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Do salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation? | Compared with other non-steroid anti-inflammatory drugs (NSAIDs), aspirin is not correlated to hypertension. It has been shown that aspirin has unique vasodilator action in vivo, offering an explanation for the unique blood pressure effect of aspirin. In the present study, we investigate the mechanism whereby salicylates (aspirin and sodium salicylate) dilate blood vessels. Rat aortic or mesenteric arterial rings were used to test the vascular effect of salicylates and other NSAIDs. RhoA translocation and the phosphorylation of MYPT1, the regulatory subunit of myosin light chain phosphatase, were measured by western blot, as evidenced for RhoA/Rho-kinase activation. Salicylates, but not other NSAIDs, relaxed contraction induced by most tested constrictors except for calyculin A, indicating that RhoA/Rho-kinase-mediated calcium sensitization is involved. The involvement of RhoA/Rho kinase in vasodilation by salicylates was confirmed by measurements of RhoA translocation and MYPT1 phosphorylation. The calculated half maximal inhibitory concentration (IC(50)) of vasodilation was apparently higher than that of cyclooxygenase inhibition, but comparable to that of proline-rich tyrosine kinase 2 (PYK2) inhibition. Over-expression of PYK2 induced RhoA translocation and MYPT1 phosphorylation, and these effects were markedly inhibited by sodium salicylate treatment. Consistent with the ex vitro vascular effects, sodium salicylate acutely decreased blood pressure in spontaneous hypertensive rats but not in Wistar Kyoto rats. | To investigate whether expression of cancer stem cell (CSC) markers is associated with recurrence and survival in hepatocellular carcinoma (HCC) patients. A consecutive series of 90 HCC patients who underwent curative hepatectomy between April 2007 and April 2009 were analyzed. Of the 90 patients, 38 (42%) experienced recurrence within two years of surgery. To adjust for baseline differences between this early recurrence group and the other patients, propensity-score matching was used to generate 25 pairs of patients. Immunohistochemistry was used to compare expression of CD133, CD90, and epithelial cell adhesion molecule (EpCAM) in liver tissues from propensity score-matched patients and from 10 healthy adults. Associations of the three markers with HCC, clinicopathological characteristics, early recurrence, and survival time were explored. The expression of all three CSC markers was significantly higher in HCC tissue than in healthy liver tissue (P < 0.001 for all). Among the HCC clinicopathology characteristics examined, the absence of tumor capsule was associated with CD133 expression (P = 0.005); higher histopathology grade and larger tumor size were associated with CD90 expression (P = 0.010 and 0.034, respectively); and elevated serum alpha-fetoprotein levels were associated with EpCAM expression (P = 0.021). Expression of CD90 and EpCAM was significantly higher in the early recurrence group than in other patients (P = 0.001 and 0.045, respectively), whereas CD133 expression was not significantly different between the two groups (P = 0.440). Multivariate analysis identified only CD90 expression as significantly associated with early recurrence. Log-rank analysis identified expression of both CD90 and EpCAM as significantly associated with survival time of HCC patients. Cox regression identified EpCAM expression as an independent predictor of survival time. |
Is stellate ganglion block associated with increased tibial nerve muscle sympathetic activity in humans? | Left stellate ganglion block has been shown to increase heart rate and blood pressure, possible because of blockage of afferent vagal fibers from arterial baroreceptors in the aortic arch. Because efferent muscle sympathetic nerve activity (MSNA) is influenced by the arterial baroreflex, the hypothesis that left stellate ganglion block increases efferent MSNA recorded from the tibial nerve of humans was tested. Twenty healthy male volunteers were sequentially assigned to one of three groups: stellate ganglion block (n = 10), in which 7 ml 1% mepivacaine was injected into the left stellate ganglion; placebo (n = 5), in which 7 ml of saline was injected into the left stellate ganglion; and intramuscular injection (n = 5), in which 7 ml mepivacaine was injected into the left deltoid muscle. Direct intraneural microneurographic recording with a tungsten microelectrode was used to record MSNA in the left tibial nerve. MSNA, heart rate, and blood pressure were recorded before and after injection in all groups. An additional five volunteers were studied with transthoracic echocardiography to examine the effect of stellate ganglion block on preload changes. Tibial nerve MSNA increased after mepivacaine injection to the left stellate ganglion but was unchanged after saline injection to the left stellate ganglion or mepivacaine injection into the deltoid muscle. Heart rate increased significantly after the left stellate ganglion block but did not change significantly after saline injection to the left stellate ganglion or after mepivacaine injection to the deltoid muscle. Systemic blood pressure did not change significantly in all groups. Left ventricular end-diastolic area and left ventricular end-diastolic circumference did not change after stellate ganglion block. | The adaptive immune system seems to play an essential role in the natural course of ovarian cancer. Aim of this study was to establish whether disease-specific survival for patients expressing the tumour antigen p53 is influenced by MHC class I expression or the presence of p53 autoantibodies (p53-Aab). P53 and MHC class I expression were analysed in ovarian cancer tissue of 329 patients by immunohistochemistry using tissue microarrays. For 233 patients, pre-treatment serum samples were available to study the presence of p53 autoantibodies by ELISA. Data were linked to clinicopathological parameters and disease-specific survival. P53 overexpression, MHC class I down-regulation in neoplastic cells and serum p53 autoantibodies were observed in 49.4, 38.9 and 15.9% of patients, respectively. MHC class I down-regulation in p53-overexpressing tumours correlated with a 10-month reduced disease-specific survival in univariate analysis (log-rank 4.10; p=0.043). p53-Aab were strongly correlated with p53 overexpression (p<0.001), but did not influence disease-specific survival. |
Are oral contraceptive use in girls and alcohol consumption in boys associated with increased blood pressure in late adolescence? | Lifestyle behaviours established during adolescence may adversely affect blood pressure (BP) and contribute to gender differences in cardiovascular risk in adulthood. We aimed to assess the association of health behaviours with BP in adolescents, using data from the Western Australian Pregnancy (Raine) Study. Cross-sectional analysis on 1248 Raine Study adolescents aged 17 years, to examine associations between lifestyle factors and BP. Boys had 8.97 mmHg higher systolic BP, as compared with girls. The 30% of girls using oral contraceptives (OC) had 3.27 and 1.74 mmHg higher systolic and diastolic BP, respectively, compared with non-users. Alcohol consumption in boys, increasing body mass index (BMI) and the sodium-potassium ratio were associated with systolic BP. We found a continuous relationship between BMI and systolic BP in both genders; however, the gradient of this relationship was significantly steeper in boys, compared with girls not taking OC. In boys, systolic BP was 5.7 mmHg greater in alcohol consumers who were in the upper quartile of BMI and the urinary sodium-potassium ratio compared with teetotallers in the lowest quartile. In girls, systolic BP was 5.5 mmHg higher in those taking OC, in the highest BMI and urinary sodium-potassium ratio quartile as compared to those not taking the OC pill and in the lowest quartile. | Tetrahydrocurcumin (THC) is an active metabolite of curcumin. It has been reported to have similar pharmacological activity to curcumin. The proteases that participate in extracellular matrix (ECM) degradation are involved in cancer cell metastasis. The present study investigates the effect of an ultimate metabolite of curcumin, THC, on the invasion and motility of highly-metastatic HT1080 human fibrosarcoma cells. The effect of THC on HT1080 cell invasion and migration was determined using Boyden chamber assay. Cell-adhesion assay was used for examining the binding of cells to ECM molecules. Zymography assay was used to analyze the effect of THC on matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion from HT1080 cells. Tissue inhibitor of metalloproteinase (TIMP)-2 and membrane-type 1 matrix metalloproteinase (MT1-MMP) proteins levels were analyzed by Western blotting. Treatment with THC reduced HT1080 cell invasion and migration in a dose-dependent manner. THC also decreased the cell adhesion to Matrigel and laminin-coated plates. Analysis by zymography demonstrated that treatment with THC reduced the levels of MMP-2, MMP-9, and uPA. THC also inhibited the levels of MT1-MMP and TIMP-2 proteins detected by Western blot analysis. |
Does hemopexin-dependent heme uptake via endocytosis regulate the Bach1 transcription repressor and heme oxygenase gene activation? | Intracellular heme plays versatile roles in a variety of physiological processes including mitochondrial respiration. Heme also induces the expression of genes such as heme oxygenase-1 (HO-1) by inactivating the transcription repressor Bach1 through direct binding. However, the source of heme for the regulation of the Bach1-HO-1 axis has been unclear. Considering that extracellular heme exists as a complex with hemopexin (Hx) in serum under the physiological conditions, heme-Hx complex may deliver heme for the gene regulation. Using a mammalian expression system, high secretory recombinant Hx (rHx) was developed. We examined the effects of rHx-bound heme on HO-1 expression and Bach1 in Hepa-1c1c7 liver cells and THP-1 macrophage cells. We investigated the uptake pathway of rHx-bound heme by treating cells with chlorpromazine (CPZ). rHx-bound heme induced the expression of HO-1 and decreased the level of Bach1 protein. CPZ inhibited the induction of the HO-1 expression by rHx-bound heme. | Vitamin D is associated with a number of inflammatory diseases and plays a significant role in regulating bone metabolism. Serum calcifediol was demonstrated to be potentially associated with periodontal disease. The purpose of this study was to evaluate whether an association exists between plasma calcifediol concentrations and aggressive periodontitis (AgP) and whether plasma levels of bone-related biomarkers (osteocalcin, alkaline phosphatase, calcium, and phosphorus) regulated by vitamin D are related to AgP. Sixty-six patients with generalized AgP, 52 patients with chronic periodontitis, and 60 healthy controls were included in this study. Periodontal examination consisted of probing depth, attachment loss, and bleeding index measurements. Hematic calcifediol and bone-related biomarker levels were detected using radioimmunity assay kits or a biochemical analyzer. Plasma calcifediol levels in patients with AgP were higher than those of healthy controls (29.28 versus 21.60 nmol/l; P <0.05) and were statistically significantly correlated with bleeding index (r = 0.321; P <0.05). Plasma osteocalcin concentrations in patients with AgP were higher than those of healthy controls (0.90 versus 0.70 ng/ml; P <0.05). Serum inorganic phosphorus values of both periodontitis groups were lower than those of healthy controls (1.06 +/- 0.18 mmol/l and 1.10 +/- 0.15 mmol/l versus 1.26 +/- 0.17 mmol/l; P <0.05). |
Does spinal manipulative therapy reduce inflammatory cytokines but not substance P production in normal subjects? | To examine the effect of a single spinal manipulation therapy (SMT) on the in vitro production of inflammatory cytokines, tumor necrosis factor alpha, and interleukin (IL) 1beta, in relation to the systemic (in vivo) levels of neurotransmitter substance P (SP). Sixty-four asymptomatic subjects were assigned to SMT, sham manipulation, or venipuncture control group. SMT subjects received a single adjustment in the thoracic spine. Blood and serum samples were obtained from subjects before and then at 20 minutes and 2 hours after intervention. Whole-blood cultures were activated with lipopolysaccharide (LPS) for 24 hours. Cytokine production in culture supernatants and serum SP levels were assessed by specific immunoassays. Over the study period, a significant proportion (P </= .05) of sham and control subjects demonstrated progressive increases in the synthesis of tumor necrosis factor alpha and IL-1beta. Conversely, in a comparable proportion of cultures from SMT-derived subjects, the production of both cytokines decreased gradually. Normalization of the observed alterations to reflect the changes relative to self-baselines demonstrated that, within 2 hours after intervention, the production of both cytokines increased significantly (P < .001 to .05) in both controls. In contrast, a significant (P < .001 to .05) reduction of proinflammatory cytokine secretion was observed in cultures from SMT-receiving subjects. In all study groups, serum levels of SP remained unaltered within 2 hours after intervention. | Lynch syndrome (LS) is clinically defined by the Amsterdam criteria (AC) and by germline mutations in mismatch-repair (MMR) genes leading to microsatellite instability (MSI) at the molecular level. Patients who do not fulfil AC are considered suspected-Lynch according to the less stringent Bethesda guidelines (BG) and should be tested for MSI and MMR germline mutations. BRAF mutations have been proposed as a marker to exclude LS because they are generally absent in LS patients and present in sporadic colorectal cancer (sCRC) with MSI due to promoter hypermethylation of the MLH1 gene. Our aim was to verify whether BRAF mutations may improve the criteria to select patients for germline MMR mutation assessment. We analyzed 303 formalin-fixed paraffin-embedded CRC samples including 174 sCRC, 28 patients fulfilling AC, and 101 suspected-Lynch patients fulfilling BG. We analyzed MSI and BRAF mutations in all CRC samples. MLH1, MSH2 and MSH6 germline mutations were investigated in MSI patients fulfilling AC or BG. sCRC samples showed MSI in 20/174 (11%) cases. BRAF mutations were detected in 10/174 (6%) sCRC cases and were significantly correlated with MSI (P = 0.002). MSI was observed in 24/28 (86%) Amsterdam cases which were BRAF wild-type. MMR gene mutation was detected in 22/26 (85%) AC cases, all showing MSI. Suspected-Lynch cases carried MSI in 41/101 (40%) and BRAF mutations in 7/101 (7%) cases. MMR gene mutation was detected in 13/28 (46%) evaluable MSI patients of this group and only in cases characterized by a wild-type BRAF gene. |
Is miR-1290 a potential prognostic biomarker in non-small cell lung cancer? | miR-1290 is a newly discovered microRNA (miRNA), and its role in non-small cell lung cancer (NSCLC) remains unknown. This study aimed to evaluate the expression levels of miR-1290 in NSCLC tissues and serum, and explore its associations with clinicopathological characteristics and prognosis of NSCLC patients. A total of 33 pairs of tissues and 73 serum samples were obtained from NSCLC patients and expression levels of miR-1290 were detected by specific TaqMan qRT-PCR. The relationship between miR-1290 expression levels in NSCLC tissues and serum and clinicopathological characteristics was estimated respectively. The correlation between serum miR-1290 expression levels and overall survival of NSCLC patients was performed by Kaplan-Meier analysis and Cox proportional hazards model. We determined that miR-1290 expression levels were increased significantly in NSCLC tissues compared with non-tumor adjacent normal tissues, and higher miR-1290 expression levels were positively correlated with high tumor stage (P=0.004) and positive lymph node metastasis (P=0.013). Compared with benign lung disease and healthy controls, serum levels of NSCLC patients exhibited higher expression of miR-1290. Furthermore, the up-regulation of serum miR-1290 more frequently occurred in NSCLC patients with high TNM stage, positive lymph node metastasis (P=0.022 and P=0.024, respectively). Kaplan-Meier analysis demonstrated that high serum miR-1290 expression levels predicted poor survival (P=0.022). Cox proportional hazards risk analysis indicated that miR-1290 was an independent prognostic factor for NSCLC. | The interactions among experience, emotion, and memory are considered to be instrumental in the ontogeny and maintenance of acquired emotional and behavioral disorders (e.g., phobias). Here we address the question whether an anxiety-like state can associate with taste to produce conditioned taste aversion (CTA). We have used an anxiogenic agent, the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP), to induce an anxiety-like emotional state in rats after consumption of an unfamiliar tastant. The anxiogenic agent induced CTA. The mCPP-induced CTA could be prevented by concomitant administration of ethanol, which is known to reverse mCPP-induced anxiety-like behavior, at a concentration that had no effect on CTA memory. In contrast, ethanol did not prevent LiCl-induced CTA. Administration of mCPP before the consumption of the tastant had no effect on the preference for that tastant. |
Do high plasma triglyceride levels strongly correlate with low kisspeptin in the arcuate nucleus of male rats? | It is well known that reproductive capacity is lower in obese individuals, but what mediators and signals are involved is unclear. Kisspeptin is a potent stimulator of GnRH release, and it has been suggested that kisspeptin neurons located in the arcuate nucleus transmit metabolic signals to the GnRH neurons. In this study, we measured body weight and plasma concentrations of leptin, insulin, testosterone, and triglycerides after high fat diet exposure and correlated these parameters with the number of kisspeptin-immunoreactive neurons in the arcuate nucleus of male rats. In this model, a high fat diet (45% or 60% energy from fat, respectively) or a control diet (10% energy from fat) was provided after weaning for three months. We find a significant increase in body weight and plasma leptin concentration, but no change in the number of kisspeptin-immunoreactive cells with increased fat in the diet. Kisspeptin-immunoreactive cells are not correlated with body weight, testosterone, leptin or insulin. However, we find that the number of kisspeptin-immunoreactive cells is strongly and negatively correlated with the level of plasma triglycerides (R2=0.49, p=0.004). | Endothelial injury is an important prognostic factor in acute respiratory distress syndrome (ARDS). Vascular endothelial growth factor (VEGF) plays a critical role in endothelial destruction and angiogenesis. Genetic variations of the VEGF gene have been associated with VEGF production. A study was undertaken to investigate the impact of VEGF gene polymorphisms on the clinical outcomes of ARDS. Three VEGF polymorphisms (-460C/T, +405C/G and +936C/T) were determined in 1253 patients in an intensive care unit with risk factors for ARDS, 394 of whom developed ARDS. Patients were followed for assessment of 60 day survival. Plasma VEGF levels were measured in 71 patients with ARDS. The +936TT (OR 4.29, 95% CI 1.12 to 16.40, p = 0.03) and +936CT+TT (OR 1.98, 95% CI 1.14 to 3.42, p = 0.01) genotypes were significantly associated with increased mortality from ARDS. Plasma VEGF levels in patients with ARDS with the +936CT+TT genotype were significantly lower than in subjects with the +936CC genotype (median 49 (IQR 16-98) pg/ml vs 112 (IQR 47-162) pg/ml, p = 0.02). At the haplotype level, haplotype TCT (-460T+405C+936T) was significantly associated with a higher rate of mortality (OR 2.89, 95% CI 1.30 to 6.43, p = 0.009) and haplotype CGT (-460C+405G+936T) was associated less strongly with increased mortality (OR 1.90, 95% CI 0.94 to 3.83, p = 0.07) in patients with ARDS. Lower plasma VEGF levels were correlated with the probability of haplotype CGT (coefficient = -0.26, p<0.05), but the same trend of correlation was not significant to haplotype TCT. |
Does urolithin A cause p21 up-regulation in prostate cancer cells? | Walnuts contain several bioactive compounds, including pedunculagin, a polyphenol metabolized by microbiota to form urolithins, namely urolithin A (UA). The aim of this study was to determine gene expression changes in prostate cancer cells after incubation with UA. We performed a genomic analysis to study the effect of UA on LNCaP prostate cells. Cells were incubated with 40 µM UA for 24 h, and RNA was extracted and hybridized to Affymetrix Human Genome U219 array. Microarray results were analyzed using GeneSpring v13 software. Differentially expressed genes (p < 0.05, fold change > 2) were used to perform biological association networks. Cell cycle was analyzed by flow cytometry and apoptosis measured by the rhodamine method and by caspases 3 and 7 activation. Cell viability was determined by MTT assay. We identified two nodes, FN-1 and CDKN1A, among the differentially expressed genes upon UA treatment. CDKN1A was validated, its mRNA and protein levels were significantly up-regulated, and the promoter activation measured by luciferase. Cell cycle analysis showed an increase in G1-phase, and we also observed an induction of apoptosis and caspases 3 and 7 activation upon UA treatment. | To investigate the potential of specific angiotensin II subtype 1 (AT1) receptor blockade to modify the mesenteric hemodynamic response to acute hypovolemia and retransfusion. Prospective, randomized, controlled experimental study. University-affiliated animal research laboratory. Fasted, anesthetized, ventilated, juvenile domestic pigs of both sexes. Acute, graded hypovolemia by 20% and 40% of the total estimated blood volume followed by retransfusion in control animals (CTRL; n = 10) and animals pretreated with the AT1 receptor blocker candesartan (CAND; n = 10). Invasive monitoring of arterial and central venous blood pressures, cardiac output, portal venous blood flow, and jejunal mucosal blood flow. Blood gases were repeatedly analyzed to calculate oxygen delivery and consumption. Thirty minutes after each level of hypovolemia at 20% and 40%, cardiac output was decreased in CTRL animals from a baseline of 2.9 +/- 0.1 to 1.8 +/- 0.2 and 1.1 +/- 0.2 L/min, with no differences compared with CAND animals. Cardiac output was restored to 3.0 +/- 0.3 L/min 30 mins after retransfusion in CTRL animals, with no significant intergroup differences. Baseline portal venous blood flow (Q(MES)) and jejunal mucosal perfusion (PU(JEJ)) were greater in CAND animals compared with CTRL animals. During graded hypovolemia, CAND animals maintained Q(MES) and PU(JEJ) at significantly higher levels compared with CTRL animals, particularly after 40% hemorrhage (+221% and + 244%, respectively, relative to the mean values in CTRL animals). The same pattern was observed after retransfusion. Moreover, the calculated mesenteric critical oxygen delivery was significantly greater in CTRL animals (74 mL/min) compared with CAND animals (34 mL/min). No animals died in the CAND group, whereas four animals died during 40% hypovolemia or retransfusion in the CTRL group. |
Does hCV NS5A inhibit interferon-alpha signaling through suppression of STAT1 phosphorylation in hepatocyte-derived cell lines? | HCV NS5A appears to play an important role in HCV resistance to IFN-alpha but the molecular mechanism is not fully elucidated. Most studies regarding the involvement of signal transducer and activator of transcription 1 (STAT1) in inhibition of IFN-alpha signaling by NS5A were performed in non-hepatic cell lines and their relevance may be debatable. We analyzed the effects of NS5A on IFN-alpha signaling through STAT1 phosphorylation in three hepatocyte-derived cell lines, Hep3B, J5 and Huh7. Interaction of NS5A and STAT1 was also investigated with co-immunoprecipitation and confocal microscopy. IFN-alpha induces STAT1 activation in Hep3B cells in a dose- and time-dependent manner. Transient or stable NS5A expression inhibits STAT1 phosphorylation in a dose-dependent manner in hepatocyte-derived cell lines, whereas the levels of STAT1 phosphorylation remain unchanged in non-hepatocyte HeLa and COS7 cells despite increasing amounts of NS5A. The NS5A may interact with STAT1, specifically, the N-terminal 488 amino acids of STAT1. Furthermore, NS5A inhibits activation of interferon-stimulated gene factor 3 (ISGF3) and interferon-stimulated response element (ISRE)-driven gene expression, as demonstrated by electrophoretic mobility shift assay and luciferase assay, respectively. | To investigate vessel density changes with increasing age in three areas of the brain and to correlate these changes with leukoaraiosis (LA) on the basis of magnetic resonance (MR) images and location in deep white matter (WM). Internal review board approval or informed consent from next of kin was not required. Brains of 21 subjects (mean age, 72.5 years; 12 men, nine women) were evaluated at autopsy with MR imaging. The presence of LA was indicated by confluent or patchy areas of hyperintensity in deep WM. Microvascular density (percentage of vessel area divided by total area) in subjects with LA was measured with computerized morphometric analysis in LA lesions, healthy-appearing WM at MR imaging, and the cortex. These measurements were compared with each other and with measurements from corresponding areas in healthy subjects. Afferent vasculature was stained with alkaline phosphatase in celloidin sections. Hypotheses were tested with computation of a series of repeated-measures linear mixed models. Autopsy brains from 12 subjects with LA (mean age, 72 years; six men, six women) and nine subjects without LA (mean age, 73 years; six men, three women) were studied. Afferent microvascular density +/- standard deviation in LA lesions in deep WM (2.56% +/- 1.56) was significantly lower than that in corresponding deep WM of healthy subjects (3.20% +/- 1.82) (P = .018). Subjects with LA demonstrated decreased afferent vascular density at early ages in all three areas of the brain when compared with healthy subjects of the same age. |
Do tumor necrosis factor microsatellites define a Crohn 's disease-associated haplotype on chromosome 6? | HLA class II associations have been described in Crohn's disease (CD) and ulcerative colitis (UC) and may be markers for other closely linked genes that are involved in disease pathogenesis. The tumor necrosis factor (TNF) locus, which contains the genes for TNF-alpha and TNF-beta, is located on chromosome 6 within the major histocompatibility complex loci. To investigate potential genetic associations in inflammatory bowel disease at the TNF locus, we studied 75 patients with CD, 73 patients with UC, and 60 ethnically matched controls using microsatellite markers. Five TNF microsatellite loci (TNFa, TNFb, TNFc, TNFd, and TNFe) were typed using polymerase chain reaction. A CD-associated allelic combination, TNFa2b1c2d4e1, was found in 24% of patients with CD, 4.1% of patients with UC (P=0.001; odds ratio, 7.4; CD vs. UC), and 6.7% of control subjects (P=0.01; odds ratio, 4.4 CD vs. controls). This TNF haplotype was associated with the previously described HLA-DR1/DQ5 combination in CD. | Apelin has been shown ex vivo to be a potent cardiac inotrope. This study was undertaken to evaluate the in vivo effects of apelin on cardiac function in native and ischemic cardiomyopathic rat hearts using a novel combination of a perivascular flow probe and a conductance catheter. Native rats (n =32) and rats in heart failure 6 weeks after left anterior descending coronary artery ligation (n =22) underwent median sternotomy with placement of a perivascular flow probe around the ascending aorta and a pressure volume conductance catheter into the left ventricle. Compared with sham-operated rats, the ligated rats had significantly decreased baseline Pmax and max dP/dt. Continuous infusion of apelin at a rate of 0.01 microg/min for 20 minutes significantly increased Pmax and max dP/dt compared with infusion of vehicle alone in both native and failing hearts. Apelin infusion increased cardiac contractility, indicated by a significant increase in stroke volume (SV) without a change in left ventricular end diastolic volume (102+/-16% change from initial SV versus 26+/-20% for native animals, and 110+/-30% versus 26+/-11% for ligated animals), as well as an increase in preload recruitable stroke work (180+/-24 mm Hg versus 107+/-9 mm Hg for native animals). |
Does exogenous androstenedione induce formation of follicular cysts and premature luteinization of granulosa cells in the ovary? | To investigate the effects of androstenedione on ovarian follicle development. Experimental study. University research laboratory. Female Wistar-Imamichi rats and BDF1 mice. Rats were injected with androstenedione. Ovarian follicles of mice were cultured in the presence of androstenedione. Ovarian morphology; ovarian cell types undergoing apoptosis; ovarian expression of cytochrome P450 aromatase (P450arom), cytochrome P450 side-chain cleavage (P450scc), and cyclin-dependent kinase inhibitor p27(kip1); serum levels of T, E(2), and P in rats; and ultrastructure of granulosa cells from cultured follicles of mice. In androstenedione-treated rat ovaries, follicular cysts were formed, and apoptotic cells were found in the inner part of granulosa cell layers of antral follicles. Androstenedione administration down-regulated expression of P450arom but up-regulated expression of P450scc and p27(Kip1) in the granulosa cells of antral follicles. Serum T levels were significantly increased in androstenedione-treated rats. In mouse follicles exposed to androstenedione, the granulosa cells contained abundant lipid droplets and mitochondria with complex tubular cristae. | Galectin-3 is a marker of myocardial fibrosis that has been implicated in the pathophysiologic pathway of fibrosis; its association with all-cause and cardiovascular disease (CVD) mortality in a community-based cohort free of baseline CVD has not been reported. Our aim was to determine the association between galectin-3 levels and all-cause and CVD mortality in community-dwelling older adults without known CVD. We measured plasma galectin-3 levels in 1,393 Rancho Bernardo Study participants without CVD with a mean age of 70 years. Participants were followed up for a mean of 11 years for coronary heart disease, CVD mortality, and all-cause mortality. During follow-up, 436 participants died (169 from CVD). In models adjusted for traditional CVD risk factors and renal function, galectin-3 was a significant predictor of CVD mortality (hazard ratio [HR] per SD log increase 1.30, 95% CI 1.10-1.53) and all-cause mortality (HR 1.12, 1.01-1.24), but not coronary heart disease (HR 1.09, 0.92-1.30). After further adjusting for N-terminal pro B-type natriuretic peptide, galectin-3 remained an independent predictor (HR 1.24, 1.05-1.47) of CVD mortality. Galectin-3 improved the c statistic (0.847-0.851, P = .003) for prediction of CVD death. Net reclassification improvement (>0) with the addition of galectin-3 was 35% (P < .0001); the integrated discrimination index was also significant (P = .03). Participants with both galectin-3 and N-terminal pro B-type natriuretic peptide above the median had increased risk of CVD death vs those with higher levels of only 1 of these markers (HR 1.74, 1.24-2.43). |
Does chronic prenatal stress epigenetically modify spinal cord BDNF expression to induce sex-specific visceral hypersensitivity in offspring? | Irritable bowel syndrome (IBS) is a heterogeneous disorder with abdominal pain as one of the primary symptoms. The etiology of IBS remains unknown. Epidemiological studies found that a subset of these patients have a history of adverse early-life experiences. We tested the hypothesis that chronic prenatal stress (CPS) epigenetically enhances brain-derived neurotrophic factor (BDNF) in spinal cord to aggravate colon sensitivity to colorectal distension (CRD) differentially in male and female offspring. We used heterotypic intermittent chronic stress (HeICS) protocols in pregnant dams from E11 until delivery. Chronic prenatal stress induced significant visceral hypersensitivity (VHS) to CRD in male and female offspring. A second exposure to HeICS in adult offspring exacerbated VHS greater in female offspring that persisted longer than in male offspring. Chronic prenatal stress upregulated BDNF expression in the lumbar-sacral dorsal horn that correlated with the exacerbation of VHS in female, but not in male offspring. The upregulation of BDNF was due to a significant increase in RNA Pol II binding, histone H3 acetylation, and significant decrease in histone deacetylase 1 association with the core promoter of BDNF in female offspring. Other chronic prenatal and neonatal stress protocols were less effective than HeICS. | The main objective of the present study was the investigation of possible influence of lens opacification on macular pigment optical density (MPOD) measurements. Eighty-six eyes of 64 patients (mean age 73.4 ± 8.3 years) were included in the study. MPOD was prospectively measured using the one-wavelength reflection method (Visucam500, Carl Zeiss Meditec AG) before and after cataract extraction, with implantation of a blue-light filtering intraocular lens (AlconSN60WF). The median of the maximum optical density (MaxOD) and the median of the mean optical density (MeanOD) measurements of macular pigment across the subject group were evaluated. Statistically significant differences were noticed between pre-operative and post-operative measurements, the absolute values were generally lower after cataract extraction. The following median (lower/upper quartile) differences across the group were determined: MaxOD -33.8 % (-46.2 to -19.1 %), MeanOD -44.0 % (-54.6 to -26.6 %). Larger changes were observed in elderly patients [<70 years of age (n = 25 eyes): MaxOD -13.4 % (-20.5 to 3.6 %), MeanOD -23.6 % (-30.5 to -15.3 %) versus patients ≥70 years (n = 61 eyes) MaxOD -40.5 % (-53.2 to -30.1 %), MeanOD -47.2 % (-57.8 to -40.1 %)] and in patients with progressed stage of cataract. MaxOD for lens opacification grade 1 (n = 9 eyes): -27.4 % (-42.1 to -19.6 %), grade 2 (n = 26 eyes): -35.0 % (-44.2 to -25.3 %), grade 3 (n = 21 eyes): -34.4 % (-45.4 to -11.4 %), grade 4 (n = 25 eyes): -32.6 % (-53.2 to -6.4 %), and grade 5 (n = 5 eyes): -53.5 % (-61.7 to -38.7 %) and MeanOD for cataract stage 1 (n = 9 eyes): -42.6 % (-46.0 to -26.0 %), stage 2 (n = 26 eyes): -44.1 % (-51.8 to -26.2 %), stage 3 (n = 21 eyes): -45.7 % (-54.7 to -24.7 %), stage 4 (n = 25 eyes): -39.5 % (-59.4 to -26.1 %), and stage 5 (n = 5 eyes): -57.0 % (-66.1 to -51.4 %). |
Does long-term reduction of T-cell intracellular antigens lead to increased beta-actin expression? | The permanent down-regulated expression of T-cell intracellular antigen (TIA) proteins in HeLa cells improves cytoskeleton-mediated functions such as cell proliferation and tumor growth. Making use of human and mouse cells with knocked down/out expression of T-cell intracellular antigen 1 (TIA1) and/or TIA1 related/like (TIAR/TIAL1) proteins and classical RNA (e.g. reverse transcription-quantitative polymerase chain reaction, polysomal profiling analysis using sucrose gradients, immunoblotting, immunoprecipitation, electrophoretic mobility shift assays, ultraviolet light crosslinking and poly (A+) test analysis) and cellular (e.g. immunofluorescence microscopy and quimeric mRNA transfections) biology methods, we have analyzed the regulatory role of TIA proteins in the post-transcriptional modulation of beta-actin (ACTB) mRNA. Our observations show that the acquisition of above cellular capacities is concomitant with increased expression levels of the actin beta subunit (ACTB) protein. Regulating TIA abundance does not modify ACTB mRNA levels, however, an increase of ACTB mRNA translation is observed. This regulatory capacity of TIA proteins is linked to the ACTB mRNA 3'-untranslated region (3'-UTR), where these proteins could function as RNA binding proteins. The expression of GFP from a chimeric reporter containing human ΑCΤΒ 3'-UTR recapitulates the translational control found by the endogenous ACTB mRNA in the absence of TIA proteins. Additionally, murine embryonic fibroblasts (MEF) knocked out for TIA1 rise mouse ACTB protein expression compared to the controls. Once again steady-state levels of mouse ACTB mRNA remained unchanged. | We investigated the prevalence of anxiety and depressive symptoms in patients with an implantable cardioverter defibrillator (ICD) and their partners, and the role of personality factors and social support as determinants of distress. Of all surviving patients (n = 221) having had an ICD implanted between October 1998 and January 2003, 182 patients and 144 partners completed the Hospital Anxiety and Depression Scale, the Type D Personality Scale, and the Perceived Social Support Scale. Type D personality defines those who tend to experience increased negative distress and who do not express these negative emotions in social interactions. Clinical variables for the patients were obtained from medical records. Thirty-one percent of patients versus 42% of partners suffered from symptoms of anxiety (p =.048); symptoms of anxiety were particularly prevalent in male partners. Twenty-eight vs. 29% suffered from depressive symptoms (p =.901). In patients, Type D personality was independently related to anxiety (OR: 7.03; 95% CI: 2.32-21.32) and depressive symptoms (OR: 7.40; 95% CI: 2.49-21.94) adjusting for all other variables. Underlying cardiac disease pathology did not explain differences in patient distress. In partners, Type D personality was independently associated with increased symptoms of anxiety (OR: 8.77; 95% CI: 3.19-24.14) and depression (OR: 4.40; 95% CI: 1.76-11.01). |
Does a prenatal prediction model for total nucleated cell count increase the efficacy of umbilical cord blood banking? | The most important factor for the selection of an umbilical cord blood unit (CBU) for hematopoietic stem cell transplantation is the total nucleated cell (TNC) count as a surrogate marker for stem cell content in the CBU. At present, about one in five donors can provide a CBU with a sufficient TNC count for umbilical cord blood (UCB) banking. It is labor-intensive to obtain consent of all eligible donors and optimization of the selection is needed. The purpose of this study was to investigate prenatal clinical predictors for TNC count that would help to identify successful UCB donors already on admission to the delivery unit. This study was a retrospective analysis of 758 cryopreserved CBUs, collected from 2002 to 2006. Maternal and fetal factors analyzed were maternal age, gravidity, parity, weight, height, diabetes, premature rupture of membranes, gestational age, fetal sex, and birthweight. The impact on a high TNC count (<150 × 10(7) vs. ≥ 150 × 10(7)) of the CBU was modeled in a multivariate analysis model. Fetal birthweight was the strongest predictor (p < 0.001) of TNC count of at least 150 × 10(7). With a composite score of parity, gestational week, maternal weight and height, fetal sex, and birthweight, a nomogram was developed that increased banking rates from 22.7% to 31.9% while decreasing the number of banked CBUs from 149 to 79. | Herbivory induces the activation of mitogen-activated protein kinases (MAPKs), the accumulation of jasmonates and defensive metabolites in damaged leaves and in distal undamaged leaves. Previous studies mainly focused on individual responses and a limited number of systemic leaves, and more research is needed for a better understanding of how different plant parts respond to herbivory. In the wild tobacco Nicotiana attenuata, FACs (fatty acid-amino acid conjugates) in Manduca sexta oral secretions (OS) are the major elicitors that induce herbivory-specific signaling but their role in systemic signaling is largely unknown. Here, we show that simulated herbivory (adding M. sexta OS to fresh wounds) dramatically increased SIPK (salicylic acid-induced protein kinase) activity and jasmonic acid (JA) levels in damaged leaves and in certain (but not all) undamaged systemic leaves, whereas wounding alone had no detectable systemic effects; importantly, FACs and wounding are both required for activating these systemic responses. In contrast to the activation of SIPK and elevation of JA in specific systemic leaves, increases in the activity of an important anti-herbivore defense, trypsin proteinase inhibitor (TPI), were observed in all systemic leaves after simulated herbivory, suggesting that systemic TPI induction does not require SIPK activation and JA increases. Leaf ablation experiments demonstrated that within 10 minutes after simulated herbivory, a signal (or signals) was produced and transported out of the treated leaves, and subsequently activated systemic responses. |
Is non-extracorporeal circulation for coronary artery bypass graft surgery more beneficial than extracorporeal circulation? | The objective of this study was to compare coronary artery bypass graft (CABG) surgery with non-extracorporeal vs. extracorporeal circulation. The study outcomes included operative time, number of graft vessels, pulmonary infection rates, and systemic inflammatory markers. 96 patients received selective CABG, either with non-extracorporeal (study group; n = 48) or extracorporeal circulation (control group; n = 48). Operative time, pulmonary infection rates, and blood levels of inflammatory markers TNF-α, IL-6, and IL-8 before and 4, 24, and 48 hours after the surgery were quantified. Graft vessels were quantified using computed tomography. Operative time was significantly shorter in study group (4.58 ± 0.91 vs. 5.36 ± 1.12 hours in control group; p < 0.05). The number of graft vessels and pulmonary infection rates were comparable between both techniques. However, systemic inflammatory markers were significantly (p < 0.05) lower in study group at 4 and, partly, 24 hours after the surgery. | To analyze the combined impact of the histone deacetylase inhibitor (HDACI) Trichostatin A (TSA) and the extracellular-signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 on gastric cancer (GC) cell line SGC7901 growth. SGC7901 cells were treated with TSA, PD98059 or with a TSA-PD98059 combination. Effects of drug treatment on tumor cell proliferation, apoptosis, cell cycle progression, and cell signaling pathways were investigated by MTS assay, flow cytometry, Western blotting, chromatin immunoprecipitation (ChIP) assay, electrophoretic mobility shift assay (EMSA), and luciferase reporter assay, respectively. PD98059 enhanced TSA-induced cell growth arrest, apoptosis and activation of p21(WAF1/CIP1), but reversed TSA-induced activation of ERK1/2 and nuclear factor-κB (NF-κB). TSA alone up-regulated Notch1 and Hes1, and down-regulated Notch2, but PD98059 did not affect the trends of Notch1 and Notch2 induced by TSA. Particularly, PD98059 did potentiate the ability of TSA to down-regulate phospho-histone H3 protein, but increased levels of the acetylated forms of histone H3 bound to the p21(WAF1/CIP1) promoter, leading to enhanced expression of p21(WAF1/CIP1) in SGC7901 cells. |
Does [ Atopic dermatitis aggravate the allergic airways inflammation in acute viral bronchiolitis ]? | Exhaled nitric oxide (FeNO) is a putative non-invasive marker of eosinophilic airway inflammation with a good predictive value for allergic asthma in preschool children. The aim of the present study was to compare FeNO after acute viral bronchiolitis (AVB) in children aged less than 2 years without atopic dermatitis (AD) vs those with atopic dermatitis, as well as children with AD without any history of AVB. Forty-two children (mean age +/- SD: 12.3 +/- 5.2 months; range 5.0-23.5; sex-ratio M: F=1.3: 1) were included in this prospective study, > 8 wks after an episode of AVB. The patients' atopic status was assessed both by clinical phenotype and IgE- mediated response to inhaled and/or food allergens. FeNO (ppb) was measured off-line by the chemoluminescence method on samples obtained from gas collected in a balloon during tidal breathing. There was a significant difference between the AVB/AD (23.4 +/- 14.3 ppb, n=15) vs the AVB without AD group (13.5 +/- 10. 1 ppb, n=13) or the AD without AVB group (11.0 +/- 8.3 ppb, n=14). Maternal feeding for more than 2 months decreased FeNO by 50%. | To test whether oral L-81 treatment could improve the condition of mice with diabetes and to investigate how L-81 regulates microsomal triglyceride transfer protein (MTP) activity in the liver. Genetically diabetic (db/db) mice were fed on chow supplemented with or without L-81 for 4 wk. The body weight, plasma glucose level, plasma lipid profile, and adipocyte volume of the db/db mice were assessed after treatment. Toxicity of L-81 was also evaluated. To understand the molecular mechanism, HepG2 cells were treated with L-81 and the effects on apolipoprotein B (apoB) secretion and mRNA level of the MTP gene were assessed. Treatment of db/db mice with L-81 significantly reduced and nearly normalized their body weight, hyperphagia and polydipsia. L-81 also markedly decreased the fasting plasma glucose level, improved glucose tolerance, and attenuated the elevated levels of plasma cholesterol and triglyceride. At the effective dosage, little toxicity was observed. Treatment of HepG2 cells with L-81 not only inhibited apoB secretion, but also significantly decreased the mRNA level of the MTP gene. Similar to the action of insulin, L-81 exerted its effect on the MTP promoter. |
Does pAR-2 activating peptide-induced stimulation of pregnant rat myometrium contractile activity partly involve the other membrane receptors? | To study if spontaneous contractions augmented by proteinase-activated receptor-2 (PAR-2)-activating peptide serine-leucine-isoleucine-glycine-arginine-leucine (SLIGRL) involve coactivation of membrane chemoceptors and are associated with expression of PAR-2 mRNA in non-pregnant and pregnant rat myometrium. Non-pregnant, mid-pregnant, and late pregnant rat uterine horn and small intestine segments were snap-frozen in liquid nitrogen to determine PAR-2 mRNA levels by real time polymerase chain reaction (PCR). Uterine rings were used for isometric tension recording. Effect of SLIGRL (0.1 mM) on spontaneous contractions before and after exposure to ibuprofen (cyclooxygenase inhibitor, 1.0 microM), SQ-29548 (thromboxane A(2) receptor inhibitor, 1.0 microM), ketotifen (histamine 1 receptor inhibitor, 10 microM), WEB-2170BS (platelet-activating factor (PAF) receptor inhibitor, 10 microM), atropine (muscarinic receptor inhibitor, 0.1 microM), or ketanserin (serotonin receptor inhibitor, 10 microM) were compared. Paired t-test and one-way ANOVA followed by Dunnett's or Newman-Keuls post hoc tests were used for statistical analysis when appropriate. | The authors investigated the additive prognostic value of the 6-minute walk test (6MWT) to Euroscore in patients with severe aortic stenosis undergoing aortic valve replacement (AVR) METHODS AND RESULTS: 208 patients with severe AS underwent the 6MWT before AVR, as part of a randomised trial (ASSERT) comparing stented and stentless aortic valves. Clinical follow-up was available for 200 patients up to 12 months. The rate of death, myocardial infarction (MI) or stroke (time to first event) was 13% (n = 14) in patients walking <300 metres compared to 4% (n = 4) in those who walked > or =300 metres (p = 0.017). When rate of death, MI or stroke by Euroscore risk was stratified by 6-minute walking distance, the 6MWT added prognostic information. In a Cox regression analysis 6MWT distance was the only variable retained as an independent predictor of the composite outcome of death, MI or stroke at 12 months (HR 0.28 95% CI 0.09 to 0.85, p = 0.025). |
Does zinc have insulin-mimetic properties which enhance spinal fusion in a rat model? | Previous studies have found that insulin or insulin-like growth factor treatment can stimulate fracture healing in diabetic and normal animal models, and increase fusion rates in a rat spinal fusion model. Insulin-mimetic agents, such as zinc, have demonstrated antidiabetic effects in animal and human studies, and these agents that mimic the effects of insulin could produce the same beneficial effects on bone regeneration and spinal fusion. The purpose of this study was to analyze the effects of locally applied zinc on spinal fusion in a rat model. Institutional Animal Care and Use Committee-approved animal study using Sprague-Dawley rats was used as the study design. Thirty Sprague-Dawley rats (450-500 g) underwent L4-L5 posterolateral lumbar fusion (PLF). After decortication and application of approximately 0.3 g of autograft per side, one of three pellets were added to each site: high-dose zinc calcium sulfate (ZnCaSO4), low-dose ZnCaSO4 (half of the high dose), or a control palmitic acid pellet (no Zn dose). Systemic blood glucose levels were measured 24 hours postoperatively. Rats were sacrificed after 8weeks and the PLFs analyzed qualitatively by manual palpation and radiograph review, and quantitatively by micro-computed tomography (CT) analysis of bone volume and trabecular thickness. Statistical analyses with p-values set at .05 were accomplished with analysis of variance, followed by posthoc tests for quantitative data, or Mann-Whitney rank tests for qualitative assessments. Compared with controls, the low-dose zinc group demonstrated a significantly higher manual palpation grade (p=.011), radiographic score (p=.045), and bone formation on micro-CT (172.9 mm(3) vs. 126.7 mm(3) for controls) (p<.01). The high-dose zinc also demonstrated a significantly higher radiographic score (p=.017) and bone formation on micro-CT (172.7 mm(3) vs. 126.7 mm(3)) (p<.01) versus controls, and was trending toward higher manual palpation scores (p=.058). | Allergic rhinitis (AR) is a complex chronic inflammatory disease of the nasal mucosa, caused by an interaction between genetic and environmental factors. As evidence suggests that some genetic variants may increase susceptibility to both AR and asthma, the objective of this study was to identify asthma susceptibility variants associated with AR in the Chinese population. A cohort of 402 individuals with physician-diagnosed AR and 416 healthy controls were recruited from the Han Chinese population in Beijing. DNA was extracted from the peripheral blood and a total of 12 single-nucleotide polymorphisms (SNPs) shown to be associated with asthma in Japanese subjects were selected for genotyping using the SequenomMassARRAY technology platform. Analysis of frequency differences of allele between the AR patients and control subjects showed that the C allele of rs204993 in the pre-B-cell leukemia homeobox 2 (PBX2) gene from the 6p21.3 locus was significantly associated with AR (p = 0.0006, pcorrected = 0.0340). Genotype analysis further confirmed the difference in distribution of this variant between AR patients and controls in the both the dominant (pT/C+C/C vs T/T = 7.37×10(-5) ) and co-dominant (pT/C vs T/T = 1.98 × 10(-4) , pC/C vs T/T = 0.004) models. |
Do fasting glucose levels within the high normal range predict cardiovascular outcome? | Diabetes mellitus and impaired glucose metabolism are associated with increased risk for cardiovascular disease (CVD). However, it is still not clear whether glucose levels can predict CVD risk among patients without diabetes. The primary aim of this study is to assess whether normoglycemic fasting plasma glucose (FPG) is associated with increased risk of CVD outcomes in healthy patients. We obtained blood measurements, data from physical examination, and medical and lifestyle information from 10,913 men and women who were evaluated in the Institute for Preventive Medicine of Sheba Medical Center. Enrolled were participants with FPG <100 mg/dL as well as 100 to 125 mg/dL, who were free of diagnosis of CVD. The participants were actively screened for coronary disease using a stress test. Primary end points were coronary heart disease or self-reported cerebral vascular disease. A total of 1,119 incident cases of CVD occurred during a mean follow-up of 4.3 years. Subjects with fasting glucose levels in the high normal range (95-99 mg/dL) had an increased CVD risk when compared with levels <80 mg/dL, (HR 1.53;CI 95% [1.22-1.91], P < .001). A multivariate model, adjusted for age, sex, family history of CVD, blood pressure, body mass index, smoking status, pharmacologic treatment, serum triglycerides, and high-density lipoprotein and low-density lipoprotein cholesterol levels, revealed an independent increased risk of CVD with rising FPG levels in the normal range. | Combination therapy has generated a significant interest in the clinical setting since certain agents, with known mechanisms of action and non-overlapping toxicities may increase the therapeutic potential of anticancer drugs by decreasing systemic toxicity and overcoming drug resistance. Doxorubicin and docetaxel, two standard antineoplastic agents in hormone-refractory prostate cancer (HRPC) therapy and ciprofloxacin were evaluated singly and in several simultaneous and sequential drug combination schemes, against PC-3 and LNCaP cell lines. Cellular viability was determined by the resazurin assay and the assessment of synergism, additivity or antagonism was carried out by the median effect analysis. The importance of dose, exposure time and type of administration were investigated and compared. Ciprofloxacin-doxorubicin or docetaxel combinations resulted in prominent additive or synergistic effects in both cell lines, when the cells were pre-treated with ciprofloxacin. These results suggest a rationale for dose reduction of doxorubicin and docetaxel in prostate cancer therapy, since the doses needed to achieve 50% cell death may be decreased by approximately 4- to 15-fold or 3- to 8-fold, respectively, after a pre-treatment with ciprofloxacin. In contrast, the referred combinations yielded moderate antagonistic effects when used concurrently in this in vitro system. |
Does a tourniquet assisted cardiopulmonary resuscitation augment myocardial perfusion in a porcine model of cardiac arrest? | During cardiopulmonary resuscitation (CPR), myocardial blood flow generated by chest compression rarely exceeds 35% of its normal level. Cardiac output generated by chest compression decreases gradually with the prolongation of cardiac arrest and resuscitation. Early studies have demonstrated that myocardial blood flow during CPR is largely dependent on peripheral vascular resistance. In this study, we investigated the effects of chest compression in combination with physical control of peripheral vascular resistance assisted by tourniquets on myocardial blood flow during CPR. Ventricular fibrillation was induced and untreated for 7 min in ten male domestic pigs weighing between 33 and 37 kg. The animals were then randomized to receive CPR alone or a tourniquet assisted CPR (T-CPR). In the CPR alone group, chest compression was performed by a miniaturized mechanical chest compressor. In the T-CPR group, coincident with the start of resuscitation, the thin elastic tourniquets were wrapped around the four limbs from the distal end to the proximal part. After 2 min of CPR, epinephrine (20 μg/kg) was administered via the femoral vein. After 5 min of CPR, defibrillation was attempted by a single 150 J shock. If resuscitation was not successful, CPR was resumed for 2 min before the next defibrillation. The protocol was continued until successful resuscitation or for a total of 15 min. Five minutes after resuscitation, the elastic tourniquets were removed. The resuscitated animals were observed for 2h. T-CPR generated significantly greater coronary perfusion pressure, end-tidal carbon dioxide and carotid blood flow. There was no difference in both intrathoracic positive and negative pressures between the two groups. All animals were successfully resuscitated with a single shock in both groups. There were no significant changes in hemodynamics observed in the animals treated in the T-CPR group before-and-after the release of tourniquets at post-resuscitation 5 min. | There is an increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). The aim of this study was to compare the prevalence of left sided adenomas in patients with IBD aged 55-64 years with a local age matched control population. A review of clinical notes. The prevalence of adenomas in patients with IBD attending for either sigmoidoscopy or colonoscopy was compared with local age matched controls that participated in the national screening trial for colorectal cancer with flexible sigmoidoscopy. Of 106 patients (61 male, 45 female, mean age of 59 years), 80 suffered from ulcerative colitis, 20 from Crohn's disease, and six from indeterminate colitis. All patients had undergone at least one flexible sigmoidoscopy and 75 had a colonoscopy. Distal adenomas were found in three patients with ulcerative colitis compared with 67 of 749 controls (2.8% v 8.9%, chi(2) = 4.6, p = 0.03). |
Do culturable bacterial endophytes isolated from Mangrove tree ( Rhizophora apiculata Blume ) enhance seedling growth in Rice? | Endophytic bacteria do have several potential applications in medicine and in other various sectors of biotechnology including agriculture. Bacterial endophytes need to be explored for their potential applications in agricultural biotechnology. One of the potential applications of bacterial endophytes in agricultural is to enhance the growth of the agricultural crops. Hence, this study was undertaken to explore the plant growth promoting potential application of bacterial endophytes. The objective of this study was to examine the effect of endophytic bacteria from mangrove tree (Rhizophora apiculata Blume) for their efficacy in promoting seedling growth in rice. Eight endophytic bacterial isolates (EBIs) isolated from twig and petiole tissues of the mangrove were identified based on their 16S ribosomal ribonucleic acid (rRNA) gene sequence homology. Separately, surface sterilized paddy seeds were treated with cell-free broth and cell suspension of the EBIs. Rice seedlings were analyzed by various bioassays and data was recorded. The gene sequences of the isolates were closely related to two genera namely, Bacillus and Pantoea. Inoculation of EBIs from R. apiculata with rice seeds resulted in accelerated root and shoot growth with significant increase in chlorophyll content. Among the isolates, Pantoea ananatis (1MSE1) and Bacillus amyloliquefaciens (3MPE1) had shown predominance of activity. Endophytic invasion was recognized by the non-host by rapid accumulation of reactive oxygen species (ROS) and was counteracted by the production of hydrogen peroxide (H2O2) and lipid peroxide. The results demonstrated that EBIs from mangrove tree can increase the fitness of the rice seedlings under controlled conditions. | To determine whether the responses of elders compared with younger patients differed significantly on a structured dizziness case history. Retrospective case reviews. Outpatient balance function testing center. Two-hundred thirty-three adults who underwent vestibular function testing and completed a structured case history. The mean age of the adult group (18-64 yr) was 46.4 years. The mean age of the old adult group (65 yr and older) was 76.2 years. Patient's self-reported symptoms on a structured case history questionnaire. Younger adults reported significantly more complaints of true vertigo and associated nausea and vomiting compared with older patients. Older patients tended to report symptoms of unsteadiness or falling. Despite the lack of vertiginous symptoms, BPPV was common in older adults. |
Is overweight associated with decreased cognitive functioning among school-age children and adolescents? | Childhood overweight and obesity have increased substantially in the past two decades, raising concerns about their psychosocial and cognitive consequences. We examined the associations between academic performance (AP), cognitive functioning (CF), and increased BMI in a nationally representative sample of children. Participants were 2,519 children aged 8-16 years, who completed a brief neuropsychological battery and measures of height and weight as a part of the Third National Health and Nutrition Examination Survey, a cross-sectional survey conducted between 1988 and 1994. Z-scores were calculated for each neuropsychological test, and poor performance was defined as z-score <2. The association between BMI and AP was not significant after adjusting for parental/familial characteristics. However, the associations between CF remained significant after adjusting for parental/familial characteristic, sports participation, physical activity, hours spent watching TV, psychosocial development, blood pressure, and serum lipid profile. Z-scores on block design (a measure of visuospatial organization and general mental ability) among overweight children and children at risk of overweight were below those of normal-weight children by 0.22 (s.e. = 0.16) and 0.10 (s.e. = 0.10) unit, respectively (P for trend <0.05). The odds of poor performance on block design were 1.97 (95% confidence interval: 1.01-3.83) and 2.80 (1.16-6.75), respectively, among children at risk or overweight compared to normal-weight peers. | Circulating tumor cells (CTCs) are commonly isolated from the blood by targeting the epithelial cell adhesion molecule (EpCAM) through positive selection. However, EpCAM can be downregulated during metastatic progression, or it can be initially not present. We designed the present prospective trial to characterize CTCs as well as other circulating cell populations in blood samples from women with metastatic breast cancer without EpCAM-dependent enrichment and/or isolation technology. A total of 32 patients with metastatic breast cancer were enrolled, and blood samples were processed using a previously described negative depletion immunomagnetic methodology. Samples from healthy volunteers were run as controls (n = 5). Multistep sequential labeling was performed to label and fix cell-surface markers followed by permeabilization for cytokeratins (CK) 8, 18 and 19. Multiparametric flow cytometry (FCM) analysis was conducted using a BD LSR II flow cytometer or a BD FACSAria II or FACSAria III cell sorter. Immunocytochemical staining on postenrichment specimens for DAPI, EpCAM, CD45, CK, epidermal growth factor receptor and vimentin was performed. Expression of these markers was visualized using confocal microscopy (CM). CD45-negative/CK-positive (CD45- CK+) populations with EpCAM + and EpCAM - expression were identified with both FCM and CM from the negatively enriched patient samples. In addition, EpCAM + and EpCAM - populations that were CK + and coexpressing the pan-hematopoietic marker CD45 were also noted. There were more CK + EpCAM - events/ml than CK + EpCAM + events/ml in both the CD45- and CD45+ fractions (both statistically significant at P ≤ 0.0005). The number of CK + CD45- and CK + CD45+ events per milliliter in blood samples (regardless of EpCAM status) was higher in patient samples than in normal control samples (P ≤ 0.0005 and P ≤ 0.026, respectively). Further, a significant fraction of the CK + CD45+ events also expressed CD68, a marker associated with tumor-associated macrophages. Higher levels of CD45-CK + EpCAM - were associated with worse overall survival (P = 0.0292). |
Does collagen remodeling and peripheral immune cell recruitment characterize the cutaneous Langerhans cell histiocytosis microenvironment? | Langerhans cell histiocytosis (LCH) is a rare and potentially fatal disorder of unknown etiology arising from the accumulation of epidermal Langerhans-like cells in bone, skin, or other tissues. Tissue damage and morbidity results from lesional cytokine release, and we sought to investigate the LCH microenvironment using a combination of histological stains and immunohistochemistry. CD1a immunoreactivity was used to identify lesional cells in archival paraffin-embedded samples of cutaneous LCH. A combined Orcein and Giemsa stain identified immune cells in general (particularly granulocytes and mast cells) and extracellular matrix (particularly elastic fibers), while CD3 and CD68 staining identified T cells and macrophages, respectively. Collagen synthesis was investigated with Herovici staining, which discriminates newly synthesized from mature collagen, while cross-polar microscopy of picrosirius-stained sections identified changes in matrix organization. Immune cells were consistently identified at the periphery of cutaneous LCH lesions. We quantified an increased number of thickened and disorganized elastic fibers surrounding lesions and an absence of elastic fibers within lesions. Furthermore, lesions exhibited a decrease in mature collagen fibers and a loss of supporting collagen matrix within lesions and compromised collagen integrity in adjacent tissue. | Partial adherence to antihypertensive therapy remains a public health challenge and may be associated with increased cardiovascular risk. We quantitatively evaluated cardiovascular risk inherent in partial therapy adherence in spontaneously hypertensive rats with accelerated hypertension. Adult spontaneously hypertensive rats were divided into 5 groups; Group 1 (controls) did not receive any treatment, whereas all other rats (Groups 2-5) were given nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester (L-NAME) to exacerbate hypertension. Group 2 (untreated/nonadherers) was given L-NAME but not antihypertensive medication; Group 3 (Perfect Adherers) was treated daily with candesartan (10 mg/kg); Group 4 was given candesartan 3 times a week, whereas Group 5 received candesartan only during the last 6 days of the 3-week experiment (Partial Adherers). At the end, indices of systemic and regional (kidneys, brain, and heart) hemodynamics, and indices of left ventricular function were determined. Treatment with L-NAME aggravated hypertension, adversely affected target organ blood flows and resistances, and grossly impaired ventricular function. Perfect adherence with candesartan completely reversed the adverse cardiovascular effects of L-NAME intervention. In partial adherers (Groups 4 and 5), arterial pressure decreased and reached control values. However, target organ hemodynamics and heart function showed only slight improvements, if any. |
Is chronic venous insufficiency associated with elevated level of circulating microparticles? | Chronic venous insufficiency (CVI) results when the veins in the legs no longer pump blood back to the heart effectively. Microparticles (MPs) are small membrane vesicles released by several circulating and vascular cells upon activation or apoptosis. The purpose of this study was to assess the subpopulations of circulating endothelial (EMPs) and platelet microparticles (PMPs) in CVI, and to disclose their contribution in mediating dysfunction of human peripheral venules. Human peripheral venules were explanted during leg surgery on patients with CVI and on control subjects (C); concurrently, blood samples were collected and circulating MPs isolated. The techniques used were: flow cytometry, fluorescence and electron microscopy, myograph technique and western-blotting technique. The results showed that compared with controls, patients with CVI had: (i) a marked elevation of circulating EMPs and PMPs; (ii) a structural modification of the venous wall consisting of activation of endothelial and smooth muscle cells, an abundance of intermediary filaments and synthesis of hyperplasic-multilayered basal lamina; (iii) a significantly altered reactivity of the venous wall, closely associated with EMPs and PMPs adherence; (iv) altered contractile response to noradrenaline, acetylcholine, 5-hydroxytryptamine and KCl, and an impeded relaxation in response to sodium nitroprusside; and (iv) a substantially increased protein expression of tissue factor (TF) and of P-Selectin both in the venular vascular wall and on the surface of EMPs and PMPs. | Young adults are a population at great risk for problematic health behaviors. Alcohol mixed with energy drink (AmED) consumption is a relatively popular health risk behavior among young adults. AmED consumption continues to illustrate negative outcomes in the research literature, having been linked with other substance use, high-risk sexual behavior, and sexual victimization. Limited research to date has examined associations between AmED consumption and patterns of alcohol dependence. Undergraduate college students (n=757) filled out an online survey which assessed their drinking habits in the past week and month, including their consumption of AmED beverages, personality characteristics, substance use, and problematic alcohol consumption via the Alcohol Use Disorders Identification Test (AUDIT). A minority of participants reported AmED consumption in both the past month (11.6%) and past week (9.7%). Compared to their alcohol-only drinking counterparts, AmED consumers scored significantly higher on measures of impulsivity, and lower on anxiety sensitivity when compared to their alcohol-only drinking counterparts. In multivariate analyses, AmED consumption was robustly associated with patterns of alcohol dependence (AUDIT score≥8) among young adult college students, while controlling for energy drink use, alcohol use, personality factors, substance use, and demographic variables. |
Does preservation of the right atrial appendage improve reduced plasma atrial natriuretic peptide levels after the maze procedure? | The present study was conducted to determine whether preservation of the right atrial appendage lessens the decrease of plasma atrial natriuretic peptide levels after the maze procedure and whether the increase of plasma atrial natriuretic peptides improves the ability of the kidneys to excrete the fluid load after the operation. We evaluated 42 patients who underwent the maze procedure. The right atrial appendage was preserved in 22 patients but not in 20. Blood samples were obtained before and after the operation for measurement of atrial natriuretic peptides. To evaluate the influence of atrial natriuretic peptides on the ability of the kidneys, we also measured body weight, fluid balance, and the doses of furosemide and dopamine administered after the operation. The restoration to sinus rhythm at 1 month after was comparable in the two groups. Plasma atrial natriuretic peptide levels significantly increased after the operation in patients in whom the right atrial appendage was preserved (1 day after: 23.4 +/- 17.8 vs 3 days after: 42.7 +/- 23.6 and 7 days after: 36.3 +/- 23.7 pg/mL, P <.05) but not in patients in whom the right atrial appendage was not preserved (1 day after: 20.0 +/- 19.6, 3 days after: 28.5 +/- 19.3, and 7 days after: 23.0 +/- 16.1 pg/mL). Furthermore, plasma atrial natriuretic peptide levels were significantly lower in patients in whom the right atrial appendage was not preserved than in patients in whom the right atrial appendage was preserved at 3 and 7 days after the operation. The fluid balance during the first 7 days of the postoperative period was comparable in the two groups, although the total dose of dopamine used in the same period was significantly smaller in patients in whom the right atrial appendage was preserved than in patients in whom the right atrial appendage was not preserved (155.3 +/- 119.0 vs 244.9 +/- 129.0 microg/kg, P <.05). | We investigated the response of oral cancer cells to intracellular invasion of Porphyromonas gingivalis to define changes in the biological characteristics of oral cancer cells evoked by the presence of oral pathogenic bacteria within a tumour microenvironment. The proliferative activity, cell cycle, and autophagic response were evaluated in oral cancer cells infected with P. gingivalis 381. ROS generation was detected in these cells by DCFDA assay, and its role in the responses of oral cancer cells to P. gingivalis infection was further investigated. P. gingivalis inhibited proliferation of oral cancer cells by inducing G1 cell cycle arrest, but had no effect on apoptosis. Following infection with P. gingivalis, the expression of cyclin D1 and cdk4 was decreased in oral cancer cells, whereas p21, a Cdk inhibitor, was upregulated, in comparison with non-infected controls. Autophagy was prominently enhanced in these infected cells, presumably contributing to the suppressed proliferation. Further experiments revealed that such autophagic response was activated by the formation of reactive oxygen species, as evidenced by the lack of autophagic response and cell proliferation upon removal of reactive oxygen species. |
Does laser microdissection allow detection of abnormal gene expression in cystic adenomatoid malformation of the lung? | Congenital cystic adenomatoid malformation (CCAM) of the lung may result from a localized aberrant epithelial-mesenchymal interaction during lung development. We used laser microdissection (LMD) to isolate the epithelium and mesenchyme of CCAM, and studied candidate gene expression in these pure cell populations. Congenital cystic adenomatoid malformation tissue was obtained from fetal (n = 5) and postnatal (n = 5) surgical specimens. Normal fetal lung (n = 10) was obtained from abortus material, and normal postnatal lung (n = 5) was identified from surgical specimens. Whole tissue was analyzed using immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). Using LMD, columnar bronchiolar type epithelium and underlying mesenchyme were isolated. Multiplex nested RT-PCR was then used to detect message levels of candidate genes. Reverse transcriptase polymerase chain reaction performed on LMD-isolated tissue, but not whole tissue homogenate, revealed differences between CCAM and normal lung. In this report, we focus on the fibroblast growth factor (FGF) family. By RT-PCR, there was 4-fold more epithelial expression of FGF9 in fetal CCAM vs normal fetal lung (P < .07). This was qualitatively confirmed by immunohistochemistry. We also detected decreased FGF7 expression in CCAM mesenchyme (P < .05) but no significant differences in FGF10 or FGFR2. | Shift-work and a sedentary lifestyle are risk factors for raised blood pressure (BP). Exercise can reduce BP in diurnally-active individuals, but it is unknown whether postexercise hypotension persists when people are active and eating at night. We present the first investigation into the acute effects of exercise on BP monitored during simulated night-work. Nine normotensive participants, aged 20-42 years, completed at least two crossover trials beginning at 1800 hours. Between 1900 and 2000 hours, participants either rested or exercised at 50% peak oxygen uptake (VO(2peak)) and then remained awake throughout the night, completing various tasks until 0515 hours. Six participants completed a total of four trials in which they exercised or rested, whereas either one standardized (60 kJ/kg) meal at 2200 hours or two smaller (30 kJ/kg) meals at 2200 and 0200 hours were eaten. Systolic and diastolic BP, mean arterial pressure (MAP), heart rate (HR), and wrist activity were recorded every 30 min. Following exercise, MAP was significantly (P < 0.0005) lower throughout the night-shift compared with no prior exercise (95% confidence limits for reduction: 4-7 mm Hg). The postexercise reductions in systolic BP and MAP were not moderated by diet, but the reduction in diastolic BP was slightly greater when only one meal was eaten (P < 0.0005). BP was lower even though wrist activity and HR were significantly higher following exercise (P < 0.0005). |
Do feasibility of using tissue Doppler velocities in stress echo during upright bicycle exercise? | There are several studies on myocardial tissue Doppler velocities during dobutamine stress, but few studies on the same parameters during bicycle exercise. We wanted to examine how sample sites affected velocities, beat-to-beat variability and segments eligible for analysis. Twenty patients with normal coronary arteries were included in the study. Echocardiograms were obtained at rest and at peak exercise on the exercise bike and were analyzed off line by two independent raters. | The development of preimplantation mammalian embryos in vitro is less than optimal. Follicular fluid and cumulus cells have both been used, independently, to improve preimplantation embryo quality in culture. To determine the ability of mouse cumulus cell coculture in the presence of human follicular fluids to support preimplantation mouse Balb/cJ embryo development in vitro. Culture of preimplantation mouse Balb/cJ embryo's independently in human follicular fluid or on mouse cumulus cells had no significant affect on blastocyst. The coculture of mouse Balb/cJ preimplantation-stage embryos on mouse cumulus cells in the presence of human follicular fluid significantly (P < 0.01) improved blastocyst development and the total number of cells per blastocyst. |
Are paraoxonase-1 gene Leu-Met55 and Gln-Arg192 polymorphisms associated with carotid artery atherosclerosis in a population-based cohort? | Paraoxonase-1 (PON1) is an enzyme that prevents low-density lipoprotein (LDL) oxidation. The role of polymorphisms of PON1 determining early atherosclerotic changes is currently unclear. Cross sectional cohort study. Nine hundred and ninety-nine subjects from a population-based cohort were screened. Intima-media thickness (IMT) was measured by ultrasonography. Leu-Met55 and Gln-Arg192 polymorphism were determined. No association between PON1 genotypes and IMT was found. This finding remained after adjusting for confounding factors. | To study the effects of strychnos alkaloids on the proliferation of adult rat neuroprogenitor cells. Strychnos alkaloids free of strychnine and brucine were extracted from Strychnos nux vomica, and the effects of Strychnos alkaloids on the survival of HEK293 and PC12 cells were evaluated using MTT assay. In vitro cultured adult rat neuroprogenitor cells isolated from the hippocampus were treated with different concentrations of Strychnos alkaloids for 2 days, and the cell proliferation was assessed using BrdU incorporation assay. At the concentration above 0.5 mg/ml, Strychnos alkaloids produced toxic effect against HEK293 cells (P<0.0001), while for PC12 cells, Strychnos alkaloids inhibited the cell survival at the concentration as low as 5 microg/ml (P<0.0001). After 2 days of exposure to 50 microg/ml Strychnos alkaloids, the neuroprogenitor cells showed significantly decreased number of BrdU-positive cells (P<0.01), but the total cell number remained stable when compared with that of the control cells (P>0.05), whereas at the concentration of 100 microg/ml, Strychnos alkaloids produced obvious cytotoxicity against the neuroprogenitor cells. |
Do internal medicine residents accurately assess their medical knowledge? | Medical knowledge is essential for appropriate patient care; however, the accuracy of internal medicine (IM) residents' assessment of their medical knowledge is unknown. IM residents predicted their overall percentile performance 1 week (on average) before and after taking the in-training exam (ITE), an objective and well accepted method to assess medical knowledge to study resident assessment accuracy. Ordinary least squares regression was used to study the association between the absolute accuracy of their predictions of their percentile performance on the ITE examination and their actual percentile performance. Ninety-three percent of our 28 residents participated. Residents were highly inaccurate in predicting their percentile performance. Only 31% had ITE scores that were within 10 points of their predictions. On average, most residents were pessimistic about their overall percentile performance with 18 (69%) underestimating their performance. Having just taken the examination and previous experience with the examination did not improve predictions of percentile performance. | To investigate whether the signaling events occurring in Fas-mediated apoptosis alter raft membrane formation in human RPE cells. Formation of lipid rafts in cultured human retinal pigment epithelial cells (ARPE-19) was studied by confocal microscopy, with fluorescein-labeled cholera toxin subunit B binding protein (BODIPY)-labeled ganglioside GM1 lipid after Fas-L induction of apoptosis. Apoptosis was assessed by fluorescein-labeled annexin V detection of phosphatidylserine externalization and quadrant analysis with flow cytometry. Membrane rafts were localized into membrane vesicles by passing BODIPY-labeled GM1 RPE cells through a 2-microm-pore polycarbonate membrane using an extruder device. The labeled fractions, containing vesicles enriched in GM1, were detected by flow cytometry and then analyzed for the presence of Fas protein. Differential punctate staining of membrane rafts was demonstrated in normal and FasL-induced apoptotic human ARPE-19 cells in culture by confocal microscopy, using cholera toxin B and GM1 labeling of extruded vesicles. The lipid raft-associated vesicles were derived by plasma membrane dissociation, via a newly developed whole-cell extrusion technique that produced 2-microm vesicles with both GM1 lipid and Fas protein abundance enriched in a subpopulation of the membrane-derived vesicles. The amount of Fas protein in the vesicles containing raft domains markedly increased in FasL-treated cells. Treatment of human ARPE 19 cells with methyl beta-cyclodextrin after FasL induction of apoptosis resulted in cellular cholesterol depletion and markedly reduced the incidence of Fas-receptor localization in GM1 rafts. |
Does the mechanism of formation of bony spur ( enthesophytes ) in the achilles tendon? | To investigate the early stages in the formation of bony spurs in relation to normal enthesis development. Histologic sections of rat Achilles tendons, stained with toluidine blue or Masson's trichrome, were examined in animals ranging from 2 weeks to 1 year of age. Further material prepared for immunohistochemistry was labeled with monoclonal antibodies for laminin and type IV collagen to highlight the presence of small blood vessels at the enthesis. Sections of small spurs from the Achilles tendons of elderly humans were also examined for comparison. As a part of normal development, bone grows into the Achilles tendon as the calcaneus enlarges. Ossification is preceded by vascular invasion, which occurs along rows of enthesis fibrocartilage cells. Small bony spurs develop when ossification at one point on the enthesis outstrips that on either side. | Hospital readmissions are costly and associated with inferior patient outcomes. There is limited knowledge related to readmissions after esophagectomy for malignancy. Our aim was to determine the impact on survival of readmission after esophagectomy. This cohort study utilizes Surveillance, Epidemiology, and End Results-Medicare data (2002 to 2009). Survival, length of stay, 30-day readmissions, and discharge disposition were determined. Multivariate logistic regression models were created to examine risk factors associated with readmission. In all, 1,744 patients with esophageal cancer underwent esophagectomy: 80% of patients (1,390) were male, and mean age was 73 years; 71.8% of tumors (1,251) were adenocarcinomas, and 72.5% (1,265) were distal esophageal tumors; 38% of patients (667) received induction therapy. Operative approach was transthoracic in 52.6% of patients (918) and transhiatal in 37.4% (653), and required complex reconstruction (intestinal interposition) in 9.9% (173). Stage distribution was as follows: stage I, 35.3% (616); stage II, 32.5% (566); stage III, 27.9% (487); and stage IV, 2.3% (40). Median length of stay was 13 days, hospital mortality was 9.3% (158 patients), and 30-day readmission rate was 18.6% (212 of 1,139 home discharges); 25.4% of patients (443) were discharged to institutional care facilities. Overall survival was significantly worse for patients who were readmitted (p < 0.0001, log rank test). Risk factors for readmission were comorbidity score of 3+, urgent admission, and urban residence. |
Is apoE phenotype associated with inflammatory markers in middle-aged subjects? | Apolipoprotein (apo) E phenotype has been associated with inflammation markers. The determinants of these associations and the relationship between novel inflammation marker, resistin, and apoE phenotype are studied here. Middle-aged subjects of the population- based cohort (n = 526) of the OPERA- study were studied. Intima-media thickness (IMT) was measured with carotid ultrasound. The results suggest that, apoE phenotype was a significant independent predictive factor for resistin (p < 0.01) and hsCRP (p < 0.01) levels. The association of ApoE phenotype with hsCRP was seen among the subjects with the normal renal function (p = 0.005). ApoE4 was associated (p < 0.01) with the lowest hsCRP in the lowest IMT quartile while it's relation with the highest resistin levels was evident in the highest IMT quartile. | Steatohepatitis is a type of histopathological liver injury that can be caused by chemotherapy [chemotherapy-associated steatohepatitis (CASH)] and can progress to liver fibrosis or cirrhosis. CASH impairs liver functions, including liver regeneration. Impaired liver regeneration reduces the number of patients who can undergo liver resection and reduces opportunities for curative therapies. Transforming growth factor-beta (TGFβ) is a potent mitotic inhibitor that participates during the last phase of liver regeneration. TGFβ has been studied as a potential solution to the development of liver fibrosis or hepatocellular carcinoma. The first aim of our study was to establish a large animal model of toxic liver injury and test the ability of a monoclonal antibody against TGFβ (MAB-TGFβ) to increase liver-regeneration capacity. The second aim was to evaluate the degree to which early preoperative administration of MAB-TGFβ influenced hepatic parenchyma regeneration following healthy liver resection in a swine experimental model. Toxic liver injury was induced by alcohol consumption and regular intraperitoneal administration of carbon tetrachloride (CCl4) to piglets for 10 weeks. After 10 weeks, the piglets underwent liver resection of the left lateral and left medial liver lobes. Twenty-four hours after liver resection, MAB-TGFβ was administered to the experimental group (10 piglets) and a physiological solution to the control group (10 piglets) through an implemented port-a-cath. In the second part of the study, either MAB-TGFβ or a saline solution control were administered at 12 and 4 days prior to resection of the right lobes of healthy liver (six experimental and 10 control group subjects). Observation and follow-up was performed throughout the entire experiment. Ultrasound and biochemical tests (for albumin, cholinesterase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, bilirubin, urea, creatinine and ammonia levels) were performed on postoperative days 1, 3, 7, 10 and 14. A histopathological examination was performed after sacrificing the animals on the 14th postoperative day. No significant differences were observed between groups when using ultrasound volumetry to assess the regenerative volume of the liver in both experiments. The only significant differences found when comparing biochemical parameters between groups were higher serum levels of both creatinine and γ-glutamyl transferase in the experimental group with preoperative administration of MAB-TGFβ. There were no differences in the histological analyses of hepatic lobule cross-sectional area nor in the proliferative index between animals receiving MAB-TGFβ and those treated with physiological saline solution before resection. Hepatocytic cross-sectional areas were larger in animals treated with physiological solution versus those treated with MAB-TGFβ on the operative day; however, these values were comparable between groups by 14 days following resection. |
Are plasma levels of amyloid beta-protein 42 increased in women with mild cognitive impairment? | Accumulation in the brain of small aggregates of amyloid beta-protein 42 (Abeta42) is the major pathogenic event of Alzheimer disease (AD). In familial early-onset AD this event is likely the result of Abeta42 overproduction; in the most common sporadic late-onset form of the disease the mechanisms of Abeta42 accumulation are unknown. To address this issue the authors analyzed plasma levels of Abeta42 in 88 elderly patients with amnestic mild cognitive impairment (MCI), chosen as paradigm of preclinical sporadic AD. The authors found a significant increase of Abeta42 plasma levels in women with MCI, in comparison to the affected men and 72 cognitively normal age-matched subjects. The levels were independent of variables in education, apolipoprotein E genotype, cholesterol, and creatinine plasma concentrations, as well as hemoglobin content. | Linitis plastica-type gastric carcinoma remains a disease with poor prognosis despite an aggressive surgical approach. Although a prominent pattern of disease failure is peritoneal carcinomatosis, some patients experience rapid disease progression without signs of the peritoneal disease. Clinicopathologic data from 178 patients with linitis plastica-type gastric cancer operated on between 1991 and 2000 were analyzed. Survival stratified by curability of surgery, pN stage, and patterns of failure were evaluated by using the Kaplan-Meier method, and chi(2) test was used to evaluate correlation between the number of metastatic lymph nodes in terms of pN categories and the incidence of various patterns of metastasis and recurrence. Cox regression hazard model was used to identify independent prognostic factors. R0 resection was performed only among 82 patients (46% of those who underwent laparotomy). Node metastasis was frequent with only 22 patients classified as pN0. Peritoneal carcinomatosis was observed in 131 patients and was the commonest pattern of recurrence. Bone metastasis, found in 13 patients, was associated with poor outcome, and its incidence was significantly correlated with the number of metastatic nodes. pT4 status and pN3 status were identified as significant independent prognostic determinants. |
Does characterization of 1577 primary prostate cancers reveal novel biological and clinicopathologic insights into molecular subtypes? | Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG) and SPINK1 overexpression. Clinical assessment may aid in disease stratification, complementing available prognostic tests. To determine the analytical validity and clinicopatholgic associations of microarray-based molecular subtyping. We analyzed Affymetrix GeneChip expression profiles for 1577 patients from eight radical prostatectomy cohorts, including 1351 cases assessed using the Decipher prognostic assay (GenomeDx Biosciences, San Diego, CA, USA) performed in a laboratory with Clinical Laboratory Improvements Amendment certification. A microarray-based (m-) random forest ERG classification model was trained and validated. Outlier expression analysis was used to predict other mutually exclusive non-ERG ETS gene rearrangements (ETS(+)) or SPINK1 overexpression (SPINK1(+)). Associations with clinical features and outcomes by multivariate logistic regression analysis and receiver operating curves. | Nitric oxide is now recognized to regulate immune responses and cell viability in various organs. The present study was designed to clarify whether NO released from Kupffer cells modulates the lymphokine-activated killer (LAK) activity of interleukin 2 (IL-2)-treated splenocytes. Splenocytes and Kupffer cells were isolated from male Wistar rats and cocultured for 48 hours in the presence of lipopolysaccharide (1 microgram/mL). The splenocyte LAK activity and expression of IL-2 receptor were determined. Kupffer cells with lipopolysaccharide reduced the IL-2 receptor expression and LAK activity of splenocytes. The addition of either NG-monomethyl-L-arginine, an inhibitor of NO synthesis, or aminoguanidine, an inhibitor of inducible NO synthase, to the medium reversed the suppression of IL-2 receptor expression and LAK activity by lipopolysaccharide-stimulated Kupffer cells. 8-bromoguanosine 3',5'-cyclic monophosphate and NO donors decreased the splenocyte LAK activity and IL-2 receptor expression. Treatment with lipopolysaccharide increased the inducible NO synthase activity as well as the nitrite and nitrate levels in the culture medium of Kupffer cells but not in splenocytes. |
Is cYP2C19 polymorphism a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori? | Proton pump inhibitors, metabolized by the polymorphic enzyme cytochrome P450 (CYP) 2C19, are essential drugs for Helicobacter pylori eradication. It was reported that patients with CYP2C19 wild type in Asia had lower eradication rates. This study tests the hypothesis that CYP2C19 wild type ( wt/wt ) in white patients is also associated with a higher probability of treatment failure. This was a cohort study involving 131 H pylori -positive white (German) patients treated by quadruple therapy including lansoprazole (30 mg twice daily for 5 days). Eradication success, as well as lansoprazole trough steady-state serum concentrations, was determined according to different CYP2C19 genotypes. We found 3 homozygous variant patients (2.3%) ( mt/mt, CYP2C19*2/*2 ), 42 heterozygous patients (32.1%) ( wt/mt, CYP2C19*1/*2 ), and 86 wild-type individuals (65.6%). Significant differences in eradication success could be found between wt/wt patients (80.2%) versus combined mt/mt (100%) and wt/mt patients (97.8%) ( P <.01; odds ratio, 10.8 [confidence interval, 1.4-84]), which were associated with corresponding changes in the serum levels of lansoprazole (median, 753 ng/mL for mt/mt, 59 ng/mL for wt/mt, and 21 ng/mL for wt/wt; P <.001). Apart from antibiotic resistance, CYP2C19 polymorphism was the most important influencing factor for eradication success on multivariate analysis ( P <.0001). | Degenerative disc disease is a common pathologic disorder accompanied by both structural and biochemical changes. Changes in stress distribution across the disc can lead to annulus fibrosus (AF) damage that can affect the strength and integrity of the disc. Given that some present degeneration therapies incorporate biological regrowth of the nucleus pulposus (NP), it is crucial that the AF remains capable of containing this newly grown material. To examine the resistance of AF to delamination using an adhesive peel test in experimentally degenerated rabbit discs. Experimentally induced disc degeneration; excised AF tissue study. Disc degeneration was induced in eight New Zealand white rabbits by annular puncture; four additional rabbits served as controls. In experimental rabbits, an 18-gauge needle was inserted into the anterolateral AF region of levels L2-L3 and L4-L5, and disc height was monitored by X-ray. Animals were sacrificed at 4 and 12 weeks postsurgery and magnetic resonance images and X-rays were taken. Four discs were excised from the experimental animals; two punctured (L2-L3 and L4-L5) and two controls (L3-L4 and L6-L7). The same four discs were also excised from the age-matched control animals and served as nonpunctured control discs. To determine resistance to delamination, AF samples were dissected from each disc and subjected to a mechanical peel test at 0.5 mm/s. Magnetic resonance imaging and X-ray images confirmed dehydration of the NP and reduced disc height, similar to that found in clinical degeneration. Resistance to delamination was significantly lower in punctured/degenerated discs compared with both the nonpunctured discs from the same animal (27% lower) and the nonpunctured control discs (30% lower) (p=.024). |
Does epigenome-wide DNA methylation assay reveal placental epigenetic markers for noninvasive fetal single-nucleotide polymorphism genotyping in maternal plasma? | The use of DNA methylation difference between maternal blood cell and fetal (placental) DNA is one of the main areas of interest for the development of fetal epigenetics markers in maternal plasma. We employed a methylation array (HumanMethylation450 array, Illumina, Inc.) to identify novel biomarkers that are specially hypermethylated in placental DNA versus maternal blood cells in a genome-wide basis. Validation by bisulfite genomic sequencing was performed and the priority was given to potential targets that harbor differential methylated CpG sites overlapped with at least two methylation-sensitive restriction enzyme (MSRE) recognizing sites, as well as one polymorphic single-nucleotide polymorphism (SNP), within a short DNA stretch. Three candidate regions of PSMB8, SKI, and CHST11 gene were selected for developing a preliminary polymerase chain reaction assay with MSRE digestion of maternal plasma DNA. SNP genotypes were confirmed by direct sequencing. We identified 2944 and 5218 fetal-specific hypermethylated CpG sites in the first- and third-trimester placenta, respectively, of which 2613 were overlapped, suggesting a consistency of differential methylation during the whole pregnancy. The array results were confirmed by bisulfite genomic sequencing. The preliminary tests in maternal plasma showed that postdigestion hypermathylated versions of these candidate molecules were detectable only in pregnant women. We further revealed that methylated targets in maternal plasma possessed the fetal SNP genotypes. | Although most humeral nonunions are successfully treated with a single procedure, some humeral nonunions are more difficult to heal and require multiple procedures. Current literature does not provide evidence describing how the prognosis for surgical repair in patients who develop humeral diaphyseal nonunions may be affected by initial operative versus nonoperative treatment. The purpose of this study was to assess whether operative versus nonoperative treatment of acute humeral shaft fractures impacts outcome of subsequent repairs of humeral nonunions (NU) including the need for additional surgery and a comparison of pain relief (Visual Analogue Scale for pain) and functional outcome (Short Musculoskeletal Functional Assessment). Thirty-four patients with humeral shaft nonunion were evaluated of which 15 patients had been treated operatively (OF), and 19 patients had been treated nonoperatively (NO) for their initial humerus shaft fracture. All patients underwent plating with autogenous bone graft or allograft ± bone morphogenic protein (BMP) 2 or 7 as their final NU repair surgery prior to healing. We compared functional outcome and pain for both cohorts and determined risk factors for requiring more than 1 nonunion repair surgery. The mean time of final follow-up was 14.7 ± 10.4 months. Thirty-three of 34 NUs (97.1%) healed. Patients who underwent OF of their original fracture were more likely to require more than 1 NU repair surgery (66.7 vs. 0%, p < 0.01). Of the 15 patients who underwent initial OF, 33.0% required 1 NU surgery, 33.0% required 2 NU surgeries, and 33.0% required 3 NU surgeries. Patients who underwent initial OF were more likely to require >6 months to achieve union (40.0 vs. 10.5%, p = 0.04). At final follow-up, there was no difference in functional outcome or pain scores. Initial OF was the only independent predictor of needing more than 1 NU repair surgery (OR 70.1 CI 2.8-1762.3) to achieve healing. |
Does treatment of eating disorders improve eating symptoms but not alexithymia and dissociation proneness? | Eating disorders have been reported to increase in frequency, but it is yet unclear what psychological characteristics increase the proneness toward the development of eating disorders. Alexithymia (AL; a difficulty in awareness to one's emotions) and dissociation proneness are 2 such plausible features. In this study, we evaluated the efficacy of a combined intervention (group therapy, individual therapy, and pharmacologic therapy) in a group of soldiers with eating disorders (n = 30) in the Israel Defense Forces. Moreover, we examined whether AL and dissociation proneness were frequent in this group and whether clinical improvement was associated with an improvement in these factors as well. High scores on the AL and dissociation measures were noted. The intervention was associated with a 50% decrease in the Eating Attitudes Test and Eating Disorders Inventory scores, consistent with our clinical impression of improvement in the eating symptoms. However, the decrease observed on the Dissociative Experiences Scale and Toronto Alexithymia Scale scores was minimal. | Reactive oxygen species (ROS) are involved in a wide range of cellular processes. However, few studies have examined the generation and function of ROS in human embryonic vascular development. In this study, the sources of ROS and their roles in the vascular differentiation of human embryonic stem cells (hESCs) were investigated. During vascular differentiation of hESCs, CD34(+) cells had quiescence-related gene expression profiles and a large fraction of these cells were in G0 phase. In addition, levels of ROS, which were primarily generated through NOX4, were substantially higher in hESC-derived CD34(+) cells than in hESC-derived CD34(-) cells. To determine whether excess levels of ROS induce quiescence of hESC-derived CD34(+) cells, ROS levels were moderately reduced using selenium to enhance antioxidant activities of thioredoxin reductase and glutathione peroxidase. In comparison to untreated CD34(+) cells, selenium-treated CD34(+) cells exhibited changes in gene expression that favoured cell cycle progression, and had a greater proliferation and a smaller fraction of cells in G0 phase. Thus, selenium treatment increased the number of hESC-derived CD34(+) cells, thereby enhancing the efficiency with which hESCs differentiated into vascular endothelial and smooth muscle cells. |
Is prostate specific membrane antigen ( PSMA ) a tissue-specific target for adenoviral transduction of prostate cancer in vitro? | Adenovirus binds to the coxsackievirus and adenovirus receptor (CAR) as a first step in the process of cellular infection. This dependence on CAR potentially limits the use of adenovirus in gene therapy, since CAR is expressed in many tissues of the body, and expression of CAR may be low or lost upon progression of certain tumors. These limitations may be overcome by transductional targeting of adenovirus towards other cell surface molecules. We have evaluated the pantumoral epithelial cell adhesion molecule (EpCAM) and prostate specific membrane antigen (PSMA) as possible targets for adenoviral transduction of prostate cancer cells. Bispecific antibodies, constructed as conjugates between an anti-adenovirus fiber knob Fab' fragment and anti-EpCAM or anti-PSMA monoclonal antibodies, were incubated with an eGFP-expressing adenovirus to retarget this vector. A cell panel, that includes two prostate cancer cell lines and four non-prostate control lines, were infected with serial dilutions of the retargeted vector and specificity of infection was determined. Receptor-specific transduction was obtained for both EpCAM and PSMA. PSMA-retargeting was shown to be selective for the prostate cancer cell lines. | The use of digital reactive hyperemia as a measure of endothelial function among children and adolescents is becoming increasingly common. However, unexpected observations of low reactive hyperemic index values in younger children in our laboratory led us to conduct a study evaluating the influence of age, sex, height, weight, blood pressure, body mass index (BMI), and finger volume on RHI values. Endothelial function, measured by digital reactive hyperemia (reactive hyperemic index: RHI) was assessed in 113 children and adolescents (mean age 12.4 ± 3.8 years; 64 males), with 102 also assessed for brachial artery flow-mediated dilation (FMD) using ultrasound imaging. Associations with age, sex, height, weight, systolic and diastolic blood pressure (SBP, DBP), BMI, and finger volume were evaluated. Using GLM regression, age (β = 0.03, P = 0.014) and SBP (β = 0.015, P = 0.004) were significantly associated with RHI. No measures were associated with FMD. In the subset of individuals with measured finger volume, age (β = 0.025, P = 0.037) was the only measure significantly associated with log RHI. Similarly, no measures were associated with FMD. |
Is sULF2 , a heparan sulfate endosulfatase , present in the blood of healthy individuals and increases in cirrhosis? | SULF2 is an extracellular sulfatase that acts on heparan sulfate proteoglycans and modulates multiple signaling pathways. It is normally bound to the cell surface but can be released into the medium of cultured cells. SULF2 is known to be increased in cirrhotic liver compared to healthy liver. We asked whether SULF2 protein was present in the blood of healthy controls and increased in patients with liver cirrhosis. We devised a sandwich ELISA for SULF2 using 2 novel monoclonal antibodies (mAbs) and measured its levels in sera of normal individuals and cirrhosis patients. SULF2 was higher in cirrhosis patients (1460 ± 1160 pg/ml, N=34) than in healthy individuals (728 ± 400 pg/ml, N=37). SULF2 levels increased with age in both healthy and patient groups. | Tropical rain forests are the most diverse terrestrial ecosystems on the planet. How this diversity evolved remains largely unexplained. In Africa, rain forests are situated in two geographically isolated regions: the West-Central Guineo-Congolian region and the coastal and montane regions of East Africa. These regions have strong floristic affinities with each other, suggesting a former connection via an Eocene pan-African rain forest. High levels of endemism observed in both regions have been hypothesized to be the result of either 1) a single break-up followed by a long isolation or 2) multiple fragmentation and reconnection since the Oligocene. To test these hypotheses the evolutionary history of endemic taxa within a rain forest restricted African lineage of the plant family Annonaceae was studied. Molecular phylogenies and divergence dates were estimated using a Bayesian relaxed uncorrelated molecular clock assumption accounting for both calibration and phylogenetic uncertainties. Our results provide strong evidence that East African endemic lineages of Annonaceae have multiple origins dated to significantly different times spanning the Oligocene and Miocene epochs. Moreover, these successive origins (c. 33, 16 and 8 million years--Myr) coincide with known periods of aridification and geological activity in Africa that would have recurrently isolated the Guineo-Congolian rain forest from the East African one. All East African taxa were found to have diversified prior to Pleistocene times. |
Does [ Human cytomegalovirus induce apoptosis of ECV304 endothelial-like cells ]? | To investigate the mechanisms for the cytopathic effect (CPE) of human cytomegalovirus (HCMV) in ECV304 endothelial-like cells. PCR and indirect immunofluorescence were used to detect HCMV infection by examining immediate-early (IE) gene and protein expression of the virus in ECV304 cells. Phase-contrast and electron microscopies were performed to observe the morphological changes of the infected and uninfected cells, and DNA ladder analysis and flow cytometry were carried out to study HCMV-induced cell apoptosis. In HCMV-infected ECV304 cells, cytopathic effects were first observed at approximately 72 h post-infection. The cells with CPE changes exhibited detachment from the monolayer, cell rounding and shrinkage. The expression of the IE gene was detected. Chromatin condensation and nuclear fragmentation along with dramatic changes of the mitochondria were observed by electron microscopy at 96 h post-infection. Cellular DNA fragmentation was observed in the infected cells, which had cells apoptotic rates of 4.1% and 45.7% at 96 h and 144 h post-infection, respectively. | Measures for assessing patient-reported outcomes (PROs) that may have initially been developed for research are increasingly being recommended for use in clinical practice as well. Although psychometric rigor is essential, this article focuses on pragmatic characteristics of PROs that may enhance uptake into clinical practice. Three sources were drawn on in identifying pragmatic criteria for PROs: (1) selected literature review including recommendations by other expert groups; (2) key features of several model public domain PROs; and (3) the authors' experience in developing practical PROs. Eight characteristics of a practical PRO include: (1) actionability (i.e., scores guide diagnostic or therapeutic actions/decision making); (2) appropriateness for the relevant clinical setting; (3) universality (i.e., for screening, severity assessment, and monitoring across multiple conditions); (4) self-administration; (5) item features (number of items and bundling issues); (6) response options (option number and dimensions, uniform vs. varying options, time frame, intervals between options); (7) scoring (simplicity and interpretability); and (8) accessibility (nonproprietary, downloadable, available in different languages and for vulnerable groups, and incorporated into electronic health records). |
Is community readiness for adolescents ' overweight and obesity prevention low in urban South Africa : a case study? | South Africa is undergoing epidemiological and nutrition transitions with associated increases in the incidence of overweight, obesity and diet-related chronic diseases. With the emergence of the nutrition transition in South Africa, there is an urgent need for interventions to prevent overweight and obesity in children and adolescents as risk factors for chronic diseases in adolescence may track throughout later life. This research explored the potential for faith-based organisations (FBOs) to be used as community organisations for overweight and obesity prevention interventions in adolescents by assessing the readiness of religious leaders to engage in such interventions. Surveys and focus group discussions (FGDs) were conducted with 51 religious leaders in Johannesburg and Soweto. The Community Readiness Model (CRM) survey was chosen to determine the stage of readiness of this community regarding overweight and obesity prevention. Six different dimensions were assessed in the CRM (community efforts, knowledge of efforts, leadership, community climate, knowledge of the issue, resources). The surveys were scored according to the CRM protocol. The survey data were supplemented with findings from FGDs. Thematic analysis was used to analyse the FGDs. The mean community readiness score was 2.57 ± 0.76 which equates with the "denial/resistance stage". The mean readiness score for resources was the highest of all the dimensions (3.77 ± 0.28), followed by knowledge of the issue (3.20 ± 0.51). The lowest score was seen for community knowledge of efforts (1.77 ± 1.50), followed by community climate (2.00 ± 0.64). FGDs helped interpret the CRM scores. FGDs showed that religious leaders were enthusiastic and recognised that their role was not limited solely to spiritual guidance and mentoring, but also to physical well-being. | Sensory processing deficits are common in autism spectrum disorders, but the underlying mechanisms are unclear. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism. Electrophysiological responses in humans with FXS show reduced habituation with sound repetition and this deficit may underlie auditory hypersensitivity in FXS. Our previous study in Fmr1 knockout (KO) mice revealed an unusually long state of increased sound-driven excitability in auditory cortical neurons suggesting that cortical responses to repeated sounds may exhibit abnormal habituation as in humans with FXS. Here, we tested this prediction by comparing cortical event related potentials (ERP) recorded from wildtype (WT) and Fmr1 KO mice. We report a repetition-rate dependent reduction in habituation of N1 amplitude in Fmr1 KO mice and show that matrix metalloproteinase-9 (MMP-9), one of the known FMRP targets, contributes to the reduced ERP habituation. Our studies demonstrate a significant up-regulation of MMP-9 levels in the auditory cortex of adult Fmr1 KO mice, whereas a genetic deletion of Mmp-9 reverses ERP habituation deficits in Fmr1 KO mice. Although the N1 amplitude of Mmp-9/Fmr1 DKO recordings was larger than WT and KO recordings, the habituation of ERPs in Mmp-9/Fmr1 DKO mice is similar to WT mice implicating MMP-9 as a potential target for reversing sensory processing deficits in FXS. Together these data establish ERP habituation as a translation relevant, physiological pre-clinical marker of auditory processing deficits in FXS and suggest that abnormal MMP-9 regulation is a mechanism underlying auditory hypersensitivity in FXS. |
Is zFX a Strong Predictor of Poor Prognosis in Renal Cell Carcinoma? | This study was designed to assay the expression of zinc finger protein X-linked (ZFX) in renal cell carcinoma (RCC) tissues and evaluate the correlation between ZFX expression and prognosis of RCC patients. The expressions of ZFX mRNA in 53 RCC tissues and 51 normal tissues were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry (IHC) technology was used to measure the expression of ZFX protein. Then chi-square test was conducted to verify the association between ZFX expression and clinical parameters. Next, we explored the overall survival rate of RCC patients with Kaplan-Meier analysis. Finally, the correlation between ZFX expression and the prognosis of RCC patients was evaluated by Cox regression analysis. The qRT-PCR result showed that the ZFX was significantly up-regulated in RCC tissues. As for the IHC consequence, the positive rate of ZFX expression in RCC specimens was 79.2%, while that in the normal control tissues was only 17.6%. Chi-square test showed that ZFX expression shared no close relationship with age, sex, or smoking (P>0.05), but was tightly associated with TNM stage, tumor size, and lymph node metastasis (P<0.05). Kaplan-Meier analysis showed that patients with ZFX positive expression had higher mortality than those with negative expression (P<0.05). Cox regression analysis revealed that ZFX expression had tight correlation with prognosis of RCC patients (HR=4.997, P=0.045, 95%CI=1.033-24.180). | We investigated whether patient-controlled epidural analgesia in labor with bupivacaine and fentanyl provides more satisfaction to mothers than intermittent bolus epidural analgesia or patient-controlled epidural analgesia with plain bupivacaine. Ninety mothers with term, uncomplicated pregnancies were randomized to receive intermittent bolus epidural analgesia (bupivacaine + fentanyl), patient-controlled epidural analgesia (bupivacaine + fentanyl), or patient-controlled epidural analgesia (bupivacaine). Pain during labor was evaluated with a visual analog scale. Obstetric and neonatal outcomes were recorded. After delivery, the mothers were given a questionnaire covering the following themes: experience of labor pain, feeling of control, fears and expectations associated with pregnancy/with delivery/with becoming a mother, as well as pain, physical condition and emotions after delivery. To elaborate on these answers, 30 mothers were further randomized to a semistructured interview, in which the same topics were discussed. The main outcome measure was maternal satisfaction. The intermittent bolus epidural analgesia group felt they could influence labor most (p = 0.03), and in the interview they expressed most satisfaction. In this group, the total drug utilization was smallest (bupivacaine: p <0.0001 comparing all groups, fentanyl: p = 0.03 comparing the two fentanyl-receiving groups). No differences in pain occurred. Vomiting (p = 0.04) and pruritus (p <0.0001) were more common or more severe in the groups receiving fentanyl. |
Is nutrition knowledge associated with greater weight loss in obese and overweight low-income mothers? | To examine if greater nutrition knowledge vs gains in knowledge promote more successful weight loss in low-income, overweight and obese mothers with young children. A convenience sample of mothers and their children were measured for height and weight; mothers completed demographic and nutrition knowledge questionnaires pre- and post-intervention. Participants (N=141) were recruited from government and public health clinics and elementary schools. Inclusion criteria for mothers were: family income <200% federal poverty level; overweight/obese; and Hispanic, African-American, or white race/ethnicity. Eight weekly weight-loss classes emphasizing diet, physical activity, and behavior modification based on Social Cognitive Theory were administered to mothers. Improvements in maternal nutrition knowledge and weight loss. Paired-samples t tests, repeated measures analysis of variance, analysis of covariance, Pearson correlations, and chi(2) statistics. Nutrition knowledge of mothers increased in all areas. Participants with weight loss > or =2.27 kg (responders) had greater knowledge than those who did not; however, the actual net gain was similar for those who lost and did not lose weight. Weight gainers only improved in two areas on the test, whereas weight-loss responders increased knowledge in all six. Responders appeared more cognizant of diet, weight loss, and health information. | We investigated the effects of neutrophil elastase inhibitor ONO-5046 Na on lung ischemia-reperfusion injury in a canine model of single lung transplantation. 24 mongrel dogs, 12 donors and 12 recipients, were used for single lung transplantation. Lung grafts were preserved for 18 h by cold ischemia then transplanted into the left thoracic cavity of recipients. In 6 recipients (ONO group), a bolus of ONO-5046 Na (10 mg/kg) was introduced before reperfusion and followed by continuous infusion (10 mg/kg/h). The remaining 6 recipients (control group) did not receive ONO-5046 Na and thus served as controls. We evaluated lung function and respiratory parameters over 240 min. The total cell number in bronchoalveolar lavage fluid increased significantly in the control group in comparison to that in the ONO group. Histologic scores after 4 h of reperfusion and myeloperoxidase activity were significantly lower in the ONO group than in the control group. |
Does a focal cryogenic brain lesion reduce the minimum alveolar concentration for halothane in rats? | A focal cortical cryogenic brain injury has been reported to reduce the brain pentobarbital concentrations needed to prevent movement in response to pain in rats. This occurred despite any apparent behavioral changes in the awake animals. To determine whether this was true with other anesthetics, the authors determined the minimum alveolar concentration (MAC) for halothane in normothermic, normocarbic ventilated Sprague-Dawley rats previously subjected to a freezing injury of the parietal cortex. Injury was produced in halothane-anesthetized rats by applying a cold (-70 degrees C), 4-mm-diameter brass rod to the exposed dura for 5 or 15 s. Animals then were studied 3 days after injury, a time when cerebral metabolism in the ipsilateral hemisphere reaches a minimum. Minimum alveolar concentration was determined using a tail-clamp stimulus, combined with end-tidal anesthetic sampling. In addition, exploratory activity was measured by the open field test just before MAC determination, and spontaneous nocturnal motility was monitored by an electronic motion sensor during the night before testing. In normal animals subjected only to preparatory surgery, MAC was 1.10 +/- 0.07% (mean +/- SD). Almost identical values were found in rats subjected to 5- and 15-s cryogenic injuries (1.11 +/- 0.07% and 1.08 +/- 0.06%, respectively). There were no intergroup differences in open field test results or in spontaneous nocturnal activity. | A psoriasis susceptibility locus on chromosome 16q was identified recently. This region coincides with a locus predisposing to Crohn's disease. Patients with Crohn's disease have a fivefold greater relative risk for development of psoriasis. In Crohn's disease mutation of the caspase recruitment domain family, member 15 (CARD15) gene (chromosome 16q12.1) confers susceptibility. In light of the overlap in linkage data, and the observation of comorbidity between Crohn's disease and psoriasis, it is plausible that both diseases share a common genetic factor. To assess the genetic contribution of CARD15 single nucleotide polymorphisms (SNPs) in the pathogenesis of type I psoriasis. Eight SNPs in CARD15 were genotyped in 148 patients with type I psoriasis and 192 unrelated controls, following a test for population stratification. Genotype and allele frequencies were compared along with estimated SNP haplotype frequencies. No differences were observed in genotype allele or haplotype frequencies between the case and control cohorts. |
Do human keratin 8 variants promote mouse acetaminophen hepatotoxicity coupled with c-jun amino-terminal kinase activation and protein adduct formation? | Keratins 8 and 18 (K8/K18) are the intermediate filaments proteins of simple-type digestive epithelia and provide important cytoprotective function. K8/K18 variants predispose humans to chronic liver disease progression and poor outcomes in acute acetaminophen (APAP)-related liver failure. Given that K8 G62C and R341H/R341C are common K8 variants in European and North American populations, we studied their biological significance using transgenic mice. Mice that overexpress the human K8 variants, R341H or R341C, were generated and used together with previously described mice that overexpress wild-type K8 or K8 G62C. Mice were injected with 600 mg/kg of APAP or underwent bile duct ligation (BDL). Livers were evaluated by microarray analysis, quantitative real-time polymerase chain reaction, immunoblotting, histological and immunological staining, and biochemical assays. Under basal conditions, the K8 G62C/R341H/R341C variant-expressing mice did not show an obvious liver phenotype or altered keratin filament distribution, whereas K8 G62C/R341C animals had aberrant disulphide cross-linked keratins. Animals carrying the K8 variants displayed limited gene expression changes, but had lower nicotinamide N-methyl transferase (NNMT) levels and were predisposed to APAP-induced hepatotoxicity. NNMT represents a novel K8/K18-associated protein that becomes up-regulated after K8/K18 transfection. The more pronounced liver damage was accompanied by increased and prolonged JNK activation; elevated APAP protein adducts; K8 hyperphosphorylation at S74/S432 with enhanced keratin solubility; and prominent pericentral keratin network disruption. No differences in APAP serum levels, glutathione, or adenosine triphosphate levels were noted. BDL resulted in similar liver injury and biliary fibrosis in all mouse genotypes. | Basic calcium phosphate (BCP) particulates are commonly found in cartilage and synovial fluid of osteoarthritis (OA) joints with the amount of BCP correlating with knee OA severity. How cartilage mineralization affects joint degeneration has yet to be determined. The objective of this study was to determine whether BCP in the synovial fluid affects the rat knee joint coefficient of friction (COF). The COFs of knees from both hind limbs of four mature male rats were measured post mortem using a pendulum apparatus with an infrared tracking system. The three conditions evaluated were (1) the naïve state, (2) after the injection of 100 μL of phosphate buffered saline (PBS) (sham) and (3) after the injection of 100 μL of a 1 mg/mL BCP suspension. The decrease in the pendulum amplitude (decay) was fit using two friction models: (1) a one parameter Stanton linear decay model and (2) a two parameters combination Stanton linear decay and viscous damping exponential decay model. The COF increased 17.6% after injection of BCP compared to the naïve (P = 0.0012) and 16.0% compared to the saline injected (P = 0.0018) joints as derived from the one parameter model. The COF did not differ between naïve and saline injected joints. Results from the two parameters model showed a similar increase in COF after injection of BCP while the viscous damping was not significantly different between conditions. |
Does the HeartShield device reduce the risk for right ventricular damage in patients with deep sternal wound infection? | Right ventricular rupture, resulting in serious bleeding, is a life-threatening complication associated with negative-pressure wound therapy (NPWT) in cardiac surgery. The use of a rigid barrier between the heart and the sharp sternal edges has been successfully tested on pigs. In the present article, we demonstrate increased safety in NPWT through the use of the HeartShield device. Six patients were treated with a specially designed device in combination with NPWT. The device consists of a horizontally placed disk covered in foam. The back of the T-shaped device sticks up between the sternal edges and up above skin level. This part of the device is also covered in foam. Drainage is performed through two holes at the top of the device. The device and foam are changed every second to third day, and -120 mm Hg of continuous therapy is used. Six patients were treated with traditional NPWT, serving as control group. No signs of calluslike formation were seen on the right ventricle in the group treated with the HeartShield device. In the conventional NPWT control group, all six patients had calluslike formation (>1 × 2 cm2) on the anterior part of the right ventricle. All patients in the HeartShield group had grade 1 epicardial petechial bleeding (<0.5 cm2) on the right ventricle. In the control group, one patient had grade 1 (<0.5 cm2), three patients had grade 2 (0.5-2.0 cm2), and two patients had grade 3 (>2.0 cm2) epicardial petechial bleeding on the right ventricle. No major bleeding or mortality was observed in either group during the course of the study. | PLA2G6 mutations are known to be responsible for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA). In addition, novel mutations in PLA2G6 have recently been associated with dystonia-parkinsonism in two unrelated consanguineous families. Direct sequencing analysis of the PLA2G6 gene. Here, we report the segregation of R632W with disease in an Iranian consanguineous dystonia-parkinsonism pedigree. The identical mutation was previously observed in a patient affected with NBIA. |
Does chemotherapy regimen predict steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases? | Chemotherapy before resection of hepatic colorectal metastases (CRM) may cause hepatic injury and affect postoperative outcome. Four hundred six patients underwent hepatic resection of CRM between 1992 and 2005. Pathologic review of the nontumorous liver was performed using established criteria for steatosis, steatohepatitis, and sinusoidal injury. The effect of chemotherapy and liver injury on perioperative outcome was analyzed. One hundred fifty-eight patients (38.9%) received no preoperative chemotherapy, whereas 248 patients (61.1%) did. The median duration of chemotherapy was 16 weeks (range, 2 to 70 weeks). Chemotherapy consisted of fluoropyrimidine-based regimens (fluorouracil [FU] alone, 15.5%; irinotecan plus FU, 23.1%; and oxaliplatin plus FU, 19.5%) and other therapy (3.0%). On pathologic analysis, 36 patients (8.9%) had steatosis, 34 (8.4%) had steatohepatitis, and 22 (5.4%) had sinusoidal dilation. Oxaliplatin was associated with sinusoidal dilation compared with no chemotherapy (18.9% v 1.9%, respectively; P < .001; odds ratio [OR] = 8.3; 95% CI, 2.9 to 23.6). In contrast, irinotecan was associated with steatohepatitis compared with no chemotherapy (20.2% v 4.4%, respectively; P < .001; OR = 5.4; 95% CI, 2.2 to 13.5). Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis (14.7% v 1.6%, respectively; P = .001; OR = 10.5; 95% CI, 2.0 to 36.4). | Caveolin-1 is a fundamental signalling scaffold protein involved in contraction; however, the role of caveolin-1 in airway responsiveness remains unclear. We evaluated the relationship between caveolin-1 expression in airway smooth muscle (ASM) and antigen-induced airway responsiveness and obstruction in a guinea pig asthma model. Airway obstruction in sensitised guinea pigs, induced by antigenic (ovalbumin) challenges administered every 10 days, was measured. Antigen-induced responsiveness to histamine and the expression of caveolin-1 and cavin 1, 2 and 3 were evaluated at the third ovalbumin challenge. The control group received saline solution instead of ovalbumin. After the first challenge, antigen exposure induced a transient airway obstruction and airway hyperresponsiveness, high levels of IL-4 and IL-5 in lung and airway globet cells proliferation at the third antigenic challenge. Caveolin-1 mRNA levels in total lung decreased in the experimental group compared with controls. Flow cytometric analysis of ASM from the experimental group showed a high number of cells expressing caveolin-1 compared with controls. This increase was confirmed by western blot. Airway obstruction and hyperresponsiveness correlated with the degree of increased caveolin-1 expression in ASM cells (P < 0.05; r = 0.69 and -0.52, respectively). The expression of cavins 1, 2 and 3 in ASM also increased in the experimental group compared to controls. Immunohistochemical findings reveal that differences in ASM caveolin-1 were not evident between groups. Nevertheless, a marked decrease in caveolin-1 and caspase 3 was observed in the pulmonary vascular smooth muscle of asthma model compared with controls. Histological analysis did not reveal differences in smooth muscles mass or subepithelial fibrosis levels in airways between groups. However, an enlargement of smooth muscle mass was observed in the pulmonary microvessels of experimental animals. This enlargement did not induce changes in pulmonary or systemic arterial pressures. |
Are fetal cells in maternal plasma found in a late state of apoptosis? | The present study was designed to give possible answers to some of the discrepancies regarding the presence or not of intact fetal cells in maternal plasma during pregnancy. 12-mL peripheral blood was collected from 33 pregnant women in the second trimester: 6 mL was harvested by 3-step Percoll gradient centrifugation and plasma cells were analyzed by FISH with X/Y chromosome specific probes. From the remaining 6 mL, plasma-derived cells were isolated with three different gradient centrifugation protocols and apoptosis was determined following EthBr staining. The number of cells recovered ranged from 900 to 3000. At least one Y positive signal was seen in 12 out of 17 cases with male fetuses at a frequency of 0.12% (range 0.05-0.27%). No XY cells were detected in the plasma of women carrying female fetuses. Hybridization efficiency was <60%. EthBr staining demonstrated that the majority of these cells were in their late apoptosis. | Between-study heterogeneity plays an important role in random-effects models for meta-analysis. Most clinical trials are small, and small trials are often associated with larger effect sizes. We empirically evaluated whether there is also a relationship between trial size and heterogeneity (τ). We selected the first meta-analysis per intervention review of the Cochrane Database of Systematic Reviews Issues 2009-2013 with a dichotomous (n = 2,009) or continuous (n = 1,254) outcome. The association between estimated τ and trial size was evaluated across meta-analyses using regression and within meta-analyses using a Bayesian approach. Small trials were predefined as those having standard errors (SEs) over 0.2 standardized effects. Most meta-analyses were based on few (median 4) trials. Within the same meta-analysis, the small study τS(2) was larger than the large-study τL(2) [average ratio 2.11; 95% credible interval (1.05, 3.87) for dichotomous and 3.11 (2.00, 4.78) for continuous meta-analyses]. The imprecision of τS was larger than of τL: median SE 0.39 vs. 0.20 for dichotomous and 0.22 vs. 0.13 for continuous small-study and large-study meta-analyses. |
Does mMP-9 in serum correlate with the development of pulmonary complications in experimental acute pancreatitis? | The prediction of the course of acute pancreatitis and its arising complications is of clinical importance. The aim of this study was to judge the time course and relevance of matrix metalloproteinase-9 (MMP-9), a PMN-derived protease, for the development of pulmonary complications in two models of acute pancreatitis. MMP-9 was evaluated in a standardized experimental model of acute pancreatitis. Mild edematous (n = 12) and severe necrotizing pancreatitis (n = 48) were induced by intravenous cerulein or intravenous cerulein and intraductal application of glycodeoxycholic acid and compared to control animals. 1, 6, 9, 12, 24 and 72 h after induction, rats were sacrificed and damage to the lung and the pancreas was quantified by histology and extravasation of Evans blue. At 1, 6, 9, 12, 24 and 72 h, we determined MMP-9 in serum by ELISA. In our model, MMP-9 in serum was increased in the group with severe acute pancreatitis in comparison to mild edematous pancreatitis and controls at each evaluated time point (p < 0.05). The maximum release of MMP-9 preceded the development of pulmonary complications, verified by histology and extravasation of Evans blue. MMP-9 showed a negative predictive value of 96.2% and a positive predictive value of 100% for the development of pulmonary complications. | Skeletal muscle is an important target tissue for thyroid hormone (TH). It is currently unknown which genes are regulated by physiological TH levels. We examined the effects of l-thyroxine on human skeletal muscle transcriptome. Microarray analysis of transcript levels was performed using skeletal muscle biopsies from patients under euthyroid and hypothyroid conditions. The study was conducted in a university hospital laboratory. We studied skeletal muscle obtained from 10 thyroidectomized patients with differentiated thyroid carcinoma on and after 4 wk off L-thyroxine replacement. Gene expression changes were measured using microarrays. Results were analyzed using dedicated statistical methods. We detected 607 differentially expressed genes on L-thyroxine treatment, of which approximately 60% were positively and approximately 40% were negatively regulated. Representative genes were validated by quantitative PCR. Genes involved in energy and fuel metabolism were overrepresented among the up-regulated genes, of which a large number were newly associated with thyroid state. L-thyroxine therapy induced a large down-regulation of the primary transcripts of the noncoding microRNA pair miR-206/miR-133b. |
Does microRNA-29b regulate migration in oral squamous cell carcinoma and its clinical significance? | MicroRNA (miRNA) machinery regulates cancer cell behavior, and has been implicated in patients' clinical status and prognosis. We found that microRNA-29b (miR-29b) increased significantly in advanced migratory cells. However, miR-29b controls the migration ability, and its regulatory mechanism in oral squamous cell carcinoma (OSCC) remains unknown. We triggered miR-29b expression in OSCC patients and cell lines by conducting real-time quantitative PCR. We determined the functions of miR-29b in the migration of OSCC cells by using gain- and loss-of-function approaches. We elevated the target genes of miR29b through software predictions and a luciferase report assay. We used an orthotopic OSCC animal model to investigate the effects of miR29b on OSCC cell metastasis in vivo. The clinical data revealed that miR-29b expression was correlated with lymph node metastasis and an advanced tumor stage in 98 OSCC patients. Furthermore, multivariate analysis revealed that miR-29b expression was significantly correlated with recurrence, and indicated poor survival. MiR-29b promoted OSCC cell migration and downregulated CX3CL1, a cell-cell adhesion regulator, which plays an essential role in miR-29b-regulated OSCC cell migration machinery. Furthermore, we found that CX3CL1 expression was correlated with lymph node metastasis and an early tumor stage in OSCC patients, and negatively correlated with miR-29b expression. | To conduct a randomized prospective trial of immune globulin treatment for 105 Rh+ children with newly-diagnosed immune thrombocytopenic purpura and a platelet count<20,000/microL, to determine whether anti-D immune globulin (anti-D) is as effective as intravenous immune globulin (IVIg). Eligible patients received either a single intravenous dose of 50 microg/kg anti-D (anti-D50), 75 microg/kg anti-D, (anti-D75), or 0.8 g/kg IVIg, (IVIg). Patients were monitored for response to treatment and adverse events. By 24 hours after treatment 50%, 72%, and 77% of patients in the anti-D50, anti-D75, and IVIg groups, respectively, had achieved a platelet count>20,000/microL (P=.03). By day 7, hemoglobin concentrations decreased by 1.6 g/dL, 2 g/dL, and 0.3 g/dL in the anti-D50, anti-D75, and IVIg groups, respectively. Headache, fever, or chills occurred least often in the anti-D50 group. |
Is formyl Peptide receptor 1 expression associated with tumor progression and survival in gastric cancer? | Formyl peptide receptor 1 (FPR1) as a regulator of innate inflammatory response has been implicated in tumor progression of gliomas. The purpose of the present study was to evaluate the prognostic significance and the ligand-receptor interaction of FPR1 in gastric cancer (GC). FPR1 was immunohistochemically-analyzed in tissue sections originating from 116 GC patients. Reverse transcription-polymerase chain reaction (RT-PCR) was used for the assessment of interaction between FPR1 and the FPR1 ligand annexin A1 (AnxA1) in GC cells. High FPR1 expression was significantly associated with stage IV disease, submucosal invasion, serosal invasion, and clinical outcome of GC. Multivariate analysis showed that high FPR1 expression was an independent risk factor of poor overall survival in GC patients. FPR1 expression increased significantly when AnxA1 overexpression was present in GC cells. A positive feedback regulation of FPR1 was involved in the AnxA1-FPR1 signal transduction. | A breadth of literature exists that explores the utilization of research evidence in policy change processes. From this work, a number of studies suggest research evidence is applied to change processes by policy change stakeholders primarily through instrumental, conceptual, and/or symbolic applications, or is not used at all. Despite the expansiveness of research on policy change processes, a deficit exists in understanding the role of research evidence during change processes related to the implementation of structural interventions for HIV prevention among injection drug users (IDU). This study examined the role of research evidence in policy change processes for the implementation of publicly funded syringe exchange services in three US cities: Baltimore, MD, Philadelphia, PA, and Washington, DC. In-depth qualitative interviews were conducted with key stakeholders (n=29) from each of the study cities. Stakeholders were asked about the historical, social, political, and scientific contexts in their city during the policy change process. Interviews were transcribed and analyzed for common themes pertaining to applications of research evidence. In Baltimore and Philadelphia, the typological approaches (instrumental and symbolic/conceptual, respectively) to the applications of research evidence used by harm reduction proponents contributed to the momentum for securing policy change for the implementation of syringe exchange services. Applications of research evidence were less successful in DC because policymakers had differing ideas about the implications of syringe exchange program implementation and because opponents of policy change used evidence incorrectly or not at all in policy change discussions. |
Are postoperative plasma 8-iso-prostaglandin F2α levels associated with delirium and cognitive dysfunction in elderly patients after hip fracture surgery? | Oxidative stress may be involved in occurrence of postoperative delirium (POD) and cognitive dysfunction (POCD). 8-iso-Prostaglandin F2α (8-iso-PGF2α), an isoprostane derived from arachidonic acid via lipid peroxidation, is considered a gold standard for measuring oxidative stress. The present study aimed to investigate the ability of postoperative plasma 8-iso-PGF2α levels to predict POD and POCD in elderly patients undergoing hip fracture surgery. Postoperative plasma 8-iso-PGF2α levels of 182 patients were measured by an enzyme-linked immunosorbent assay. We assessed the relationships between plasma 8-iso-PGF2α levels and the risk of POD and POCD using a multivariate analysis. Plasma 8-iso-PGF2α levels and age were identified as the independent predictors for POD and POCD. Based on areas under receiver operating characteristic curve, the predictive values of 8-iso-PGF2α were obviously higher than those of age for POD and POCD. In a combined logistic-regression model, 8-iso-PGF2α significantly enhanced the areas under curve of age for prediction of POD and POCD. | Human bocavirus (HBoV) is a newly identified human parvovirus that was originally detected in the respiratory secretions of children with respiratory infections. This study aimed to learn about the importance of HBoV infections by revealing the prevalence of serum antibodies against HBoV in Beijing population. Two batches of serum specimens collected in different periods were tested by Western blotting for specific IgG against HBoV using recombinant VP2 as antigen. Out of 677 serum specimens collected during April 1996 to March 1997, 400 (59.1%) were positive and antibody positive rate for another batch of 141 serum specimens collected in August, 2005 from adults aged from 20 years to over 60 years was 78.7% (111/141). Comparison of the sero-prevalence profiles for serum specimens collected during 1996 - 1997 to those collected in 2005 indicated that the antibody positive rate for specimens collected in 2005 was higher than that of the corresponding age groups collected during 1996 - 1997. |
Is platelet-activating factor acetylhydrolase associated with carotid intima-media thickness in hypercholesterolemic Sicilian individuals? | Atherosclerosis is a complex, chronic disease that usually arises from the converging action of several pathogenic processes, including hypertension, hyperlipidemia, obesity, and the accumulation of oxidized LDL. Platelet-activating factor acetylhydrolase (PAF-AH) is a LDL- and HDL-bound enzyme that hydrolyzes and inactivates PAF and prevents LDL-cholesterol oxidation, thus delaying the onset of atherosclerotic disease. We evaluated the relationship between variants of the PAF-AH gene polymorphisms Arg92His, Ile198Thr, and Ala379Val and the presence of carotid atherosclerosis in 190 hypercholesterolemic Sicilian individuals. Carotid artery intima-media wall thickness (IMT) was measured as an indicator of early atherosclerotic disease. The participants were classified according to having normal (< or =1 mm) or abnormal (> or =1 mm) IMT and were also investigated for physical characteristics and biochemical indices, including PAF-AH activity. PAF-AH activity and LDL concentrations were significantly correlated in hypercholesterolemic patients, but plasma PAF-AH activity and HDL were not significantly correlated in either IMT group. No significant differences were detected among the PAF-AH gene polymorphisms in both groups after correction for age, sex, body mass index, plasma glucose and lipid concentrations, PAF-AH activity, blood pressure, and smoking habits. The analysis of PAF-AH genotype distribution showed no significant differences in percentage of 92, 198, and 379 genotypes in both IMT groups. | To evaluate the influence of subtotal radiofrequency (RF) ablation on a tumor-specific immune response in a murine tumor model and to explore the role of intratumoral dendritic cells (ITDCs) in mediating this effect. Animal work was performed according to an approved protocol and in compliance with the National Cancer Institute Animal Care and Use Committee guidelines and regulations. A murine urothelial carcinoma (MB49) model expressing the male minor histocompatibility (HY) antigen was inoculated subcutaneously in female mice. Fourteen days later, splenic T cells were analyzed with enzyme-linked immunosorbent spot for HY immune response (n = 57). In subsequent experiments, mice were randomized into control (n = 7), RF ablation, ITDC (n = 9), and RF ablation + ITDC (n = 9) groups and monitored for tumor growth. Eleven days after treatment, tumors were harvested for histologic and immunohistochemical analysis. Animals demonstrating complete tumor regression were rechallenged in the contralateral flank. Animals treated with subtotal RF ablation showed significant increases in tumor-specific class I and II responses to HY antigens and tumor regression. RF ablation, ITDC, and combined groups demonstrated similar levels of antigen-presenting cell infiltration; all groups demonstrated greater levels of infiltration compared with untreated controls. ITDC injection also resulted in tumor regression. However, combination therapy did not enhance tumor regression when compared with either treatment alone. Rechallenged mice in RF ablation, ITDC, and combination groups demonstrated significant tumor growth inhibition compared with controls. |
Is positive adnexal or uterine serosal involvement in stage IIIC endometrial cancer an adverse factor for recurrence? | Clinical and pathological significance of stage IIIC endometrial cancer is unclear. Our study was designed to determine the risk of recurrence among patients with stage IIIC endometrial cancer according to different pathological findings. We retrospectively reviewed all patients with FIGO IIIC endometrial carcinoma (n = 48) treated in our institution between 1996 and 2005. Patients without comprehensive surgical staging were excluded. Patients were classified into two groups: with adnexae and/or uterine serosal metastasis (group A, n = 18) and without metastasis (group B, n = 20). Cox proportional hazards model was used for multiple regression analysis. Mean age was 64 years (range 46-90). Eighteen patients received adjuvant chemotherapy and pelvic radiotherapy, 17 received pelvic radiotherapy alone, and 11 received chemotherapy or hormonotherapy. At a median follow-up of 26.7 months, 12 had recurrence of the disease. Serosal and/or adnexal involvement was a negative independent prognostic factor for disease-free survival [relative risk = 3.75 (1.01-13.9); p = 0.04], whereas histological type, grade, depth of invasion and age at diagnosis had no influence. | Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood. Septic stress induces glucocorticoids production which triggers thymocyte apoptosis. Here, we used scavenger receptor BI (SR-BI)-null mice, which are completely deficient in inducible glucocorticoids in sepsis, to investigate the regulation of thymocyte apoptosis in sepsis. Cecal ligation and puncture induced profound thymocyte apoptosis in SR-BI(+/+) mice, but no thymocyte apoptosis in SR-BI(-/-) mice because of lack of inducible glucocorticoids. Unexpectedly, supplementation of glucocorticoids only partly restored thymocyte apoptosis in SR-BI(-/-) mice. We demonstrated that high-density lipoprotein (HDL) is a critical modulator for thymocyte apoptosis. SR-BI(+/+) HDL significantly enhanced glucocorticoid-induced thymocyte apoptosis, but SR-BI(-/-) HDL had no such activity. Further study revealed that SR-BI(+/+) HDL modulates glucocorticoid-induced thymocyte apoptosis via promoting glucocorticoid receptor translocation, but SR-BI(-/-) HDL loses such regulatory activity. To understand why SR-BI(-/-) HDL loses its regulatory activity, we analyzed HDL cholesterol contents. There was 3-fold enrichment of unesterified cholesterol in SR-BI(-/-) HDL compared with SR-BI(+/+) HDL. Normalization of unesterified cholesterol in SR-BI(-/-) HDL by probucol administration or lecithin cholesteryl acyltransferase expression restored glucocorticoid-induced thymocyte apoptosis, and incorporating unesterified cholesterol into SR-BI(+/+) HDL rendered SR-BI(+/+) HDL dysfunctional. Using lckCre-GR(fl/fl) mice in which thymocytes lack cecal ligation and puncture-induced thymocyte apoptosis, we showed that lckCre-GR(fl/fl) mice were significantly more susceptible to cecal ligation and puncture-induced septic death than GR(fl/fl) control mice, suggesting that glucocorticoid-induced thymocyte apoptosis is required for protection against sepsis. |
Is increased risk of radiographic emphysema in HIV associated with elevated soluble CD14 and nadir CD4? | The association between HIV and emphysema remains incompletely understood. We sought to determine whether HIV is an independent risk factor for emphysema severity and whether markers of HIV severity and systemic biomarkers of inflammation (IL-6), altered coagulation (D-dimer), and immune activation (soluble CD14) are associated with emphysema. We performed a cross-sectional analysis of 114 participants with HIV infection and 89 participants without HIV infection in the Examinations of HIV-Associated Lung Emphysema (EXHALE) study. Participants underwent chest CT imaging with blinded semiquantitative interpretation of emphysema severity, distribution, and type. We generated multivariable logistic regression models to determine the risk of HIV for radiographic emphysema, defined as > 10% lung involvement. Similar analyses examined associations of plasma biomarkers, HIV RNA, and recent and nadir CD4 cell counts with emphysema among participants with HIV infection. Participants with HIV infection had greater radiographic emphysema severity with increased lower lung zone and diffuse involvement. HIV was associated with significantly increased risk for > 10% emphysema in analyses adjusted for cigarette smoking pack-years (OR, 2.24; 95% CI, 1.12-4.48). In multivariable analyses restricted to participants with HIV infection, nadir CD4 < 200 cells/μL (OR, 2.98; 95% CI, 1.14-7.81), and high soluble CD14 level (upper 25th percentile) (OR, 2.55; 95% CI, 1.04-6.22) were associated with increased risk of > 10% emphysema. IL-6 and D-dimer were not associated with emphysema in HIV. | Veterinarians have observed a putative change in the location of humeral stress remodelling in Thoroughbred racehorses with change from dirt to synthetic racetrack surfaces. To determine whether the location and severity of humeral stress remodelling differs between Thoroughbred racehorses exercising on dirt and synthetic racetrack surfaces, the potential significance of different locations of stress remodelling, and the potential usefulness of scintigraphy for prevention of complete humeral fracture. Scintigraphic images of humeri from 841 Thoroughbred racehorses at 3 racetracks during 2 years before and after conversion from dirt to synthetic surfaces were evaluated for location and severity of lesions. The effects of surface on lesion distributions were examined using Chi-square or Fisher's exact tests. Archived fractured humeri were examined to determine the location and severity of stress remodelling associated with complete fracture. Databases were queried to determine whether racehorses with scintigraphic lesions suffered humeral fracture and whether racehorses with a complete humeral fracture had had a scintigraphic examination. Horses at synthetic racetracks had a greater proportion of distal humeral lesions, whereas horses at dirt racetracks had a greater proportion of caudoproximal lesions (P<0.001). Proximal lesions were more likely to be severe than distal lesions (P<0.001). Most complete fractures were associated with caudoproximal lesions, which were more often severe than distal lesions (P = 0.002). None of the horses with a scintigraphic lesion had a complete humeral fracture. None of the horses with a complete humeral fracture underwent scintigraphic examination. |
Does basic fibroblast growth factor restore endothelium-dependent responses after balloon injury of rabbit arteries? | After experimental angioplasty, partial or complete reendothelialization of the denuded surface occurs; the function of the regenerated endothelium has, however, been shown to be abnormal. Basic fibroblast growth factor (bFGF) is mitogenic for endothelial cells in vitro and in vivo. We investigated whether chronic administration of bFGF in a rabbit model of balloon denudation might not only improve endothelial regrowth but also restore normal physiological responses to endothelium-dependent agonists. Thirty-nine New Zealand White rabbits underwent balloon denudation of the right iliac artery. Twenty rabbits received intravenous administration of bFGF (2.5 micrograms twice a week for 2 weeks). Nineteen rabbits receiving saline injections served as controls. Animals were killed on day 28 for assessment of reendothelialization and neointimal thickening and for analysis of in vitro vasoreactivity. Animals in the bFGF group had a significantly (P<.005) greater degree of reendothelialization than controls (115 +/- 13 versus 55 +/- 6 mm2). Neointimal thickening was similar in the two groups. Four weeks after denudation, endothelium-independent responses did not differ significantly between the two groups. In contrast, the maximal endothelium-dependent acetylcholine-induced relaxation of the bFGF-treated animals (Emax, 40 +/- 7%) was significantly greater than that of the control group (Emax, 11 +/- 9%; P<.05). | To investigate whether glutathione S-transferases (GST) genetic polymorphisms (GSTT1 rs1049055, GSTM1 rs10712361, and GSTP1 rs1695) are associated with susceptibility to noise-induced hearing loss (NIHL). These polymorphisms were analyzed in 444 NIHL and 445 normal hearing workers. In addition, total plasma GST activity was measured in all subjects. Individuals with the GSTM1 null genotype had a statistically significantly increased risk of NIHL (odds ratio [OR] = 1.64, 95% confidence interval [CI] = 1.26 to 2.13) compared with those carrying a wild-type GSTM1 genotype. This effect was more pronounced among the workers exposed to 86 to 91 dB(A) (OR = 3.35, 95% CI = 1.54 to 7.31). Glutathione S-transferase activity of the NIHL workers was also lower than that of normal hearing workers (14.5 ± 5.1 U/ml vs 15.9 ± 6.3 U/ml, P = 0.010). |
Do identification of neonatal near miss by systematic screening for metabolic acidosis at birth? | To evaluate the relevance of systematic screening for neonatal metabolic acidosis at birth as part of perinatal audit. For every baby, born in Ziekenhuis Oost Limburg, Genk Belgium between 1/1/2010 and 31/12/2010, cord blood was analysed to diagnose metabolic acidosis, defined as arterial or venous pH ≤ 7.05 or 7.17 respectively, in association with base excess of ≤ -10 mmol/L. Three observers identified indicators for suboptimal peripartal care with likely contribution to metabolic acidosis. In a multidisciplinary consensus meeting, these indicators were classified into 5 categories : (a) fetal monitoring error (b) labour management error, (c) instrumental vaginal delivery for fetal distress within 2 h of second stage, (d) non-obstetric medical complications, (e) preterm births or accidental cases at term. In a total of 2117 neonates, there were 11 intra-uterine, 1 intrapartum and 3 early neonatal deaths, bringing early perinatal mortality rate at 7.1‰. Metabolic acidosis was identified in 23 (1.1%) babies, of which 21 (91.3%) left hospital in good clinical condition. Two babies (0.9‰), born in category c, had chronic neurologic symptoms. | Adenovirus binds to the coxsackievirus and adenovirus receptor (CAR) as a first step in the process of cellular infection. This dependence on CAR potentially limits the use of adenovirus in gene therapy, since CAR is expressed in many tissues of the body, and expression of CAR may be low or lost upon progression of certain tumors. These limitations may be overcome by transductional targeting of adenovirus towards other cell surface molecules. We have evaluated the pantumoral epithelial cell adhesion molecule (EpCAM) and prostate specific membrane antigen (PSMA) as possible targets for adenoviral transduction of prostate cancer cells. Bispecific antibodies, constructed as conjugates between an anti-adenovirus fiber knob Fab' fragment and anti-EpCAM or anti-PSMA monoclonal antibodies, were incubated with an eGFP-expressing adenovirus to retarget this vector. A cell panel, that includes two prostate cancer cell lines and four non-prostate control lines, were infected with serial dilutions of the retargeted vector and specificity of infection was determined. Receptor-specific transduction was obtained for both EpCAM and PSMA. PSMA-retargeting was shown to be selective for the prostate cancer cell lines. |
Is rabeprazole superior to omeprazole for the inhibition of peptone meal-stimulated gastric acid secretion in Helicobacter pylori-negative subjects? | Peptone meal-stimulated gastric acid output is considered to be a reliable means to evaluate drug-mediated inhibition of stimulated gastric acid output, an important measure of the efficacy of the agents--such as proton pump inhibitors--used to treat acid-related disorders. To compare the initial and overall inhibitory effects on peptone meal-stimulated gastric acid secretion of rabeprazole and omeprazole, 20 mg, in Helicobacter pylori-negative subjects on the first and eighth days of treatment. Healthy volunteers (n = 27) were randomized in a single-centre, double-blind, double-dummy, 2 x 2 cross-over study. Subjects received an oral dose of rabeprazole or omeprazole, 20 mg once daily, for 8 days. After a 2-4-week washout period, subjects were crossed over to receive the other medication for 8 days. Peptone meal-stimulated gastric acid secretion was measured at hours 11 and 23 at baseline and on days 1 and 8 of treatment. On days 1 and 8, rabeprazole demonstrated a significantly greater inhibition of peptone meal-stimulated gastric acid secretion compared with omeprazole at all time points (P < 0.03). Median values of steady-state inhibition on day 1 were statistically significant at hour 23 (rabeprazole 100% vs. omeprazole 74%, P < 0.02). | Previous research in fetuses with increased nuchal translucency (NT) showed abnormal lymphatic endothelial differentiation characteristics, including increased vascular endothelial growth factor (VEGF)-A expression, and aberrant smooth muscle cells (SMCs) surrounding enlarged jugular lymphatic sacs (JLS). We hypothesized that abnormal Sonic hedgehog (Shh) expression would result in altered VEGF-A signaling in the lymphatic endothelial cells of the JLS and that aberrant acquisition of SMCs could be caused by downregulation of forkhead transcription factor FOXC2 and upregulation of platelet-derived growth factor (PDGF)-B in the lymphatic endothelial cells of the JLS. Five trisomy 21 fetuses and four controls were investigated using immunohistochemistry for Shh, VEGF-A, FOXC2 and PDGF-B expression in the lymphatic endothelial cells of the JLS. An increased Shh, VEGF-A and PDGF-B expression, and decreased FOXC2 expression were shown in the lymphatic endothelial cells of the JLS of the trisomic fetuses. |
Do psychiatric symptoms and distress differ between patients with postherpetic neuralgia and peripheral vestibular disease? | No previous studies have investigated the psychiatric characteristics of patients with postherpetic neuralgia (PHN). Similarly, no studies have been performed on patients with different chronic somatic symptoms due to a defined medical disease to compare the characteristics of psychiatric morbidity associated with each etiology. After completing the subscales of the Symptom Checklist 90-R, a psychiatrist administered the Diagnostic Interview Schedule to all subjects. The psychiatric comorbidity in 35 patients with pain due to PHN was compared with a control group of 34 patients with the nonpainful aversive symptom of vertigo due to a peripheral vestibular disorder that caused unilateral hypofunction. PHN patients had significantly more symptoms of major depression and somatization disorder. No significant differences were found between groups for psychiatric diagnoses. Patients with PHN reported significantly less acutely distressing somatic symptoms. | 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. |
Is increased p38-MAPK responsible for chemotherapy resistance in human gastric cancer cells? | Chemoresistance is one of the main obstacles to successful cancer therapy and is frequently associated with Multidrug resistance (MDR). Many different mechanisms have been suggested to explain the development of an MDR phenotype in cancer cells. One of the most studied mechanisms is the overexpression of P-glycoprotein (P-gp), which is a product of the MDR1 gene. Tumor cells often acquire the drug-resistance phenotype due to upregulation of the MDR1 gene. Overexpression of MDR1 gene has often been reported in primary gastric adenocarcinoma. This study investigated the role of p38-MAPK signal pathway in vincristine-resistant SGC7901/VCR cells. P-gp and MDR1 RNA were detected by Western blot analysis and RT-PCR amplification. Mitgen-activated protein kinases and function of P-gp were demonstrated by Western blot and FACS Aria cytometer analysis. Ap-1 activity and cell apoptosis were detected by Dual-Luciferase Reporter Assay and annexin V-PI dual staining. The vincristine-resistant SGC7901/VCR cells with increased expression of the multidrug-resistance 1 (MDR1) gene were resistant to P-gp-related drug and P-gp-unrelated drugs. Constitutive increases of phosphorylated p38-MAPK and AP-1 activities were also found in the drug-resistant cells. Inhibition of p38-MAPK by SB202190 reduced activator protein-1 (AP-1) activity and MDR1 expression levels and increased the sensitivity of SGC7901/VCR cells to chemotherapy. | Nitric oxide (NO) and its role in surgical inflammation are well documented; demonstrating the role of NO in necrotizing enterocolitis (NEC) and ways in which it may be suppressed may provide avenues for immune modulation in the treatment of NEC. We sought to demonstrate an increase in inducible nitric oxide synthase (iNOS) mRNA and nitric oxide in an experimental model of necrotizing enterocolitis. In addition, we hypothesized that interleukin-10 (IL-10) would attenuate this response. Newborn rats were treated with 25 microliters intraperitoneal IL-10 or vehicle prior to laparotomy, 1 h superior mesenteric artery (SMA) occlusion, 50 micrograms/kg intraluminal platelet activating factor administration, and SMA reperfusion. iNOS mRNA and nitric oxide levels were measured in the liver, small bowel, and serum and compared using Student's t-test. Small bowel iNOS mRNA increased after NEC induction from 0.058 +/- 0.02 to 0.144 +/- 0.05 relative intensity units (RIU) at 2 h (p < 0.01) and from 0 to 0.09 +/- 0.02 RIU at 6 h (p < 0.03). Liver mRNA increased from 0.026 +/- 0.002 to 0.485 +/- 0.09 RIU (p < 0.002) and from 0 to 0.069 +/- 0.02 RIU (p < 0.0001) at 2 and 6 h, respectively. Serum nitric oxide increased in NEC induced animals at 2 h from 28.04 +/- 10.5 to 45.18 +/- 6.8 microM (p < 0.001). IL-10 suppressed iNOS mRNA and nitric oxide expression at 2 h in small bowel, liver, and serum by 60%, 89%, and 11%, respectively. |
Do distinct resting-state perfusion patterns underlie psychomotor retardation in unipolar vs. bipolar depression? | Psychomotor abnormalities characterize both unipolar (UP) depression and bipolar (BP) depression. We aimed to assess their neurobiological correlates in terms of motor activity (AL) and resting-state cerebral blood flow (rCBF) and investigate their association in BP, UP, and healthy controls (HC). We enrolled 42 depressed patients (22 BP, 20 UP) and 19 HC matched for age, gender, education, income. AL and rCBF were objectively assessed with the use of wrist actigraphy and arterial spin labeling. Group differences and the association of AL and rCBF were computed. Activity level was significantly reduced in patients, but no difference was found between BP and UP. Increased perfusion was found in BP compared with UP and HC, in multiple brain areas. We found positive correlations of rCBF and AL in BP and UP, in different parts of the insula and frontal regions. Only BP showed a cluster in the left precentral gyrus. In HC, only inverse correlations of AL and rCBF were found. | Lymph node metastasis is one of the most important prognostic factors in patients with esophageal squamous cell carcinoma (ESCC). Neoadjuvant treatment can reduce micrometastasis in lymph nodes to enable curative resection by down staging. The aim of this study was to evaluate the histological effect of neoadjuvant therapy on lymph node metastasis of ESCC by performing immunohistochemistry for cytokeratin staining. A total of 3061 lymph nodes were examined from 62 patients who received neoadjuvant treatment followed by esophagectomy with lymphadenectomy. We observed positive staining for cytokeratin in 276 (9.0%) lymph nodes, which included overt metastasis, micrometastasis and hyalinized cytokeratin particles (HCP). Patients with HCPs in lymph nodes had better outcomes than patients without HCPs in lymph node. A significant prognostic difference between the patients with HCPs and without HCPs was observed in a subgroup of patients with nodal metastasis. |
Is the Conjunctiva in Normal Tension Glaucoma Patients Thinner Than in Primary Open-Angle Glaucoma Patients : A Comparative Histologic Study? | To compare histologically the thickness of conjunctival specimens of normal tension glaucoma (NTG) patients with primary open-angle glaucoma (POAG) patients. In this prospective study, 54 patients scheduled for trabeculectomy were categorized into NTG and POAG based on their maximum untreated intraocular pressure at any time (IOPmax) as measured by Goldmann applanation tonometry. Sixteen patients with NTG (IOPmax≤21 mm Hg) and 36 patients with high tension POAG (IOPmax>21 mm Hg) were included in the study. Biopsies were taken from the superior bulbar conjunctiva during trabeculectomy. The specimens were fixed in formalin, embedded in methacrylate, histologically sectioned, stained with toluidine blue, and analyzed with a light microscope. The stromal conjunctival thickness (CT) was measured in a standardized way and compared between the 2 groups. Intergroup comparisons were performed using the Mann-Whitney U test for continuous variables and the Fisher exact test for categorical variables. The correlation between the central cornea thickness (CCT) and the CT was investigated by the Spearman test. The stromal CT was significantly thinner in NTG compared with POAG (64±31 vs. 103±44 µm, respectively; P=0.002). Stromal CT of the whole group was positively correlated with IOPmax (r=0.41; P=0.002; 95% confidence interval, 0.15-0.62) but not with central cornea thickness (r=-0.005; P=0.97; 95% confidence interval, -0.28 to 0.27). | Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily and are key regulators of fatty acid oxidation (FAO) in the heart. Systemic carnitine deficiency (SCD) causes disorders of FAO and induces hypertrophic cardiomyopathy with lipid accumulation. We hypothesized that activation of PPARalpha by fenofibrate, a PPARalpha agonist, in addition to conventional L-carnitine supplementation may exert beneficial effects on the lipotoxic cardiomyopathy in juvenile visceral steatosis (JVS) mouse, a murine model of SCD. Both wild-type (WT) and JVS mice were fed a normal chow, 0.2% fenofibrate containing chow (FE), a 0.1% L-carnitine containing chow (CA) or a 0.1% L-carnitine + 0.2% fenofibrate containing chow (CA + FE) from 4 weeks of age. Four to 8 animals per group were used for each experiment and 9 to 11 animals per group were used for survival analysis. At 8 weeks of age, JVS mice exhibited marked ventricular hypertrophy, which was more attenuated by CA + FE than by CA or FE alone. CA + FE markedly reduced the high plasma and myocardial triglyceride levels and increased the low myocardial ATP content to control levels in JVS mice. In JVS mice, myocardial 1,2-diacylglycerol (DAG) was significantly increased and showed a distinct fatty acid composition with elevation of 18:1(n-7,9) and 18:2(n-6) fatty acids compared with that in WT mice. CA + FE significantly altered the fatty acid composition of DAG and inhibited the membrane translocation of cardiac protein kinase C beta2 in JVS mice. Furthermore, CA + FE prevented the progressive left ventricular dysfunction and dramatically improved the survival rate in JVS mice (survival rate at 400 days after birth: 89 vs. 0%, P < 0.0001). |
Does vitamin D reverse aPL-induced inflammation and LMWH-induced sFlt-1 release by human trophoblast? | Women with antiphospholipid syndrome (APS) are at increased risk of recurrent pregnancy loss (RPL) and preeclampsia. Antiphospholipid antibodies (aPL) directly alter trophoblast function. Treatment with low molecular weight heparin (LMWH) reduces the risk of RPL but not preeclampsia. Moreover, LMWH stimulates trophoblast sFlt-1 release, an anti-angiogenic factor associated with preeclampsia. Since vitamin D deficiency is associated with APS and preeclampsia, this study sought to determine the effect of vitamin D on trophoblast function in the setting of aPL and LMWH. A human first trimester trophoblast cell line (HTR8) and primary trophoblast cultures were treated with or without aPL in the presence and absence of vitamin D, LMWH or both. Trophoblast secretion of inflammatory cytokines and angiogenic factors were measured by ELISA. Vitamin D alone or in combination with LMWH attenuated the aPL-induced trophoblast inflammatory response in the HTR8 cells and primary cultures. While vitamin D did not have any impact on aPL-mediated modulation of angiogenic factors in the primary trophoblast, it significantly inhibited LMWH-induced sFlt-1 release. | After stroke, 80% of patients experience acute paresis of the upper extremity and only approximately one-third achieve full functional recovery. Predicting functional recovery for these patients is highly important to provide focused, cost-effective rehabilitation. Our purpose was to examine if early measures of upper extremity active range of motion (AROM) could predict recovery of upper extremity function, and to describe the trajectory of upper extremity AROM recovery over time. Thirty-three subjects were tested at 1 month and then at 3 months after stroke. Upper extremity function was measured with 6 standardized clinical tests that were synthesized into a single, sensitive score for upper extremity function using principal component analysis. The ability to move each segment (AROM) was measured using a 3-dimensional electromagnetic tracking system. Stepwise multiple regression revealed that AROM of the shoulder and middle finger segments taken at 1 month could predict 71% of the variance in upper extremity function at 3 months. All segments of the upper extremity recover similarly and no evidence of a proximal to distal gradient in motor deficits appeared over time. |
Does surgical result after unilateral laminectomy for the removal of spinal cord tumors? | To reduce the risk of postoperative spinal instability or deformity, unilateral laminectomy (UL) has been recommended to remove spinal space-occupying lesions. The purpose of this study was to determine whether there were any advantages of UL for removal of spinal cord tumors. From May 1995 to May 2010, 94 patients with spinal cord tumors, who underwent tumor removal via UL in our institute, were enrolled in this study. Intramedullary spinal cord tumors were excluded. Simple radiographs were obtained for accessing the restoration of the spinal column. Spinal magnetic resonance imaging (MRI) was also obtained during the follow-up period to evaluate tumor recurrence. There were 51 women and 43 men; their mean age was 47.8 years (range, 9-83 years). The mean follow-up period was 52.6 months (range, 24 month-16 years). The sites of the tumors were cervical in 21 cases, thoracic in 37, lumbar in 33, and sacral in 3. These cases included 85 intradural extramedullary (IDEM) and 9 extradural (ED) lesions. IDEM tumors consisted mainly of neurilemmomas (56.3%) and meningiomas (22.3%).Tumors were totally removed in 80 cases and subtotally removed in 14 cases. Postoperative neurological status was improved in 53 cases, unchanged in 31 cases, and worsened in 10 cases. During follow-up, MRI showed tumor recurrence in 4 patients. Histopathologically, three cases were meningiomas and one case was neurilemmoma. None of the patients showed spinal instability or kyphotic deformity at last follow-up. | Rhinoviruses (RVs) are responsible for the majority of acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations. RVs infect the lower airways and induce the production of pro-inflammatory and remodelling-associated mediators. Budesonide (BUD) and formoterol (FORM) synergize in controlling asthma and COPD exacerbations; however, their effects on virus-induced inflammation and remodelling are less known. We investigated whether BUD and FORM synergize in suppressing RV-induced inflammation and remodelling in the airways. In vitro models of RV infection of BEAS-2B and primary normal human bronchial epithelial (NHBE) cells were used. We assessed the effects of individual and combined drugs administered post-infection, at a clinically relevant concentration range (10(-6)-10(-10) m), on the production of CCL5, CXCL10, CXCL8, IL-6 and the remodelling-associated VEGF and bFGF, using ELISA and RT-PCR. BUD effectively suppressed RV-mediated induction of all mediators studied, in a concentration-dependent manner. FORM alone suppressed the production of CXCL8 and bFGF. The combination of BUD and FORM had concentration-dependent, additive or synergistic effects in the suppression of RV-induced CCL5, CXCL8 and CXCL10 in both cell types as well as VEGF in NHBE only. Combination treatment also resulted in an enhanced suppression of RV-induced IL-6, and CCL5 at the mRNA level as compared with BUD or FORM alone. |
Are well differentiation and intact Smad4 expression specific features of groove pancreatic ductal adenocarcinomas? | We aimed to select true groove pancreatic ductal adenocarcinomas (GPDACs) and define their specific features. We performed histopathologic and immunohistochemical comparisons of 6 GPDACs with 6 duodenal adenocarcinomas (DACs) and 24 conventional pancreatic ductal adenocarcinomas (cPDACs). Both groups were adjusted to ensure similar mean tumor size. Representative loupe image showed prominent duodenal invasion and slight pancreatic invasion. Groove pancreatic ductal adenocarcinomas exhibited different mucins and cytokeratin profiles in DACs, but cPDACs and small branch pancreatic ducts had the same profiles. Histopathologic analysis of GPDACs showed a significantly higher incidence of duodenal invasion and well differentiation than cPDACs, although the incidences of lymph node metastasis, angiolymphatic invasion, and neural invasion were similar. Immunohistochemical analysis of GPDACs showed a significantly lower frequency of abnormal Smad4 immunolabeling, and fewer GPDAC samples exhibited abnormal immunolabeling for MUC1, p16, Smad4, and p53 than cPDACs. | Recent work has identified deficits in dual-task gait balance control for up to 2 months after adolescent concussion; however, how resumption of preinjury physical activities affects recovery is unknown. The objective of this study is to examine how return to activity (RTA) affects recovery from concussion on measures of symptom severity, cognition, and balance control during single-task and dual-task walking. Nineteen adolescents with concussion who returned to preinjury activity within 2 months after injury and 19 uninjured, matched controls completed symptom inventories, computerized cognitive testing, and single-task and dual-task gait analyses. Concussion participants were assessed at five time points: within 72 h, 1 wk, 2 wk, 1 month, and 2 months postinjury. Control participants were assessed at the same time points as their matched concussion counterparts. RTA day was documented as the postinjury day in which physical activity participation was allowed. The effect of returning to physical activity was assessed by examining the percent change on each dependent variable across time before and directly after the RTA. Data were analyzed by two-way mixed effects ANOVAs. After the RTA day, concussion participants significantly increased their total center-of-mass medial/lateral displacement (P = 0.009, ηp = .175) and peak velocity (P = 0.048, ηp = 0.104) during dual-task walking when compared with pre-RTA data, whereas no changes for the concussion group or between groups were detected on measures of single-task walking, forward movement, or cognition. |
Does bMP-7 counteract TGF-beta1-induced epithelial-to-mesenchymal transition in human renal proximal tubular epithelial cells? | A large proportion of interstitial fibroblasts actually originate from tubular epithelial cells via the epithelial-to-mesenchymal transition (EMT) in renal fibrogenesis. Transforming growth factor-beta1 (TGF-beta1) is capable of initiating and completing the entire EMT course. Bone morphogenetic protein-7 (BMP-7) is a member of the TGF-beta superfamily. Recent studies indicate that BMP-7 could reverse established renal fibrosis in mice, primarily through counteracting TGF-beta1-mediated EMT. Therefore, we tested the hypothesis that BMP-7 functions by antagonizing profibrogenic events that are induced by TGF-beta1 in cultured human renal proximal tubular epithelial (HK-2) cells. Cultured HK-2 cells were treated with TGF-beta1 (3 ng/mL) or a combination of TGF-beta1 and BMP-7 (100-400 ng/mL) for 48 hours. Morphological changes were assessed by phase contrast microscopy. The expression of alpha-smooth muscle actin (alpha-SMA), E-cadherin, fibronectin, collagen I and connective tissue growth factor (CTGF) was analyzed by immunofluorescence, reverse transcriptase polymerase chain reaction and Western blotting. Incubation of HK-2 cells with 3 ng/mL TGF-beta1 for 48 hours induced EMT, in association with decreased E-cadherin expression, increased alpha-SMA, fibronectin, collagen I and CTGF expression, and loss of epithelial morphology. BMP-7 inhibited all these effects in a dose-dependent manner. In addition, 200 ng/mL BMP-7 reversed TGF-beta1-induced EMT, in association with reexpression of endogenous E-cadherin. | Evidence of attack-related cognitive dysfunction in migraine is growing. Controversy exists on whether cognitive dysfunction, mainly executive, may persist between attacks. Measuring the impact of cognitive function is gaining importance in clinical and research settings in migraine. To compare the performance of interictal migraine patients to controls in an assembled neuropsychological battery focused on executive functions and to study the practice effect of its repeated applications. Assembly of the battery that was then applied twice within 6 weeks to interictal migraineurs and matched healthy controls. Migraine patients (n = 24) and controls (n = 24) had similar performance in both applications of the battery. There was a slight practice effect between the first and second evaluation, significant in Stroop Interference test (P = 0.002, multiplicity corrected); a meaningful score change was determined for each raw test scores. |
Do cLINICAL CHARACTERISTICS AND TREATMENT OUTCOMES OF COATS DISEASE IN A SAUDI ARABIAN POPULATION? | To present the clinical aspects and treatment outcomes of Coats disease in Saudi Arabia. A retrospective chart review was performed of 92 patients (97 eyes) diagnosed with Coats disease at King Khalid Eye Specialist Hospital from 1983 to 2010. The most common presenting complaint was decreased visual acuity followed by strabismus and then leukocoria. Snellen visual acuity was 20/20 to 20/50 in 9 eyes (9%), 20/50 to 20/160 in 11 eyes (11%), 20/200-counting fingers in 29 eyes (30%), and hand motion to no light perception in 24 eyes (25%). Telangiectasia was located in the preequatorial area in 71 eyes (73%) and most commonly involved the temporal retina in 67 eyes (69%). In eyes with clear view to the fundus, quadrant involvement by telangiectasia had the following distribution: 1) quadrant (n = 36, 37%); 2) quadrants (n = 26, 27%); 3) quadrants (n = 8, 8%); and 4 quadrants (n = 15, 15%). Total retinal detachment was present at presentation in 28 eyes (29%) and neovascular glaucoma in 8 (8%). Based on the Shields classification, the eyes were Stage 1 (n = 1, 1%), Stage 2A (n = 7, 7%), Stage 2B (n = 23, 24%), Stage 3A1 (n = 26, 27%), Stage 3A2 (n = 12, 12%), Stage 3B (n = 16, 17%), Stage 4 (n = 11, 11%), and Stage 5 (n = 5, 1%). Stage 3A was the most commonly presented stage (39%). Primary management included cryotherapy (19%), laser photocoagulation (64%), intravitreal agents (9%), and surgical drainage (4%). Combination treatment was performed in 29% of eyes. Thirteen eyes (13%) were enucleated because of clinical suspicion of retinoblastoma or the presence of glaucoma. Factors that were associated with a poor visual outcome of 20/200 or worse included age less than 10 years (relative risk: 1.27), Stages 3 and 4 disease (relative risk: 1.40), presence of subretinal fluid in all 4 quadrants including the fovea (relative risk: 14.25), and initial visual acuity of 20/200 (relative risk: 6.72) or worse (P < 0.005 for all factors). | Macrophage accumulation of cholesterol leads to foam cell formation which is a major pathological event of atherosclerosis. Recent studies have shown that microRNA (miR)-19b might play an important role in cholesterol metabolism and atherosclerotic diseases. Here, we have identified miR-19b binding to the 3'UTR of ATP-binding cassette transporter A1 (ABCA1) transporters, and further determined the potential roles of this novel interaction in atherogenesis. To investigate the molecular mechanisms involved in a miR-19b promotion of macrophage cholesterol accumulation and the development of aortic atherosclerosis. We performed bioinformatics analysis using online websites, and found that miR-19b was highly conserved during evolution and directly bound to ABCA1 mRNA with very low binding free energy. Luciferase reporter assay confirmed that miR-19b bound to 3110-3116 sites within ABCA1 3'UTR. MiR-19b directly regulated the expression levels of endogenous ABCA1 in foam cells derived from human THP-1 macrophages and mouse peritoneal macrophages (MPMs) as determined by qRT-PCR and western blot. Cholesterol transport assays revealed that miR-19b dramatically suppressed apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux, resulting in the increased levels of total cholesterol (TC), free cholesterol (FC) and cholesterol ester (CE) as revealed by HPLC. The excretion of (3)H-cholesterol originating from cholesterol-laden MPMs into feces was decreased in mice overexpressing miR-19b. Finally, we evaluated the proatherosclerotic role of miR-19b in apolipoprotein E deficient (apoE(-/-)) mice. Treatment with miR-19b precursor reduced plasma high-density lipoprotein (HDL) levels, but increased plasma low-density lipoprotein (LDL) levels. Consistently, miR-19b precursor treatment increased aortic plaque size and lipid content, but reduced collagen content and ABCA1 expression. In contrast, treatment with the inhibitory miR-19b antisense oligonucleotides (ASO) prevented or reversed these effects. |
Does subthalamic deep brain stimulation improve auditory sensory gating deficit in Parkinson 's disease? | While motor effects of dopaminergic medication and subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients are well explored, their effects on sensory processing are less well understood. Here, we studied the impact of levodopa and STN-DBS on auditory processing. Rhythmic auditory stimulation (RAS) was presented at frequencies between 1 and 6Hz in a passive listening paradigm. High-density EEG-recordings were obtained before (levodopa ON/OFF) and 5months following STN-surgery (ON/OFF STN-DBS). We compared auditory evoked potentials (AEPs) elicited by RAS in 12 PD patients to those in age-matched controls. Tempo-dependent amplitude suppression of the auditory P1/N1-complex was used as an indicator of auditory gating. Parkinsonian patients showed significantly larger AEP-amplitudes (P1, N1) and longer AEP-latencies (N1) compared to controls. Neither interruption of dopaminergic medication nor of STN-DBS had an immediate effect on these AEPs. However, chronic STN-DBS had a significant effect on abnormal auditory gating characteristics of parkinsonian patients and restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. | Mannose-binding lectin (MBL) is a protein of the innate immune system that participates in host defense and the tissue injury/repair process, enhancing the clearance of apoptotic cells by macrophages. The aim is to characterize the relationship between pre-transplant MBL levels, histological lesions and number of apoptotic cells in early surveillance renal allograft biopsies. Consecutive renal transplant recipients were recruited and MBL levels were classified into tertiles. The first tertile was considered the low MBL group. Surveillance biopsies were done during the first 6 months and were evaluated according to Banff criteria. Renal inflammatory infiltrates were studied by immunohistochemical techniques. Apoptosis was studied using morphological methods in renal tubular cells and was expressed as the number of apoptotic cells/mm(2). MBL was determined in 126 patients and a surveillance biopsy with sufficient tissue was obtained in 41 of them. Patients with low pre-transplant MBL levels showed a higher acute Banff index (3.14 ± 1.96 vs. 1.88 ± 1.56, p = 0.044) and an increased proportion of biopsies with tubular cell apoptosis The proportion of biopsies with tubular cell apoptosis was higher in patients with low pre-transplant MBL levels in comparison with patients with high MBL levels (4.3 ± 3.6 versus 0.2 ± 0.9 p = 0.012) and increased interstitial number of inflammatory cells and significantly the macrophages/mm(2) (109 ± 118 vs. 32 ± 46; p = 0.04). |
Does cerebral oxygen desaturation predict cognitive decline and longer hospital stay after cardiac surgery? | Previous studies have reported an 11% to 75% incidence of postoperative cognitive decline among cardiac surgery patients. The INVOS Cerebral Oximeter (Somanetics Corp, Troy, MI) is a Food and Drug Administration approved device that measures regional cerebral oxygen (rSo(2)) saturation. The purpose of this study is to examine whether decreased rSo(2) predicts cognitive decline and prolonged hospital stay after coronary artery bypass grafting (CABG). The rSo(2) was monitored intraoperatively in a cohort of primary CABG patients. Patients were prospectively randomized to a blinded control group or an unblinded intervention group. Cognitive function was assessed preoperatively, postoperatively, and at 3 months using a battery of standardized neurocognitive tests. Cognitive decline was defined as a decrease of one standard deviation or more in performance on at least one neurocognitive measure. The rSo(2) desaturation score was calculated by multiplying rSo(2) below 50% by time (seconds). Multivariate logistic regression models were used to assess cognitive decline and hospital stay. The change in cognitive performance was also assessed using a multivariate linear regression model. Patients with rSo(2) desaturation score greater than 3,000%-second had a significantly higher risk of early postoperative cognitive decline [p = 0.024]. Patients with rSo(2) desaturation score greater than 3,000%-second also had a near threefold increased risk of prolonged hospital stay (>6 days) [p = 0.007]. | Statins, hydroxymethylglutaryl-coenzyme A reductase inhibitors, have been reported to have antiinflammatory and/or immunomodulatory effects and prophylactic and therapeutic effects in collagen-induced arthritis, an experimental model of rheumatoid arthritis (RA). The authors undertook to determine the effect of atorvastatin on the expressions of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) in RA fibroblast-like synoviocytes (FLSs), to identify the mechanisms responsible for these effects, and to determine whether the statin inhibits osteoclastogenesis. FLSs isolated from five RA patients were cultured in the presence of 20 ng/ml of tumor necrosis factor-α (TNF-α) with or without atorvastatin. RANKL expressions were assayed with Western blotting and enzyme-linked immunosorbent assay. RANKL, RANK, and OPG expression were assayed with reverse transcription-polymerase chain reaction (RT-PCR). Osteoclast formation was assayed by counting cells after staining for tartrate-resistant acid phosphatase in cocultures of peripheral blood mononuclear cells (PBMCs) and RA FLSs. Atorvastatin inhibited the expression of RANKL in RA FLSs in a dose-dependent manner, and the suppression of RANKL was prevented by mevalonate. However, OPG expression was not affected by atorvastatin in RA FLSs, and atorvastatin did not affect RANK expression in CD14⁺ cells. Conversely, atorvastatin suppressed TNF-α-induced p38 phosphorylation in RA FLSs and significantly reduced TRAP-positive multinucleated osteoclast formation in the coculture of PBMCs and RA FLSs. |
Does short-hairpin RNA-mediated MTA2 silencing inhibit human breast cancer cell line MDA-MB231 proliferation and metastasis? | To observe the effects of metastasis-associated tumor gene family 2 (MTA2) depletion on human breast cancer cell proliferation and metastasis. A short-hairpin RNA targeting MTA2 was chemically synthesized and transfected into a lentivirus to construct Lv-shMTA2 for infection into the MDA-MB231 human breast cancer cell line. At 48 hours after infection cells were harvested and mRNA and protein levels of MTA2 were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. Cell viability and metastasis were assessed by CCK-8, wound-healing assay and Transwell assay, respectively. In addition, a xenograft model of human breast cancer was constructed to investigate cancerous cell growth and capacity for metastasis. After infection with Lv-shMTA2, mRNA and protein levels of MTA2 was significantly reduced (p<0.05) and MDA-MB231 cell proliferation and metastasis were inhibited (p<0.05). In addition, mean tumor size was smaller than that in control group nude mice (p<0.05) and numbers of metastatic deposits in lung were lower than in control group mice (p<0.05). Depletion of MTA2 affected MMP-2 and apoptosis-related protein expression. | Most patients with idiopathic ventricular premature depolarizations (VPDs) complain of symptoms related to this arrhythmia, but some patients are asymptomatic even with a high VPD burden. Our understanding of the relationship between symptoms and cardiomyopathy related to this arrhythmia remains limited. We evaluated 801 subjects (381 men; mean age, 55 ± 17 years) who visited our outpatient clinic. All subjects were diagnosed with frequent VPDs (1% or >1000 beats/day). The patients were divided into two groups according to the presence or absence of typical VPD symptoms (palpitations or skipped beats during VPDs): symptomatic patients (n = 455) and asymptomatic patients (n = 346). Clinical and electrocardiogram parameters were compared between these two groups. In the symptomatic group, palpitations were the most frequent symptom (91%). Daily VPD burden (P = 0.90) and electrocardiogram parameters (P>0.05) did not differ significantly between groups. The incidence of frequent VPDs with left ventricular dysfunction was significantly higher in the asymptomatic group (symptomatic patients, 3.0%; asymptomatic patients, 10.5%; P < 0.001). |
Do hB-EGF-induced VEGF production and eNOS activation depend on both PI3 kinase and MAP kinase in HaCaT cells? | Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of growth factors that have been implicated in skin patho-physiology. Although endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) appear to be involved in mitogenesis and chemotaxis in epidermal keratinocytes, the activation of eNOS and VEGF production induced by HB-EGF and its signaling mechanism remains undefined. We examined possible signal transduction pathways by which HB-EGF leads to eNOS activation and VEGF production in human epidermal keratinocyte cell line (HaCaT cells). The phosphorylation of epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK; p42/p44 MAPK), Akt and eNOS were examined by Western blotting analysis. VEGF production was determined by enzyme-linked immunosorbent assay. Various inhibitors were utilized to investigate the signaling mechanisms of eNOS activation and VEGF production. HB-EGF-induced phosphorylation of EGFR with maximum phosphorylation at 1h. HB-EGF-induced phosphorylation of p42/p44 MAPK in a few minutes. It activated Akt with maximum phosphorylation at 1h and eNOS with maximum phosphorylation at 3h. The HB-EGF-induced eNOS activation was significantly blocked by the p42/p44 MAPK inhibitor U0126 and the phosphatidylinositol 3-kinase (P13K) inhibitor LY294002. HB-EGF increased VEGF production. The HB-EGF-induced VEGF production was blocked by U0126 and LY294002. Finally, the HB-EGF-induced activation of Akt and eNOS was suppressed by VEGF competitive antagonist, CBO-P11. | We studied the relations between bone geometry and density and the mechanical properties of human cadaveric tibiae. Bone geometry, assessed by MRI and pQCT, and bone density, assessed by DXA, were significantly associated with bone's mechanical properties. However, cortical density assessed by pQCT was not associated with mechanical properties. The primary objective of this study was to determine the contribution of cross-sectional geometry (by MRI and pQCT) and density (by pQCT and DXA) to mechanical properties of the human cadaveric tibia. We assessed 20 human cadaveric tibiae. Bone cross-sectional geometry variables (total area, cortical area, and section modulus) were measured with MRI and pQCT. Cortical density and areal BMD were measured with pQCT and DXA, respectively. The specimens were tested to failure in a four-point bending apparatus. Coefficients of determination between imaging variables of interest and mechanical properties were determined. Cross-sectional geometry measurements from MRI and pQCT were strongly correlated with bone mechanical properties (r(2) range from 0.55 to 0.85). Bone cross-sectional geometry measured by MRI explained a proportion of variance in mechanical properties similar to that explained by pQCT bone cross-sectional geometry measurements and DXA measurements. |
Does next-generation sequencing reveal large connected networks of intra-host HCV variants? | Next-generation sequencing (NGS) allows for sampling numerous viral variants from infected patients. This provides a novel opportunity to represent and study the mutational landscape of Hepatitis C Virus (HCV) within a single host. Intra-host variants of the HCV E1/E2 region were extensively sampled from 58 chronically infected patients. After NGS error correction, the average number of reads and variants obtained from each sample were 3202 and 464, respectively. The distance between each pair of variants was calculated and networks were created for each patient, where each node is a variant and two nodes are connected by a link if the nucleotide distance between them is 1. The work focused on large components having > 5% of all reads, which in average account for 93.7% of all reads found in a patient. | Spinal reflex excitability study in sensory-motor incomplete spinal cord-injured (SCI) and spinal intact subjects. To investigate the effects of plantar cutaneous afferent excitation on the soleus H-reflex and flexion reflex in both subject groups while seated. Rehabilitation Institute of Chicago and City University of New York, USA. The flexion reflex in SCI subjects was elicited by non-nociceptive stimulation of the sural nerve. In normal subjects, it was also elicited via innocuous medial arch foot stimulation. In both cases, reflex responses were recorded from the ipsilateral tibialis anterior muscle. Soleus H-reflexes were elicited and recorded via conventional methods. Both reflexes were conditioned by plantar cutaneous afferent stimulation at conditioning test intervals ranging from 3 to 90 ms. Excitation of plantar cutaneous afferents resulted in facilitation of the soleus H-reflex and late flexion reflex in SCI subjects. In normal subjects, the soleus H-reflex was depressed while the late flexion reflex was absent. The early flexion reflex was irregularly observed in SCI patients, while in normal subjects a bimodal reflex modulation pattern was observed. |
Does autologous platelet-rich plasma reduce transfusion of homologous blood products in patients undergoing repeat valvular surgery? | Patients undergoing cardiac surgery employing cardiopulmonary bypass frequently require transfusion of homologous blood products and, therefore, are exposed to the risk of transfusions. Autologous platelet-rich plasma administration may reduce homologous transfusion and attendant risks. In a blinded, randomized fashion, patients undergoing repeat sternotomy and valvular surgery received either a sham product (n = 28) or autologous platelet-rich plasma (n = 28) at the conclusion of cardiopulmonary bypass. Perioperative blood loss, coagulation profiles, and transfusion requirements were compared between the two groups. In the first 24 h postoperatively, both the platelet-rich plasma and sham groups received a median of 10.5 units of homologous blood products. Total median perioperative homologous transfusion requirements were 13 and 11.5 units for the platelet-rich plasma and sham groups, respectively. There was no significant difference in intraoperative or postoperative bleeding between the groups. | Glucobrassicin (GBS), a glucosinolate contained in many brassica vegetables, is the precursor of chemopreventive compounds such as indole-3-carbinol. Large amounts of GBS would be needed to perform studies aimed at elucidating its role in the diet. This study was mainly undertaken to evaluate the flower buds of Isatis canescens as a source for GBS purification. In order to investigate the health-promoting potential of this species, glucosinolate, phenol and flavonoid content as well as the whole antioxidant capacity were also determined. Flower bud samples were collected in four localities around Mount Etna in Sicily, Italy, where I. canescens is widespread, as they are locally traditionally eaten. I. canescens flower buds displayed high GBS concentrations, up to 60 µmol g(-1) dry weight. The purification method consisted of two chromatographic steps, which made it possible to obtain GBS with a purity of 92-95%, with a yield of 21 g kg(-1) . The total glucosinolates, phenols, flavonoids and antioxidant activity were considerable, with the southern locality showing the highest concentrations for all the phytochemicals. |
Does hydrogen sulfide regulate cardiac function and structure in adriamycin-induced cardiomyopathy? | The present study was designed to investigate if hydrogen sulfide (H2S), a novel gasotransmitter, might have a regulatory effect on cardiac function and structure, as well as oxidative stress, in adriamycin (ADR)-induced cardiomyopathy. Hemodynamic measurements, histopathological examination and stereological ultrastructural analysis of mitochondria in ADR-treated rats showed characteristics of cardiomyopathy with remarkable greater size and smaller number of cardiomyocytic mitochondria and a significantly low H2S content in plasma and myocardium, but increased levels of thiobarbituric acid reactive substance (TBARs) and decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in plasma and myocardium compared with controls (P<0.01). However, administration of the H2S donor, NaHS, markedly improved cardiac function, as demonstrated by elevated left ventricular developed pressure (+/-LVdp/dtmax; P<0.01) with ameliorated morphological alterations in the myocardium. Myocardial TBARs content decreased, whereas the activities of SOD and GSH-Px increased (P<0.01 and P<0.05, respectively). | Fifteen human tissue kallikrein (KLK) genes have been identified as a cluster on chromosome 19. KLK expression is associated with various human diseases including cancers. Noncoding RNAs such as PCA3/DD3 and PCGEM1 have been identified in prostate cancer cells. Using massively parallel signature sequencing (MPSS) technology, RT-PCR, and 5' rapid amplification of cDNA ends (RACE), we identified and cloned a novel gene that maps to the KLK locus. We have characterized this gene, named as KLK31P by the HUGO Gene Nomenclature Committee, as an unprocessed KLK pseudogene. It contains five exons, two of which are KLK-derived while the rest are "exonized" interspersed repeats. KLK31P is expressed abundantly in prostate tissues and is androgen regulated. KLK31P is expressed at lower levels in localized and metastatic prostate cancer cells than in normal prostate cells. |
Is vasodilation in resistance arteries related to the apolipoprotein B/A1 ratio in the elderly : the Prospective Investigation of the Vasculature in Uppsala Seniors ( PIVUS ) study? | Recent studies have shown the apolipoprotein B to apolipoprotein A1 ratio (apoB/A1) to be superior to LDL-cholesterol measurements to predict cardiovascular events. The present study aims to relate apoB/A1 to endothelium-dependent vasodilation, an early marker of atherosclerosis, in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study. In this population-based study, 1016 subjects aged 70 years were evaluated by the invasive forearm technique with acetylcholine (EDV), brachial artery ultrasound to assess flow-mediated vasodilation (FMD) and pulse wave analysis with a beta-2 receptor agonist challenge, terbutaline. EDV and the pulse wave response, but not FMD, were related to apoB/A1 levels (r=-0.11, p=0.0038 for EDV, r=-0.16, p<0.0001 for the pulse wave analysis and r=0.01, p=0.65 for FMD). Neither LDL-cholesterol, nor non-HDL-cholesterol, was significantly related to the measurements of endothelium-dependent vasodilation. Also endothelium-independent vasodilation (EIDV) evaluated by the invasive forearm technique with sodium nitroprusside was related to apoB/A1 levels (r=-0.12, p<0.0016). | Streptococcus agalactiae (group B Streptococcus; GBS) is a significant bacterial pathogen of neonates and an emerging pathogen of adults. Though transcriptional regulators are abundantly encoded on the GBS genome, their role in GBS pathogenesis is poorly understood. The mtaR gene encodes a putative LysR-type transcriptional regulator that is critical for the full virulence of GBS. Previous studies have shown that an mtaR- mutant transports methionine at reduced rates and grows poorly in normal human plasma not supplemented with methionine. The decreased virulence of the mtaR mutant was correlated with a methionine transport defect; however, no MtaR-regulated genes were identified. Microarray analysis of wild-type GBS and an mtaR mutant revealed differential expression of 12 genes, including 1 upregulated and 11 downregulated genes in the mtaR mutant. Among the downregulated genes, we identified a cluster of cotranscribed genes encoding a putative methionine transporter (metQ1NP) and peptidase (pdsM). The expression of four genes potentially involved in arginine transport (artPQ) and arginine biosynthesis (argGH) was downregulated and these genes localized to two transcriptional units. The virulence factor cspA, which encodes an extracellular protease, was downregulated. Additionally, the SAN_1255 locus, which putatively encodes a protein displaying similarity to plasminogen activators, was downregulated. |
Does homocysteine enhance apoptosis in human bone marrow stromal cells? | High plasma homocysteine (Hcy) levels have been associated with increased risk of fracture. Since Hcy has been shown to induce apoptosis in many cell types, including vascular endothelial cells, we hypothesized that Hcy would have a similar apoptotic effect on osteoblasts, leading to osteoporosis by reducing bone formation. Using primary human bone marrow stromal cells (hBMSC) and HS-5 cell line (human bone marrow stromal cell line), we investigated the effects of Hcy on these cells by cell viability assay and analysis of cytoplasmic histone-associated DNA fragments. Caspase activity assay, Western blots, and electrophoresis mobility shift assay (EMSA) were performed to find the mechanism of apoptosis. Intracellular reactive oxygen species (ROS) were measured by spectrometry using dichlorofluorescein diacetate, and cellular total glutathione level was determined by a commercially available kit. N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) were used as tools for investigating the role of ROS and nuclear factor-kappaB (NF-kappaB), respectively. Hcy induced apoptosis in primary human bone marrow stromal cells and the HS-5 cell line, and this apoptotic effect was caspase-dependent. In addition, Hcy increased cytochrome c release into the cytosol, and activated caspase-9 and caspase-3, but not caspase-8, indicating that Hcy induces apoptosis via the mitochondria pathway. Hcy increased ROS, and NAC inhibited the apoptotic effect of Hcy. Western blot and EMSA showed that Hcy activated the NF-kappaB pathway. PDTC blocked Hcy-induced caspase-3 activation and apoptosis. | Development of fibrosis and subsequent stricture formation in Crohn's disease (CD) increases morbidity and rates of surgery and reduces patients' quality of life. There are currently no biomarkers of intestinal fibrosis that might allow earlier identification and better management of patients at increased risk of stricture formation. MicroRNA profiling of serum from CD patients was used to identify microRNAs associated with stricture formation. Differential expression of miR-19a-3p and miR-19b-3p was validated by quantitative PCR in independent CD cohort of stricturing and nonstricturing patients (n = 46 and n = 62, respectively). Levels of miR-19a-3p and miR-19b-3p were also quantified in baseline serum samples, and expression compared between CD patients who subsequently developed stricture and those who did not (n = 11 and n = 44, respectively). Serum levels of miR-19a-3p and miR-19b-3p in the array were lower in CD patients with a stricturing phenotype than in control CD patients (P = 0.007 and 0.008, respectively). The reduction in miR-19a-3p and 19b-3p was verified in a second cohort (P = 0.002). The association of miR-19-3p with stricturing CD was independent of potential confounding clinical variables, including disease duration, disease activity, site, gender, and age. Serum analyses in patients with 4 years of follow-up support the hypothesis that reduced miR-19a-3p and miR-19b-3p predate stricture development with a trend toward significance (P = 0.077 and P = 0.060, respectively). |
Does transjugular intrahepatic portosystemic shunt placement increase feasibility of colorectal surgery in cirrhotic patients with severe portal hypertension? | Colorectal resection in cirrhotic patients is associated with high mortality and morbidity related to portal hypertension and liver insufficiency. This retrospective study evaluated the clinical outcomes of cirrhotic patients who underwent transjugular intrahepatic porto-systemic shunt (TIPS) placement before colorectal resection for cancer. Main outcomes measures were postoperative morbidity and mortality rates. TIPS placement was successful in all eight patients and significantly decreased the mean hepatic venous pressure gradient from 15.5 ± 2.9 to 7.5 ± 1.9 mmHg (p = 0.02). Surgical procedures included right colectomy (n = 3), left colectomy (n = 2), and proctectomy with total mesorectal excision (n=3). Post-operatively, two patients (25%) died of multiple organ failure. The overall postoperative morbidity rate was 75%, and major complications were seen in 25%. | Recent epidemiological evidence suggests that modifying lifestyle by increasing physical activity could be a non-pharmacological approach to improving symptoms and slowing disease progression in Alzheimer's disease and other tauopathies. Previous studies have shown that exercise reduces tau hyperphosphorylation, however, it is not known whether exercise reduces the accumulation of soluble or insoluble tau aggregates and neurofibrillary tangles, which are both neuropathological hallmarks of neurodegenerative tauopathy. In this study, 7-month old P301S tau transgenic mice were subjected to 12-weeks of forced treadmill exercise and evaluated for effects on motor function and tau pathology at 10 months of age. Exercise improved general locomotor and exploratory activity and resulted in significant reductions in full-length and hyperphosphorylated tau in the spinal cord and hippocampus as well as a reduction in sarkosyl-insoluble AT8-tau in the spinal cord. Exercise did not attenuate significant neuron loss in the hippocampus or cortex. Key proteins involved in autophagy-microtubule-associated protein 1A/1B light chain 3 and p62/sequestosome 1 -were also measured to assess whether autophagy is implicated in the exercised-induced reduction of aggregated tau protein. There were no significant effects of forced treadmill exercise on autophagy protein levels in P301S mice. |
Does practical skills training influence knowledge and attitude of dental students towards emergency medical care? | Medical emergencies in dental practice are generally perceived as being rare. Nonetheless, recent studies have shown that incidents occur on a regular basis. Therefore, patients have the right to expect necessary skills to manage life-threatening situations from every dentist. To observe students' attitude and self-assessment towards emergency medical care (EMC) and its practical appliance. Students of dentistry took part in small group sessions for adult and paediatric basic life support. Participants filled out pre-post questionnaires regarding knowledge and attitude towards EMC (6, respectively, 10-point Likert scale). Additionally, feedback was asked for the quality of course and tutors. Forty dental students in their last 2 years of study registered for the EMC courses. The majority had never attended any first-aid course; the mean age was 25% and 75% were women. A comparison between pre- and post-evaluation showed that the participation in practical training easily enhances the students' awareness of EMC importance as well as self-confidence in managing emergencies. After the course, 71% shared the opinion that retraining should be obligatory for all medical personnel. At the same time, students' self-assessment of confidence for specific tasks got significant upgrades in every aspect. | Acute rejection is the major risk factor for the development of subsequent chronic allograft nephropathy (CAN), which is the primary reason for late allograft loss in kidney transplantation. Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are the main mitogens mediating mesenchymal cell proliferation. Their early post-transplant induction may start cascades leading to the development of CAN. An immunosuppressive drug, FK778, inhibits de novo pyrimidine biosynthesis and several receptor tyrosine kinases (RTKs). Here we investigated its effects on acute and chronic rejection as well as post-transplant PDGF and TGF-beta expression in combination therapy with calcineurin inhibitors (CNIs). Kidney transplantations were performed from DA to WF rats. Syngenic DA-DA grafts were used as controls. Allografts were immunosuppressed with a combination of FK778 (10 mg/kg/day p.o.) and CsA (1.5 mg/kg/day s.c.) or tacrolimus (Tac) (1.5 mg/kg/day p.o.). Grafts were harvested 5 and 90 days after transplantation for histology and immunohistochemistry (PDGF-A, PDGF-B, PDGFR-alpha, PDGFR-beta, TGF-beta, TGF-betaR). The dose response of FK778 on acute rejection was studied with monotherapy of 5, 10 and 20 mg/kg/day. Chronic changes were scored according to the Chronic Allograft Damage Index (CADI). FK778 ameliorated the early post-transplant inflammatory response dose dependently. Additive effects were seen with FK778 and CNIs. Significantly lower CADI scores were seen in combination therapy of FK778 and CNIs compared with CNI monotherapies. FK778 also significantly reduced both early and late PDGF and TGF-beta expression when combined with CNIs. |
Is periodontitis an independent risk indicator for atherosclerotic cardiovascular diseases among 60 174 participants in a large dental school in the Netherlands? | The association between periodontitis and atherosclerotic cardiovascular diseases (ACVD) has been established in some modestly sized studies (<10 000). Rarely, however, periodontitis has been studied directly; often tooth loss or self-reported periodontitis has been used as a proxy measure for periodontitis. Our aim is to investigate the adjusted association between periodontitis and ACVD among all individuals registered in a large dental school in the Netherlands (Academic Centre for Dentistry Amsterdam (ACTA)). Anonymised data were extracted from the electronic health records for all registered patients aged >35 years (period 1998-2013). A participant was recorded as having periodontitis based on diagnostic and treatment codes. Any affirmative answer for cerebrovascular accidents, angina pectoris and/or myocardial infarction labelled a participant as having ACVD. Other risk factors for ACVD, notably age, sex, smoking, diabetes, hypertension, hypercholesterolaemia and social economic status, were also extracted. Logistic regression analyses were used to evaluate the adjusted associations between periodontitis and ACVD. 60 174 individuals were identified; 4.7% of the periodontitis participants (455/9730) and 1.9% of the non-periodontitis participants (962/50 444) reported ACVD; periodontitis showed a significant association with ACVD (OR 2.52; 95% CI 2.3 to 2.8). After adjustment for the confounders, periodontitis remained independently associated with ACVD (OR 1.59; 95% CI 1.39 to 1.81). With subsequent stratification for age and sex, periodontitis remained independently associated with ACVD. | Regulated secretion of specialized neuropeptides in the vertebrate neuroendocrine system is critical for ensuring physiological homeostasis. Expression of these cell-specific peptide markers in the differentiating hypothalamus commences prior to birth, often predating the physiological demand for secreted neuropeptides. The conserved function and spatial expression of hypothalamic peptides in vertebrates prompted us to search for critical neuroendocrine genes in newly hatched zebrafish larvae. We screened mutant 5 days post-fertilization zebrafish larvae that fail to undergo visually mediated background adaptation for disruption in hypothalamic pomc expression. To our surprise, the ATPase N-ethylmaleimide sensitive factor (nsf) was identified as an essential gene for maintenance of neuroendocrine transcriptional programs during the embryo-to-larva transition. Despite normal hypothalamic development in nsf(st53) mutants, neuropeptidergic cells exhibited a dramatic loss of cell-specific markers by 5 days post-fertilization that is accompanied by elevated intracellular neuropeptide protein. Consistent with the role of NSF in vesicle-membrane fusion events and intracellular trafficking, cytoplasmic endoplasmic reticulum-like membranes accumulate in nsf(-/-) hypothalamic neurons similar to that observed for SEC18 (nsf ortholog) yeast mutants. Our data support a model in which unspent neuropeptide cargo feedbacks to extinguish transcription in neuropeptidergic cells just as they become functionally required. In support of this model we found that gnrh3 transcripts remained unchanged in pre-migratory, non-functional gonadotropin-releasing hormone (GnRH) neurons in nsf(-/-) zebrafish. Furthermore, oxytocin-like (oxtl, intp) transcripts, which are found in osmoreceptive neurons and persist in mutant zebrafish, drop precipitously after mutant zebrafish are acutely challenged with high salt. |
Is time point important for effects of syngeneic bone marrow transplantation for type 1 diabetes in mice? | Autologous hematopoietic stem cell transplantation (HSCT) has recently become a novel therapy for patients with new-onset type 1 diabetes (T1D). However, the optimal time points for HSCT are still unknown. By using multiple low-dose streptozotocin (STZ)-induced T1D mice models, we performed syngeneic bone marrow transplantation (syn-BMT) in diabetic mice at various time points new-onset day 3 (n = 12); new-onset day 10 (n = 13); later-onset day 20 (n = 12); and day 40 (n = 7), respectively. At 120 days after syn-BMT, we examined pancreata histology, serum insulin, and CD4(+)CD25(+)FoxP3(+) T regulatory lymphocytes (Tregs). Our previous results showed that syn-BMT can overcome diabetes when performed on day 10, but not at day 40. Our new data showed BMT only attenuated diabetes when done on day 3 or day 20. Moreover, the percentage of Tregs in the spleen correlated with the attenuation of hyperglycemia. | To evaluate the diagnostic significance of CT scan in the localization of the stricture in the upper airway in patients with obstructive sleep apnea syndrome (OSAS). Fifty-four patients with OSAS were included in this study. CT scan evaluated the upper airway from the roof of nasopharynx to the glottis using a Phlips Tomoscan AV Expander E1 spiral scanner. The areas and the dimensions of palate, uvula, lingua and epiglottis region, as well as the thickness of retropharyngeal and lateral pharyngeal tissue was evaluated. The reference values had been set-up in 225 normal adult upper airways CT scan, some patients' results were compared with the CT scan results during apnea. There were no any upper airway stricture in 12 patients with OSAS, and there were one or more upper airway stricture sites in other 42 patients. Twenty-four patients had only one stricture site. Fourteen patients had 2 adjacent stricture sites. One patient had three stricture sites. Three patients had 4 upper airway strictures. There was a good concordance between the results of CT scans during awakening and sleeping in 14 patients. |
Is the Need for a Step-up in Postoperative Medical Care Predictable in Orthopedic Patients Undergoing Elective Surgery? | The goal of elective orthopedic surgery is to return patients to their expected level of activity without an increased incidence of postoperative complications. The first step is identifying patient and/or surgical characteristics responsible for these complications. This study sought to identify predictors of a step-up in medical care after non-ambulatory elective orthopedic surgery. At a single specialty orthopedic hospital, we identified all in-hospital postoperative patients who were transferred to a higher level of medical care ((PACU) post-anesthesia care unit). The characteristics of both transferred and non-transferred patients were compared. A model was built which incorporated predictors of return to a higher level of care. During a 1-year period, 155 of 7967 patients (1.95%) required transfer to the PACU within 5 days of surgery. Cardiac complications were the major reason for transfer (50.3%), followed by pulmonary (11.0%) and neurological complications (9.7%). Patients who returned to the PACU were older, had more Exlihauser comorbidities, and had obstructive sleep apnea (OSA). In a model adjusting for all patient characteristics: age, American Society of Anesthesiologists (ASA) status, congestive heart failure (CHF), the Charlson comorbidity index and OSA predicted return to the PACU. | To study the anti-tumor immunotherapeutic effect induced by the suicidalcancer vaccine FC/TK, and to evaluate the safety of this vaccine. The suicidal cancer vaccine, named FC/TK, was prepared by fusion of suicide gene (HSVI,-TK gene) -modified ovarian carcinoma NuTu-19 cells with rat bone marrow-derived dendritic cells (DCs). The morphology of FC/TK was evaluated by scanning electron microscopy. The stimulatory effect of FC/TK on T cells was determined by T cell proliferation assay. In immunotherapeutic studies in vivo, Fischer344 rats were injected subcutaneously with NuTu-19 cells, followed by treatment of FC/TK on days 7 and 14, compared to controls treated with irradiated FC/TK, FC or PBS, respectively. Tumor incidence and volume were measured in 90 days after challenge. To determine the killing effect of FC/TK in vivo, TUNEL assays were applied to detect apoptotic cell death in spleen of vaccinated rats with prodrug ganciclovir administration. FC/TK cells were of irregular shape with surface membrane processes. Compared to the control groups, FC/TK significantly promoted T cell proliferation (P <0.01). The rats vaccinated with FC/TK and FC significantly inhibited the tumor growth compared to rats vaccinated with irradiated FC/TK (P <0.05) or with PBS ( P <0.01). The immunotherapeutic effect induced by FC/TK was similar to that using FC. Fluorescence microscopy showed that fluorescein-stained FC/TK cells migrated into spleen also showed to be TUNEL-positive, suggesting that the FC/TK cells were killed by ganciclovir in vivo. |
Are body mass index curves for Italian preterm infants comparable with American curves for infants born before 34 weeks of gestational age? | Body mass index (BMI)-for-age curves have been developed in the USA, but not compared with other populations. This study created gender-specific intrauterine BMI-for-age curves for Italian preterm infants and compared them with the USA version. Data on 92 262 newborn infants, born at 26-42 weeks of gestational age in the north-eastern Italian region of Friuli Venezia Giulia between 2005 and 2013, were analysed to create gender-specific BMI-for-age curves. Gender-specific and age-specific BMI Z scores for Italian infants were calculated using the parameters of the USA growth curves and the World Health Organization charts. Gender-specific BMI-for-age at birth curves were developed for premature Italian infants from 26 gestational weeks. The comparison with the USA charts showed no significant difference in BMI percentiles in Italian infants born at ≤33 gestational weeks, but infants born at ≥34 gestational weeks had a significantly higher BMI than the USA population, by 0.2 standard deviations. | Immunochemical therapy combining cytokines and chemotherapeutic agents is expected to be effective for treating advanced renal cell carcinoma (RCC). We investigated the mechanism underlying the synergism of interferon-alpha (IFN-alpha) and 5-fluorouracil (5-FU) and the effect of p53 status on the synergy of the combined therapy in RCC cell lines. The synergy of IFN-alpha and 5-FU was analyzed by isobolographic analysis in five RCC cell lines. The effect of combined treatment on apoptosis induction was measured by flow cytometric analysis, Hoechst staining, and caspase activity assay; PCNA expression was investigated by Western blotting to examine the effect of combined treatment on the antiproliferative effect. We demonstrated synergy of IFN-alpha and 5-FU in five RCC cell lines with wild-type p53. IFN-alpha suppressed the proliferation of RCC cells via G1 or G2/M cell cycle arrest without inducing apoptosis, whereas 5-FU induced apoptosis in a dosage-dependent manner. IFN-alpha enhanced the apoptosis of RCC cells induced by 5-FU, whereas 5-FU did not increase the antiproliferative effect of IFN-alpha. However, the synergistic inhibition by IFN-alpha and 5-FU was abolished when the cell lines were transfected with p53 dominant-negative vector. |
Does dentin enhance the effectiveness of bioactive glass S53P4 against a strain of Enterococcus faecalis? | 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. | Elevated adrenal androgen levels are common in polycystic ovary syndrome (PCOS), but the underlying pathogenetic mechanism is poorly understood. In the rare cortisone reductase deficiency, impaired regeneration of active cortisol from inert cortisone by 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) results in compensatory activation of ACTH secretion and adrenal hyperandrogenism. 11beta-HSD1 deficiency may protect against obesity and its metabolic consequences because of impaired regeneration of cortisol in adipose tissue. Our objective was to investigate a functional polymorphism in HSD11B1 (T-->G in the third intron rs12086634, which associates with lower 11beta-HSD1 activity) in PCOS with and without obesity. We conducted a case-control study in lean and obese PCOS patients and controls at an academic hospital. Participants included 102 Caucasian PCOS patients and 98 controls comparable for age, weight, and race. We assessed genotype distribution and influence of genotypes on clinical, hormonal, and metabolic parameters. The G allele was significantly related to PCOS status (P = 0.041), and this association was mainly attributable to lean (P = 0.025), rather than obese (P = 0.424), PCOS patients. The G allele was associated with lower 0800-0830 h plasma cortisol (P < 0.001) and higher cortisol response to ACTH(1-24) (P < 0.001) in all women with PCOS and with higher dehydroepiandrosterone sulfate levels (P < 0.001), greater suppression of dehydroepiandrosterone sulfate by dexamethasone (P < 0.001), and lower fasting plasma low-density lipoprotein cholesterol (P = 0.002) levels in lean PCOS women. |
Are atherogenic index of plasma and atherogenic coefficient increased in major depression and bipolar disorder , especially when comorbid with tobacco use disorder? | There is a robust comorbidity between mood disorders and cardiovascular disorder (CVD). The atherogenic index of plasma (AIP) and the atherogenic coefficient (AC) are important atherogenic indexes. The aims of this study were to delineate whether AIP and AC are increased in mood disorders especially when comorbid with tobacco use disorder (TUD). In this case-control study we included 134 patients with mood disorders, bipolar disorder and unipolar depression (cases), and 197 individuals without mood disorder (controls) divided into those with and without TUD (defined as never-smokers). Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc) were measured. AIP and AC were computed as log (TG/HDLc) and non-HDLc/HDLc, respectively. The AIP and AC indexes were significantly increased in patients with mood disorders versus controls, both in depression and bipolar disorder. Patients with mood disorder without TUD and patients with TUD without mood disorder showed higher AIP and AC values than never-smokers while those with comorbid mood disorders and TUD showed significantly higher AIP and AC levels than all other individuals. A large part of the variance in the AIC (26.4%) and AC (20.4%) was explained by mood disorders, TUD, male gender and body mass index. | Three noncontiguous spinal implant sites in 1 rabbit were challenged with Staphylococcus aureus and local antibiotic prophylaxis was given with gentamicin in controlled-release microspheres (poly(lactic-coglycolic-acid) [PLGA]). Postoperative biomaterial-centered infection on and around the titanium rods was assessed using standard bacterial quantification essays. To assess surgical site and biomaterial-centered infection reduction with controlled release gentamicin from microspheres against S. aureus. A postoperative biomaterial-centered infection can be devastating after successful thoracolumbar spinal surgery and puts a high burden on patients, families, surgeons, and hospitals, endangering both our healthcare budget and our ability to perform challenging cases in patients with increasing numbers of comorbidities. Systemic antibiotics often do not reach "dead-space" hematomas where bacteria harbor after surgery, whereas local, controlled release gentamicin prophylaxis through PLGA microspheres showed favorable pharmacokinetics data to achieve local bactericidal concentrations for up to 7 days after surgery. A well published rabbit spinal implant model with systemic cephalosporin prophylaxis was challenged to create a baseline infection of approximately 70% in control sites. We then challenged 3 noncontiguous titanium rods inside the laminectomy defect with 10e6 colony forming units S. aureus and randomly treated 2 sites with gentamicin PLGA microspheres and 1 site with PLGA carrier only (control). Standard quantification techniques were used to assess biomaterial centered and soft tissue bacterial growth after 7 days. After establishing reliable infection rates in control sites, the therapeutic arm of the study was started. Surgical site infections were found in 75% of control sites, whereas gentamicin microspheres reduced the incidence down to 38% in the same rabbits. Biomaterial-centered infection was reduced from 58% to 23% only in all sites challenged with 10e6 S. aureus. |
Do the Military Health Care System May Have the Potential to Prevent Health Care Disparities? | The existence of health disparities in military populations has become an important topic of research. However, to our knowledge, this is the first study to examine health disparities, as related to access to care and health status, among active duty soldiers and their families. Specifically, the purpose of this analysis was to evaluate whether health disparities exist in access to care and health outcomes of patient satisfaction, physical health status, and mental health status according to race, gender, and sponsor rank in the population of active duty soldiers and their family members. In this cross-sectional study, active duty army soldiers and family members were recruited from either one particular army health clinic where they received their health care or from an adjacent shopping center frequented by eligible participants. Data were collected using validated measures to assess concepts of access to care and health status. Statistical analysis, including one-way analysis of variance (ANOVA) was performed to investigate differences in study outcome measures across four key demographic subgroups: race, gender, sponsor rank, and component (active soldier or family member). A total of 200 participants completed the study questionnaires. The sample consisted of 45.5 % soldiers and 54.5 % family members, with 88.5 % reporting a sponsor rank in the category of junior or senior enlisted rank. Mean scores for access to care did not differ significantly for the groups race/ethnicity (p = 0.53), gender (p = 0.14), and sponsor rank (p = 0.10). Furthermore, no significant differences were observed whether respondents were active soldiers or their family members (p = 0.36). Similarly, there were no statistically significant subgroup (race/ethnicity, gender, sponsor rank, or component) differences in mean patient satisfaction, physical health, and mental health scores. | Uterine vascular remodeling at mid gestation includes the thinning of the vessel walls and, typically, an increase in lumen diameter. This study aimed to elucidate any differences in structural remodeling in normal murine pregnancies versus those differences that resulted from the crossing of CBA/J female mice by DBA/2 male mice, a combination that is known to exhibit recurrent resorption/pregnancy loss. CBA/J female mice that were pregnant by DBA/2 male mice (abnormals) and DBA/2 female mice that were pregnant by CBA/J male mice (normals) were killed at mid gestation, which is a time when fetal resorption can be identified. Tissues were collected for permanent fixation and gene expression studies with complementary DNA macroarrays that were specific for extracellular matrix proteins. A 2-fold increase in expression or a 50% decline was considered significant. Expression changes were confirmed by real-time reverse transcriptase-polymerase chain reaction. The vessel-to-lumen diameter ratios were found to be significantly greater for the CBA/J implantation sites (1.50 +/- 0.05 vs 1.22 +/- 0.02, respectively; P < .0001), which indicates a lack of vascular remodeling. There was also a trend towards smaller lumen diameters for the CBA/J vessels, but this was not statistically significant (78.2 +/- 4.4 microm vs 93.5 +/- 6.8 microm, respectively; P = .22). The mean coefficient of variation for lumen measurements was 0.8% and for vessel diameter was 0.3%. The ranges were 0 to 3.2% and 0 to 1.4%, respectively. Tissue inhibitor of metalloproteinase 2 expression was up-regulated in the placentas of the group with higher resorption rates when compared with normals. This was confirmed with reverse transcriptase-polymerase chain reaction, where abnormals exhibited 2.6-fold greater tissue inhibitor of metalloproteinase 2 protein quantities when compared with normal controls (P = .03). |
Does aortic prosthesis-patient mismatch strongly affect early results of double valve replacement? | The aim of this retrospective single-center study was to assess the authors' results in mitral-aortic double valve replacement (DVR), with attention focused on the risk factors of in-hospital mortality (HM). As the initial results showed a strong relationship between HM and aortic prosthesis-patient mismatch (PPM), this led to an assessment of the impact of PPM on the early results of DVR. Data from 196 consecutive patients (mean age 60 +/- 10 years) who had undergone DVR between January 1996 and December 2011 at the authors' institution were analyzed. A statistical comparison was made of groups defined by the presence/absence of in-hospital death, postoperative complications, and aortic PPM. A logistic regression analysis of the factors associated with HM and their postoperative evolution was also conducted. Surgery was mostly performed on an elective basis (89.3%), using mainly bileaflet mechanical valves (93.9%). The rate of associated coronary bypass (CABG) was 11.2%. Aortic PPM (i.e., an effective orifice area index (EOAI) < or = 0.85 cm2/m2) was noted in 28.1% of patients. HM (6.63%) was significantly related to PPM (p < 0.002), greater age (p < 0.003), a smaller EOAI (p = 0.005), associated CABG (p < 0.008), and a longer aortic cross-clamp time (p < 0.03). Patients with aortic PPM had a significantly worse early outcome, with higher overall (p < 0.0007) and cardiac (p < 0.05) complication rates, a longer intensive care unit stay (p < 0.03), and an almost six-fold higher rate of HM (16.4% versus 2.8%; p < 0.002). PPM and age as risk factors were included in a predictive model of HM based on logistic regression; a similar model for postoperative complications highlighted PPM, age and cardiopulmonary bypass time as significant risk factors. | Despite increased identification of spotted fever group rickettsioses (SFGR) in animals and arthropods, human SFGR are poorly characterized in Taiwan. Patients with suspected Q fever, scrub typhus, murine typhus, leptospirosis, and dengue fever from April 2004 to December 2009 were retrospectively investigated for SFGR antibodies (Abs). Sera were screened for Rickettsia rickettsii Abs by indirect immunofluorescence antibody assay (IFA), and those with positive results were further examined for Abs against R. rickettsii, R. typhi, R. felis, R. conorii, and R. japonica using micro-immunofluorescence (MIF) tests. Polymerase chain reaction (PCR) for detection of SFGR DNA was applied in those indicated acute infections. Case geographic distribution was made by the geographic information system software. A total of 413 cases with paired serum, including 90 cases of Q fever, 47 cases of scrub typhus, 12 cases of murine typhus, 6 cases of leptospirosis, 3 cases of dengue fever, and 255 cases of unknown febrile diseases were investigated. Using IFA tests, a total of 49 cases with 47 (11.4%) and 4 (1.0%) cases had sera potentially positive for R. rickettsii IgG and IgM, respectively. In the 49 cases screened from IFA, MIF tests revealed that there were 5 cases of acute infections (3 possible R. felis and 2 undetermined SFGR) and 13 cases of past infections (3 possible R. felis and 10 undetermined SFGR). None of the 5 cases of acute infection had detectable SFGR DNA in the blood specimen by PCR. Possible acute infection of R. felis was identified in both one case of Q fever and scrub typhus. The geographic distribution of SFGR cases is similar with that of scrub typhus. |
Is for patients with predicted low risk for choledocholithiasis undergoing laparoscopic cholecystectomy , selective intraoperative cholangiography and postoperative endoscopic retrograde cholangiopancreatography an effective strategy to limit unnecessary procedures? | There is debate about whether intraoperative cholangiography (IOC) should be performed routinely or selectively during laparoscopic cholecystectomy (LC) in patients with suspected choledocholithiasis. The timing of endoscopic retrograde cholangiopancreatography (ERCP) in these patients also is an issue. We reviewed the experience in our center, where a management algorithm limiting ERCP in relation to LC was adopted. We retrospectively reviewed every LC performed by one surgeon during 6 years and the related ERCPs. A total of 264 LCs were performed. In 30 patients, stones were cleared or excluded by preoperative ERCP. In the remaining 234 LCs, 31 of 34 IOCs were successfully performed. Two of 31 IOCs were positive for bile duct stones; stone removal was successful in each patient at subsequent ERCP. Only 10 of 201 patients who did not have IOC required postsurgical ERCP within 10 weeks of LC, 3 of whom had common bile duct stones at ERCP. | This study was aimed to investigate the effects of carbon monoxide releasing molecule (CORM-2), a novel carbon monoxide carrier, on the reendothelialization of carotid artery in rat endothelial denudation model. Male rats subjected to carotid artery balloon injury were treated with CORM-2, inactive CORM-2 (iCORM-2) or dimethyl sulfoxide (DMSO). The reendothelialization capacity was evaluated by Evans Blue dye and the immunostaining with anti-CD31 antibody. The number of circulating endothelial progenitor cells (EPCs) was detected by flow cytometry. The proliferation, migration, and adhesion of human umbilical vein endothelial cells (HUVECs) were assessed by using [3H]thymidine, Boyden chamber and human fibronectin respectively. The expressions of protein were detected by using western blot analysis. CORM-2 remarkably accelerated the re-endothelialization 5 d later and inhibited neointima formation 28 d later. In addition, the number of peripheral EPCs significantly increased in CORM-2-treated rats than that in iCORM-2 or DMSO-treated rats after 5 d later. In vitro experiments, CORM-2 significantly enhanced the proliferation, migration and adhesion of HUVECs. The levels of Akt, eNOS phosphorylation, and NO generation in HUVECs were also much higher in CORM-2 treated group. Blocking of PI3K/Akt/eNOS signaling pathway markedly suppressed the enhanced migration and adhesion of HUVECs induced by CORM-2. |
Is sprouty4 , a suppressor of tumor cell motility , down regulated by DNA methylation in human prostate cancer? | Alterations of fibroblast growth factors (FGFs) and their receptors contribute to prostate cancer progression by enhancing cellular proliferation, survival, and motility. The Sprouty gene family negatively regulates FGF signaling and may limit the ability of FGFs to enhance tumor progression. Sprouty1 is down regulated in human prostate cancers and Sprouty1 expression can markedly inhibit prostate cancer proliferation in vitro. Sprouty4 has been shown to negatively regulate both proliferation and cell migration in other systems. We therefore examined whether Sprouty4 expression was altered in prostate cancer. Expression of Sprouty4 was examined by in situ hybridization and quantitative RT-PCR. Methylation of the Sprouty4 gene promoter was assessed using bisulfite modification and sequencing. The effect of Sprouty4 expression on cell migration was determined using an in vitro wounding assay. By in situ hybridization Sprouty4 is expressed in normal prostatic epithelial cells and is decreased in a subset of prostate cancers. Quantitative RT-PCR confirms that Sprouty4 expression is decreased in approximately one half of prostate cancers. Analysis of the 5'-regulatory region revealed a CpG island approximately 1 kb upstream of the transcription initiation site, the proximal portion of which was preferentially methylated in prostate cancer tissues. More than one half of all prostate cancer DNAs were methylated in this region and methylation was significantly correlated with decreased Sprouty4 expression as determined by quantitative RT-PCR. When overexpressed in prostate cancer cell lines, Sprouty4 did not inhibit cell proliferation but did inhibit cell migration. | Intraoperative transesophageal echocardiography has become a routine part of monitoring in patients with cardiac disease. However, insertion of a transesophageal echocardiography probe can be associated with oropharyngeal, esophageal, and gastric injuries. The purpose of this study was to determine whether insertion of a transesophageal echocardiography probe under direct laryngoscopic visualization can reduce the incidence of oropharyngeal mucosal injury. Eighty patients undergoing surgery with general anesthesia were randomly allocated to either the conventional group, in which the probe was inserted blindly, or the laryngoscope group, in which a rigid laryngoscope was used to visualize the passage of the probe. The incidence of oropharyngeal mucosal injury, the number of insertion attempts, and odynophagia were assessed. There was no significant difference in demographic and hemodynamic parameters between the 2 groups. The incidence of oropharyngeal mucosal injury was higher in the conventional group than in the laryngoscope group (55% vs. 5%, P < 0.05). The incidence of odynophagia was higher in the conventional group than in the laryngoscope group (32.5% vs. 2.5%, P < 0.05). The number of insertion attempts was also higher in the conventional group than in the laryngoscope group. |
Is percutaneous transluminal angioplasty feasible and effective in patients on chronic dialysis with severe peripheral artery disease? | Peripheral arterial disease (PAD) is common among patients on chronic dialysis. Despite severe clinical manifestations, the indication for bypass surgery is controversial, because of the high morbidity and mortality rate of these patients. The less invasive percutaneous transluminal angioplasty (PTA) is a possible alternative, but data about PTA in dialysis patients are scarce. We followed 107 dialysis patients (mean age 67+/-10, 75 males) with 132 ischaemic limbs (97% with critical limb ischaemia and ischaemic foot lesions or rest pain) consecutively treated by PTA. PTA was successful in 97% of cases. Median follow-up was 22 months. Cumulative limb salvage rates at 12, 24, 36 and 48 months were 86, 84, 84 and 62%, respectively. Log-rank test showed an association between major amputation and baseline presence of foot lesions (P=0.04). This association was confirmed by a Cox survival multivariate analysis [hazard ratio (HR)=7.03, 95% confidence interval (CI)=1.1-43.0, P=0.035]. Limb salvage without any new intervention on the same leg was achieved in 70% of the cases, and was associated with the absence of diabetes mellitus (P=0.01), lower number of treated lesions (P=0.04) and proximal level (iliac and/or femoro-popliteal) of PTA (P<0.001). Independent predictors were diabetes mellitus (HR=3.47, 95% CI=1.31-9.17, P=0.01) and proximal PTA (HR=0.28, 95% CI=0.08-0.94, P=0.04). Fifty-three (49%) patients died during follow-up. Patients older than 67 years (the median value in our sample) had a 2.4-fold increase in mortality risk (95% CI=1.4-4.1, P<0.001). | We were interested in exploring the molecular mechanisms underlying the observed difference in histamine (H) responsiveness between seasonal allergic rhinitic (SAR) and nonrhinitic (NR) subjects. We hypothesized that SAR subjects express higher nasal mucosal histamine receptor 1 (H1R) and 2 (H2R) levels than do NR subjects. In addition, we examined expression of genes involved in regulating the glandular response, including epidermal growth factor (EGF), EGF receptor (EGFR), and mucins (Muc5Ac and Muc5B). Fourteen subjects, seven SAR and seven NR, were provoked during pollen season with doubling doses of H (0.125-8.0 mg/ml). Nasal airway resistance (NAR) was measured by active posterior rhinomanometry. Provocation was halted when NAR exceeded 150% of baseline. Prior to provocation, nasal scrapings were obtained and mRNA quantified using two-step real-time PCR. The mean PD50 (concentration of H producing a 50% increase in NAR) was significantly lower in the SAR than NR group (0.36 vs 1.32 mg/ml; P < 0.05). The ratio of relative gene copy numbers between the SAR and NR groups were as follows: H1R, 0.85 (P = 0.52); H2R, 0.67 (P = 0.35); EGF, 1.02 (P = 0.93), and EGFR, 103.5 (P < 0.05). |
Are soluble CD40L levels regulated by the -3459 A > G polymorphism and predict myocardial infarction and the efficacy of antithrombotic treatment in non-ST elevation acute coronary syndrome? | Current evidence suggests the CD40-CD40L pathway as a key process in the development, progression, and outcome of acute coronary syndrome (ACS). The aim was to investigate the prognostic importance of soluble (s) CD40L levels, single nucleotide polymorphisms (SNP) in the CD40LG gene, and the relation between sCD40L and SNPs in patients with acute coronary syndromes (ACS). Samples were obtained on admission from 2359 patients with non-ST elevation ACS randomized to an early invasive versus a conservative and to placebo controlled long-term dalteparin treatment in the FRISC-II study. The -3459 A>G SNP was identified as a novel regulator of sCD40L levels (P = 0.001). In the placebo-treated group, sCD40L levels above median were associated with a 2.5-fold increased risk of myocardial infarction (MI) (P < or = 0.001) but not with raised mortality. In the dalteparin treated group, sCD40L showed no association with MI (P = 0.75). Consequently, dalteparin treatment was effective in reducing the risk of MI only in patients with sCD40L levels above median. A combined assessment of troponin-T and sCD40L complemented the prognostic information on risk of MI. | To investigate the effects of lipoic acid in the prevention of postoperative pelvic adhesions by a visual scoring system and immunohistochemistry in a rat uterine horn model with full thickness injury. Twenty-eight female Wistar albino rats were randomised into four groups: uterine trauma control, 15 days and 30 days, and uterine trauma + lipoic acid, 15 days and 30 days. A full thickness defect was established by incising a segment of approximately 1.0 cm in length from each uterine horn, leaving the mesometrium intact. Extension and severity of the adhesions in each group were scored by a visual scoring system and evaluated immunohistochemically. Adhesion scores were 2.00±0.81, 2.14±0.69 0.71±0.75, and 0.85±0.69 for extent and 2.28±0.48, 2.14±0.69, 0.85±0.69, and 1.14±0.69 for severity in Groups 1, 2, 3 and 4, respectively. Adhesion extent and severity were significantly less for groups treated by lipoic acid but no difference was observed between long and short administration. Both Vitronectin and u-PAR staining were significantly increased in treatment groups when compared to the control group. |
Does flightless I Homolog repress Prostate Cancer Progression through Targeting Androgen Receptor Signaling? | Flightless I (FLII), member of the gelsolin superfamily of actin-remodeling proteins, functions as a transcriptional coregulator. We aim to evaluate a tumor-suppressive function of FLII in regulating androgen receptor (AR) in prostate cancer progression. We examined FLII protein and mRNA expression in clinical prostate cancer specimens by immunohistochemistry. Kaplan-Meier analysis was conducted to evaluate the difference in disease-overall survival associated with the expression levels of FLII and AR. Prostate cancer cells stably expressing FLII or shRNA knockdown were used for functional analyses. Immunoprecipitation, Luciferase reporter, and immunofluorescence staining assays were performed to examine the functional interaction between FLII and AR. Our analysis of the expression levels of FLII in a clinical gene expression array dataset showed that the expression of FLII was positively correlated with the overall survival of prostate cancer patients exhibiting high levels of AR expression. Examination of protein and mRNA levels of FLII showed a significant decrease of FLII expression in human prostate cancers. AR and FLII formed a complex in a ligand-dependent manner through the ligand-binding domain (LBD) of AR. Subsequently, we observed a competitive binding to AR between FLII and the ligand. FLII inhibited AR transactivation and decreased AR nuclear localization. Furthermore, FLII contributed to castration-sensitive and castration-resistant prostate cancer cell growth through AR-dependent signaling, and reintroduction of FLII in prostate cancer cells sensitized the cells to bicalutamide and enzalutamide treatment. | Patient simulators incorporate a range of technical features. An understanding of which features are most valuable and which may be less so is important for simulator design and utilization. In this study, we attempted to answer the question of whether or not certain simulator features are perceived by learners as more useful than others in achieving specified educational objectives. The subjects were third and fourth year medical students participating in an Emergency Medicine Simulation Workshop (n = 97). Following the Workshop, subjects rated each of 13 simulator features on a 5-point scale from distracting to extremely useful in achieving specified educational objectives; and then identified the most and least useful features. There were significant differences between the scores of the most highly rated features (vital sign display, interactive voice, chest rise, and palpable pulse), and those of the features with the lowest ratings (abnormal breath sounds, prerecorded voice, IV arm, and heart tones) (4.75 vs. 3.93, P < 0.0001). Three features (heart tones, abnormal breath sounds, and prerecorded voice) were rated by more than one third of the students as distracting, not useful, or uncertain if useful. On the ranking scale, highly rated features tended to be identified as most useful, and those with the lowest ratings were more often ranked as least useful. There was a statistically significant (P < 0.0001) correlation between rating and rankings. |
Does recombinant human epidermal growth factor accelerate recovery of mouse small intestinal mucosa after radiation damage? | To determine whether systemically administered recombinant human epidermal growth factor (rhEGF) accelerates the recovery of mouse small intestinal mucosa after irradiation. A mouse mucosal damage model was established by administering radiation to male BALB/c mice with a single dose of 15 Gy applied to the abdomen. After irradiation, rhEGF was administered subcutaneously at various doses (0.04, 0.2, 1.0, and 5.0 mg/kg/day) eight times at 2- to 3-day intervals. The evaluation methods included histologic changes of small intestinal mucosa, change in body weight, frequency of diarrhea, and survival rate. The recovery of small intestinal mucosa after irradiation was significantly improved in the mice treated with a high dose of rhEGF. In the mice that underwent irradiation without rhEGF treatment, intestinal mucosal ulceration, mucosal layer damage, and severe inflammation occurred. The regeneration of villi was noticeable in mice treated with more than 0.2 mg/kg rhEGF, and the villi recovered fully in mice given more than 1 mg/kg rhEGF. The frequency of diarrhea persisting for more than 3 days was significantly greater in the radiation control group than in the rhEGF-treated groups. | Depression predicts prognosis in many cardiac conditions, including congestive heart failure (CHF). Despite heightened cardiac risk in patients with comorbid atrial fibrillation (AF) and CHF, depression has not been studied in this group. This substudy, from the AF-CHF Trial of rate- versus rhythm-control strategies, investigated whether depression predicts long-term cardiovascular mortality in patients with left ventricular ejection fraction <or=35%, CHF symptoms, and AF history who receive optimal medical care. Depression symptoms (Beck Depression Inventory-II) were assessed in 974 participants (833 men), with 32.0% showing elevated scores (Beck Depression Inventory-II >or=14). Over a mean follow-up of 39 months, there were 246 cardiovascular deaths (111 presumed arrhythmic; 302 all-cause deaths). Cox proportional hazards models adjusted for other prognostic factors (including age, marital status, cause of CHF, creatinine level, left ventricular ejection fraction, paroxysmal AF, previous AF hospitalization, previous electrical conversion, and baseline medications) showed that elevated depression scores significantly predicted cardiovascular mortality (primary outcome), arrhythmic death, and all-cause mortality. The adjusted hazard ratios were 1.57 (95% confidence interval 1.20 to 2.07, P<0.001), 1.69 (95% confidence interval 1.13 to 2.53, P=0.01), and 1.38 (95% confidence interval 1.07 to 1.77, P=0.01), respectively. The risks associated with depression and marital status were additive, with the highest risk in depressed patients who were unmarried. |
Does growth hormone receptor antagonist treatment reduce exercise performance in young males? | The effects of GH on exercise performance remain unclear. The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance. Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment period, they exercised to determine exercise performance and hormonal and metabolic responses. Twenty healthy males participated in the study. Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed a maximal oxygen uptake (VO(2 max)) test and a prolonged exercise test, consisting of 60 min of submaximal cycling followed by exercise to fatigue at 90% of VO(2 max). VO(2 max) was measured before and after the treatment period. Hormonal and metabolic responses and time to exhaustion during prolonged exercise were determined. Resting serum IGF-I concentration decreased by 20% in the GHR antagonist-treated group (P < 0.05), whereas no change was observed in the placebo group. Conversely, resting serum GH concentration was significantly higher in the treatment group compared with the placebo group (P < 0.01). VO(2 max) did not change significantly in either group after the treatment period. Time to exhaustion at 90% of VO(2 max) was significantly shorter in the treatment group (P < 0.05). No significant differences were observed between the groups in terms of changes in serum free fatty acids, glycerol, VO(2), or relative fat oxidation. | Centrosome orientation toward the leading edge of migrating cells depends on dynein and microtubules (MTs), as well as a number of signaling factors at the leading edge. However, centrosomes are maintained at the cell center during orientation in fibroblasts, suggesting that factors working at sites other than the leading edge may also be involved. In a search for factors that function with dynein in centrosome orientation, we found that the polarity protein Par3 associated with dynein and that knockdown of Par3 inhibited centrosome orientation by disrupting the position of the centrosome at the cell center; this disrupted centrosome positioning is the same phenotype as that observed with dynein inhibition. Par3 associated with dynein through its N-terminal dimerization and PDZ1 domains and interacted specifically with dynein light intermediate chain 2 (LIC2). siRNA knockdown of LIC2, but not LIC1, or overexpression of LIC2 or the N-terminal domain of Par3, also inhibited centrosome orientation by disrupting centrosome position. In wound-edge fibroblasts, Par3 specifically localized to cell-cell contacts where it overlapped with MT ends and dynein puncta in a LIC2-dependent fashion. Live imaging showed that MTs exhibited increased pausing at cell-cell contacts compared to the leading edge and that this elevated pausing was dependent on Par3 and LIC2. |
Does corneal endothelial morphology result in the Menicon Z 30-day continuous-wear contact lens clinical trial? | This evaluation was conducted as part of a protocol entitled Evaluation of the Menicon Z Rigid Gas Permeable Contact Lens for up to 30 Days Extended Wear. The purpose of the protocol was to compare corneal endothelial morphology changes after wearing rigid gas-permeable (RGP) Menicon Z contact lenses, continuously for up to 30 days, with ACUVUE (Johnson & Johnson Vision Care) hydrogel contact lenses, worn for up to 6 nights of extended wear. Sixty patients, who were adapted to RGP daily wear and soft contact lens daily wear, were recruited at two study sites. The thirty subjects who wore RGP daily wear lenses were fitted with the Menicon Z (tisilfocon A, oxygen permeablility [Dk] = 163) RGP contact lens comprised the test group. The control group subjects (n = 30 former users of daily wear soft contact lenses) were fitted with ACUVUE (etafilcon A, Dk = 28) hydrogel contact lenses. After a 2-week adaptation period of daily wear, subjects began extended wear. Endothelial imaging was performed at the two study sites in this multicenter study (University Hospitals of Cleveland/Case Western Reserve University Department of Ophthalmology [CWRU] and The Ohio State University [OSU]). The hydrogel lens group was instructed to wear their lenses for 7 days and 6 nights before discarding the lenses and to sleep with no lenses on the seventh night. The RGP group was permitted to wear the lenses for up to 30 days and 29 consecutive nights before removing the lenses for cleaning and overnight soaking. CWRU had 24 patients (12 soft contact lens and 12 rigid contact lens) and OSU had 21 patients (12 soft contact lens and 9 rigid contact lens) who completed the study and were included in the analyses. Patients who were withdrawn from the study at CWRU included one RGP patient dropped out because of pregnancy; one RGP patient developed vascularized limbal keratitis and discomfort; one could not be fitted with a bitoric RGP; two soft lens patients moved from the area, and one dropped out because of dry eyes. At OSU, four patients dropped out due to discomfort (two in each lens type);one moved from the study area; one decided not to participate soon after the consent visit; one had worries of reduced vision at 6 months; one subject's attitude changed prior to the 6 month visit; and one subject was withdrawn for reasons of poor study schedule compliance. | Metabolic adverse effects of atypical antipsychotics (AAP) contribute significantly to increased risk of cardiovascular morbidity and mortality in patients suffering from schizophrenia. Extensive preclinical research has addressed this issue over the past years, though mechanisms underlying these adverse effects of AAP are still not understood completely. Recently, attention is drawn towards the role of adipose tissue metabolism and neurohormonal regulations. The aim of this study was to evaluate the time-dependent effects of olanzapine depot administration at clinically relevant dosing on the regulation of energy homeostasis, glucose and lipid metabolism, gastrointestinal and adipose tissue-derived hormones involved in energy balance regulations in female Sprague-Dawley rats. The study lasted 8 weeks and the markers were assayed at day 8, 15, 29, 43 and 57. The results indicate that in the absence of hyperphagia, olanzapine chronic exposure induced weight gain from the beginning of the study. In the later time-point, increased adiposity was also observed. In the initial phase of the study, lipid profile was altered by an early increase in triglyceride level and highly elevated leptin level was observed. Clear bi-phasic time-dependent effect of olanzapine on leptin serum concentration was demonstrated. Olanzapine treatment did not lead to changes in serum levels of ghrelin, FGF-21 and pro-inflammatory markers IL-1a, IL-6 and TNF-α at any time-point of the study. |
Is obesity associated with greater inflammation and monocyte activation among HIV-infected adults receiving antiretroviral therapy? | Among virally suppressed HIV-infected persons, we examined the relationship between obesity and alterations in key clinical markers of immune activation and inflammation. These markers have also been associated with excess HIV-related cardiovascular disease and mortality. We evaluated data from virally suppressed participants in the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy, including inflammatory biomarkers (interleukin-6 and highly sensitive C-reactive protein), monocyte biomarkers [soluble CD163 (sCD163), sCD14], and monocyte immunophenotypes. We assessed associations with these immunologic measures and obesity, via logistic regression preadjustment and postadjustment for demographic and clinical factors, homeostatic model assessment of insulin resistance, and leptin levels. Among 452 evaluable participants, median (interquartile range) age was 41 (36-48) years, CD4 cell count was 475 (308-697) cells/μl, and 21% were obese (BMI ≥ 30 kg/m). In univariable models, obesity, smoking, and lower CD4 cell count were associated with higher measures of inflammation and monocyte activation. After adjustment, obesity remained independently associated with elevated levels (highest vs. lower two tertiles) of interleukin-6 [odds ratio (OR) 1.96; P = 0.02], highly sensitive C-reactive protein (OR 2.79; P < 0.001) and sCD163 (OR 1.94; P = 0.02), and elevated frequency of CD14CD16 (OR 1.77; P = 0.03) and CD14dimCD16 (OR 1.97; P = 0.01). Adjusting for homeostatic model assessment of insulin resistance and leptin modestly affected associations for obesity with inflammation and monocyte activation. | To analyze long-term clinical results of coagulation lesions of the dorsal root entry zone (DREZ) in patients with deafferentation pain due to brachial plexus avulsion and to correlate the pain relief after DREZ coagulation with pain duration before the DREZ coagulation. Twenty-six patients with intractable deafferentation pain after brachial plexus avulsion lesion were treated for pain at the Department of Neurosurgery. Junctional coagulation lesion was made with bipolar forceps along the DREZ. The patients assessed post-operative analgesic effect using a visual analog scale at 1 week, 1 year, 3 years, and 5 years after the surgery. The greatest pain relief was reported immediately after the DREZ procedure. Over the 5-year follow-up period, the pain relief effect gradually and significantly decreased. There were no significant differences between the pain relief evaluated at 1 week and after 1 year and between the pain relief evaluated at 1 week and after 3 years. There was a correlation between the pain duration before the surgery and pain relief after the surgery, with best correlation found between pain duration before surgery and pain relief 5 years after DREZ procedure (r = 0.623, P = 0.007). |
Is functional half-life a meaningful descriptor of steady-state pharmacokinetics of an extended-release formulation of a rapidly cleared drug : as shown by once-daily divalproex-ER? | For many drugs, steady-state concentration-time profiles are often not optimally characterised by the intrinsic terminal elimination half-life for various reasons, including multiexponential disposition with minimal contribution of the terminal phase to steady-state exposure or use of controlled-release formulations with extended zero- or mixed zero-/first-order absorption. In such cases, 'effective' or 'functional' half-life (t((1/2)F)) has often been used to characterise steady-state pharmacokinetics. Valproic acid, commonly used in neuropsychiatry, has an elimination half-life of 4-16 hours in different populations (children vs adults, enzyme-induced vs uninduced). Divalproex-ER, a once-daily extended- release divalproex sodium formulation, is designed to release valproic acid over >18 hours. Hence the steady-state divalproex-ER concentration-time profiles have small peak-trough fluctuations that are not optimally characterised by valproic acid elimination half-life. In this study, the value of t((1/2)F) was calculated to characterise divalproex-ER steady-state concentration-time profiles. The value of t((1/2)F), defined as the time taken for the concentration to drop by one-half during a dosing interval (tau) at steady state, was derived using steady-state maximum (C(max)) and minimum (C(min)) plasma concentration and tau values, and calculated as ln(2)/(ln [C(max)/C(min)]/tau). The t((1/2)F) values of valproic acid in adult hepatic enzyme-uninduced healthy subjects and enzyme-induced epilepsy patients were calculated from five pharmacokinetic studies in which divalproex-ER was administered once daily for 6-14 days. The estimated geometric mean t((1/2)F) in uninduced adults was 40.0 hours versus the expected elimination half-life of 12-16 hours in this population (including patients on valproic acid monotherapy); for induced patients, t((1/2)F) was 26.9 hours versus the expected elimination half-life of 6-12 hours. | Interleukin-8 (IL-8), a CXC chemokine that induces the migration and proliferation of endothelial cells and smooth muscle cells, is a potent angiogenic factor that may play a role in atherosclerosis. Previously, IL-8 has been reported in atherosclerotic lesions and circulating macrophages from patients with atherosclerosis. Therefore, we sought to determine whether IL-8 plays a role in mediating angiogenic activity in atherosclerosis. Homogenates from 16 patients undergoing directional coronary atherectomy (DCA) and control samples from the internal mammary artery (IMA) of 7 patients undergoing bypass graft surgery were assessed for IL-8 content by specific ELISA, immunohistochemistry, and in situ hybridization for IL-8 mRNA. The contribution of IL-8 to net angiogenic activity was assessed using the rat cornea micropocket assay and cultured cells. IL-8 expression was significantly elevated in DCA samples compared with IMA samples (1.71+/-0.6 versus 0.05+/-0.03 ng/mg of total protein; P<0.01). Positive immunolocalization of IL-8 was found exclusively in DCA tissue sections, and it correlated with the presence of factor VIII-related antigen. In situ reverse transcriptase polymerase chain reaction revealed the expression of IL-8 mRNA in DCA tissue. Corneal neovascular response, defined by ingrowth of capillary sprouts toward the implant, was markedly positive with DCA pellets, but no constitutive vessel ingrowth was seen with IMA specimens. Neutralizing IL-8 attenuated both the in vivo corneal neovascular response and the in vitro proliferation of cultured cells. |
Does a novel mutation in the ELOVL4 gene cause autosomal dominant Stargardt-like macular dystrophy? | To conduct clinical and genetic studies in a European family with autosomal dominant Stargardt-like macular dystrophy (adSTGD-like MD) and to investigate the functional consequences of a novel ELOVL4 mutation. Ophthalmic examination and mutation screening by direct sequencing of the ELOVL4 gene was performed in two affected individuals. Wild-type and mutant ELOVL4 genes were expressed as enhanced green fluorescent protein (EGFP) fusion proteins in transient transfection in NIH-3T3 and HEK293 cells. To determine the subcellular localization of ELOVL4, an endoplasmic-reticulum (ER)-specific marker for pDsRed2-ER was cotransfected with ELOVL4 constructs. Transfected cells were viewed by confocal microscopy. Western blot analysis was performed to assess protein expression using an anti-GFP antibody. Affected patients exhibited macular atrophy with surrounding flecks characteristic of adSTGD-like MD. A novel ELOVL4 p.Tyr270X mutation was detected in affected individuals. In cell-transfection studies, wild-type ELOVL4 localized preferentially to the ER. In contrast, the mutant protein appeared to be mislocalized within transfected cells. | The purpose of this study was to assess the usefulness of stroke volume variations to monitor the early fluid resuscitation in mechanically ventilated burn ICU patients. Data of 29 burn patients (APACHE II - 9.8±3.6, SAPS II - 29±5, TBSA - 39.5±14) were prospectively included in this observational study. Hemodynamic parameters were determined using arterial pressure wave analysis for up to 36h after burn. Statistically significant changes in cardiac index (CI), systemic vascular resistance index (SVRI), stroke volume variation (SVV) were recorded during the observation period. There were significant correlations between CI and SVV (r=-0.454, p=0.03), SVV and SVRI (r=0.482, p=0.02) at 16 h postburn; CI and SVV (r=-0.513, p=0.012), SVV and SVRI (r=0.480, p=0.02) at 24 h postburn, CI and SVV at 36 h postburn (r=-0.478, p=0.021). Significant changes in CI (1.9±1 vs. 3.4±0.9), p=0.02 and in SVV (24.9±3 vs. 14.6±2, p=0.01) were observed in patients with low cardiac output state after administration of 10 ml/kg of Ringer lactate. |
Does muscovite reverse gastric gland atrophy and intestinal metaplasia by promoting cell proliferation in rats with atrophic gastritis? | To detect whether muscovite exerts its protective role in the progression of atrophic gastritis (AG) and evaluate the possible mechanism. AG rats were established and then randomly divided into groups administrated with different doses of muscovite for 8 weeks. Histological changes in gastric antrum and the number of parietal cells, chief cells, and G/D cells were observed. Serum gastrin and prostaglandin E2 (PGE2) were evaluated by enzyme-linked immunosorbent assay (ELISA). The expression of proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR), C-erbB-2, p21, p53, p16 and bcl-2 in gastric tissue were detected by immunohistochemistry. The concentrations of TNF-alpha and IL-1beta secreted by THP-1 cells were detected when incubated with different doses of muscovite. The grade of inflammation in muscovite groups was lower (p < 0.05), while the thickness and number of gastric glands were significantly elevated in muscovite groups (p < 0.01). The expression height of PCNA in the muscovite group was higher than in the AG group (p < 0.01). Immunohistochemistry results showed a positive expression rate of EGFR; p16 in muscovite-treated AG rats was increased (p < 0.05), while C-erbB-2 and p21 were decreased (p < 0.05). Serum gastrin and PGE2 were significantly elevated in the high-dose muscovite-treated rats (p < 0.05). In vitro studies showed that muscovite had a dose-dependent adsorption of TNF-alpha and IL-1beta. | The PlA1/A2 polymorphism of platelet glycoprotein IIIa (GPIIIa) has been implicated in the pathogenesis of type 2 diabetes. We studied this polymorphism in a homogenous, extensively phenotyped cohort using the candidate gene approach. The PlA1/A2 polymorphism was determined in 1051 patients with type 2 diabetes and in 2247 individuals without type 2 diabetes. In patients with type 2 diabetes, genotype frequencies were as follows: PlA1/A1 71.4%, PlA1/A2 26.0%, and PlA2/A2 2.7%. In individuals without type 2 diabetes, genotype frequencies were 71.6%, 25.7% and 2.8%, respectively. The PlA2 allele was not associated with fasting and postprandial glucose, glycated haemoglobin, insulin, proinsulin, C-peptide and calculated indices of insulin resistance or pancreatic beta cell function. The PlA2 allele was also not significantly associated with angiographic CHD (adjusted odds ratio [OR] 1.13; 95% CI, 0.93-1.39) or with a history of previous myocardial infarction (adjusted OR 1.09; 95% CI, 0.87-1.37). |
Does use of activated protein C have no avail in the early phase of acute pancreatitis? | Sepsis and acute pancreatitis have similar pathogenetic mechanisms that have been implicated in the progression of multiple organ failure. Drotrecogin alfa, an analogue of endogenous protein C, reduces mortality in clinical sepsis. Our objective was to evaluate the early therapeutic effects of activated protein C (APC) in a rat model of acute necrotizing pancreatitis. Acute necrotizing pancreatitis was induced by intraductal injection of 5% Na taurocholate. Hourly bolus injections of saline or recombinant human APC (drotrecogin alfa) was commenced via femoral venous catheter four hours after the induction of acute pancreatitis. The experiment was terminated nine hours after pancreatitis induction. Animals in group one (n=20) had a sham operation while animals in group two (n=20) received saline and animals in group three (n=20) received drotrecogin alfa boluses after acute pancreatitis induction. Pancreatic tissue for histopathologic scores and myeloperoxidase, glutathione reductase, glutathione peroxidase, and catalase activities were collected, and blood for serum amylase, urea, creatinine, and interleukin-6 measurements was withdrawn. Serum amylase activity was significantly lower in the APC treated group than the untreated group (17,435+/-432 U/L vs. 27,426+/-118 U/L, respectively). While the serum interleukin-6 concentration in the APC untreated group was significantly lower than the treated group (970+/-323 pg/mL vs. 330+/-368 pg/mL, respectively). | To investigate the effect of ginsenoside Rg1 on the migration, adhesion, proliferation, and VEGF expression of endothelial progenitor cells (EPCs). EPCs were isolated from human peripheral blood and incubated with different concentrations of ginsenoside Rg1 (0.1, 0.5, 1.0, and 5.0 micromol/L) and vehicle controls. EPC migration was detected with a modified Boyden chamber assay. EPC adhesion was determined by counting adherent cells on fibronectin-coated culture dishes. EPC proliferation was analyzed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In vitro vasculogenesis was assayed using an in vitro vasculogenesis detection kit. A VEGF-ELISA kit was used to measure the amount of VEGF protein in the cell culture medium. Ginsenoside Rg1 promoted EPC adhesion, proliferation, migration and in vitro vasculogenesis in a dose- and time-dependent manner. Cell cycle analysis showed that 5.0 micromol/L of ginsenoside Rg1 significantly increased the EPC proliferative phase (S phase) and decreased the resting phase (G(0)/G(1) phase). Ginsenoside Rg1 increased vascular endothelial growth factor production. |
Does integration of Bayesian molecular clock methods and fossil-based soft bounds reveal early Cenozoic origin of African lacertid lizards? | Although current molecular clock methods offer greater flexibility in modelling evolutionary events, calibration of the clock with dates from the fossil record is still problematic for many groups. Here we implement several new approaches in molecular dating to estimate the evolutionary ages of Lacertidae, an Old World family of lizards with a poor fossil record and uncertain phylogeny. Four different models of rate variation are tested in a new program for Bayesian phylogenetic analysis called TreeTime, based on a combination of mitochondrial and nuclear gene sequences. We incorporate paleontological uncertainty into divergence estimates by expressing multiple calibration dates as a range of probabilistic distributions. We also test the reliability of our proposed calibrations by exploring effects of individual priors on posterior estimates. According to the most reliable model, as indicated by Bayes factor comparison, modern lacertids arose shortly after the K/T transition and entered Africa about 45 million years ago, with the majority of their African radiation occurring in the Eocene and Oligocene. Our findings indicate much earlier origins for these clades than previously reported, and we discuss our results in light of paleogeographic trends during the Cenozoic. | Increased systemic levels of inflammatory mediators are seen after open abdominal operations. Macrophages that are exposed to lipopolysaccharide secrete cytokines. Peritoneal macrophages normally reside in a pO(2) of 40 mm Hg. We hypothesize that exposure of lipopolysaccharide-stimulated macrophages to "non-physiologic" pO(2) augments cytokine secretion. Murine macrophages were preconditioned to a pO(2) of 40 mm Hg for 24 hours. The medium then was discarded and exchanged for a medium containing a pO(2) of 40, 150, or 440 mm Hg. Macrophages were incubated in the desired pO(2) for 6 and 24 hours while stimulated with lipopolysaccharide (0 to 100 ng/mL). The effect of pO(2) was compared. Supernatant tumor necrosis factor (TNF) and interleukin-6 were measured with enzyme-linked immunosorbent assay. Statistics were performed with analysis of variance. We found dose-dependent lipopolysaccharide-stimulated TNF and interleukin-6 production with macrophages incubated at physiologic pO(2). Higher pO(2) did not stimulate TNF and interleukin-6 in the absence of lipopolysaccharide. However, a pO(2) of 150 and 440 mm Hg significantly (P <.05) increased lipopolysaccharide-stimulated TNF and interleukin-6 production versus 45 mm Hg. |
Does mild hyponatremia carry a poor prognosis in community subjects? | Hyponatremia has been shown to predict adverse outcome in congestive heart failure and pneumonia among other common clinical entities, but its significance in the general population is elusive. The population-based Copenhagen Holter Study included 671 men and women aged 55 to 75 years with no history of cardiovascular disease, stroke, or cancer. Baseline evaluation included 48-hour ambulatory electrocardiogram monitoring, blood tests, and a questionnaire. Hyponatremia was defined as s-Na < or = 134 mEq/L or s-Na < or = 137 mEq/L according to previously accepted definitions. An adverse outcome was defined as deaths or myocardial infarction. Median follow-up was 6.3 years. Fourteen subjects (2.1%, group A) had s-Na < or = 134 mEq/L, and 62 subjects (9.2%, group B) had s-Na < or = 137 mEq/L. No subject had s-Na < 129 mEq/L. An adverse outcome occurred in 43% of group A, 27% of group B, and 14% of subjects with s-Na >137 mEq/L (controls) (P < .002). Adjusted hazard ratio for adverse outcome was 3.56 (95% confidence interval [CI], 1.53-8.28, P < .005) in group A compared with controls and 2.21 (95% CI, 1.29-3.80, P < .005) in group B after controlling for age, gender, smoking, diabetes, low-density lipoprotein cholesterol, and blood pressure. The hazard ratios were robust for additional adjusting for variables showing univariate association to hyponatremia (ie, beta-blocker and diuretic use, heart rate variability, creatinine, C-reactive protein, and NT-pro brain natriuretic peptide). By excluding diuretic users (18% of subjects), the adjusted hazard ratio for adverse outcome was 8.00 (95% CI, 3.04-21.0, P < .0001) in group A and 3.17 (95% CI, 1.76-5.72, P = .0001) in group B compared with controls. | Tendon tissue engineering (TTE) tries to produce tendinous tissue of high quality to replace dysfunctional tissue. One possible application of TTE might be the replacement of ruptured tissue of the rotator cuff. Autologous tenocytes seem to be most suitable as no differentiation in vitro is necessary. Today it is still uncertain if there is a difference between tendon-derived cells (TDC) of different native tissues. Moreover, the search for suitable scaffolds is another important issue in TTE. This study compared TDC of the long head of the biceps tendon (LHB), the anterior cruciate ligament (ACL) and the tendon of the musculus semitendinosus (TMS). The TDC were isolated using the cell migration method. Cell morphology was assessed using light microscopy and gene expression was performed using polymerase chain reaction (PCR). Afterwards, cell seeding efficiency and proliferation were tested on a collagen I scaffold using the WST-1 assay. Results were confirmed using H + E staining. The TDC of the LHB showed higher expression levels of collagen type I and decorin (p < 0.01) compared to TDC of other origin. Results showed efficient cell seeding and proliferation within the scaffold. Proliferation within the scaffold was not as high as when cells were cultivated without a scaffold. |
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