthy individuals (P < 0.01 and P < 0.01, respectively). DcR3 overexpression correlated with lymph node metastases and TNM stages (P < 0.05 and P < 0.05, respectively). Median overall survival for the high DcR3 group was 16.3 months, compared to 21.6 months for the low DcR3 group (P < 0.05). In the low DcR3 group, no significant difference was found in the overall survival between patients who underwent standard pancreatoduodenectomy (SPD) and those who had radical pancreatoduodenectomy (RPD) (P > 0.05). In the high DcR3 group, the median overall survival rates were 16.8 months in the RPD group and 13.5 months in the SPD group (P < 0.05). |
Are creatinine and eGFR similarly predictive of outcome of acute coronary syndrome? | This study aimed to compare the ability of creatinine and estimated glomerular filtration rate (eGFR) to predict outcome in unselected patients with acute coronary syndrome (ACS). Data on renal function at admission and in-hospital outcome were available for 781 of 1165 consecutive admissions with definite or suspected ACS to two Scottish district general hospitals. The c-statistic was used to compare the ability of serum creatinine and eGFR to predict in-hospital death or major acute coronary event (MACE) defined as recurrent myocardial infarction, recurrent ischaemia requiring percutaneous intervention or death. There were no significant differences between the c-statistic for prediction of death (creatinine 0.76 (95% CI 0.68-0.84), eGFR 0.80 (95% CI 0.73-0.87)) or MACE (creatinine 0.63 (95% CI 0.57-0.69), eGFR 0.61 (95% CI 0.55-0.67)). | To investigate the impact of arachidonic acid (AA) and docosahexaenoic acid (DHA) and their combination on colon cancer cell growth. The LS-174T colon cancer cell line was used to study the role of the prostaglandin precursor AA and the omega-3 polyunsaturated fatty acid DHA on cell growth. Cell viability was assessed in XTT assays. For analysis of cell cycle and cell death, flow cytometry and DAPI staining were applied. Expression of cyclooxygenase-2 (COX-2), p21 and bcl-2 in cells incubated with AA or DHA was examined by real-time RT-PCR. Prostaglandin E(2) (PGE(2)) generation in the presence of AA and DHA was measured using a PGE(2)-ELISA. AA increased cell growth, whereas DHA reduced viability of LS 174T cells in a time- and dose-dependent manner. Furthermore, DHA down- regulated mRNA of bcl-2 and up-regulated p21. Interestingly, DHA was able to suppress AA-induced cell proliferation and significantly lowered AA-derived PGE(2) formation. DHA also down-regulated COX-2 expression. In addition to the effect on PGE(2) formation, DHA directly reduced PGE(2)-induced cell proliferation in a dose-dependent manner. |
Does carotid artery elasticity decrease during pregnancy - the Cardiovascular Risk in Young Finns study? | The aims were to evaluate the effect of pregnancy on carotid artery elasticity and determine the associations between maternal lipids, endothelial function and arterial elasticity during pregnancy. We examined 99 pregnant and 99 matched non-pregnant control women as part of a population-based prospective cohort study. Carotid artery elasticity indexes; carotid artery distensibility (CAD), Young's elastic modulus (YEM) and stiffness index (SI) as well as brachial artery flow-mediated dilation (FMD) were assessed using ultrasound; serum lipid levels were also determined. SI was 57% and YEM 75% higher and CAD 36% lower in the third trimester group than the corresponding values in the first trimester group. Serum cholesterol and triglyceride levels were significantly higher in women at the end of the pregnancy than at the beginning of pregnancy (P < 0.001) and in controls (P < 0.001). In multivariate analysis, gestational age was the only independent correlate of arterial elasticity in pregnant women. In controls, age (P ≤ 0.001) and common carotid diameter (P = 0.001-0.029) were associated with SI, YEM and CAD. | Translationally controlled tumor protein (TCTP), alternatively called fortilin, is believed to be involved in the development of the chemoresistance of tumor cells against anticancer drugs such as etoposide, taxol, and oxaliplatin, the underlying mechanisms of which still remain elusive. Cell death analysis of TCTP-overexpressing HeLa cells was performed following etoposide treatment to assess the mitochondria-dependent apoptosis. Apoptotic pathway was analyzed through measuring the cleavage of epidermal growth factor receptor (EGFR) and phospholipase C-γ (PLC-γ), caspase activation, mitochondrial membrane perturbation, and cytochrome c release by flow cytometry and western blotting. To clarify the role of TCTP in the inhibition of apoptosome, in vitro apoptosome reconstitution and immunoprecipitation was used. Pull-down assay and silver staining using the variants of Apaf-1 protein was applied to identify the domain that is responsible for its interaction with TCTP. In the present study, we confirmed that adenoviral overexpression of TCTP protects HeLa cells from cell death induced by cytotoxic drugs such as taxol and etoposide. TCTP antagonized the mitochondria-dependent apoptotic pathway following etoposide treatment, including mitochondrial membrane damage and resultant cytochrome c release, activation of caspase-9, and -3, and eventually, the cleavage of EGFR and PLC-γ. More importantly, TCTP interacts with the caspase recruitment domain (CARD) of Apaf-1 and is incorporated into the heptameric Apaf-1 complex, and that C-terminal cleaved TCTP specifically associates with Apaf-1 of apoptosome in apoptosome-forming condition thereby inhibiting the amplification of caspase cascade. |
Does apolipoprotein E modify neurological outcome by affecting cerebral edema but not hematoma size after intracerebral hemorrhage in humans? | To address the mechanisms by which apoE polymorphism affects functional outcome after intracerebral hemorrhage in humans, we tested the hypothesis that the presence of the APOE4 allele results in amplified inflammatory responses and increased cerebral edema. We prospectively enrolled and collected data on 21 adult patients consecutively admitted to Duke University Hospital with supratentorial intracerebral hematoma including hemorrhage volume, midline shift, modified Rankin Score, Glasgow Outcome Score, and APOE genotype. Hemorrhage size (cm(3)) and midline shift (mm), at the level of the thalamus, were measured by computed tomography within 36 hours of admission. Rankin and Glasgow Scores were determined at discharge. Student's t-test was used to analyze hemorrhage size, midline shift, and Glasgow Outcome Score and logistical regression were used to measure allele affect on modified Rankin Score. When analyzing modified Rankin Score, patients were grouped by favorable outcome (0-2) or unfavorable (3-6). Out of 21 patients, 11 possessed at least 1 APOE4 allele (APOE4+). There was no difference in hemorrhage volume (25.8 v 38.3 mm for APOE4- v APOE4+, respectively) between the groups, but there was a significant difference in midline shift (P = .04, 0.7 v 4 mm). Functional outcomes were worse for the patients possessing at least 1 APOE4 allele (P = .04) | There are no conclusive studies evaluating the interaction between icariin and exercise for treatment of osteoporosis; the efficacy and safety of this treatment combination remains to be evaluated. The purpose of this study was to investigate the effects of icariin treatment combined with exercise therapy on bone parameters and body weight of ovariectomized rats. Ovariectomized rats were used as a model of postmenopausal osteoporosis and were exposed to either icariin treatment, exercise, hormone replacement therapy, or a combination of the above. Untreated, ovariectomized rats and sham operated rats were used as controls. After 3 months of experimental interventions the effects of the treatments on the body and uterine weights, the physical and biomechanical properties of bones, and the expression of the osteoblast-specific gene Osterix (Osx), were assessed. The weight gain of the ovariectomized rats was greater than that of the treated experimental groups. Uterine weight and serum estradiol levels were significantly greater in sham operated and estrogen-treated ovariectomized rats than in the other groups. Biomechanical parameters were improved significantly in ovariectomized rats treated with exercise alone or treated with exercise and icariin. Osx expression was increased in ovariectomized rats treated with exercise and icariin or treated with just icariin. |
Does hydrochloric acid aspiration increase right ventricular systolic pressure in rats? | Pulmonary aspiration of gastric acid is a serious complication during anaesthesia and may cause aspiration pneumonitis and adult respiratory distress syndrome. The development of pulmonary hypertension may aggravate the initial course of the aspiration pneumonitis. The authors hypothesized that acid aspiration induces an acute increase in right ventricular pressure in the rat heart. Additionally, it was hypothesized as a secondary study that endothelin levels would be increased in this rat model. Male Sprague Dawley rats, anaesthetized with sevoflurane, underwent tracheostomy, and catheters were inserted into the carotid and right ventricle. Lung injury was induced by instillation of 0.4 ml kg(-1) 0.1 mol l(-1) HCl; a control group received the same volume of 0.9% NaCl. Rats were then ventilated for 6 hours. p(a)O2, mean arterial blood pressures and right ventricular systolic pressures were documented every 30 minutes, and arterial blood gases were measured at baseline, 30, 90, 180, 270 and 360 min. Wet/dry ratio was performed and additionally endothelin-1 levels were examined before and 180 and 360 min after aspiration. p(a)O2 values were lower, whereas right ventricular systolic pressures were significantly higher in the HCl group. Mortality rate was 50% after HCl aspiration, whereas 100% of the rats survived NaCl aspiration. Wet/dry ratio and endothelin-1 levels showed a significant increase after 180 and 360 min of HCl aspiration. | Raloxifene is a selective estrogen receptor (ER) modulator (SERM) used for the treatment of osteoporosis. However, its efficacy and also its safety vary greatly among treated patients, and it might be influenced by the individuals' genetic background. As the receptor activator of the nuclear factor κB (RANK) ligand (RANKL)/RANK/osteoprotegerin (OPG) system is essential for osteoclastogensis and Wnt signaling pathway for osteoblastogenesis, we decided to evaluate the raloxifene treatment in regard to selected polymorphisms in key genes of these two main bone regulatory pathways. Fifty-six osteoporotic postmenopausal women treated with raloxifene were genotyped for 11 polymorphisms located in six genes: -290C>T, -643C>T, and -693G>C in tumor necrosis factor receptor superfamily member 11 (TNFSF11), +34694C>T, +34901G>A, and +35966insdelC in tumor necrosis factor receptor superfamily member 11A (TNFRSF11A), K3N and 245T>G in tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), A1330V in LRP5, I1062V in LRP6, and -1397_-1396insGGA in SOST. For evaluation of treatment efficacy, bone mineral density (BMD) and biochemical markers of bone turnover were measured. One-year change in total hip BMD was associated with +34901G>A in TNFRSF11A (p=0.040), whereas, for lumbar spine BMD, the association was shown for -1397_-1396insGGA in SOST (p=0.015). C-terminal crosslinking telopeptides of type I collagen (CTX) concentrations showed significant association with -643C>T single nucleotide polymorphism (SNP) in TNFSF11 (p=0.049) and +34694C>T in TNFRSF11A (p=0.022). No other association was found between 1-year change in BMDs or biochemical markers and the studied SNPs. |
Does increased Ratio of Visceral to Subcutaneous Adipose Tissue in Septic Patients be Associated With Adverse Outcome? | Visceral and subcutaneous adipose tissue may contribute differentially to the septic inflammatory response. Accordingly, we tested the hypothesis that the ratio of visceral to subcutaneous adipose tissue is associated with altered sepsis outcome. A retrospective analysis from a cohort of sepsis patients admitted between 2004 and 2009. A mixed medical-surgical ICU at St. Paul's Hospital in Vancouver, Canada. Patients older than 16 years old who had sepsis and underwent abdominal CT scan (n = 257) for clinical reasons. None. We measured the visceral adipose tissue and subcutaneous adipose tissue areas and calculated the visceral adipose tissue-to-subcutaneous adipose tissue ratio. Visceral adipose tissue/subcutaneous adipose tissue was not correlated with body mass index (r = -0.015, p = NS) and therefore provides additional unique information independent of body mass index. Sepsis patients with higher visceral adipose tissue/subcutaneous adipose tissue had greater 90-day mortality than patients with lower visceral adipose tissue/subcutaneous adipose tissue (log-rank test, linear-by linear association p < 0.005). After adjustment for significant covariates using Cox regression, increased visceral adipose tissue/subcutaneous adipose tissue quartile was significantly associated with increased 90-day mortality with hazard ratios of 2.01 (95% CI, 1.01-3.99) for the third visceral adipose tissue/subcutaneous adipose tissue quartile compared with the first quartile and 2.32 (95% CI, 1.15-4.69) for the highest visceral adipose tissue/subcutaneous adipose tissue quartile when compared with the first quartile. Increased mortality for patients with higher visceral adipose tissue/subcutaneous adipose tissue was found for both patients with body mass index less than 25 kg/m (p = 0.004) and for body mass index greater than or equal to 25 kg/m (p = 0.023). Furthermore, we found significantly greater need for mechanical ventilation, renal replacement therapy, and ICU stay in patients in the highest visceral adipose tissue/subcutaneous adipose tissue quartile. The ratio of proinflammatory (interleukin-8) to anti-inflammatory (interleukin-10) plasma cytokine levels was greater in patients with higher visceral adipose tissue/subcutaneous adipose tissue than in those with lower visceral adipose tissue/subcutaneous adipose tissue (p = 0.043). | It remains unclear which gene induction effectively generates photoreceptor-specific phenotypes from nonretinal tissues. The purpose of this study was to determine whether Crx and Otx2--homeobox genes related to photoreceptor development--can induce the generation of these phenotypes in cells derived from adult ciliary and iris tissue and in mesencephalon-derived neural stem cells. Crx and Otx2 were transferred into adult rat ciliary- and embryonic mesencephalon-derived neurospheres and adult rat iris-derived cells with the aid of a recombinant retrovirus. The presence of photoreceptor-specific phenotypes was confirmed by immunocytochemistry and Western blot analysis. More than 90% of the Crx- and Otx2-transfected ciliary- and iris-derived cells exhibited rod opsin immunoreactivity, whereas few of the similarly transfected mesencephalon-derived neural stem cells expressed rod opsin. At least two additional key components of the phototransduction cascade, recoverin and Gdeltat1, were expressed by Crx- and Otx2-transfected iris-derived cells. |
Do treatment of serpiginous choroiditis with intravitreous fluocinolone acetonide implant? | To describe a case in which a fluocinolone acetonide implant was used in a patient with serpiginous choroiditis. Case report. A 57-year-old woman with active serpiginous choroiditis threatening the fovea of her right eye received one intravitreous triamcinolone acetonide injection, leading to immediate disease control. An intravitreous fluocinolone acetonide implant was placed, and resulted in ongoing control of the disease as of her 14 months postoperative follow-up. | Severe obesity is the fastest growing subgroup of obesity in youth. We sought to explore the association between severe obesity and subclinical measures of cardiac and vascular structure and function in adolescents and young adults. This was a cross-sectional comparison of 265 adolescents and young adults with severe obesity (defined as body mass index [BMI] ≥120% of the 95th percentile) to 182 adolescents and young adults with obesity (defined as BMI ≥100-119th of the 95th percentile) at tertiary medical center. Noninvasive measures of cardiac and vascular structure and function were assessed. Participants were a mean age of 17.9 years, 62% were non-Caucasian, and 68% were female. Systolic blood pressure, fasting insulin, C-reactive protein, IL-6, and frequency of type 2 diabetes were higher in participants with severe obesity (all P < .05). Arterial thickness and stiffness, cardiac structure, and diastolic function were also significantly worse in youth with severe obesity as measured by higher left ventricular mass index, worse diastolic function, higher carotid intima media thickness, and pulse wave velocity and lower brachial distensibility (all P < .05). Regression modeling showed that severe obesity (compared with obesity) was independently associated with each of the above outcomes after adjustment for age, race, sex, blood pressure, lipids, and inflammatory markers (P < .05). |
Does small heterodimer partner attenuate profibrogenic features of hepatitis C virus-infected cells? | An atypical orphan nuclear receptor small heterodimer partner (SHP) is known to be regulated by AMP-activated protein kinase (AMPK). Both of them inhibit TGF-β and Smad signalling and exhibit antifibrotic activity in the liver. However, little is known about the protective effects of SHP and AMPK against hepatitis c virus (HCV)-induced hepatic fibrosis. Levels of SHP, p-AMPK and fibrotic markers in HCV-infected human liver and in Huh-7.5 cells infected with HCV genotype 2a (JFH-1) were investigated. The effect of adenovirus-mediated overexpression of SHP (Ad-SHP) and AMPK activation via metformin and 5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) on fibrotic gene expression was evaluated in HCV-infected cells. Finally, we examined the effect of Ad-SHP and AMPK activators on invasion and activation of LX2 human HSCs induced by conditioned media from HCV-infected hepatocyte (CM). In HCV-infected human livers and Huh-7.5 cells infected with HCV, SHP mRNA and protein levels were diminished compared with controls, whereas profibrotic factors were increased. Pharmacological AMPK activation recovered SHP expression, and Ad-SHP inhibited HCV-induced fibrotic gene expression. This finding was accompanied by inhibition of HCV-stimulated nuclear factor-kappa B, an inducer of TGF-β. Moreover, CytoSelect invasion assay revealed that enhanced activity and invasiveness of hepatic stellate cells induced by CM. | Haemostatic biomarkers associated with poor outcome in acute ischemic stroke (AIS). The objective of the study was to evaluate the predictive value of plasma D-dimer (D-D) on functional outcome at 90-day follow-up from stroke onset. We conducted a prospective, observational cohort study in the emergency department and enrolled 220 patients with AIS. Plasma D-D concentrations, determined by a particle-enhanced, immunoturbidimetric assay, were measured. Each patient's medical record was reviewed, and demographic, clinical, laboratory and neuroimaging information was abstracted. There was a positive correlation between levels of D-D and the NIHSS (r = 0.361, p<0.001), and the infarct volume (r = 0.449, p<0.001). In the 69 patients with an unfavorable functional outcome, D-D levels were higher compared with those in patients with a favorable outcome [3.24(IQR, 2.18-4.60)mg/L vs 0.88(IQR, 0.35-1.77) mg/L; p<0.001]. After adjusting for all other significant outcome predictors, D-D level remained an independent predictor for unfavorable functional outcome and mortality with an odds ratio of 2.18 (95% CI, 1.55-2.83), 3.22 (95% CI, 2.05-6.43); respectively. |
Does syngap1 haploinsufficiency damage a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly? | Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders. A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development. Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults. | Because of the immunomodulatory effects of transfusion, we attempted to identify factors associated with blood product use and determine the association of transfusion quantity with postoperative infection. We studied total perioperative transfusion of blood products for 15,592 cardiovascular operations performed from July 1998 to May 2003. Infection end points were septicemia/bacteremia (n=351, 2.2%) and superficial (n=353, 2.3%) and deep (n=212, 1.4%) sternal wound infections. Factors associated with blood product administration were used to form balancing scores to adjust for differences in patient characteristics among those receiving and not receiving blood products. Fifty-five percent of patients received packed red blood cells (RBC), 21% received platelets, 13% got fresh frozen plasma (FFP), and 3% got cryoprecipitate. Factors associated with RBC use included older age, female gender, higher New York Heart Association class, lower hematocrit, reoperation, and longer cardiopulmonary bypass time--all indicative of higher-risk patients. The more RBC units transfused, the higher was the occurrence of septicemia/bacteremia (p < 0.0001) and superficial (p=0.0007) and deep (p < 0.0001) sternal wound infection. Use of FFP (septicemia/bacteremia) and platelets (septicemia/bacteremia and deep sternal wound infection) mitigated against this association only slightly. |
Are postgastrectomy Syndrome Assessment Scale ( PGSAS ) -45 and changes in body weight useful tools for evaluation of reconstruction methods following distal gastrectomy? | Billroth-I (BI) and Roux-en-Y (RY) are well-known reconstruction methods that are conducted following distal gastrectomy. However, the relative merits of these 2 methods are not well documented. The newly developed Postgastrectomy Syndrome Assessment Scale (PGSAS)-45 is an integrated questionnaire consisting of 45 items, including 8 items from the 8-Item Short-Form Health Survey (SF-8), 15 items from the Gastrointestinal Symptom Rating Scale, and 22 items selected by gastric surgeons. Postoperative QOL ratings were evaluated for each reconstruction method using PGSAS-45. The PGSAS-45 questionnaire was distributed to 2,922 patients who underwent gastrectomies at 52 medical institutions. Among the questionnaires distributed, 2520 (86 %) were retrieved and 2368 (81 %) met eligibility requirements. Statistical analyses were conducted to compare 1,384 of the eligible questionnaires, including responses from patients who underwent BI (n = 909) and RY (n = 475) procedures. BI procedures were associated with significantly longer postoperative periods, a significantly greater size of gastric remnants, and a higher frequency of laparoscopic approaches and celiac branch preservation. Postoperative QOL analysis indicated that BI procedures resulted in significantly lower postoperative weight loss and significantly higher esophageal reflux symptoms than RY procedures. There was no significant difference between the two groups on other outcome measures. | Ornithine decarboxylase (ODC) is the first key enzyme in the polyamine biosynthesis pathway. Polyamine is believed to participate in cellular proliferation and differentiation. To study the relationship between ODC and the pathogenesis of benign prostatic hyperplasia (BPH), the polyamine levels, ODC activities, and expression of ODC mRNA in benign hyperplastic and normal human prostates were assayed. Polyamine contents and ODC activities in tissue extracts were determined by reverse-phase high-performance liquid chromatography and spectrophotometric procedures, respectively. The ODC mRNA levels were assayed by Northern blot analysis. The contents of putrescine, spermidine, and spermine in BPH tissues were 2.2, 3.4, and 6.0 times higher than those in normal tissues, respectively; the ODC activity of BPH tissue was about 3.2 times higher than in normal tissue; the expression level of ODC mRNA in the BPH tissues was greater than that of normal tissues. |
Are free-fatty-acid-regulating effects of fermented red ginseng mediated by hormones and by the autonomic nervous system? | Understanding what causes changes in the flux of free fatty acids (FFA) is important to elucidate the etiology of metabolic syndrome. The first aim of this study was to test whether or not hormones and the autonomic nervous system influence blood FFA levels. A secondary aim was to test by means of a multiple group path analysis whether the consumption of fermented red ginseng (FRG; Panax ginseng) would influence those causal relationships. Ninety-three postmenopausal women (age 50-73 yr) were randomly divided into two groups. One group (44 women; age, 58.4 ± 5.9 yr; body mass index, 23.6 ± 2.5 kg/m(2)) was supplied placebo capsules and the other group (49 women, age 58.4 ± 5.5 yr; body mass index, 22.9 ± 2.4 kg/m(2)) was supplied FRG capsules. Both prior to and after the study (2 wk), blood samples were collected from the participants and several blood variables were measured and analyzed. Squared multiple correlations of FFA were 0.699 in the placebo group and 0.707 in the FRG group. The unstandardized estimate of estradiol (E2) for FFA was 0.824 in both groups. | An in vitro cadaveric study comparing cage-vertebra interface strengths for 3 different screw-cement configurations. To determine the effects of cement augmentation of pedicle screws on cage-vertebra interface failure properties for 2 interbody device shapes (elliptical or cloverleaf); and to compare between pedicle and anterior vertebral body screws with cement augmentation. Pedicle or anterior screw fixation is commonly used with interbody device fixation. Cement has recently been shown to augment screw fixation in the osteoporotic spine by improving the screw-bone interface strength. The effect of cement augmentation of pedicle or anterior screws on cage-vertebra interface properties has not been previously studied or compared. An elliptical or a cloverleaf-shaped indentor covering 40% of the endplate was axially compressed against the superior endplate of 48 thoracolumbar vertebrae. Each vertebra had polymethylmethacrylate cement augmentation of 1) anterior screws, 2) pedicle screws, or 3) pedicle screws without cement. Compressive load was applied through a mechanism that allowed unconstrained rotation of the indentors. Cement augmentation of pedicle screws resulted in significantly higher failure loads (54%) and failure strength (69%) for both shaped indentors when compared with uncemented pedicle screws. There was no significant difference in failure load and failure strength between pedicle and anterior screws with cement augmentation. Indentor shape was not a significant factor on failure load or failure strength. |
Is synapse formation enhanced by oral administration of uridine and DHA , the circulating precursors of brain phosphatides? | The loss of cortical and hippocampal synapses is a universal hallmark of Alzheimer's disease, and probably underlies its effects on cognition. Synapses are formed from the interaction of neurites projecting from "presynaptic" neurons with dendritic spines projecting from "postsynaptic" neurons. Both of these structures are vulnerable to the toxic effects of nearby amyloid plaques, and their loss contributes to the decreased number of synapses that characterize the disease. A treatment that increased the formation of neurites and dendritic spines might reverse this loss, thereby increasing the number of synapses and slowing the decline in cognition. We observe that giving normal rodents uridine and the omega-3 fatty acid docosahexaenoic acid (DHA) orally can enhance dendritic spine levels (3), and cognitive functions (32). Moreover this treatment also increases levels of biochemical markers for neurites (i.e., neurofilament-M and neurofilament-70) (2) in vivo, and uridine alone increases both these markers and the outgrowth of visible neurites by cultured PC-12 cells (9). A phase 2 clinical trial, performed in Europe, is described briefly. | To assess the ability of C-reactive protein (CRP) to predict long-term outcomes in a chest pain population. CRP was measured at presentation in 446 emergency department patients with acute coronary syndromes. All-cause mortality and hospital discharges for acute myocardial infarction (AMI) and congestive heart failure (CHF) were obtained for up to 8 years following the event. Kaplan-Meier analyses indicated that patients with CRP concentrations above the American Heart Association scientific statement cut-off had a higher rate for death and CHF admissions. After adjusting for troponin concentrations, in a Cox proportional hazard model, only CRP concentrations indicative of an acute phase response (i.e., >7.44 mg/L) were associated with a significant risk for death after 5 years and CHF readmission after 2 years. |
Do phosphotyrosine antibodies preferentially react with basal epithelial cells in the dog prostate? | Considering the hypothesis that androgen-independent but growth factor dependent epithelial cell division may be important in the development and progression of prostate cancer and that protein tyrosine kinases and phosphotyrosine protein phosphatases are key enzymes modulating the levels of specific phosphotyrosylated proteins implicated in several growth factor regulated signal transduction pathways, our aim was to study the cellular distribution of phosphotyrosine proteins in normal and hyperplastic dog prostates as well as in those of castrated dogs supplemented with either androgens or estrogens in order to modify the relative proportion of basal versus secretory epithelial cells. Following the determination of optimal conditions to specifically detect phosphotyrosine proteins by a rabbit polyclonal antibody directed against phosphotyrosine, immunohistochemistry was performed on prostate tissue sections from these experimental animals. In addition to morphological criteria, an antibody to high molecular weight cytokeratins and antisera against arginine esterase were used to selectively identify basal and secretory cells. Since prostatic acid phosphatase may be involved in the local regulation of phosphotyrosine proteins, its distribution was also evaluated with a human prostatic acid phosphatase antiserum. In all prostatic tissues examined, basal epithelial cells were preferentially and specifically stained with antiphosphotyrosine. The staining intensity per basal cell was highest in the estrogen-supplemented dogs. In addition, basal cells were numerically increased and all were highly immunoreactive for high molecular weight cytokeratins. In prostates displaying a well-differentiated glandular epithelium, the number of positive basal cells and their staining intensity varied in the following order: normal < hyperplastic < androgen-supplemented dogs. At all times, the levels of phosphotyrosine proteins in prostatic acid phosphatase and arginine esterase positive cells (secretory) remained low. Fibroblasts and smooth muscle cells were unreactive to antiphosphotyrosine, even though estrogen supplementation increased the prostatic stromal volume. | Evidence regarding the mortality rate after administration of the pandemic influenza A (H1N1) 2009 vaccine on patients with underlying diseases is currently scarce. We conducted a case-control study in Japan to compare the mortality rates of patients with idiopathic interstitial pneumonia after the vaccines were administered and were not administered. Between October 2009 and March 2010, we collected clinical records in Japan and conducted a 1:1 matched case-control study. Patients with idiopathic interstitial pneumonia who died during this period were considered case patients, and those who survived were considered control patients. We determined and compared the proportion of each group that received the pandemic influenza A (H1N1) 2009 vaccine and estimated the odds ratio. Finally, we conducted simulations that compensated for the shortcomings of the study associated with adjusted severity of idiopathic interstitial pneumonia. The case and control groups each comprised of 75 patients with idiopathic interstitial pneumonia. The proportion of patients who received the pandemic influenza A (H1N1) 2009 vaccine was 30.7% and 38.7% for the case and control groups, respectively. During that winter, the crude conditional odds ratio of mortality was 0.63 (95% confidence interval, 0.25-1.47) and the adjusted conditional odds ratio was 1.18 (95% confidence interval, 0.33-4.49); neither was significant. The simulation study showed more accurate conditional odds ratios of 0.63-0.71. |
Do dystrophic neurites express C9orf72 in Alzheimer 's disease brains? | Chromosome 9 open reading frame 72 (C9orf72) is an evolutionarily conserved protein with unknown function, expressed at high levels in the brain. An expanded hexanucleotide GGGGCC repeat located in the first intron of the C9orf72 gene represents the most common genetic cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Previous studies by immunohistochemistry with two different anti-C9orf72 antibodies named sc-138763 and HPA023873 showed that C9orf72 is expressed chiefly in the cytoplasm of neurons, and is concentrated in the synaptic terminals in the brains of FTD/ALS with or without C9orf72 repeat expansion as well as those of controls. At present, a pathological role of C9orf72 in the process of neurodegeneration remains unknown. Using immunohistochemistry we studied C9orf72 expression in the frontal cortex and the hippocampus of six Alzheimer's disease (AD) and 13 control cases, including ALS, Parkinson's disease, multiple system atrophy, and non-neurological cases. The HPA023873 antibody showed a cross-reactivity to glial fibrillary acidic protein, and therefore stained intensely reactive astrocytes in AD and non-AD brains. Both sc-138763 and HPA023873 antibodies labeled the neuronal cytoplasm and the neuropil with variable intensities, and intensely stained a cluster of p62-negative, UBQLN1-positive swollen neurites, which were distributed in the CA1 region and the molecular layer in the hippocampus of both AD and non-AD brains. Most notably, both of these antibodies reacted strongly with dystrophic neurites accumulated on senile plaques in AD brains. | Plasma levels of adrenomedullin, a potent vasodilator peptide, are increased in cirrhotic patients, whereas its role in vascular hyporeactivity in cirrhosis has not been clarified. Adrenomedullin expression was evaluated by radioimmunoassay and reverse-transcription polymerase chain reaction. Vascular reactivity to phenylephrine, alpha-adrenoceptor agonist, was investigated in the aortic rings from control rats and CCl-induced cirrhotic rats with ascites in the presence of the neutralizing antibody against adrenomedullin, human adrenomedullin and/or N-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor. Plasma adrenomedullin levels were significantly higher in cirrhotic rats than in controls (16.3 +/- 2.9 versus 7.4 +/- 1.7 fmol/mL, P < 0.05) and correlated negatively with systemic arterial pressure (r = -0.62, P < 0.05). Gene expression of adrenomedullin in various organs (liver, kidney, lung) and vessels (portal vein, aorta) was enhanced in cirrhotic rats compared with controls. Neutralizing antibody against adrenomedullin ameliorated the blunted contractile response to phenylephrine in cirrhotic aorta (Rmax: 1.5 +/- 0.1 versus 1.0 +/- 0.1 g/mg tissue, P < 0.05), whereas contraction remained unchanged in control aorta (Rmax: 1.9 +/- 0.2 versus 1.9 +/- 0.2 g/mg tissue). Intravenous infusion of human adrenomedullin induced a reduction of mean arterial pressure together with an increase of serum nitrate levels, which was abolished by neutralizing antibody against adrenomedullin. Human adrenomedullin caused a blunted contractile response to phenylephrine in both control and cirrhotic aortas, which was not observed in the presence of N-nitro-L-arginine methyl ester. |
Is recovery from a cycling time trial enhanced with carbohydrate-protein supplementation vs. isoenergetic carbohydrate supplementation? | In this study we assessed whether a liquid carbohydrate-protein (C+P) supplement (0.8 g/kg C; 0.4 g/kg P) ingested early during recovery from a cycling time trial could enhance a subsequent 60 min effort on the same day vs. an isoenergetic liquid carbohydrate (CHO) supplement (1.2 g/kg). Two hours after a standardized breakfast, 15 trained male cyclists completed a time trial in which they cycled as far as they could in 60 min (AM(ex)) using a Computrainer indoor trainer. Following AM(ex), subjects ingested either C+P, or CHO at 10, 60 and 120 min, followed by a standardized meal at 4 h post exercise. At 6 h post AM(ex) subjects repeated the time trial (PM(ex)). There was a significant reduction in performance for both groups in PM(ex) versus AM(ex). However, performance and power decreases between PM(ex) and AM(ex) were significantly greater (p </= 0.05) with CHO (-1.05 +/- 0.44 km and -16.50 +/- 6.74 W) vs C+P (-0.30 +/- 0.50 km and -3.86 +/- 6.47 W). Fat oxidation estimated from RER values was significantly greater (p </= 0.05) in the C+P vs CHO during the PM(ex), despite a higher average workload in the C+P group. | To examine CD99 expression and its functional role in ICAM-1 induction in human gingival fibroblasts (HGFs) and human gingival epithelial cells (HGECs) by activating cells with anti-CD99 monoclonal antibody, MT99/3. Engagement of CD99 with agonistic antibodies has been shown to regulate immune responses, cell adhesion and migration, and cell death in several studies. Particularly, this engagement results in transendothelial migration of leukocytes mediated by intercellular adhesion molecule-1 (ICAM-1) induction in endothelial cells. Total mRNA and protein were isolated from HGFs and HGECs for analyses of CD99 and ICAM-1 expression. Surface expression of CD99 and ICAM-1 was analysed by flow cytometry, and the detection of soluble ICAM-1 was assayed by immunoprecipitation and ELISA. CD99 surface expression was constitutive on HGFs to a greater extent than that on HGECs. CD99 ligation with MT99/3 induced ICAM-1 mRNA expression in HGFs, but not in HGECs. Interestingly, CD99 ligation led to an increased level of soluble ICAM-1 detected in culture supernatant, whereas interleukin-1β (IL-1β) treatment induced expression of membrane-bound ICAM-1. Furthermore, ICAM-1 induction by CD99 engagement was demonstrated to involve the activation of the p50 subunit of nuclear factor-kappaB (NF-κB), extracellular signal-regulated kinase, and p46 c-Jun N-terminal kinase that differed from that by IL-1β treatment. |
Does transparent and open discussion of errors increase malpractice risk in trauma patients? | We set out to determine if there is an increased medical malpractice lawsuit rate when trauma patient cases are presented at an open, multidisciplinary morbidity and mortality conference (M&M). Patient safety proponents emphasize the importance of transparency with respect to medical errors. In contrast, the tort system focuses on blame and punishment, which encourages secrecy. Our question: Can the goals of the patient safety movement be met without placing care providers and healthcare institutions at unacceptably high malpractice risk? The trauma registry, a risk management database, along with the written minutes of the trauma morbidity and mortality conference (M&M) were used to determine the number and incidence of malpractice suits filed following full discussion at an open M&M conference at an academic level I trauma center. A total of 20,749 trauma patients were admitted. A total of 412 patients were discussed at M&M conference and a total of seven lawsuits were filed. Six of the patients were not discussed at M&M prior to the lawsuit being filed. One patient was discussed at M&M prior to the lawsuit being filed. The incidence of lawsuit was calculated in three groups: all trauma patients, all trauma patients with complications, and all patients presented at trauma M&M conference. The ratio of lawsuits filed to patients admitted and incidence in the three groups is as follows: All Patients, 7 lawsuits/20,479 patients (4.25 lawsuits/100,000 patients/year); M&M Presentation, 1 lawsuit/421 patients (29.6 lawsuits/100,000 patients/year); All Trauma Complications, 7 lawsuits/6,225 patients (14 lawsuits/100,000 patients/year). Patients with a complication were more likely to sue (P < 0.01); otherwise, there were no statistical differences between groups. | Aging and obesity are associated with elevated pro-inflammatory cytokines such as monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)α, which are linked to insulin resistance. Anti-inflammatory agents have marginal effect in improving insulin resistance. Hence, agents are needed to improve glycemic control despite the inflammation. Ad36, a human adenovirus, increases TNFα and MCP1 mRNA in adipose tissue, yet improves glycemic control in mice. Ad36 via its E4orf1 gene, up-regulates AKT/glucose transporter (Glut)-4 signaling to enhance cellular glucose uptake. Directly test a role of Ad36, or E4orf1 in enhancing cellular glucose uptake in presence of inflammatory cytokines. Experiment 1: 3T3-L1 preadipocytes were treated with 0, 10 or 100 ng/mL lipopolysaccharides (LPS), and infected with 0 or 5 plaque forming units (PFU) of Ad36/cell. 3T3-L1 cells that stably and inducibly express E4orf1 or a null vector (pTRE-E4orf1 or pTRE-null cells), were similarly treated with LPS and then with doxycycline, to induce E4orf1. Experiment 2: 3T3L1 preadipocytes were treated with 25 nM MCP1 or 20 nM TNFα for 16 h, followed by infection with 0 or 5 PFU of Ad36/cell. Experiment 3: pTRE-E4orf1 or -null cells were similarly treated with MCP1 or TNFα followed by doxycycline to induce E4orf1. Cellular glucose uptake and cellular signaling were determined 72 h post-Ad36 infection or E4orf1-induction, in continued presence of MCP1 or TNFα. In 3T3-L1 preadipocytes, Ad36, but not E4orf1, increased MCP1 and TNFα mRNA, in presence of LPS stimulation. Ad36 or E4orf1 up-regulated AKT-phosphorylation and Glut4 and increased glucose uptake (P < 0.05) in the presence of MCP1 or TNFα. |
Does qS-21 enhance the early antibody response to oil adjuvant foot-and-mouth disease vaccine in cattle? | One of the most important tools against foot-and-mouth disease, a highly contagious and variable viral disease of cloven-hoofed animals, is vaccination. However, the effectiveness of foot-and-mouth disease vaccines on slowing the spread of the disease is questionable. In contrast, high potency vaccines providing early protection may solve issues with the spread of the disease, escaping mutants, and persistency. To increase the potency of the vaccine, additives such as saponin and aluminium hydroxide are used. However, the use of saponin with an oil adjuvant is not common and is sometimes linked to toxicity. QS-21, which is less toxic than Quil A, has been presented as an alternative for use with saponin. In this study, the addition of QS-21 to a commercially available foot-and-mouth disease water-in-oil-in-water emulsion vaccine was evaluated in cattle. After vaccination, serum samples were collected periodically over 3 months. Sera of the QS-21 and normal oil vaccine groups were compared via serum virus neutralization antibody titre and liquid phase blocking enzyme-linked immunosorbent assay antibody titre. The results showed that there was a significant early antibody increase in the QS-21 group. | Managing aggressive breast cancers with enhanced chromosomal instability (CIN) is a significant challenge in clinics. Previously, we described that a cell cycle-associated kinase called Tousled-like kinase 2 (TLK2) is frequently deregulated by genomic amplifications in aggressive estrogen receptor-positive (ER |
Is high-dose plasmid-mediated VEGF gene transfer safe in patients with severe ischemic heart disease ( Genesis-I ) . A phase I , open-label , two-year follow-up trial? | We aimed to assess safety and, secondarily, the efficacy of intramyocardial high-dose plasmid-vascular endothelial growth factor (VEGF) 165 (pVEGF165) gene transfer in no-option patients with coronary artery disease (CAD). Controlled trials of pVEGF165 in CAD have shown little benefit. One possible reason is shortness of dosage. We have shown in large mammalian models of chronic myocardial ischemia and acute myocardial infarction that intramyocardial pVEGF165 at doses significantly higher than those used in recent phase II trials is safe and efficacious on myocardial perfusion, left ventricular function, and infarct size limitation. Using an injection catheter, 10 patients with severe CAD not amenable for revascularization received 10 intramyocardial injections of 0.38 mg (total dose, 3.8 mg) pVEGF165 in zones exhibiting myocardial ischemia, as assessed by combined stress 99mTc-sestamibi single-photon emission computed tomography and stress echocardiography. No serious adverse events related to either VEGF or the injection procedure occurred over the 2-year follow-up. One patient suffered femoral artery thrombosis after a follow-up coronary angiography, successfully resolved with medical treatment. Six patients suffered uncomplicated coronary ischemic events during the second year follow-up. Angina functional class decreased from 2.6 ± 0.2 to 1.2 ± 0.3 (mean ± SEM, P < 0.05), quality of life increased from 56.9 ± 3.2 to 82.6 ± 2.4 (P < 0.05), the summed difference score of myocardial perfusion decreased from 13.4 ± 2 to 7.7 ± 1.8 (P < 0.04), and stress ejection fraction did not change (44.2 ± 3.6% to 47.8 ± 3.1%, P = NS). | Since manganese (Mn) is capable of stimulating the hypothalamic-pituitary unit and advancing female puberty, we assessed the possibility that this element might overcome some of the detrimental effects of prepubertal alcohol (ALC) exposure on the hypothalamic control of pituitary function. Rats received either saline or Mn (10mg/kg) daily by gastric gavage from day 12 to day 31. After weaning, all rats were provided Lab Chow diet ad libitum until day 27 when they began receiving either the Bio Serv control or ALC diet regime. On day 31, the medial basal hypothalamus (MBH) was collected to assess luteinizing hormone-releasing hormone (LHRH) and cyclooxygenase 2 (COX2) protein levels. Release of prostaglandin-E2 (PGE2), LHRH and serum luteinizing hormone (LH) were also assessed. Other animals were not terminated on day 31, but remained in study to assess timing of puberty. Short-term ALC exposure caused elevated hypothalamic LHRH content, suggesting an inhibition in peptide release, resulting in a decrease in LH. Both actions of ALC were reversed by Mn supplementation. COX2 synthesis, as well as PGE2 and LHRH release were suppressed by ALC exposure, but Mn supplementation caused an increase in COX2 synthesis and subsequent PGE2 and LHRH release in the presence of ALC. Mn supplementation also ameliorated the action of ALC to delay puberty. |
Is microRNA-155 a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation? | Allergic airway inflammation is triggered by allergen exposure through several steps including release of IL-33, which promotes cytokine (IL-5, IL-13) production by type 2 innate lymphoid cells (ILC2s). MicroRNA (miR)-155 has recently been described to regulate adaptive responses in allergic inflammation. However, the role of miR-155 in the regulation of ILC2s remains unexplored. We sought to elucidate the contribution of miR-155 in ILC2 expansion using experimental murine models of allergic airway inflammation. To determine the role of miR-155 in the regulation of ILC2s in allergic airway inflammation, miR-155 deficient (miR-155 miR-155 was 10-fold upregulated in WT-derived ILC2s in response to IL-33. Furthermore, miR-155 | The aim of this study was to evaluate how closely analysis of bone quality performed using the bone mineral density (BMD) values obtained by quantitative computerized tomography (QCT) reflected the histologic bone density. Eighteen patients requiring implant therapy underwent CT scanning. Their data were processed using Image Master software, and the BMD was calculated by measuring the Hounsfield units and relating those values to a phantom (Calibration Phantom, Quantitative Technologies). Each patient wore a radiographic-surgical template in which titanium cylinders were placed as a drilling guide for preparation of the implant site. The mouth regions where the titanium guides were placed (on the CT images and in the patient's mouth) corresponded to the implant sites where the BMD was measured and where tissue specimens for histomorphometric analysis retrieved. Forty specimens measuring 6 mm in length and 2 mm in diameter were obtained. Histomorphometric analysis was performed by digitizing the images, which were subsequently analyzed using the image analysis software IAS 2000. The bone volume (BV) was calculated as a percentage by dividing the area occupied by the mineralized bone over the entire microscopic field. The results of the statistical analysis showed a Pearson correlation coefficient of 0.691 between the BV and BMD values, with a P value < 0.01, which was considered significant. |
Does overexpression of long noncoding RNA HOTAIR predict a poor prognosis in patients with cervical cancer? | The long noncoding RNA HOTAIR has been reported to be a good biomarker for poor prognosis in a variety of human cancers. However, whether HOTAIR could serve as novel biomarker to predict prognosis in cervical cancer or not is unknown. The aim of the present study was to examine the expression of HOTAIR in cervical cancers and to investigate the relationship between this lncRNA expression levels and existing clinicopathological factors and patient survival. We examined the expression of HOTAIR in 218 cervical cancer tissues and matched 218 adjacent normal tissues using quantitative real-time RT-PCR and analyzed its correlation with the clinical parameters. The results showed that HOTAIR expression in cervical cancer tissues was significantly upregulated compared with the matched nontumorous tissues (P < 0.0001). Increased HOTAIR expression was significantly correlated with FIGO stage (P < 0.0001), lymph node metastasis (P < 0.0001), depth of cervical invasion (P < 0.0001), tumor size (P = 0.006) and age (P = 0.020), but not other clinical characteristics. Moreover, cervical cancer patients with HOTAIR higher expression have shown significantly poorer overall survival (P < 0.0001) and disease-free survival (P < 0.0001) than those with lower HOTAIR expression. Univariate (P < 0.0001, HR = 4.566, 95 % CI 2.122-9.825) and multivariate (P = 0.012, HR = 2.863, 95 % CI 1.263-76.490). Cox regression analyses showed that HOTAIR expression served as an independent predictor for overall survival. | To determine the effectiveness of unsupervised Nintendo Wii Fit balance training in older adults. Forty-one older adults were recruited from local retirement villages and educational settings to participate in a six-week two-group repeated measures study. The Wii group (n = 19, 75 ± 6 years) undertook 30 min of unsupervised Wii balance gaming three times per week in their retirement village while the comparison group (n = 22, 74 ± 5 years) continued with their usual exercise program. Participants' balance abilities were assessed pre- and postintervention. The Wii Fit group demonstrated significant improvements (P < .05) in timed up-and-go, left single-leg balance, lateral reach (left and right), and gait speed compared with the comparison group. Reported levels of enjoyment following game play increased during the study. |
Does continuous insulin infusion reduce mortality in patients with diabetes undergoing coronary artery bypass grafting? | Diabetes mellitus is a risk factor for death after coronary artery bypass grafting. Its relative risk may be related to the level of perioperative hyperglycemia. We hypothesized that strict glucose control with a continuous insulin infusion in the perioperative period would reduce hospital mortality. All patients with diabetes undergoing coronary artery bypass grafting (n = 3554) were treated aggressively with either subcutaneous insulin (1987-1991) or with continuous insulin infusion (1992-2001) for hyperglycemia. Predicted and observed hospital mortalities were compared with both internal and external (Society of Thoracic Surgeons 1996) multivariable risk models. Observed mortality with continuous insulin infusion (2.5%, n = 65/2612) was significantly lower than with subcutaneous insulin (5.3%, n = 50/942, P <.0001). Likewise, glucose control was significantly better with continuous insulin infusion (177 +/- 30 mg/dL vs 213 +/- 41 mg/dL, P <.0001). For internal comparison, multivariable analysis showed that continuous insulin infusion was independently protective against death (odds ratio 0.43, P =.001). Conversely, cardiogenic shock, renal failure, reoperation, nonelective operative status, older age, concomitant peripheral or cerebral vascular disease, decreasing ejection fraction, unstable angina, and history of atrial fibrillation increased the risk of death. For external comparison, observed mortality with continuous insulin infusion was significantly less than that predicted by the model (observed/expected ratio 0.63, P <.001). Multivariable analysis revealed that continuous insulin infusion added an independently protective effect against death (odds ratio 0.50, P =.005) to the constellation of risk factors in the Society of Thoracic Surgeons risk model. | The P301S mutation in exon 10 of the tau gene causes a hereditary tauopathy. While mitochondrial complex I inhibition has been linked to sporadic tauopathies. Piericidin A is a prototypical member of the group of the piericidins, a class of biologically active natural complex I inhibitors, isolated from streptomyces spp. with global distribution in marine and agricultural habitats. The aim of this study was to determine whether there is a pathogenic interaction of the environmental toxin piericidin A and the P301S mutation. Transgenic mice expressing human tau with the P301S-mutation (P301S+/+) and wild-type mice at 12 weeks of age were treated subcutaneously with vehicle (N = 10 P301S+/+, N = 7 wild-type) or piericidin A (N = 9 P301S+/+, N = 9 wild-type mice) at a dose of 0.5 mg/kg/d for a period of 28 days via osmotic minipumps. Tau pathology was measured by stereological counts of cells immunoreative with antibodies against phosphorylated tau (AD2, AT8, AT180, and AT100) and corresponding Western blot analysis. Piericidin A significantly increased the number of phospho-tau immunoreactive cells in the cerebral cortex in P301S+/+ mice, but only to a variable and mild extent in wild-type mice. Furthermore, piericidin A led to increased levels of pathologically phosphorylated tau only in P301S+/+ mice. While we observed no apparent cell loss in the frontal cortex, the synaptic density was reduced by piericidin A treatment in P301S+/+ mice. |
Do peptidergic agonists of activity-dependent neurotrophic factor protect against prenatal alcohol-induced neural tube defects and serotonin neuron loss? | Prenatal alcohol exposure via maternal liquid diet consumption by C57BL/6 (B6) mice causes conspicuous midline neural tube deficit (dysraphia) and disruption of genesis and development of serotonin (5-HT) neurons in the raphe nuclei, together with brain growth retardation. The current study tested the hypothesis that concurrent treatment with either an activity-dependent neurotrophic factor (ADNF) agonist peptide [SALLRSIPA, (SAL)] or an activity-dependent neurotrophic protein (ADNP) agonist peptide [NAPVSIPQ, (NAP)] would protect against these alcohol-induced deficits in brain development. Timed-pregnant B6 dams consumed alcohol from embryonic day 7 (E7, before the onset of neurulation) until E15. Fetuses were obtained on E15 and brain sections processed for 5-HT immunocytochemistry, for evaluation of morphologic development of the brainstem raphe and its 5-HT neurons. Additional groups were treated either with SAL or NAP daily from E7 to E15 to assess the potential protective effects of these peptides. Measures of incomplete occlusion of the ventral canal and the frequency and extent of the openings in the rhombencephalon were obtained to assess fetal dysraphia. Counts of 5-HT-immunostained neurons were also obtained in the rostral and caudal raphe. Prenatal alcohol exposure resulted in abnormal openings along the midline and delayed closure of ventral canal in the brainstem. This dysraphia was associated with reductions in the number of 5-HT neurons both in the rostral raphe nuclei (that gives rise to ascending 5-HT projections) and in the caudal raphe (that gives rise to the descending 5-HT projections). Concurrent treatment of the alcohol-consuming dams with SAL prevented dysraphia and protected against the alcohol-induced reductions in 5-HT neurons in both the rostral and caudal raphe. NAP was less effective in protecting against dysraphia and did not protect against 5-HT loss in the rostral raphe, but did protect against loss in the caudal raphe. | Systemic sclerosis (SSc) is characterised by multi-organ tissue fibrosis including the myocardium. Diffuse myocardial fibrosis can be detected non-invasively by T1 and extracellular volume (ECV) quantification, while focal myocardial inflammation and fibrosis may be detected by T2-weighted and late gadolinium enhancement (LGE), respectively, using cardiovascular magnetic resonance (CMR). We hypothesised that multiparametric CMR can detect subclinical myocardial involvement in patients with SSc. 19 SSc patients (18 female, mean age 55 ± 10 years) and 20 controls (19 female, mean age 56 ± 8 years) without overt cardiovascular disease underwent CMR at 1.5T, including cine, tagging, T1-mapping, T2-weighted, LGE imaging and ECV quantification. Focal fibrosis on LGE was found in 10 SSc patients (53%) but none of controls. SSc patients also had areas of myocardial oedema on T2-weighted imaging (median 13 vs. 0% in controls). SSc patients had significantly higher native myocardial T1 values (1007 ± 29 vs. 958 ± 20 ms, p < 0.001), larger areas of myocardial involvement by native T1 >990 ms (median 52 vs. 3% in controls) and expansion of ECV (35.4 ± 4.8 vs. 27.6 ± 2.5%, p < 0.001), likely representing a combination of low-grade inflammation and diffuse myocardial fibrosis. Regardless of any regional fibrosis, native T1 and ECV were significantly elevated in SSc and correlated with disease activity and severity. Although biventricular size and global function were preserved, there was impairment in the peak systolic circumferential strain (-16.8 ± 1.6 vs. -18.6 ± 1.0, p < 0.001) and peak diastolic strain rate (83 ± 26 vs. 114 ± 16 s-1, p < 0.001) in SSc, which inversely correlated with diffuse myocardial fibrosis indices. |
Does p66ShcA modulate oxidative stress and survival of endothelial progenitor cells in response to high glucose? | A close relationship exists between hyperglycaemia, oxidative stress, and diabetic complications. In fact, high glucose (HG) determines the overproduction of reactive oxygen species (ROS) by the mitochondria. p66ShcA is a gene that regulates the apoptotic responses to oxidative stress. Indeed, p66ShcA knockout (ko) mice display decreased ROS production and increased resistance to ROS-induced cell death in a variety of pathophysiological settings. Reduced endothelial progenitor cell (EPC) number, differentiation, and function are relevant components of the angiogenesis impairment observed in diabetic patients. We examined the role of p66ShcA in the EPC deficit induced by HG. Mouse bone marrow-derived c-kit+ cells differentiate in endothelial-like cells when plated on fibronectin (BM-derived EPCs). We found that cell culture in the presence of HG up-regulated p66ShcA protein expression and that HG exposure markedly decreased the number of BM-derived EPCs. Conversely, p66ShcA ko BM-derived EPCs were not sensitive to HG inhibition. Indeed, the resistance of p66ShcA ko BM-derived EPCs to HG was associated with reduced levels of both apoptosis and oxidative stress. To functionally link the HG response to ROS production, p66ShcA ko BM-derived EPCs were reconstituted either with p66ShcA wild-type (wt) or with a p66ShcA allele (p66ShcA qq) that was devoid of its ROS-generating function. We found that only p66ShcA wt and not the qq mutant rescued p66ShcA ko cell sensitivity to HG. One major feature of oxidative stress is its ability to reduce the bio-availability of nitric oxide (NO) that, in turn, plays a crucial role in endothelial differentiation and function. We found that the p66ShcA deletion prevented the HG-induced increase of nitrotyrosine, and that the resistance to HG of p66ShcA ko BM-derived EPCs was prevented by NO synthase inhibition. With a reciprocal approach, the treatment of p66ShcA wt cells with a NO donor prevented the HG-induced deficit. Finally, using a Matrigel plug angiogenesis assay, we demonstrated that p66ShcA ko prevented diabetic impairment of angiogenesis in vivo. | To study the effect of using lamivudine to prevent fulminant hepatic failure (FHF) in patients with chronic hepatitis B. 164 patients were randomly put into a conventional supporting treatment control group and a lamivudine treatment group. In the latter, 82 patients were given lamivudine orally at a dose of 100 mg every day besides the support care which was also given to the control group. The rate of deterioration to chronic severe hepatitis in the lamivudine treatment group was significantly lower than that of the control group (23.2% vs. 46.3%, P < 0.01). 52.6% (20/38) with chronic severe hepatitis in the control group died. Only 26.3% (5/19) in the lamivudine treatment group succumbed to terminal liver disease (P < 0.01). There was a significant difference between the two groups in regards to the complication incidence of gastrointestinal bleeding, infections, hepatic coma, and kidney failure (P < 0.05). In addition, the recovery of liver function and liver fibrosis, and the rates of HBeAg loss and seroconversion in the lamivudine treatment group were better than those in the control group. Furthermore, the serum HBV DNA levels decreased more rapidly and continued to be substantially suppressed in the lamivudine treatment group. |
Do nBME subject examination in surgery scores correlate with surgery clerkship clinical experience? | Most medical schools in the United States use the National Board of Medical Examiners Subject Examinations as a method of at least partial assessment of student performance, yet there is still uncertainty of how well these examination scores correlate with clinical proficiency. Thus, we investigated which factors in a surgery clerkship curriculum have a positive effect on academic achievement on the National Board of Medical Examiners Subject Examination in Surgery. A retrospective analysis of 83 third-year medical students at our institution with 4 unique clinical experiences on the general surgery clerkship for the 2007-2008 academic year was conducted. Records of the United States Medical Licensing Examination Step 1 scores, National Board of Medical Examiners Subject Examination in Surgery scores, and essay examination scores for the groups were compared using 1-way analysis of variance testing. Rush University Medical Center, Chicago IL, an academic institution and tertiary care center. Our data demonstrated National Board of Medical Examiners Subject Examination in Surgery scores from the group with the heavier clinical loads and least time for self-study were statistically higher than the group with lighter clinical services and higher rated self-study time (p = 0.036). However, there was no statistical difference of National Board of Medical Examiners Subject Examination in Surgery scores between the groups with equal clinical loads (p = 0.751). | To explore the molecular mechanism via which the chemotherapeutic drug hydroxyurea (HU) enhances K562 cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Chronic myelogenous leukemia-derived K562 and SVT-35 cells were treated with recombinant soluble TRAIL (rsTRAIL) alone or combined with HU for a time course, and the cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-4-sulfophenyl-2H-tetrazolium-phenazine methosulphate assay. Western blot was performed to analyze the activation of apoptosis-related protein kinases and the expression of apoptosis inhibitor molecules. The survival rates of SVT-35 and K562 cells treated with 1 μg/ml rsTRAIL for 24 hours were 32% and 93%, respectively. HU significantly increased the sensitivity of K562 cells to rsTRAIL cytotoxicity. Combination of rsTRAIL and HU resulted in the phosphorylation of rat sarcoma (RAS), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase and in the significant reduction of apoptosis-inhibited molecule Fas associated death domain protein-like interleukin-1 beta-convening enzyme inhibitory protein and cellular inhibitor of apoptosis protein-1 in K562 cells. |
Is functional polymorphism of the NFKB1 gene promoter relevant in predisposition to celiac disease? | The nuclear factor (NF)-kappaB is one of the pivotal regulators of autoimmunity and inflammation, which has been shown to be activated in the inflamed mucosa of patients with celiac disease (CD). Recently, in the NFKB1 gene promoter region, a common insertion/deletion (-94ins/delATTG) polymorphism located between two putative key promoter regulatory elements was described. The aim of this study was to investigate the contribution of the -94ins/delATTG NFKB1 gene promoter functional variant to CD genetic predisposition. A case-control cohort comprising 478 patients with CD and 711 healthy controls as well as a panel of 196 celiac families was genotyped for the 94ins/delATTG NFKB1 polymorphism, using a polymerase chain reaction (PCR) method combined with fluorescence technology. We found no statistically significant differences between CD patients and controls when the -94ins/delATTG genotype and allele distributions were compared. Accordingly, the familial analysis did not reach statistically significant deviation in the transmission of -94ins/delATTG alleles to the affected offspring. | High incidences of acute kidney injury after cardiopulmonary bypass (CPB) were observed in previous reports. However, whether deep hypothermic circulatory arrest (DHCA) leads to more severe kidney injury than CPB without DHCA remains controversial. The aim of the study was to investigate the effects of DHCA on renal function in a novel rabbit model of using closed-thoracic DHCA. Experimental study on New Zealand white rabbits performed in the Department of Cardiac Surgery, the First Affiliated Hospital of China Medical University. Thirty rabbits were randomly divided into 3 groups : the sham-operated group (Group A, N=10), the CPB group (Group B, N=10), and the DHCA group (Group C, N=10). Serum creatinine (Scr), blood urea nitrogen (BUN), serum cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), malondialdehyde (MDA) levels, superoxide dismutase (SOD) activities, histopathologic llesions, and apoptosis were assessed. Each single rabbit in Groups B and C died during surgery. Animals received DHCA exhibited more severe kidney impairments than those received CPB and those that were sham operated. Scr and BUN concentrations at 24 and 48 hours after surgery; cystatin C and NGAL concentrations at 12, 24, and 48 hours after surgery; MDA levels, histopathological lesions, and apoptosis score of the kidneys were the highest in Group C, followed by Group B, and were the lowest in Group A (all P < .05). The activities of SOD were the lowest in Group C, followed by Group B, and were the highest in Group A (P < .05). |
Does nogo-A inhibitory peptide ( NEP1-40 ) increase pan-cadherin expression following mild cortical contusion injury in rats? | Nogo-A is a myelin-associated neurite outgrowth inhibitory protein that limits elongation of central nerve fibers, neuronal regeneration and plasticity. We investigated the effect of delivering an inhibitory peptide that neutralizes Nogo-A on neuronal recovery following mild cortical contusion injury. 41 rats were allocated into the control and NEP1-40 treatment groups. PBS was applied following trauma over the parietal cortex after opening the dura in the control group. NEP1-40 solution was immediately applied following trauma after opening the dura in the treatment group. Each group was further divided into 3 subgroups and sacrificed on the third, eighth, and 21st days after injury. The brains were removed for analysis. Immunohistochemical staining of the injured cortex for pan-cadherin revealed a significant increase in staining in the NEP 1-40 treatment group at the 8th and 21st days after injury. Electron microscopic evaluation revealed better cytoarchitectural preservation in the axons of the animals treated with NEP 1-40. | We have previously shown that the anti-inflammatory and anti-oxidant functions of HDL are impaired in T2D patients. In this study, we examined whether HDL from T2D patients contains elevated levels of oxidized fatty acids and whether those levels correlate with cardiovascular disease (CVD). HETEs and HODEs on HDL were determined by LC-MS/MS in 40 non-diabetic controls (ND), 40 T2D without CVD (D⁺CVD⁻) and 38 T2D with known history of CVD (D⁺CVD⁺). HDL oxidant index was evaluated by a cell-free assay using dichlorofluorescein. Twenty-six randomly selected subjects from the three groups underwent coronary calcium score evaluation (CAC). Major cardiovascular risk factors were similar among the groups. HETEs and HODEs content were significantly increased in HDL from D⁺CVD⁺ when compared to D⁺CVD⁻ and ND patients. HDL oxidant index was not different among the three groups; however, it was significantly higher in patients with CAC score >100 when compared to patients with CAC score <100. |
Is baseline serum cholesterol selectively associated with motor speed and not rates of cognitive decline : the Women 's Health and Aging Study II? | Although several studies have investigated the association between cholesterol and dementia, few have examined cholesterol and decline across cognitive domains. We examined serum total and high-density lipoprotein (HDL) cholesterol, total-to-HDL ratio, and trajectories across cognitive domains. Participants were 436 community-residing women (70-79 years old) in the Women's Health and Aging Study II; they were screened to be physically high-functioning and cognitively intact at baseline. Cognition and other health-related variables were assessed at five intervals spanning 9 years. Cognitive assessments included Trail Making Test Parts A (TMT-A) and B (TMT-B), Hopkins Verbal Learning Test-Revised, Purdue Pegboard, and Mini-Mental State Examination (MMSE). The association between baseline levels of serum lipids and cognitive trajectories were evaluated using Generalized Estimating Equations (GEE). Covariates included age, education, race, vascular disease, serum creatinine, depression, and lipid-lowering medications. In multivariate analyses, baseline higher total (p =.02) and HDL (p =.03) cholesterol were associated with better performance on the Purdue Pegboard. Using clinical cholesterol cutoffs, baseline serum total cholesterol levels >240 mg/dL were associated with the best performance (p =.02). Baseline lipids were not associated with any other cognitive tests; there were no Lipid x Time interactions. | Transitional cell carcinoma (TCC) of the bladder is associated with alterations in the immune system of the host. The authors demonstrated that in patients with bladder carcinoma there is a negative correlation between the levels of natural killer (NK) activity and the clinical evolution and pathologic stages of disease. The authors investigated the effect of various doses of recombinant interferon-alpha-2b (IFN-alpha-2b) for variable periods of culture on the nonmajor histocompatibility-restricted cytotoxic activity of peripheral blood mononuclear cells (PBMNC) with or without CD16 and CD3-depleted populations from patients with superficial (confined to the mucosa or lamina propria) and infiltrative (those infiltrating beyond the lamina propria) TCC of the bladder using 4-hour 51-sodium chromate (51Cr)-release cytotoxicity assays against both NK-sensitive (K562) and NK-resistant (JY) tumor target cells. The normal NK activity detected in PBMNC from patients with superficial TCC of the bladder can be significantly enhanced by short-term (18-hour) incubation with recombinant IFN-alpha (P < 0.05). The depressed NK cytotoxic activity found in PBMNC from patients with infiltrative TCC can also be significantly enhanced, but not normalized, by short-term (18-hour) incubation with recombinant IFN-alpha (P < 0.05). Short-term recombinant IFN-alpha-incubated PBMNC from patients with superficial, but not infiltrative, TCC of the bladder also showed marked cytotoxic activity against NK-resistant target cells. By selection with CD16 or CD3 monoclonal antibodies and complement, it was also found that the precursor and effector lymphocytes of this recombinant IFN-alpha-promoted cytotoxicity belong to NK lineage. In kinetic studies, it was found that the maximal levels of the recombinant IFN-alpha-promoted cytotoxic activity against NK-sensitive and NK-resistant target cells in PBMNC from patients with TCC were reached after 18 hours of culture. |
Does treadmill running improve hindlimb arteriolar endothelial function in type 1 diabetic mice as visualized by X-ray microangiography? | Vascular function is impaired in patients with diabetes, however diabetic vascular dysfunction is ameliorated by exercise training. We aimed to clarify which hindlimb arterial segments are affected by treadmill running in the hindlimbs of streptozocin-induced type 1 diabetic mice in vivo. Mice were divided into 3 groups; healthy control, diabetic control, and diabetic-running groups. The exercise regimen was performed by treadmill level running mice for 60 min/day, for 4 weeks. Thereafter, we examined the vascular response to systemic acetylcholine administration in the left hindlimb of anesthetized-ventilated mice using either 1) X-ray microangiography to visualize the arteries or 2) ultrasonic flowmetry to record the femoral arterial blood flow. X-ray imaging clearly visualized the hindlimb arterial network (~70-250 μm diameter). The vasodilator response to acetylcholine was significantly attenuated locally in the arterioles <100 μm diameter in the diabetic group of mice compared to the control group of mice. Post-acetylcholine administration, all groups showed an increase in hindlimb vascular conductance, but the diabetic mice showed the smallest increase. Overall, compared to the diabetic mice, the treadmill-running mice exhibited a significant enhancement of the vasodilator response within the arterioles with diabetes-induced vasodilator dysfunction. | To assess the prognostic value of polo-like kinase 1 (PLK1), an important regulator of cell cycle progression, in patients with gastric carcinoma. PLK1 expression was determined in 160 gastric carcinoma patients by immunohistochemistry and compared with p53 expression and the proliferating cell nuclear antigen-labeling index (PCNA-LI) to evaluate the effect of PLK1 on tumor progression. Furthermore, PLK mRNA expression was determined in 26 advanced gastric cancer patients by reverse transcription-polymerase chain reaction (RT-PCR). PLK mRNA expression was detected in 25 (96.2%) patients by RT-PCR. Immunohistochemical staining revealed PLK1 expression in 84 (52.5%) patients. There were no significant relationships between PLK1 expression and various clinicopathological factors. PLK1 expression was significantly correlated with the PCNA-LI, but not p53 expression. The prognosis of patients with PLK1-positive tumors was significantly worse than that of patients with PLK1-negative tumors (p < 0.05). Moreover, multivariate analysis revealed that PLK1 expression was an independent prognostic factor. Patients with PLK1-positive and high PCNA-LI tumors showed a significantly poorer prognosis than patients with PLK1-negative and/or low PCNA-LI tumors. Furthermore, the prognosis of patients with PLK1- and p53-positive tumors was significantly worse than that of patients with PLK1- and p53-negative or PLK1-negative and p53-positive tumors. |
Does nitric oxide block bile canalicular contraction by inhibiting inositol trisphosphate-dependent calcium mobilization? | The biochemical mechanism of bile canalicular contraction is similar to that of smooth muscle contraction. Contraction follows inositol-1,4,5-trisphosphate (InsP3)-dependent Ca2+ release, which activates actin-myosin interactions. Nitric oxide is a myorelaxant through the actions of 5'-cyclic guanosine monophosphate (cGMP) and is produced in hepatocytes exposed to endotoxin and cytokines. The aim of this study was to investigate the effect of nitric oxide on canalicular contraction and to determine the mechanism by which cGMP interferes with the contractile signal. The canalicular motility in rat hepatocyte doublets was measured by microscopic image analysis, and intracellular Ca2+ was measured by fluorescence microscopy. cGMP and InsP3 were determined by radio-immunoassay and high-pressure liquid chromatography. Ca2+ release from liver homogenate was measured by filtration and superfusion assays. Compounds that release nitric oxide stimulated hepatocellular production of cGMP and prevented agonist-induced contraction by inhibiting the increase in intracellular Ca2+. The cGMP analogue bromo-cGMP prevented contraction and the increase in Ca2+. Bromo-cGMP marginally decreased InsP3 production. cGMP blocked InsP3-dependent Ca2+ release from internal stores. | Intermountain Risk Score (IMRS) uses the admission complete blood count and basic metabolic profile to predict mortality. Intermountain Risk Score has been validated in medical patients but has not been evaluated in trauma. This study tested whether IMRS is predictive of mortality in a trauma population at a level I trauma center. Admitted trauma patients with complete blood count and basic metabolic profile from October 2005 to December 2011 were evaluated. Thirty-day and 1-year IMRS were calculated using multivariable modeling. Mortality was determined using the medical record and Social Security Administration death data. Three thousand six hundred thirty-seven females and 5901 males were evaluated. Intermountain Risk Score was highly predictive of death at 30 days (c-statistics, c = 0.772 for females; c = 0.783 males) and 1 year (c = 0.778 for females; c = 0.831 males). Cox regression analysis, adjusted for injury severity score, blunt vs penetrating, and length of stay, showed increased mortality risks among patients in the moderate- and high-risk IMRS-defined groups at both 30 days and 1 year, with hazard ratios ranging from 4.96 to 57.88 (all P < .001). |
Are 5-hydroxytryptamine-3 receptors involved in the initiation of gastric phase-3 motor activity in humans? | 5-hydroxytryptamine-3 (5-HT3) receptor antagonists inhibit gastric phase-3 motor activity in the dog. This study examined the role of 5-HT3 receptors in the generation of gastric phase 3 of the migrating motor complex in humans. Interdigestive motor activity was recorded manometrically in 16 subjects before and after administration of ondansetron, a selective 5-HT3 receptor antagonist. Plasma motilin values were also assayed in 7 individuals. The incidence of gastric activity fronts before and after ondansetron was compared with a control group that had not received ondansetron. The ability of erythromycin to induce a gastric activity front in the presence of ondansetron was also evaluated in 7 subjects. The incidence of gastric activity fronts was 69% before ondansetron vs. 19% after ondansetron. In contrast, in the control group there was no significant change in the incidence of gastric activity fronts over time. Activity fronts preceding ondansetron were associated with motilin peaks while activity fronts after ondansetron were not. Despite the previous administration of ondansetron, erythromycin induced gastric activity fronts in 89% of cases. | To investigate the relation between the quantity of human immunodeficiency virus type 1 (HIV-1) RNA in plasma and the risk for the acquired immunodeficiency syndrome (AIDS) or a decline in the CD4+ T-cell count after seroconversion. Prospective study. 62 homosexual men with documented HIV-1 seroconversion. University outpatient setting. Clinical status, CD4+ T-cell counts, and plasma and serum samples were obtained every 6 months. Human immunodeficiency virus RNA in plasma was quantitated with a branched-DNA (bDNA) assay. Serum samples were assayed for neopterin, beta 2-microglobulin, and immune complex dissociated HIV-1 p24 antigen. 18 of 62 (29%) men developed AIDS; 21 (34%) had a significant decline in the CD4+ T-cell count without AIDS; and 23 (37%) had a stable CD4+ T-cell count. For each participant, HIV-1 RNA results were categorized into one of four groups: 1) detection of HIV-1 RNA (> 1 x 10(4) genome equivalents/mL [Eq/mL]) in all samples; 2) detection in most samples (> or = 50%); 3) detection in fewer than 50% of samples; and 4) detection in none of the samples. Detection of HIV-1 RNA in all or most samples was strongly associated with AIDS (16 of 18 patients) and a decline in the CD4+ T-cell count (13 of 21 patients) compared with a stable CD4+ T-cell count (4 of 23 patients; P < 0.001). Conversely, the absence of HIV-1 RNA (< 1 x 10(4) Eq/mL) in all or most samples was associated with stable CD4+ T-cell counts (19 of 23 patients) and a lower risk for AIDS or decline in the CD4+ T-cell count (10 of 39 patients; P < 0.001). In multivariate analysis of all laboratory values at the seroconversion visit, a plasma HIV-1 RNA level greater than 1 x 10(5) Eq/mL was the most powerful predictor of AIDS (odds ratio, 10.8; P = 0.01). |
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