HariModelMaven/distilroberta-pubmed-embeddings
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Do competency assessment of primary care physicians as part of a peer review program? | To design and test a program that assesses clinical competence as a second stage in a peer review process and to determine the program's reliability. A three-cohort study of Ontario primary care physicians. Reference physicians (n = 26) randomly drawn from the Hamilton, Ontario, area; volunteer, self-referred physicians (n = 20); and physicians referred by the licensing body (n = 37) as a result of a disciplinary hearing or peer review. Standardized patients, structured oral examinations, chart-stimulated recall, objective structured clinical examination, and multiple-choice examination. Test reliability was high, ranging from 0.73 to 0.91, and all tests discriminated among subgroups. Demographic variables relating to the final category were age, Canadian or foreign graduates, and whether or not participants were certified in family medicine. | Static stretch is frequently observed in the lung. Both static stretch and cyclic stretch can induce cell death and Na(+)/K(+)-ATPase trafficking, but stretch-induced alveolar epithelial cell (AEC) functions are much less responsive to static than to cyclic stretch. AEC remodeling under static stretch may be partly explained. The aim of this study was to explore the AEC remodeling and functional changes under static stretch conditions. We used A549 cells as a model of AEC type II cells. We assessed F-actin content and cell viability by fluorescence staining at various static-stretch magnitudes and time points. Specifically, we used scanning electron microscopy to explore the possible biological mechanisms used by A549 cells to 'escape' static-stretch-induced injury. Finally, we measured choline cytidylyltransferase-alpha (CCT alpha) mRNA and protein by real-time PCR and Western blot to evaluate cellular secretory function. The results showed that the magnitude of static stretch was the primary determinant of static-stretch-induced cell death and cytoskeleton organization, but an extended duration of high static deformation/stretch (37% change in surface area) had no cumulative effects on cell death and cytoskeleton organization. AEC remodeling (expansion-contraction-reexpansion) under static stretch conditions may explain this interesting phenomenon partly. After cell remodeling, CCT alpha expression in A549 cells was influenced not only by stretch magnitude but also by stretch time. |
Is age an important determinant of the growth hormone response to sprint exercise in non-obese young men? | The factors that regulate the growth hormone (GH) response to physiological stimuli, such as exercise, are not fully understood. The aim of the present study is to determine whether age, body composition, measures of sprint performance or the metabolic response to a sprint are predictors of the GH response to sprint exercise in non-obese young men. Twenty-seven healthy, non-obese males aged 18-32 years performed an all-out 30-second sprint on a cycle ergometer. Univariate linear regression analysis was employed to evaluate age-, BMI-, performance- and metabolic-dependent changes from pre-exercise to peak GH and integrated GH for 60 min after the sprint. GH was elevated following the sprint (change in GH: 17.0 +/- 14.2 microg l(-1); integrated GH: 662 +/- 582 min microg l(-1)). Performance characteristics, the metabolic response to exercise and BMI were not significant predictors of the GH response to exercise. However, age emerged as a significant predictor of both integrated GH (beta = -0.547, p = 0.003) and change in GH (beta = -0.448, p = 0.019) after the sprint. | We have previously reported the crucial roles of oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) in inhibiting apoptosis and disrupting cell polarity via the regulation of phosphodiesterase 4 (PDE4) expression in human colorectal cancer HCT116 cells in three-dimensional cultures (3DC). Herein we evaluated the effects of resveratrol, a PDE4 inhibitor, on the luminal cavity formation and the induction of apoptosis in HCT116 cells. Apoptosis was detected by immunofluorescence using confocal laser scanning microscopy with an antibody against cleaved caspase-3 in HCT116 cells treated with or without resveratrol in a two-dimensional culture (2DC) or 3DC. Resveratrol did not induce apoptosis of HCT116 cells in 2DC, whereas the number of apoptotic HCT116 cells increased after resveratrol treatment in 3DC, leading to formation of a luminal cavity. |
Is terlipressin more effective in decreasing variceal pressure than portal pressure in cirrhotic patients? | Terlipressin decreases portal pressure. However, its effects on variceal pressure have been poorly investigated. This study investigated the variceal, splanchnic and systemic hemodynamic effects of terlipressin. Twenty cirrhotic patients with esophageal varices grade II-III, and portal pressure > or =12 mmHg were studied. Hepatic venous pressure gradient, variceal pressure and systemic hemodynamic parameters were obtained. After baseline measurements, in a double-blind administration, 14 patients received a 2mg/iv injection of terlipressin and six patients received placebo. The same measurements were repeated 60 min later. No demographic or biochemical differences were observed in basal condition between groups. Terlipressin produced significant decreases in intravariceal pressure from 20.9+4.9 to 16.3+/-4.7 mmHg (p<0.01, -21+/- 16%), variceal pressure gradient from 18.9+/-4.8 to 13.5+/-6.0 mmHg (p<0.01, -28+/-27%), estimated variceal wall tension from 78+/-29 to 59+/-31 mmHg x mm (p<0.01, -27+/-22%), and hepatic venous pressure gradient from 19.4+/-4.5 to 16.8+/-5 mmHg (p<0.01, -14+/-12%) at 60 min. The change in variceal pressure after 60 min of terlipressin administration was greater than the change in wedge hepatic venous pressure (-4.7 mmHg vs -0.5 mmHg, respectively, p<0.0001). Terlipressin also caused significant decreases in heart rate and cardiac index and increases in mean arterial pressure and peripheral vascular resistance. | Based on the theories of brain reserve and cognitive reserve, we investigated whether larger maximal lifetime brain growth (MLBG) and/or greater lifetime intellectual enrichment protect against cognitive decline over time. Forty patients with multiple sclerosis (MS) underwent baseline and 4.5-year follow-up evaluations of cognitive efficiency (Symbol Digit Modalities Test, Paced Auditory Serial Addition Task) and memory (Selective Reminding Test, Spatial Recall Test). Baseline and follow-up MRIs quantified disease progression: percentage brain volume change (cerebral atrophy), percentage change in T2 lesion volume. MLBG (brain reserve) was estimated with intracranial volume; intellectual enrichment (cognitive reserve) was estimated with vocabulary. We performed repeated-measures analyses of covariance to investigate whether larger MLBG and/or greater intellectual enrichment moderate/attenuate cognitive decline over time, controlling for disease progression. Patients with MS declined in cognitive efficiency and memory (p < 0.001). MLBG moderated decline in cognitive efficiency (p = 0.031, ηp (2) = 0.122), with larger MLBG protecting against decline. MLBG did not moderate memory decline (p = 0.234, ηp (2) = 0.039). Intellectual enrichment moderated decline in cognitive efficiency (p = 0.031, ηp (2) = 0.126) and memory (p = 0.037, ηp (2) = 0.115), with greater intellectual enrichment protecting against decline. MS disease progression was more negatively associated with change in cognitive efficiency and memory among patients with lower vs higher MLBG and intellectual enrichment. |
Do stem cells improve the quality of colonic anastomoses - A systematic review? | Stem cells have multiple ways of differentiating and restoring healing. This feature may recommend their usage for decreasing the incidence of anastomotic fistulas in the colon in case of colorectal malignancy. To determine whether stem cells are improving digestive healing, we performed a literature review using as Mesh terms: "anastomotic leak", "stem cells", and "colonic anastomoses", followed by an observational analysis on 3 experimental studies. We found that stem cells increase bursting pressure by an elevated rate of angiogenesis. In addition, the hydroxyproline content of the anastomoses is significantly increased in the stem cell group. The results concerning microscopic characteristics of digestive healing varied markedly between studies. | To investigate the effects of physical activity (PA) on dyslipidemia and elevated resting heart rate (RHR) in a large-scale cross-sectional study in China. We recruited community-based individuals who were 40-60 years old using a cluster sampling method. The PA levels of the participants were classified as low, moderate, or high, using the International Physical Activity Questionnaire. Dyslipidemia was defined as the detection of abnormalities in lipid indicators, and 4 lipid parameters were evaluated using fasting blood samples. Multivariate logistic regression analyses were used to evaluate the associations of PA with dyslipidemia and RHR. A total of 10,321 participants (38.88% men) were included in this study. The percentages of individuals with high, moderate, and low PA levels were 46.5%, 43.9%, and 9.6%, respectively. In both men and women, high PA provided odds ratios of 0.88 [95% confidence interval (CI): 0.83, 0.94] for dyslipidemia and 0.82 (95% CI: 0.73, 0.92) for elevated RHR, compared to participants with low PA. |
Is evolution of the renal function a better predictor of long-term survival than serum creatinine? | In recent years acute rejection has decreased to 10% to 20%. Therefore it is necessary to look for new endpoints in renal transplantation. Serum creatinine and changes in creatinine have been reported to be powerful predictors of long-term kidney transplant survival. Chronic renal allograft nephropathy is the primary cause of long-term graft failure but may appear at any stage in the evolution. Data from 315 patients receiving cadaver donor renal transplants between February 1987 and March 2001 that functioned for 1 year were examined for the influence of demographic characteristics and transplant variables. Creatinine clearance was estimated using the Cockroft-Gault formula. Survival was assessed with the actuarial method. The multivariate analyses were performed using Cox proportional hazard models. The 10-year graft survival showed a relative risk of 2.5 in the univariate analysis when there was more than 10% decrease in renal function at 3 months compared with nadir values. When the decrease was more than 25% of creatinine clearance at the third month, during the evolution and serum creatinine at 3 months introduced in the multivariate model, the latter was not significant, while the other variables had a RR of 4.4 and 10, respectively. | Atp13a2 (Park9) gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2), and its missense or truncation mutations leads to lysosomal dysfunction and consequently results in neuronal death in the pathogenesis of Parkinson's disease (PD). Nevertheless, the roles of ATP13A2 in the biological features of astrocytes, especially in the regulation of PD-related neuroinflammation, have not been investigated. We cultured primary neurons and astrocytes from mouse midbrain to investigate the mechanisms for astrocyte ATP13A2-regulated lysosomal function and neuroinflammation following 1-methyl-4-phenylpyridinium (MPP(+) ) treatment. We found that astrocytes expressed considerable levels of ATP13A2 and deficiency of ATP13A2 in astrocyte-induced intense inflammation, which exacerbated dopaminergic neuron damage after exposure to MPP(+) . Notably, lack of ATP13A2 increased lysosomal membrane permeabilization and cathepsin B release, which in turn exacerbated activation of nod-like receptor protein 3 (NLRP3) inflammasome to produce excess IL-1β from astrocytes. Furthermore, overexpression of ATP13A2 reversed MPP(+) -induced cathepsin B release and NLRP3 inflammasome activation in astrocytes. |
Does herring ( Clupea harengus ) supplemented diet influence risk factors for CVD in overweight subjects? | To assess the effect of a 4-week herring diet compared to a reference diet on biomarkers for cardiovascular disease in obese subjects. Randomized crossover trial. Department of Internal Medicine, Sahlgrenska University Hospital. Fifteen healthy obese men and women (age 24-70 years) included, 13 completed. Subjects were randomly assigned to four weeks of herring diet (150 g baked herring fillets/day 5, days/week) or reference diet (pork and chicken fillets) and switched diets after 2 weeks washout. P-total cholesterol, p-TAG, p-HDL, p-HDL(2), p-HDL(3), p-LDL, p-apolipoprotein A, p-apolipoprotein B, p-Lipoprotein (a), p-fibrinogen, p-C- reactive protein and p-antioxidative capacity were analysed at 0,2,4,6,8 and 10 weeks. P-HDL was significantly higher after the herring diet period compared to after the reference diet period; 1.22 vs 1.13 mmol/l (P=0.036). There was a small, but not statistically significant, decrease in TAG but no effect on other biomarkers. TEAC and FRAP, but not ORAC-values, indicated that plasma antioxidants may have been reduced. CRP tended to be lower after the herring diet compared to after the reference diet. | CD151 belongs to the group of tetraspanins and is aberrantly expressed in different tumours and differential expression has been associated with prognosis. The aim of this study was to clarify the relationship of CD151 expression with tumour phenotype and clinical outcome in bladder cancer. A bladder cancer tissue microarray containing samples from 686 urothelial bladder cancers was analysed by immunohistochemistry. Membranous CD151 immunostaining was recorded in 409 (66.0%) of 620 analysable cases. High CD151 expression was seen in normal urothelium and in most non-invasive tumours. Low CD151 expression levels were associated with a more unfavourable tumour phenotype. CD151 staining was seen in 71.5% of 284 pTa, 62.1% of 145 pT1 and 60.4% of 187 pT2-4 cancers (p = 0.0033). CD151 staining was detectable in 77.3% of 75 grade 1, 71.1% of 273 grade 2 and 57.7% of 272 grade 3 cancers (p < 0.0001). CD151 expression status was not associated with overall or tumour-specific survival in muscle-invasive cancers (pT2-4), tumour progression in pT1 and recurrences in pTa tumours. |
Does infusion of human embryonic kidney cell line conditioned medium reverse kainic acid induced hippocampal damage in mice? | Hippocampal neurodegeneration is one of the hallmarks in neurological and neurodegenerative diseases such as temporal lobe epilepsy and Alzheimer disease. Human embryonic kidney (HEK) cells are a mixed population of cells, including neurons, and their conditioned medium is enriched with erythropoietin (EPO). Because EPO is a known neuroprotectant, we hypothesized that infusion of HEK cells or HEK-conditioned medium (HEK-CM) may provide neuroprotection against kainic acid (KA)-induced hippocampal damage in mice. Adult CF1 mice were treated with KA to induce hippocampal damage. On 3rd and 5th days after KA treatment, HEK cells or HEK-CM was infused intravenously through the tail vein. On the 7th and 8th days after KA treatment, all groups of mice were subjected to cognitive and depression assessment by use of a novel object recognition test and a forced swim test, respectively. Subsequent to this assessment, mice were killed and the brain samples were used to assess the histopathology and messenger RNA expression for EPO and B-cell lymphoma-2 (Bcl-2). We found that infusion of HEK cells/HEK-CM improves cognitive function and alleviates symptoms of depression. Histological assessment demonstrates complete neuroprotection against KA-mediated excitotoxicity, and the hippocampal cytoarchitecture of HEK cells/HEK-CM treated mice was comparable to normal control mice. HEK cells/HEK-CM treatment could provide neuroprotection by upregulating the endogenous EPO and Bcl-2 in KA-treated mice. | We used optical coherence tomography (OCT) and intravascular ultrasound (IVUS) to assess the struts of implanted stents in patients with acute coronary syndrome (ACS). A totle of 10,756 stent struts were analyzed with OCT in 42 patients of ACS. Of them, both of IVUS and OCT imaging were performed in 33 patients. Appearance of stent struts was classified as well apposed, buried, malapposed, and nondetectable, and the number of stent struts were counted by OCT and IVUS was compared. Most of stent struts were well apposed (78.1%, 8,407/10,756). However, malapposed struts were 5.6% (607/10,756), and 14.1% (1,514/10,756) of stent struts were buried by thrombus. The nondetectable struts were 2.11% (228/10,756) in ACS. 94.7% (216/228) of nondetectable stent struts were associated with red thrombus, and plaque prolapse was in 5.3% (12/228). The number of stent struts counted by OCT were larger than that of IVUS. The mean number of stent struts at the proximal and distal stent edges were 24 ± 6.57 in OCT, the stent struts IVUS counted were 20 ± 4.18 (P < 0.0001). Although the frequency of malapposed struts were similar 4.6% (376/8,248) in OCT versus 4.8% (369/7,674) in IVUS (P = 0.788). Stent struts were often buried by thrombus in ACS 15.2% (1,252/8,248) in OCT versus 9.7% (747/7,674) in IVUS; P = 0.006. The nondetectable struts were fewer in IVUS than OCT 0.2% (16/7,674) in IVUS versus 2.2% (187/8,248) in OCT; P < 0.0001. |
Are circulating resistin concentrations independently associated with aortic pulse wave velocity in a community sample? | The role of the adipokine, resistin in mediating increases in aortic stiffness is uncertain. We aimed to determine independent relations between circulating resistin concentrations and aortic pulse wave velocity (PWV) and wave reflection in a community-based sample with a high prevalence of untreated hypertension and obesity. Plasma resistin, adiponectin, and C-reactive protein concentrations (ELISA); carotid-femoral (aortic) PWV and the aortic reflected wave index (applanation tonometry and SphygmoCor software) were determined in 683 randomly selected participants of African ancestry from SOWETO, South Africa who had never received antihypertensive therapy. Resistin concentrations were not independently associated with office or 24-h (n = 492) blood pressure (BP). In a stepwise regression model with BMI included in the model, age (P < 0.0001), mean arterial pressure (P < 0.0001), plasma resistin concentrations (P < 0.005), female sex (P = 0.01), and creatinine concentrations (P < 0.01) contributed independently to variations in PWV. Independent relations between resistin concentrations and PWV persisted with further adjustments for C-reactive protein concentrations (P < 0.005), and the homeostasis model of insulin resistance (P < 0.02). Similar relations were noted with waist circumference rather than BMI in the model. Resistin concentrations were not independently associated with aortic reflected wave index or aortic BP. | In a recent clinical trial, patients with newly diagnosed glioblastoma multiforme benefited from chloroquine (CQ) in combination with conventional therapy (resection, temozolomide [TMZ], and radiation therapy). In the present study, the authors report the mechanism by which CQ enhances the therapeutic efficacy of TMZ to aid future studies aimed at improving this therapeutic regimen. Using in vitro and in vivo experiments, the authors determined the mechanism by which CQ enhances TMZ cytotoxicity. They focused on the inhibition-of-autophagy mechanism of CQ by knockdown of the autophagy-associated proteins or treatment with autophagy inhibitors. This mechanism was tested using an in vivo model with subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ. Knockdown of the autophagy-associated proteins (GRP78 and Beclin) or treatment with the autophagy inhibitor, 3-methyl adenine (3-MA), blocked autophagosome formation and reduced CQ cytotoxicity, suggesting that autophagosome accumulation precedes CQ-induced cell death. In contrast, blocking autophagosome formation with knockdown of GRP78 or treatment with 3-MA enhanced TMZ cytotoxicity, suggesting that the autophagy pathway protects from TMZ-induced cytotoxicity. CQ in combination with TMZ significantly increased the amounts of LC3B-II (a marker for autophagosome levels), CHOP/GADD-153, and cleaved PARP (a marker for apoptosis) over those with untreated or individual drug-treated glioma cells. These molecular mechanisms seemed to take place in vivo as well. Subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ displayed higher levels of CHOP/GADD-153 than did untreated or individual drug-treated tumors. |
Do immunohistochemical observation of amniotic membrane patching on a corneal alkali burn in vivo? | To investigate by immunohistochemical observation the effects of amniotic membrane (AM) patching on myofibroblastic differentiation and matrix metalloproteinase (MMP) expression in the corneal stroma after an alkali burn in vivo. A corneal alkali burn was made by placing a circular piece of filter paper containing 1 N NaOH on the central cornea of rabbits. Burning was done unilaterally in each rabbit. Immediately after the wounding, in the AM group, AM was sutured onto the cornea and removed on day 1. Rabbits with no AM patching were controls. On day 14, corneas were excised and immunohistochemical observation was carried out using antibodies against alpha-smooth muscle actin (alpha-SMA), vimentin, MMP-1, MMP-2, MMP-9, and membrane-type1 (MT1)-MMP. Observation after Masson trichrome staining was also performed. In the AM group, alpha-SMA positive cells were noticeably fewer, and MMP-2, MMP-9, and MT1-MMP expression was clearly inhibited. Also, collagen fibers were more regularly arranged than in control eyes. The more proximate the cells were to the epithelial side, the fewer alpha-SMA-positive cells were observed in the AM group. | NAFLD impacts patient reported outcomes (PROs). Our aim was to assess the impact of NAFLD on patients' HRQOL. National Health and Nutrition Examination Survey (NHANES) 2001-2011 data were used to identify adult patients with NAFLD [Fatty Liver Index (FLI) > 60 in absence of other liver disease and excessive alcohol >20 g/day for men, >10 g/day for women]. Patients with other chronic diseases (ex. HIV, cancer, end-stage kidney disease) were excluded. Subjects without any of these conditions were healthy controls. HCV RNA (+) patients were HCV-controls. All patients completed NHANES HRQOL-4 questionnaire. Linear regression determined the association between NAFLD and HRQOL components adjusting for age, gender, race, and BMI. Participants with complete data were included (n = 9661); 3333 NAFLD (age 51 years and BMI 34 kg/m(2)); 346 HCV+ (age 49 years; BMI 27 kg/m(2)) and 5982 healthy controls (age 48 years and BMI 26 kg/m(2)). The proportion of subjects rating their health as "fair" or "poor" in descending order were HCV controls (30 %) NAFLD (20 %) and healthy controls (10 %) (p < 0.001). HRQOL-4 components scores 2-4 were lowest for HCV, followed by NAFLD and then healthy controls (p-values p = 0.011 to < .0001). After adjustment for age, gender, race, and BMI, NAFLD patients were 18-20 % more likely to report days when their physical health wasn't good or were unable to perform daily activities as a result (p < .0001). |
Is circulating retinol binding protein 4 associated with coronary lesion severity of patients with coronary artery disease? | This study was to examine the association between plasma retinol binding protein 4 (RBP4) levels and the complexity of angiographic coronary lesion in patients with coronary artery disease (CAD). A cross-sectional and prospective study was carried out in Guangzhou Chinese population. 672 persons were evaluated by medical history, clinical examination, coronary angiography, and fasting plasma samples, and were followed prospectively for 3 years. We measured the plasma RBP4 levels in 447 women (201 with stable CAD and 246 with acute coronary syndrome [ACS]). Coronary lesions were classified as having a simple or complex appearance based on the visual estimation of the coronary angiograms. Median plasma RBP4 levels were significantly higher in stable CAD patients with complex coronary lesions (n = 84) than in those with simple lesions (n = 117) (38.78[range 32.65-46.91] vs. 30.78 [range 24.48-36.08] μg/ml, P < 0.001). Multiple logistic regression analysis demonstrated that higher RBP4 levels were independently associated with a 23% higher risk for complex lesions (odds ratio 1.228, 95% confidence interval [CI] 1.061 to 1.358; P = 0.031). Among the ACS patients, who had higher RBP4 levels than the stable CAD patients, those with multiple complex lesions had significantly higher median RBP4 levels than those with a single complex lesion (46.47 μg/ml [range 37.68-53.29] vs. 38.15 μg/ml [range 32.26-44.56], P < 0.001). Total plasma RBP4 levels were predictors of cardiac death (hazard ratio [HR]: 1.102; 95% CI: 1.086 to 1.191; P = 0.012) after adjustment for traditional risk factors for CAD. | Functional alterations of the gastrointestinal and genitourinary tracts, and physical limitations in children with spina bifida, imperforate anus and spinal cord injury challenge the ability to have independent fecal and urinary continence. Urologists have successfully helped these patients achieve urinary continence. We report our experience with the antegrade colonic enema procedure, which allows select individuals to achieve continence of stool, enhancing quality of life. Since December 1992, 18 antegrade colonic enema procedures were performed in 12 female and 6 male patients 5 to 31 years old of whom 14 had spina bifida, 2 had imperforate anus and 2 had spinal cord injury. Simultaneous urological continence procedures were performed in 8 patients, including appendicovesicostomy in 4, augmentation cystoplasty in 2 and augmentation cystoplasty plus an ileal Mitrofanoff procedure in 2. Four patients previously underwent urological reconstruction. In 24 months of followup (average 6.6) all patients with a functioning stoma remained continent of stool and 17 were continent of urine. Complications related to the antegrade colonic enema procedure occurred in 4 children (22%) of whom 3 required further surgery. Three patients (17%) had minor stomal stenosis. |
Are hFE C282Y/H63D compound heterozygotes at low risk of hemochromatosis-related morbidity? | The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild-types at baseline and follow-up (all P < 0.02) except for females who were premenopausal at baseline, where SF was similar in both genotype groups. For subjects with serum measures from both baseline and follow-up, mean SF and TS levels did not change significantly for men or for postmenopausal women, but for premenopausal women SF levels increased from 43 to 109 microg/L for compound heterozygotes and from 35 to 64 microg/L for wild-types (both P < 0.001). Male and female compound heterozygotes had a similar prevalence of hemochromatosis-related morbidity to wild-types. One of 82 males and zero of 95 females had documented iron overload-related disease. | Spinal cord plasticity can be assessed in spinal rats using an instrumental learning paradigm in which subjects learn an instrumental response, hindlimb flexion, to minimize shock exposure. Prior exposure to uncontrollable intermittent stimulation blocks learning in spinal rats but has no effect if given before spinal transection, suggesting that supraspinal systems modulate nociceptive input to the spinal cord, rendering it less susceptible to the detrimental consequences of uncontrollable stimulation. The present study examines whether disrupting brain function with pentobarbital blocks descending inhibitory systems that normally modulate nociceptive input, making the spinal cord more sensitive to the adverse effect of uncontrollable intermittent stimulation. Male Sprague-Dawley rats received uncontrollable intermittent stimulation during pentobarbital anesthesia after (experiment 1) or before (experiment 2) spinal cord transection. They were then tested for instrumental learning at a later time point. Experiment 3 examined whether these manipulations affected nociceptive (thermal) thresholds. Experiment 1 showed that pentobarbital had no effect on the induction of the learning deficit after spinal cord transection. Experiment 2 showed that intact rats anesthetized during uncontrollable intermittent stimulation failed to learn when later transected and tested for instrumental learning. Experiment 3 found that uncontrollable intermittent stimulation induced an antinociception in intact subjects that was blocked by pentobarbital. |
Are preterm twin and triplet pregnancies at increased risk for the development of cystic periventricular leukomalacia? | An increased risk of cerebral palsy in multiples has been reported. To determine the risk for the development of periventricular leukomalacia (PVL) of twin and triplet pregnancy. Retrospective single-centre study at a tertiary care university hospital. Infants ≤ 35 weeks gestational age born between 1988 and 2008. Risk of twin and triplet compared to singleton pregnancy regarding development of PVL in one offspring. Of 6195 infants 117 singletons and 39 multiples were diagnosed as having cystic PVL. Perinatal data did not differ as did not ultrasonographic findings and neurologic outcome. The relative risk (RR) of a twin pregnancy resulting in at least one infant with PVL when born prior to 36 weeks was 2.181 (CI 95% 1.474-3.228, p < .0001), and 6.793 (CI 95% 2.470-13.108, p < .0001) of a triplet pregnancy. In-vitro fertilisation was present in 3% of affected twins compared to 100% in triplets (p < .001). | Secreted frizzled-related protein-1 (SFRP1) is a well-known inhibitor of the wingless type (WNT)-β-catenin signaling pathway and its inactivation plays an important role in the development and progression of various types of cancer. However, the clinical significance of SFRP1 expression in patients with hepatocellular carcinoma (HCC) remains unknown. A total of 63 patients with HCC who underwent hepatectomy at our Institution were enrolled in this study. A quantitative real-time polymerase chain reaction (RT-PCR) was performed to determine the SFRP1 mRNA expression level in both the tumorous and non-tumorous tissues of HCC. The patients were divided into low and high gene-expression groups based on the SFRP1 gene expression level in their tumor tissues. We analyzed the differences in clinicopathological characteristics between these two groups of patients. The expression level of SFRP1 was significantly lower in tumor tissue than in non-tumor tissue (p<0.0001). Significant correlations were observed between a high expression of SFRP1 in tumor tissue and older than 65 years (p=0.030), tumor size less than 5 cm (p=0.011); and no vascular invasion (p=0.004). Patients with high SFRP1 expression in tumor tissue had a significantly better overall survival rate (p=0.040). However, the SFRP1 expression level was not defined as an independent risk factor for patient survival based on results of multivariate analysis. |
Does staging laparoscopy improve treatment decision-making for advanced gastric cancer? | To evaluate the clinical value of staging laparoscopy in treatment decision-making for advanced gastric cancer (GC). Clinical data of 582 patients with advanced GC were retrospectively analyzed. All patients underwent staging laparoscopy. The strength of agreement between computed tomography (CT) stage, endoscopic ultrasound (EUS) stage, laparoscopic stage, and final stage were determined by weighted Kappa statistic (Kw). The number of patients with treatment decision-changes was counted. A χ(2) test was used to analyze the correlation between peritoneal metastasis or positive cytology and clinical characteristics. Among the 582 patients, the distributions of pathological T classifications were T2/3 (153, 26.3%), T4a (262, 45.0%), and T4b (167, 28.7%). Treatment plans for 211 (36.3%) patients were changed after staging laparoscopy was performed. Two (10.5%) of 19 patients in M1 regained the opportunity for potential radical resection by staging laparoscopy. Unnecessary laparotomy was avoided in 71 (12.2%) patients. The strength of agreement between preoperative T stage and final T stage was in almost perfect agreement (Kw = 0.838; 95% confidence interval (CI): 0.803-0.872; P < 0.05) for staging laparoscopy; compared with CT and EUS, which was in fair agreement. The strength of agreement between preoperative M stage and final M stage was in almost perfect agreement (Kw = 0.990; 95% CI: 0.977-1.000; P < 0.05) for staging laparoscopy; compared with CT, which was in slight agreement. Multivariate analysis revealed that tumor size (≥ 40 mm), depth of tumor invasion (T4b), and Borrmann type (III or IV) were significantly correlated with either peritoneal metastasis or positive cytology. The best performance in diagnosing P-positive was obtained when two or three risk factors existed. | PRV-1 mRNA is overexpressed by neutrophils from polycythemia vera patients and is homologous to NB1 a gene overexpressed in reactive neutrophilia. These investigations were designed to confirm searches of genome databases suggesting that PRV-1 and NB1 are alleles of the same gene, CD177, and confirm a pseudogene adjacent to CD177. Methods included polymerase chain reaction (PCR), cloning, sequencing, and fluorescent hybridization studies. The coding region of PRV-1 was PCR-amplified from human fetal RNA, cloned, and used to screen the RPCI-11 bacterial artificial chromosome (BAC) library. Five BACs were reactive with the PRV-1 probe. PCR analysis of the BACs with primers encompassing PRV-1 exons, containing four known single-nucleotide polymorphisms, followed by sequencing rendered amplicons identical to PRV-1 in all five BACs. Analysis of all five by restriction digestion yielded fragments possible only if both the gene and the pseudogene are present. End sequencing of the BACs localized them to the same chromosome region. G-banding and fluorescence in situ hybridization at the 400- and 850-band levels of resolution mapped one BAC to chromosome band 19q13.2 and sublocalized the BAC to band 19q13.31, respectively. |
Appear patients with irritable bowel syndrome in primary care to be heavy healthcare utilizers? | Irritable bowel syndrome is a frequently diagnosed gastrointestinal condition in general practice. Managing this chronic condition requires a co-ordinated effort between patient and doctor. To explore the patterns of treatment and healthcare utilization of irritable bowel syndrome cases in a Swedish primary care setting. All cases with a registered diagnosis of irritable bowel syndrome were identified retrospectively for a 5-year period through computerized medical records at three primary healthcare centres in Sweden. Documentation of diagnosis, healthcare visits, treatments, investigations, medications, referrals, laboratory tests, mental and demographic data were retrieved from the records. Of all 723 irritable bowel syndrome patients identified, only 37% had a follow-up appointment to their General Practitioner during the study period. For 80%, the General Practitioner initiated some treatment during the initial consultation and 75% were prescribed medication. Fibre and bulking laxatives and acid-suppressive drugs were the most common medication. Almost a quarter was referred for complementary investigations at hospital, only 8.9% of the irritable bowel syndrome patients were referred to a specialist investigation. Laboratory investigations varied and were ordered more frequently (P = 0.05) for men. | Changes in vascular permeability are well-known and important consequences of cerebral ischemia. The development of edema and of petechial hemorrhage is connected to altered vascular integrity. A major part in microvascular integrity is played by the basal lamina. The fates of the basal lamina components laminin, fibronectin, and type IV collagen during middle cerebral artery occlusion (2 hours, n = 3) and occlusion (3 hours) with reperfusion (1 hour, n = 3; 4 hours, n = 3; and 24 hours, n = 4) were evaluated in the nonhuman primate. Specific monoclonal antibodies against these components were used. The number and size distribution of the microvessels in each specimen were determined by video-imaging microscopy, and the relative fluorescence intensity of laminin was semiquantified by laser confocal microscopy. Basal lamina antigen presentations were compared by double-stain immunofluorescence histochemistry. The number of microvascular structures defined by the presence of each basal lamina antigen decreased significantly up to 24 hours of reperfusion (P < .0001). The ratio of laminin-containing vessels between the ischemic and nonischemic territories decreased significantly from control (0.98 +/- 0.04) to 2 hours of ischemia (0.83 +/- 0.09) and 1 hour (0.79 +/- 0.08), 4 hours (0.77 +/- 0.06), and 24 hours of reperfusion (0.55 +/- 0.07). The ratio of fibronectin (cellular) and of collagen (IV)-containing vessels decreased from 0.98 +/- 0.04 to 0.75 +/- 0.1 and from 1.02 +/- 0.03 to 0.57 +/- 0.1, respectively. Mean laminin fluorescence intensity decreased from 76.1 +/- 6.0 U (controls) to 52.0 +/- 14.6 U (24 hours of reperfusion; P < .001). |
Is serum 25-hydroxyvitamin D3 related to physical activity and ethnicity but not obesity in a multicultural workforce? | Recent research suggests that body vitamin D levels are decreased in coronary heart disease and diabetes, but it is unclear which cardiovascular risk factors are related to vitamin D status. To examine the relation between vitamin D status and major cardiovascular risk factors. Serum 25-hydroxyvitamin D3, a marker of recent sun exposure and vitamin D status, was measured in 390 New Zealand residents (95 Pacific Islanders, 74 Maori and 221 others mostly of European descent), who were part of a larger cross-sectional survey of a workforce (n = 5677) aged 40-64 years. Serum 25-hydroxyvitamin D3 levels were significantly lower in Pacific Islanders (mean (SE) = 56 (3) nmol/L; p = 0.0001) and Maoris (68 (3) nmol/L; p = 0.036) compared with Europeans (75 (2) nmol/L) after adjusting for age, sex and time of year. Also adjusting for ethnic group, 25-hydroxyvitamin D3 was higher in people doing vigorous (aerobic) leisure physical activities (71 (2) nmol/L; p = 0.0066) and moderate (non-aerobic) activities (68 (3) nmol/L; p = 0.12) compared with those who were inactive (63 (2) nmol/L). However, 25-hydroxyvitamin D3 was unrelated to body mass index, serum lipids, blood pressure or cigarette smoking. | To compare cuff pressures during nitrous oxide exposure in the new Microcuff pediatric tracheal tube (MPT) with ultrathin high volume - low pressure polyurethane cuff to a tube with a standard polyvinyl chloride (PVC) cuff. With approval of the local Ethics Committee, 30 pediatric patients requiring tracheal intubation [tube size internal diameter (ID) 4.0 mm, or ID 7.0 mm) were included. Patients were randomly divided in three groups: A) MPT, baseline cuff pressure 20 cm H(2)O; B) PVC, baseline cuff pressure 20 cm H(2)O; and C) MPT, baseline cuff pressure set to sealing pressure. Anesthesia technique and ventilator settings were standardized. The time required for cuff pressure to increase to 25 cm H(2)O was recorded and pressure reduced to baseline. The number of gas removals required during the first hour was noted. Data are median (range). Groups were compared by the Kruskal-Wallis test (P < 0.05). There were no differences between groups in patient characteristics. PVC and MPT cuffs inflated to a baseline pressure of 20 cm H(2)O were similar regarding the time to first removal of gas [A: nine minutes (4-24), B: eight minutes (4-46)], and number of removals required [A: four (2-6), B: three (1-5)]. In MPT with baseline pressure set to sealing pressure [10 cm H(2)O (8-14)] time to first gas removal and number of removals were significantly less (P < 0.05). |
Are microarousals during sleep associated with increased levels of lipids , cortisol , and blood pressure? | Previous work has demonstrated a link between restricted sleep and risk indicators for cardiovascular and metabolic disease, such as levels of cortisol, lipids, and glucose. The present study sought to identify relations between polysomnographic measures of disturbed sleep (frequency of arousals from sleep, total sleep time, and sleep efficiency) and a number of such indicators. A second purpose was to relate the number of arousals to mood, stress, work characteristics, and other possible predictors in daily life. Twenty-four people (10 men, 14 women; mean age 30 years), high vs. low on burnout, were recruited from a Swedish IT company. Polysomnographically recorded sleep was measured at home before a workday. Blood pressure, heart rate, morning blood sample, and saliva samples of cortisol were measured the subsequent working day. They were also recorded for diary ratings of sleep and stress, and a questionnaire with ratings of sleep, stress, work conditions, and mood was completed. A stepwise regression analysis using sleep parameters as predictors brought out number of arousals as the best predictor of morning cortisol (serum and saliva), heart rate, systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein (HDL)-, low-density lipoprotein (LDL)-cholesterol, and LDL/HDL-ratio. Work stress/unclear boundaries between work and leisure time was the best predictor of arousals among the stress variables. | Autologous mesenchymal stem cells (MSCs) are an attractive concept in regenerative medicine, but their mechanism of action remains poorly defined. No immune response is reported after in vivo injection of allogeneic equine MSCs or embryo-derived stem cells (ESCs) into the equine tendon, which may be due to the cells' immune-privileged properties. This study further investigates these properties to determine their potential for clinical application in other tissues. Mitomycin C-treated MSCs, ESCs, or differentiated ESCs (dESCs) were cultured with allogeneic equine peripheral blood mononuclear cells (PBMCs), and their effect on PBMC proliferation, in the presence or absence of interferon-gamma (IFN-γ) was determined. MSCs and super-antigen (sAg)-stimulated PBMCs were co-cultured directly or indirectly in transwells, and PBMC proliferation examined. Media from MSC culture were harvested and used for PBMC culture; subsequent PBMC proliferation and gene expression were evaluated and media assayed for IFN-γ, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-10 and IL-6 proteins with enzyme-linked immunosorbent assay (ELISA). Co-culture of PBMCs with ESCs or dESCs did not affect baseline proliferation, whereas co-culture with MSCs significantly suppressed baseline proliferation. Stimulation of PBMC proliferation by using super-antigens (sAgs) was also suppressed by co-culture with MSCs. Inhibition was greatest with direct contact, but significant inhibition was produced in transwell culture and by using MSC-conditioned media, suggesting that soluble factors play a role in MSC-mediated immune suppression. The MSCs constitutively secrete IL-6, even in the absence of co-culture with PBMCs. MSC-conditioned media also brought about a change in the cytokine-expression profile of sAg-stimulated PBMCs, significantly reducing PBMC expression of IL-6, IFN-γ, and TNF-α. |
Is depression a consistent syndrome : An investigation of unique symptom patterns in the STAR*D study? | The DSM-5 encompasses a wide range of symptoms for Major Depressive Disorder (MDD). Symptoms are commonly added up to sum-scores, and thresholds differentiate between healthy and depressed individuals. The underlying assumption is that all patients diagnosed with MDD have a similar condition, and that sum-scores accurately reflect the severity of this condition. To test this assumption, we examined the number of DSM-5 depression symptom patterns in the "Sequenced Treatment Alternatives to Relieve Depression" (STAR*D) study. We investigated the number of unique symptom profiles reported by 3703 depressed outpatients at the beginning of the first treatment stage of STAR*D. Overall, we identified 1030 unique symptom profiles. Of these profiles, 864 profiles (83.9%) were endorsed by five or fewer subjects, and 501 profiles (48.6%) were endorsed by only one individual. The most common symptom profile exhibited a frequency of only 1.8%. Controlling for overall depression severity did not reduce the amount of observed heterogeneity. | Point mutations within the family of the ras genes are detected in approximately 50% of human colorectal adenomas and carcinomas. Therefore, it is generally accepted that the occurrence of ras-point mutations constitute an important step in colorectal carcinogenesis. In addition, many studies have demonstrated that the tumorigenicity of the human colorectal carcinoma cell line, CaCo 2, strongly increases after transfection with the c-Ha-ras oncogene. This cell line is suitable for gaining more insight into the mechanism of c-Ha-ras induced tumorigenesis. Proliferation, differentiation, and proteolytic capacity of c-Ha-ras oncogene transfected CaCo 2 cells were studied in vitro. It was found that gelatinolytic capacity and production of urokinasetype plasminogen activator increased, whereas the production of tissue-type plasminogen activator was similar. Proliferative activity, as measured by the potential doubling time, did not alter. The expression of the differentiation markers sucraseiso-maltase, mucin, and chromogranin A was not different from that of the parental CaCo 2 cell line, which indicates that an increased tumorigenic capacity of c Ha-ras oncogene transfected CaCo 2 cells is not accompanied by loss of differentiation. |
Is iNSIG2 gene polymorphism associated with increased subcutaneous fat in women and poor response to resistance training in men? | A common SNP upstream of the INSIG2 gene, rs7566605 (g.-10,1025G>C, Chr2:118,552,255, NT_022135.15), was reported to be associated with obesity (Body Mass Index, [BMI]) in a genome-wide association scan using the Framingham Heart Study but has not been reproduced in other cohorts. As BMI is a relatively insensitive measure of adiposity that is subject to many confounding variables, we sought to determine the relationship between the INSIG2 SNP and subcutaneous fat volumes measured by MRI in a young adult population. We genotyped the INSIG2 SNP rs7566605 in college-aged population enrolled in a controlled resistance-training program, (the Functional Polymorphism Associated with Human Muscle Size and Strength, FAMuSS cohort, n = 752 volunteers 18-40 yrs). In this longitudinal study, we examined the effect of the INSIG2 polymorphism on subcutaneous fat and muscle volumes of the upper arm measured by magnetic resonance imaging (MRI) before and after 12 wks of resistance training. Gene/phenotype associations were tested using an analysis of covariance model with age and weight as covariates. Further, the % variation in each phenotype attributable to genotype was determined using hierarchical models and tested with a likelihood ratio test. Women with a copy of the C allele had higher levels of baseline subcutaneous fat (GG: n = 139; 243473 +/- 5713 mm3 vs. GC/CC: n = 181; 268521 +/- 5003 mm3; p = 0.0011); but men did not show any such association. Men homozygous for the G ancestral allele showed a loss of subcutaneous fat, while those with one or two copies of the C allele gained a greater percentage of subcutaneous fat with resistance training (GG: n = 103; 1.02% +/- 1.74% vs. GC/CC: n = 93; 6.39% +/- 1.82%; p = 0.035). | Liver ischemia reperfusion (I/R) injury is a common pathophysiological process in many clinical settings. Carvacrol, a food additive commonly used in essential oils, has displayed antimicrobials, antitumor and antidepressant-like activities. In the present study, we investigated the protective effects of carvacrol on I/R injury in the Wistar rat livers and an in vitro hypoxia/restoration (H/R) model. The hepatoportal vein, hepatic arterial and hepatic duct of Wistar rats were isolated and clamped for 30 min, followed by a 2 h reperfusion. Buffalo rat liver (BRL) cells were incubated under hypoxia for 4 h, followed normoxic conditions for 10 h to establish the H/R model in vitro. Liver injury was evaluated by measuring serum levels of alanine aminotransferase (ALT) and aspatate aminotransferase (AST), and hepatic levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondiadehyde (MDA), and hepatic histology and TUNEL staining. MTT assay, flow cytometric analysis and Hoechst 33258 staining were used to evaluate the proliferation and apoptosis of BRL cells in vitro. Protein expression was examined by Western Blot analysis. Carvacrol protected against I/R-induced liver damage, evidenced by significantly reducing the serum levels of ALT and AST, histological alterations and apoptosis of liver cells in I/R rats. Carvacrol exhibited anti-oxidative activity in the I/R rats, reflected by significantly reducing the activity of SOD and the content of MDA, and restoring the activity of CAT and the content of GSH, in I/R rats. In the in vitro assays, carvacrol restored the viability and inhibited the apoptosis of BRL cells, which were subjected to a mimic I/R injury induced by hypoxia. In the investigation on molecular mechanisms, carvacrol downregulated the expression of Bax and upregulated the expression of Bcl-2, thus inhibited the activation of caspase-3. Carvacrol was also shown to enhance the phosphorylation of Akt. |
Does frizzled10 mediate WNT1 and WNT3A signaling in the dorsal spinal cord of the developing chick embryo? | WNT1 and WNT3A drive a dorsal to ventral gradient of β-catenin-dependent Wnt signaling in the developing spinal cord. However, the identity of the receptors mediating downstream functions remains poorly understood. In this report, we show that the spatiotemporal expression patterns of FZD10 and WNT1/WNT3A are highly correlated. We further show that in the presence of LRP6, FZD10 promotes WNT1 and WNT3A signaling using an 8xSuperTopFlash reporter assay. Consistent with a functional role for FZD10, we demonstrate that FZD10 is required for proliferation in the spinal cord. Finally, by using an in situ proximity ligation assay, we observe an interaction between FZD10 and WNT1 and WNT3A proteins. | Antibodies to hepatitis C virus (anti-HCV) have typically been detected by enzyme immunoassay (EIA). A chemiluminescence assay (CA) for anti-HCV is now commercially available. We compared the positive rate for a CA in a HCV screening program for veterans with historical rates obtained with EIA. We also compared results in 2824 samples tested by both methods and assessed the significance of low signal-to-cutoff (S/C) ratios. The frequency of CA-positive results was significantly lower than with EIA (12.6% vs 16.0%; P <0.0001). The frequency of low S/C ratios was also significantly lower with CA (11.5% vs 20.0%; P <0.0001). Among low-positive values, samples positive by CA were significantly less likely to be recombinant immunoblot assay (RIBA)-negative (64% vs 84%; P <0.0005). In parallel testing, results for 111 samples (3.9%) were discrepant between the two assays; all but 6 had low S/C ratios, and confirmatory testing was performed on all but 8 samples. Of 56 EIA-positive, CA-negative samples tested by RIBA, only 1 was positive. Of 24 CA-positive, EIA-negative samples, 62% were RIBA-negative. Using a negative RIBA result as an indication of false-positive anti-HCV results, the positive predictive value of EIA was 93% compared with 98% with CA. HCV RNA was positive in 90% of samples high-positive by both CA and EIA. Only 2 of 30 (7%) low-positive CA samples were RNA-positive. |
Does analysis with support vector machine show HIV-positive subjects without infectious retinitis have mfERG deficiencies compared to normal eyes? | To test the following hypotheses: (1) eyes from individuals with human immunodeficiency virus (HIV) have electrophysiologic abnormalities that manifest as multifocal electroretinogram (mfERG) abnormalities; (2) the retinal effects of HIV in immune-competent HIV individuals differ from the effects in immune-incompetent HIV individuals; (3) strong machine learning classifiers (MLCs), like support vector machine (SVM), can learn to use mfERG abnormalities in the second-order kernel (SOK) to distinguish HIV from normal eyes; and (4) the mfERG abnormalities fall into patterns that can be discerned by MLCs. We applied a supervised MLC, SVM, to determine if mfERGs in eyes from patients with HIV differ from mfERGs in HIV-negative controls. Ninety-nine HIV-positive patients without visible retinopathy were divided into 2 groups: (1) 59 high-CD4 individuals (H, 104 eyes), 48.5 +/- 7.7 years, whose CD4 counts were never observed below 100, and (2) 40 low-CD4 individuals (L, 61 eyes), 46.2 +/- 5.6 years, whose CD4 counts were below 100 for at least 6 months. The normal group (N, 82 eyes) had 41 age-matched HIV-negative individuals, 46.8 +/- 6.2 years. The amplitude and latency of the first positive curve (P1, hereafter referred to as a) and the first negative curve (N1, referred to as b) in the SOK of 103 hexagon patterns of the central 28 degrees of the retina were recorded from the eyes in each group. SVM was trained and tested with cross-validation to distinguish H from N and L from N. SOK was chosen as a presumed detector of inner retinal abnormalities. Classifier performance was measured with the area under the receiver operating characteristic (AUROC) curve to permit comparison of MLCs. Improvement in performance and identification of subsets of the most important features were sought with feature selection by backward elimination. In general, the SOK b-parameters separated L from N and H from N better than a-parameters, and latency separated L from N and H from N better than amplitude. In the HIV groups, on average, amplitude was diminished and latency was extended. The parameter that most consistently separated L from N and H from N was b-latency. With b-latency, SVM learned to distinguish L from N (AUROC = 0.7.30 +/- 0.044, P = .001 against chance [0.500 +/- 0.051]) and H from N (0.732 +/- 0.038, P = .0001 against chance) equally well. With best-performing subsets (21 out of 103 hexagons) derived by backward elimination, SVM distinguished L from N (0.869 +/- 0.030, P < .00005 against chance) and H from N (0.859 +/- 0.029, P <.00005 against chance) better than SVM with the full set of hexagons. Mapping the top 10 hexagon locations for L vs N and H vs N produced no apparent pattern. | To investigate the protective effects of remote ischemic postconditioning (RIP) against limb ischemia-reperfusion (IR)-induced gastric mucosal injury. Gastric IR was established in male Wistar rats by placing an elastic rubber band under a pressure of 290-310 mmHg on the proximal part of both lower limbs for 3 h followed by reperfusion for 0, 1, 3, 6, 12 or 24 h. RIP was performed using three cycles of 30 s of reperfusion and 30 s of reocclusion of the femoral aortic immediately after IR and before reperfusion for up to 24 h. Rats were randomly assigned to receive IR (n = 36), IR followed by RIP (n = 36), or sham treatment (n = 36). Gastric tissue samples were collected from six animals in each group at each timepoint and processed to determine levels of malondialdehyde (MDA), superoxide dismutase (SOD), xanthine oxidase (XOD) and myeloperoxidase (MPO). Additional samples were processed for histologic analysis by hematoxylin and eosin staining. Blood samples were similarly collected to determine serum levels of lactate dehydrogenase (LDH), creatine kinase (CK), tumor necrosis factor (TNF)-α and interleukin (IL)-10. The pathologic changes in gastric tissue induced by IR were observed by light microscopy. Administration of RIP dramatically reduced the gastric damage score after 6 h of reperfusion (5.85 ± 0.22 vs 7.72 ± 0.43; P < 0.01). In addition, RIP treatment decreased the serum activities of LDH (3.31 ± 0.32 vs 6.46 ± 0.03; P < 0.01), CK (1.94 ± 0.20 vs 4.54 ± 0.19; P < 0.01) and the concentration of TNF-α (53.82 ± 0.85 vs 88.50 ± 3.08; P < 0.01), and elevated the concentration of IL-10 (101.46 ± 5.08 vs 99.77 ± 4.32; P < 0.01) induced by IR at 6 h. Furthermore, RIP treatment prevented the marked elevation in MDA (3.79 ± 0.29 vs 6.39 ± 0.81) content, XOD (7.81 ± 0.75 vs 10.37 ± 2.47) and MPO (0.47 ± 0.05 vs 0.82 ± 0.03) activities, and decrease in SOD (4.95 ± 0.32 vs 3.41 ± 0.38; P < 0.01) activity in the gastric tissue as measured at 6 h. |
Does miR-192 regulate dihydrofolate reductase and cellular proliferation through the p53-microRNA circuit? | The purpose of this study is to investigate the molecular mechanism of miR-192 in colon cancer. Human colon cancer cell lines with different p53 status were used as our model system to study the effect of miR-192 on cell proliferation, cell cycle control, and mechanism of regulation. Our results show that one of the key miR-192 target genes is dihydrofolate reductase (DHFR). miR-192 affects cellular proliferation through the p53-miRNA circuit. Western immunoblot analyses indicated that the expression of DHFR was significantly decreased by miR-192. Further investigation revealed that such suppression was due to translational arrest rather than mRNA degradation. More profound inhibition of cellular proliferation was observed by ectopic expression of miR-192 in colon cancer cell lines containing wild-type p53 than cells containing mutant p53. Thus, the effect of miR-192 on cellular proliferation is mainly p53 dependent. Overexpression of miR-192 triggered both G1 and G2 arrest in HCT-116 (wt-p53) cells but not in HCT-116 (null-p53) cells. The cell cycle checkpoint control genes p53 and p21 were highly overexpressed in cells that overexpressed miR-192. Endogenous miR-192 expression was increased in HCT-116 (wt-p53) and RKO (wt-p53) cells treated with methotrexate, which caused an induction of p53 expression. Chromatin immunoprecipitation-quantitative reverse transcription-PCR analysis revealed that the p53 protein interacted with the miR-192 promoter sequence. | Human adipose tissue produces several adipokines, including the newly identified protein cathepsin S (CTSS), a cysteine protease involved in the pathogenesis of atherosclerosis. Obesity is characterized by high levels of CTSS in the circulation and in sc white adipose tissue (scWAT). We investigated the effect of surgery-induced weight loss on circulating CTSS and its protein expression in scWAT. Fifty morbidly obese women before and 3 months after surgery and 10 healthy lean women were studied. We analyzed the relationships between circulating CTSS and clinical and biological parameters. Immunohistochemistry of the CTSS protein variations in scWAT was performed. Weight loss decreased by 42% (P < 0.0001) the circulating CTSS levels, which correlated with changes in body weight (P = 0.03). We observed a significant decrease in CTSS enzymatic activity by 25% after weight loss (P = 0.001). Adipose tissue CTSS content was reduced by 30% (P = 0.002) after surgery. The variations in CTSS expression in scWAT after surgery correlated with changes in circulating CTSS serum levels (P = 0.03). Most of the correlations between CTSS and clinical and biological parameters disappeared after adjustment for body mass index, emphasizing the strong link between CTSS and corpulence in humans. |
Are baseline metabolic tumor volume and total lesion glycolysis associated with survival outcomes in patients with locally advanced pancreatic cancer receiving stereotactic body radiation therapy? | Although previous studies have demonstrated the prognostic value of positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer has yet to be well established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiation therapy (SBRT). Thirty-two patients with LAPC in a prospective clinical trial received up to 3 doses of gemcitabine, followed by 33 Gy in 5 fractions of 6.6 Gy, using SBRT. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUVmax and SUVpeak) on pre-SBRT PET scans were calculated using custom-designed software. Disease was measured at a threshold based on the liver SUV, using the equation Livermean + [2 × Liversd]. Median values of PET parameters were used as cutoffs when assessing their prognostic potential through Cox regression analyses. Of the 32 patients, the majority were male (n=19, 59%), 65 years or older (n=21, 66%), and had tumors located in the pancreatic head (n=27, 84%). Twenty-seven patients (84%) received induction gemcitabine prior to SBRT. Median overall survival for the entire cohort was 18.8 months (95% confidence interval [CI], 15.7-22.0). An MTV of 26.8 cm(3) or greater (hazard ratio [HR] 4.46, 95% CI 1.64-5.88, P<.003) and TLG of 70.9 or greater (HR 3.08, 95% CI 1.18-8.02, P<.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19-22.21, P=.029) and TLG (HR 3.34, 95% CI 1.07-10.48, P=.038) remained independently associated with overall survival in separate multivariate analyses. | Adolescence is a period of life with its own unique characteristics. To provide an in-depth understanding of the impact of skin disease on different aspects of adolescents' health-related quality of life (HRQoL). Semi-structured qualitative interviews were conducted with a sample of dermatology patients between 12 and 19 years of age, attending the dermatology outpatient clinic of a secondary referral centre. Participants were invited to talk in detail about all the ways their lives had been affected by their skin disease. Interviews were transcribed verbatim. Thirty-two adolescents (males = 10, females = 22) with a mean age of 15.7 years (range = 12-18 years) participated in the interviews. Twenty-eight HRQoL themes adversely affected by skin diseases were identified from the interviews which were grouped under 6 main HRQoL domains - psychological impact (91% of patients), physical impact (81%), social impact (81%), impact on lifestyle (63%), need for support (41%) and education and employment (34%). The number of HRQoL themes affected in each individual varied between 1 and 23 (mean = 8.1). |
Does tGF-beta1 increase proliferation of airway smooth muscle cells by phosphorylation of map kinases? | Airway remodeling in asthma is the result of increased expression of connective tissue proteins, airway smooth muscle cell (ASMC) hyperplasia and hypertrophy. TGF-beta1 has been found to increase ASMC proliferation. The activation of mitogen-activated protein kinases (MAPKs), p38, ERK, and JNK, is critical to the signal transduction associated with cell proliferation. In the present study, we determined the role of phosphorylated MAPKs in TGF-beta1 induced ASMC proliferation. Confluent and growth-arrested bovine ASMCs were treated with TGF-beta1. Proliferation was measured by [3H]-thymidine incorporation and cell counting. Expressions of phosphorylated p38, ERK1/2, and JNK were determined by Western analysis. In a concentration-dependent manner, TGF-beta1 increased [3H]-thymidine incorporation and cell number of ASMCs. TGF-beta1 also enhanced serum-induced ASMC proliferation. Although ASMCs cultured with TGF-beta1 had a significant increase in phosphorylated p38, ERK1/2, and JNK, the maximal phosphorylation of each MAPK had a varied onset after incubation with TGF-beta1. TGF-beta1 induced DNA synthesis was inhibited by SB 203580 or PD 98059, selective inhibitors of p38 and MAP kinase kinase (MEK), respectively. Antibodies against EGF, FGF-2, IGF-I, and PDGF did not inhibit the TGF-beta1 induced DNA synthesis. | Chronic opioid therapy for chronic pain treatment has increased. Hospital physicians, including hospitalists and medical/surgical resident physicians, care for many hospitalized patients, yet little is known about opioid prescribing at hospital discharge and future chronic opioid use. We aimed to characterize opioid prescribing at hospital discharge among 'opioid naïve' patients. Opioid naïve patients had not filled an opioid prescription at an affiliated pharmacy 1 year preceding their hospital discharge. We also set out to quantify the risk of chronic opioid use and opioid refills 1 year post discharge among opioid naïve patients with and without opioid receipt at discharge. This was a retrospective cohort study. From 1 January 2011 to 31 December 2011, 6,689 opioid naïve patients were discharged from a safety-net hospital. Chronic opioid use 1 year post discharge. Twenty-five percent of opioid naïve patients (n = 1,688) had opioid receipt within 72 hours of discharge. Patients with opioid receipt were more likely to have diagnoses including neoplasm (6.3% versus 3.5%, p < 0.001), acute pain (2.7% versus 1.0 %, p < 0.001), chronic pain at admission (12.1% versus 3.3%, p < 0.001) or surgery during their hospitalization (65.1% versus 18.4%, p < 0.001) compared to patients without opioid receipt. Patients with opioid receipt were less likely to have alcohol use disorders (15.7% versus 20.7%, p < 0.001) and mental health disorders (23.9% versus 31.4%, p < 0.001) compared to patients without opioid receipt. Chronic opioid use 1 year post discharge was more common among patients with opioid receipt (4.1% versus 1.3%, p < 0.0001) compared to patients without opioid receipt. Opioid receipt was associated with increased odds of chronic opioid use (AOR = 4.90, 95% CI 3.22-7.45) and greater subsequent opioid refills (AOR = 2.67, 95% CI 2.29-3.13) 1 year post discharge compared to no opioid receipt. |
Does an expression meta-analysis of predicted microRNA targets identify a diagnostic signature for lung cancer? | Patients diagnosed with lung adenocarcinoma (AD) and squamous cell carcinoma (SCC), two major histologic subtypes of lung cancer, currently receive similar standard treatments, but resistance to adjuvant chemotherapy is prevalent. Identification of differentially expressed genes marking AD and SCC may prove to be of diagnostic value and help unravel molecular basis of their histogenesis and biologies, and deliver more effective and specific systemic therapy. MiRNA target genes were predicted by union of miRanda, TargetScan, and PicTar, followed by screening for matched gene symbols in NCBI human sequences and Gene Ontology (GO) terms using the PANTHER database that was also used for analyzing the significance of biological processes and pathways within each ontology term. Microarray data were extracted from Gene Expression Omnibus repository, and tumor subtype prediction by gene expression used Prediction Analysis of Microarrays. Computationally predicted target genes of three microRNAs, miR-34b/34c/449, that were detected in human lung, testis, and fallopian tubes but not in other normal tissues, were filtered by representation of GO terms and their ability to classify lung cancer subtypes, followed by a meta-analysis of microarray data to classify AD and SCC. Expression of a minimal set of 17 predicted miR-34b/34c/449 target genes derived from the developmental process GO category was identified from a training set to classify 41 AD and 17 SCC, and correctly predicted in average 87% of 354 AD and 82% of 282 SCC specimens from total 9 independent published datasets. The accuracy of prediction still remains comparable when classifying 103 AD and 79 SCC samples from another 4 published datasets that have only 14 to 16 of the 17 genes available for prediction (84% and 85% for AD and SCC, respectively). Expression of this signature in two published datasets of epithelial cells obtained at bronchoscopy from cigarette smokers, if combined with cytopathology of the cells, yielded 89-90% sensitivity of lung cancer detection and 87-90% negative predictive value to non-cancer patients. | To determine the effects of polymyxin B sulfate in rats fed by total parenteral nutrition on norepinephrine excretion, macrophage tumor necrosis factor production, and bacterial translocation. Randomized animal study. A university teaching hospital in Seattle, Wash. Three groups of rats were studied: chow plus intravenous saline, total parenteral nutrition, or total parenteral nutrition supplemented with polymyxin B sulfate. After 5 days, urinary excretion of norepinephrine and epinephrine was calculated, peritoneal and alveolar macrophages were cultured, and their spontaneous and lipopolysaccharide-stimulated tumor necrosis factor production was measured. Mesenteric lymph nodes were cultured for bacteria. Rats fed by total parenteral nutrition had increased urine norepinephrine excretion (33%) and alveolar macrophage tumor necrosis factor production (80%) and trends for increased epinephrine excretion and bacterial translocation compared with rats fed chow. Alveolar but not peritoneal macrophage tumor necrosis factor production was significantly related to norepinephrine excretion (r = .5, P < .01). The addition of polymyxin B to total parenteral nutrition decreased weight gain (P < .05), urinary norepinephrine excretion (P < .01), and alveolar macrophage tumor necrosis factor production (P < .05) compared with rats fed by total parenteral nutrition. Polymyxin B also tended to decrease the magnitude of bacterial translocation. |
Do estrogenic Compounds Have Divergent Effects on Human Endothelial Progenitor Cell Migration according to Sex of the Donor? | Endothelial progenitor cells (EPCs) are key elements in vascular homeostasis. Their function is regulated by estrogens and estrogen receptors (ERs), but the effect of estrogenic compounds such as bisphenol A (BPA; an agonist of ER-β and agonist and antagonist of ER-α) and (R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (THC; an agonist of ER-α and antagonist of ER-β) on human EPCs is unknown. We analyzed whether BPA and THC influence the migration of human EPCs, an essential process in endothelial regeneration, in both male and female EPCs. EPCs isolated from healthy adult men and women were assayed for ER expression by Western blotting and chemotaxis assay. Male and female EPCs similarly expressed ERs and did not differ in basal migration. Interestingly, 17-β-estradiol (10(-9) and 10(-10) M) significantly inhibited migration in female EPCs but not in males. Moreover, both 10(-5) M THC and 10(-8) M BPA blocked migration in female EPCs, allowing us to hypothesize that the effect is mediated by ER-α. | We investigated whether luciferase immunoprecipitation systems (LIPS) can be the basis for a more rapid, specific, and standardized assay for the diagnosis of Strongyloides stercoralis infection. A LIPS assay was developed based on immunoglobulin (Ig) G or IgG4 antibody to a recombinant Strongyloides antigen (NIE) and was compared with an NIE enzyme-linked immunosorbent assay (ELISA). A second antigen, S. stercoralis immunoreactive antigen (SsIR), was tested alone and in combination with NIE. The assays were tested using serum samples from patients with parasitologically proven S. stercoralis or filarial infections and from healthy, uninfected control subjects. The NIE LIPS assay based on IgG antibody easily differentiated between S. stercoralis-infected and uninfected patients (P< .0001) and demonstrated improved specificity compared with the NIE ELISA (100% vs. 95%). Serum from filaria-infected patients did not cross-react when tested with the NIE LIPS assay. When SsIR was used in combination with NIE in the LIPS format, sensitivity and specificity improved to 100%, with a 7-fold difference between positive and negative values. No advantage was found in using a LIPS assay based on IgG4. At posttreatment follow-up, a significant decline in antibody titers was detected using the NIE ELISA (P< .0017) and the NIE LIPS assay (P< .0001). |
Do providers verify patient identity during computer order entry? | Improving patient identification (ID), by using two identifiers, is a Joint Commission safety goal. Appropriate identifiers include name, date of birth (DOB), or medical record number (MRN). The objectives were to determine the frequency of verifying patient ID during computerized provider order entry (CPOE). This was a prospective study using simulated scenarios with an eye-tracking device. Medical providers were asked to review 10 charts (scenarios), select the patient from a computer alphabetical list, and order tests. Two scenarios had embedded ID errors compared to the computer (incorrect DOB or misspelled last name), and a third had a potential error (second patient on alphabetical list with same last name). Providers were not aware the focus was patient ID. Verifying patient ID was defined as looking at name and either DOB or MRN on the computer. Twenty-five of 25 providers (100%; 95% confidence interval [CI] = 86% to 100%) selected the correct patient when there was a second patient with the same last name. Two of 25 (8%; 95% CI = 1% to 26%) noted the DOB error; the remaining 23 ordered tests on an incorrect patient. One of 25 (4%, 95% CI = 0% to 20%) noted the last name error; 12 ordered tests on an incorrect patient. No participant (0%, 0/107; 95% CI = 0% to 3%) verified patient ID by looking at MRN prior to selecting a patient from the alphabetical list. Twenty-three percent (45/200; 95% CI = 17% to 29%) verified patient ID prior to ordering tests. | Plasma high-density lipoprotein (HDL) level is inversely correlated with the risk of atherosclerosis. However, the cellular mechanism by which HDL exerts antiatherogenic actions is not well understood. In this study, we focus on the lipid components of HDL as mediators of the lipoprotein-induced antiatherogenic actions. HDL and sphingosine 1-phosphate (S1P) stimulated the migration and survival of human umbilical vein endothelial cells. These responses to HDL and S1P were almost completely inhibited by pertussis toxin and other specific inhibitors for intracellular signaling pathways, although the inhibition profiles of migration and survival were different. The HDL-stimulated migration and survival of the cells were markedly inhibited by antisense oligonucleotides against the S1P receptors EDG-1/S1P1 and EDG-3/S1P3. Cell migration was sensitive to both receptors, but cell survival was exclusively sensitive to S1P1. The S1P-rich fraction and chromatographically purified S1P from HDL stimulated cell migration, but the rest of the fraction did not, as was the case of the cell survival. |
Does the bradycardic agent zatebradine enhance baroreflex sensitivity and heart rate variability in rats early after myocardial infarction? | The bradycardic agent zatebradine (UL-FS 49) reduces heart rate without negative inotropic or proarrhythmic effects. The aim was to experimentally characterize the influence of zatebradine on arterial baroreflex sensitivity (BRS) and heart rate variability (HRV) which are generally considered as estimates of vagal activity and have prognostic value in patients after myocardial infarction (MI). Conscious rats were studied 3 days after left coronary artery ligation or sham-operation (SH). BRS was determined by linear regression analysis of RR-interval and mean arterial pressure changes evoked by intravenous (i.v.) injections of methoxamine and nitroprusside. HRV at rest was calculated from high-resolution electrocardiogram-recordings. In MI-rats heart rate was similar to SH-rats, mean arterial pressure was lower and both BRS and HRV were markedly reduced. Zatebradine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400 +/- 15 to 350 +/- 19 and in SH-rats from 390 +/- 19 to 324 +/- 6 beats/min without changing mean arterial pressure. Both BRS and HRV were restored in MI- and further increased in SH-rats by the drug. Effects of 0.05, 0.5 and 5 mg/kg zatebradine revealed a dose-dependency of heart rate reduction. The lowest dose enhanced reflex bradycardia despite little effect on heart rate and lack of effect on both reflex tachycardia and HRV. | Although chronic rhinosinusitis (CRS) causes very significant morbidity, much about its pathogenesis remains uncertain. Recent studies have identified polymicrobial biofilms on the surface of sinus mucosa and Staphylococcus aureus within the sinus mucosa of patients with CRS, both with and without nasal polyps. The pathogenic implications of intramucosal bacteria in CRS are unknown. This study was designed to determine the prevalence and species of bacterial colonies within the sinus mucosa of adult patients with and without CRS and to describe the relationship of these bacterial colonies to the host immune response. Sinus mucosa from patients with and without CRS was examined using Gram and Giemsa staining, immunohistochemistry, bacterial culture, and fluorescence in situ hybridization techniques. Bacterial microcolonies were observed within the mucosa in 14 of 18 patients with CRS. In 10 of these patients colonies were positively identified as S. aureus. Staphylococcal microcolonies were observed at a lower level (1 of 8 patients) in normal sinus mucosa. There was no correlation between detection of S. aureus on the mucosal surface and microcolonization of the mucosa. Surprisingly, there was no evidence of an immune reaction to microcolonies. Indeed, fewer T lymphocytes (p = 0.03) and eosinophils (p = 0.03) were counted immediately surrounding the microcolonies compared with uninfected areas of the same tissue. |
Are thyroid nodules and related symptoms stably controlled two years after radiofrequency thermal ablation? | Percutaneous radiofrequency thermal ablation (RTA) is a promising new therapeutic approach to manage thyroid nodules (TNs). The aim of this study was to investigate the long-term effectiveness of RTA in inducing shrinkage of TNs as well as in controlling compressive symptoms and thyroid hyperfunction in a large series of elderly subjects with solid or mainly solid benign TNs. Ninety-four elderly patients with cytologically benign compressive TNs were prospectively enrolled in the study; 66 of them had nontoxic goiter and 28 had toxic or pretoxic goiter. RTA was performed by using a RITA StarBurst Talon hook-umbrella needle inserted in every single TN under ultrasonographic real-time guidance. TN volume, TN-related compressive symptoms and thyroid function were evaluated at baseline and 12 to 24 months after RTA. All TNs significantly decreased in size after RTA. The mean decrease in TN volume 12 months after RTA was from 24.5 +/- 2.1 to 7.5 +/- 1.2 mL (p < 0.001), with a mean percent decrease of 78.6 +/- 2.0%. Two years after RTA, a 79.4 +/- 2.5% decrease of TNs size was observed. Compressive symptoms improved in all patients and completely disappeared in 83 of 94 (88%) patients. Hyperthyroidism resolved in most patients allowing methimazole therapy to be completely withdrawn in 79% of patients with pretoxic and toxic TNs (100% with pretoxic TNs and 53% with toxic TNs). The treatment was well tolerated by all patients. No patient needed hospitalization after RTA and no major complications were observed. | Using publicly available data from inbred mouse strains, we conducted a genome-wide association study to identify loci that accounted for liver-related phenotypes between C57BL/6J and A/J mice fed a Paigen diet. We confirmed genome-wide significant associations for hepatic cholesterol (chromosome 10A2) and serum total bile acid concentration (chromosome 12E) and identified a new locus for liver inflammation (chromosome 7C). Analysis of consomic mice confirmed that chromosome 12 A/J alleles accounted for the variance in serum total bile acid concentrations and had pleiotropic effects on liver mass, serum cholesterol, and serum alanine aminotransferase activity. Using an affected-only haplotype analysis among strains, we refined the chromosome 12E signal to a 1.95 Mb linkage disequilibrium block containing only one gene, sel-1 suppressor of lin-12-like (Sel1l). RNA sequencing and immunoblotting demonstrated that the risk allele locally conferred reduced expression of SEL1L in liver and distantly down-regulated pathways associated with hepatocyte nuclear factor 1 homeobox A (Hnf1a) and hepatocyte nuclear factor 4A (Hnf4a), known modifiers of bile acid transporters and metabolic traits. Consistent with these data, knockdown of SEL1L in HepG2 cells resulted in reduced HNF1A and HNF4A and increased bile acids in culture media; it further captured multiple molecular signatures observed in consomic mouse livers with reduced SEL1L. Finally, dogs harboring a SEL1L mutation and Sel1l(+/-) mice fed a Paigen diet had significantly increased serum total bile acid concentrations, providing independent confirmation linking SEL1L to bile acid metabolism. |
Does pretreatment with adenosine and adenosine A1 receptor agonist protect against intestinal ischemia-reperfusion injury in rat? | To examine the effects of adenosine and A1 receptor activation on reperfusion-induced small intestinal injury. Rats were randomized into groups with sham operation, ischemia and reperfusion, and systemic treatments with either adenosine or 2-chloro-N(6)-cyclopentyladenosine, A1 receptor agonist or 8-cyclopentyl-1,3-dipropylxanthine, A1 receptor antagonist, plus adenosine before ischemia. Following reperfusion, contractions of ileum segments in response to KCl, carbachol and substance P were recorded. Tissue myeloperoxidase, malondialdehyde, and reduced glutathione levels were measured. Ischemia significantly decreased both contraction and reduced glutathione level which were ameliorated by adenosine and agonist administration. Treatment also decreased neutrophil infiltration and membrane lipid peroxidation. Beneficial effects of adenosine were abolished by pretreatment with A1 receptor antagonist. | To investigate and compare topoisomerase II-alpha expression in benign prostatic hyperplasia (BPH), prostate cancer of varying Gleason scores and hormone-insensitive prostate cancer. The immunohistochemical expression of topoisomerase II-alpha antibody in the above-mentioned diagnostic categories was investigated and compared. Increased expression of topoisomerase II-alpha was seen in the prostate cancers of Gleason scores 7 and 8-10 (p = 0.000) compared with prostate cancers of Gleason score 6 and BPH (p = 0.245). Statistically significant differences were found in the topoisomerase II-alpha gene expression between prostate cancers categorised by Gleason Score. Also, increased expression of topoisomerase II-alpha was seen in the known hormone-resistant prostate carcinomas compared with prostate cancers with no hormone treatment in the subgroup with Gleason scores 8-10, which approached statistical significance (p = 0.081). No statistically significant difference was observed in topoisomerase II-alpha expression between the groups with BPH and prostate carcinoma of Gleason score 6 (p = 0.245). |
Are patients with single ventricle physiology undergoing noncardiac surgery at high risk for adverse events? | Patients with single ventricle physiology are at increased anesthetic risk when undergoing noncardiac surgery. To review the outcomes of anesthetics for patients with single ventricle physiology undergoing noncardiac surgery. This study is a retrospective chart review of all patients who underwent a palliative procedure for single ventricle physiology between January 1, 2007 and January 31, 2014. Anesthetic and surgical records were reviewed for noncardiac operations that required sedation or general anesthesia. Any noncardiac operation occurring prior to completion of a bidirectional Glenn procedure was included. Diagnostic procedures, including cardiac catheterization, insertion of permanent pacemaker, and procedures performed in the ICU, were excluded. During the review period, 417 patients with single ventricle physiology had initial palliation. Of these, 70 patients (16.7%) underwent 102 anesthetics for 121 noncardiac procedures. The noncardiac procedures included line insertion (n = 23); minor surgical procedures such as percutaneous endoscopic gastrostomy or airway surgery (n = 38); or major surgical procedures including intra-abdominal and thoracic operations (n = 41). These interventions occurred on median day 60 of life (1-233 days). The procedures occurred most commonly in the operating room (n = 79, 77.5%). Patients' median weight was 3.4 kg (2.4-15 kg) at time of noncardiac intervention. In 102 anesthetics, 26 patients had an endotracheal tube or tracheostomy in situ, 57 patients underwent endotracheal intubation, and 19 patients had a natural or mask airway. An intravenous induction was performed in 77 anesthetics, an inhalational induction in 17, and a combination technique in 8. The median total anesthetic time was 126 min (14-594 min). In 22 anesthetics (21.6%), patients were on inotropic support upon arrival; an additional 24 patients required inotropic support (23.5%), of which dopamine was the most common medication. There were 10 intraoperative adverse events (9.8%) including: arrhythmias requiring treatment (n = 4), conversion from sedation to a general anesthetic (n = 2), difficult airway (n = 1), inadvertent extubation with desaturation and bradycardia (n = 1), hypotension and desaturation (n = 1), and cardiac arrest (n = 1). Postoperative events (<48 h) included ST segment changes requiring cardiac catheterization (n = 1), and cardiorespiratory arrest (n = 1). Age, size, gender, type of cardiac palliation, patient location, procedure location, and type of procedure were not associated with adverse outcome. After 62 anesthetics (60.8%), patients went postoperatively to the cardiac ICU. There were no deaths at 48 h. | Interleukin (IL)-33 is a recently identified cytokine, which is a member of the IL-1 family and binds to a heterodimeric receptor comprising ST2 (suppression of tumorigenicity 2) and IL-1 receptor accessory protein. Serum levels of IL-33 have been reported to be upregulated in various T helper (Th)1/Th17-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease. IL-33 expression is increased in lesional skin in patients with psoriasis, but serum levels in patients with psoriasis have not yet been studied. To study serum IL-33 levels in patients with psoriasis, a Th1/Th17-mediated skin disease, before and after anti-tumour necrosis factor (TNF)-α therapy. Serum IL-33 levels were measured in patients with psoriasis vulgaris (PV), psoriatic arthritis (PsA) or pustular psoriasis (PP), and compared with those of healthy controls. Associations between serum IL-33 levels and serum TNF-α, IL-6, vascular endothelial growth factor and C-reactive protein levels were also studied. In addition, the effect of IL-33 stimulation on IL-6, IL-8, TNF-α and VEGF secretion by human keratinocyte was analysed. Serum IL-33 levels in patients with PV, PsA and PP were significantly higher than those in healthy controls. Serum IL-33 levels correlated with serum TNF-α levels in patients with psoriasis, and decreased after anti-TNF-α therapy. IL-33 stimulated IL-6 and IL-8 secretion by human keratinocytes. |
Does a group of segmental premotor interneurons regulate the speed of axial locomotion in Drosophila larvae? | Animals control the speed of motion to meet behavioral demands. Yet, the underlying neuronal mechanisms remain poorly understood. Here we show that a class of segmentally arrayed local interneurons (period-positive median segmental interneurons, or PMSIs) regulates the speed of peristaltic locomotion in Drosophila larvae. PMSIs formed glutamatergic synapses on motor neurons and, when optogenetically activated, inhibited motor activity, indicating that they are inhibitory premotor interneurons. Calcium imaging showed that PMSIs are rhythmically active during peristalsis with a short time delay in relation to motor neurons. Optogenetic silencing of these neurons elongated the duration of motor bursting and greatly reduced the speed of larval locomotion. | The neutrophil-to-lymphocyte ratio (NLR) has been shown to predict adverse outcomes in several pathologic conditions. The majority of indeterminate interferon (IFN)-γ release assays were due to inadequate IFN-γ response to the phytohemagglutinin. We sought to study the value of NLR to predict an indeterminate result of QuantiFERON-TB Gold In-Tube (QFT-GIT) performed in routine laboratory practice. Results from 2,773 QFT-GIT assays were analyzed. Data collection included demographic data, the level of IFN-γ to nil, mitogen, and TB antigen of QFT-GIT, total WBC, and a differential count. We calculated the absolute neutrophil count, lymphocyte count, and NLR. Of the total, 224 (8.1%) indeterminate results were observed. Twelve (1.8%) showed indeterminate results in the NLR range from 1.71 to 2.84, but 132 (19.2%) had indeterminate results in NLR ≥ 5.18 (p < 0.0001). The likelihood ratio for indeterminate results were 2.70 (95% CI, 2.36-3.08) in NLR ≥ 5.18 and 1.93 (95% CI, 1.64-2.27) in lymphocyte count ≤ 1050/μL. NLR and neutrophil count were independent predictors for indeterminate QFT-GIT result in multiple regression analysis. The IFN-γ response to PHA was negatively associated with NLR (r = -0.33, p < 0.001). |
Are common variants in 8q24 associated with risk for prostate cancer and tumor aggressiveness in men of European ancestry? | Recent whole genome association studies have independently identified multiple prostate cancer (PC) risk variants on 8q24. We have evaluated association of common variants in this region with PC susceptibility and tumor aggressiveness in a sample of European American men. Forty-nine tagging SNPs including three previously reported significant variants (rs1447295, rs6983267, rs16901979) and seven variants in the 5' upstream region of the MYC proto-oncogene were tested for association with susceptibility to PC and tumor aggressiveness in 596 histologically verified PC cases and 567 ethnically matched controls. Significant associations with susceptibility to PC were found at 17 SNPs, four of which (rs1016342, rs1378897, rs871135, and rs6470517) remained significant after adjusting for multiple corrections. One of the associated SNPs, rs871135, is located in the putative gene POU5F1P1 within the 8q24 region. An in slico analysis showed that the associated variant of this SNP alters a transcription factor implicating a plausible regulatory role. Additionally, one of the significantly associated SNPs, rs6470517, with PC susceptibility showed a significant over-representation of the G allele in cases with aggressive tumor. | To study the effect of dexamethasone on postextubation stridor (PS) incidence and reintubation rate due to PS in a high-risk paediatric intensive care population. All children aged between 4 wk and 6 y, who were intubated for at least 24 h and extubated between August 1999 and May 2002, were retrospectively included (n=60). Medical records of the included patients were studied; records of patients treated with dexamethasone prior to and following extubation (n=23) were compared with control patients who had not received prophylactic medication (n=37). Nine patients in the control group developed significant postextubation stridor, necessitating nebulized epinephrine or glucocorticosteroids. In six of these children, reintubation as a result of postextubation stridor was indicated. None of the patients treated with dexamethasone developed severe postextubation stridor or required reintubation. |
Does matrix metalloproteinase-9 amplify the immune response to Pseudomonas aeruginosa corneal infection? | The purpose of this study was to determine the role of matrix metalloproteinases (MMP) in Pseudomonas aeruginosa keratitis. Gene array and selective real-time PCR examined MMP expression in the cornea of susceptible (C57BL/6, B6) versus resistant (BALB/c) mice before and after infection; zymography tested enzyme activity for MMP-2 and -9. Clinical score, Langerhans cell (LC), and Neutrophil (PMN) quantitation were done in recombinant (r) MMP-9, antibody neutralized, and MMP-9(-/-) mice. The chemotactic potential of MMP-9 was tested in a Boyden chamber assay; light and transmission microscopy and immunostaining for collagen IV and MMP-9 were used to examine the effects and the source of MMP-9 after infection. ELISA was used to assess IL-1beta and MIP-2 levels. Gene array (confirmed by PCR) revealed sixfold more MMP-9, and zymography showed greater enzyme activity in the infected cornea of B6 over BALB/c mice. rMMP-9 injection of BALB/c mice enhanced, whereas MMP-9 antibody neutralization in B6 mice and its absence in MMP-9(-/-) mice decreased corneal disease. MMP-9(-/-) and antibody neutralized mice had fewer LCs in cornea; rMMP-9-treated mice had more. A myeloperoxidase (MPO) assay showed a similar pattern for PMN. MMP-9 was not chemotactic for LC or PMN. The basement membrane was more intact in MMP-9(-/-) over wild-type infected mice and correlated with staining for collagen IV; PMN was a source of MMP-9. IL-1beta and MIP-2 were increased in rMMP-9 but decreased in MMP-9 antibody neutralized and MMP-9(-/-) over control groups. | The aim was to demonstrate that a reduction in the nonlinear behavior of heart rate variability (HRV) in the preoperative period in patients undergoing coronary artery bypass graft (CABG) triggers higher morbidity and mortality rates in the postoperative stay. Seventy patients (59+/-10.3 years) were included. HRV was captured by a Polar Advanced S810 heart rate monitor and analyzed using the nonlinear variables detrended fluctuation analysis (DFA), autocorrelation (tau), Lyapunov exponent (LE), and the Poincaré plot (PP). Based on two scenarios, death vs. non-death (scenario 1) and events vs. their absence (scenario 2), the occurrence of neurological complications, infections, kidney failure, arrhythmia, and death were evaluated. Sensitivity, specificity, positive predictive value, negative predictive value, and odds ratio (95% CI) were recorded. In scenario 1, significant differences were found for DFA, alpha-2, LE, PP[SD1], and PP[SD2], with p-values of 0.0172, 0.0343, 0.0159, 0.0069, and 0.0287, respectively. In scenario 2, differences were found for alpha-1, alfa-2, tau, LE, PP[SD1], and PP[SD2], with p-values of 0.0066, 0.0426, 0.0188, 0.0108, 0.0005, and 0.0158, respectively. The best areas under ROC curve were seen in scenario 1, with values of 0.72 (tau), 0.77 (LE), and 0.78 (PP[SD1]). |
Does a novel missense mutation in ATRX uncovered in a Yemeni family lead to alpha-thalassemia/mental retardation syndrome without alpha-thalassemia? | Intellectual disability (ID) features in numerous heritable medical conditions that result from ATRX mutations. Alpha-thalassemia mental retardation syndrome (ATR-X syndrome) is the most notable manifestation of ATRX dysfunction. In addition to ID, genitourinary and craniofacial abnormalities are regularly observed with or without alpha-thalassemia. The study sought to characterize two cases of ATR-X in a Yemeni family clinically and molecularly. PCR amplification and Sanger sequencing were used to study the ATRX gene in a Yemeni family. Also, methylation-sensitive PCR was used to perform X-inactivation studies. CADD, SNAP2 and PolyPhen-2 helped to predict the functional consequences of the variant. Molecular testing revealed a novel hemizygous missense mutation (c.5666T>G) in the ATRX gene in the two Yemeni brothers. This mutation was found in a heterozygous state in the mother, with the chromosome harboring the mutated allele being under strongly skewed X-inactivation. | To assess the impact of a multimodal antiemetic protocol on postoperative nausea and vomiting (PONV) after Le Fort I osteotomy. Consecutive patients undergoing Le Fort I osteotomy with or without additional procedures at a single academic institution were recruited as the intervention cohort for an institutional review board-approved prospective clinical trial with a retrospective comparison group. The intervention cohort was managed with a multimodal antiemetic protocol, including total intravenous anesthesia; prophylactic ondansetron, steroids, scopolamine, and droperidol; gastric decompression at surgery end; opioid-sparing analgesia; avoidance of morphine and codeine; prokinetic erythromycin; and fluids at a minimum of 25 mL/kg. The comparison group consisted of consecutive patients from a larger study who underwent similar surgical procedures before protocol implementation. Data, including occurrence of PONV, were extracted from medical records. Data were analyzed in bivariate fashion with the Fisher exact and Wilcoxon rank-sum tests. Logistic regression was used to compare the likelihood of nausea and vomiting in the 2 cohorts after controlling for demographic and surgical characteristics. A P value less than .05 was considered significant. The intervention (n = 93) and comparison (n = 137) groups were similar in gender (58% and 65% female patients; P = .29), race (72% and 71% Caucasian; P = .85), age (median, 19 and 20 years old; P = .75), proportion of patients with known risk factors for PONV (P = .34), percentage undergoing bimaxillary surgery (60% for the 2 groups), and percentage for whom surgery time was longer than 180 minutes (63% and 59%; P = .51). Prevalence of postoperative nausea was significantly lower in the intervention group than in the comparison group (24% vs 70%; P < .0001). Prevalence of postoperative vomiting was likewise significantly lower in the intervention group (11% vs 28%; P = .0013). The likelihood that patients in the comparison group would develop nausea was 8.9 and that for vomiting was 3.7 times higher than in the intervention group. |
Does lidocaine reduce reperfusion injury and neutrophil migration in canine lung allografts? | Depletion of neutrophils (PMNs) and inhibition of PMN endothelial adhesion ameliorate post-ischemic lung reperfusion injury. Lidocaine reduces PMN adhesion to endothelial surfaces in vivo, and inhibits upregulation of PMN-CD11b/CD18 (Mac-1) in vitro. We evaluated the effect of lidocaine on reperfusion injury, PMN adhesion, and PMN migration in preserved lung allografts. Donor lungs were flushed with modified Euro-Collins solution (4 degrees C) after prostaglandin E1 administration (250 micrograms), inflated with 550 mL (inspired oxygen fraction = 1.0), and stored for 24 hours at 1 degree C. Left lung allotransplantation was performed in 13 mongrel dogs. Immediately after reperfusion the recipient right pulmonary artery and bronchus were ligated to permit assessment of allograft function during a 6-hour postreperfusion period. Allograft gas exchange (every 15 minutes) and hemodynamics (every 60 minutes) were assessed. Peripheral blood PMN CD11b expression was determined by flow cytometry. After sacrifice allograft bronchoalveolar lavage fluid PMN count and allograft tissue myeloperoxidase activity were measured. Two groups were studied: In group I (n = 8) lidocaine hydrochloride was added to the donor flush (20 mg/L) solution. In addition lidocaine was given to the recipient at the time of thoracotomy (intravenous bolus of 4 mg/kg) followed by a continuous infusion of 4 mg/kg/h during implantation and the assessment period. Three dogs that did not reach effective lidocaine blood levels at the time of reperfusion (3 to 4 micrograms/mL) were excluded from analysis. Group II animals (n = 5) received no lidocaine. Gas exchange in group I was superior throughout the assessment period (p < 0.05). Bronchoalveolar lavage fluid PMN count in group I was reduced (0.36 x 10(6)PMN/mL versus 6.2 x 10(6) PML/mL; p < 0.03). Group I allograft myeloperoxidase activity was 0.17 U/mg/min compared with 0.28 U/mg/min in group II (p < 0.01). In lidocaine-treated animals PMN CD11b expression was maintained at basal levels 2 hours after reperfusion, compared with group II, in which upregulation of CD11b was observed. Lower lobe wet/dry ratio was not different in the two groups. | Metabolic Syndrome (MetS) is associated with elevated risk for developing diabetes and cardiovascular disease. A key component of MetS is the development of insulin resistance (IR). The homeostatic model assessment (HOMA) model can determine IR by using insulin or C-peptide concentrations; however, the efficiency of insulin and C-peptide to determine MetS has not been compared. The aim of the study was to compare the efficiency of C-peptide and insulin to determine MetS in Mexicans. Anthropometrics, glucose, insulin, C-peptide, triglycerides, and high-density lipoproteins were determined in 156 nonpregnant females and 114 males. Subjects were separated into normal or positive for MetS. IR was determined by the HOMA2 calculator using insulin or C-peptide. Correlations were calculated using the Spearman correlation coefficient (ρ). Differences between correlations were determined by calculating Steiger's Z. The sensitivity was determined by the area under receiver operating characteristics curve (AUC) analysis. Independent of the MetS definition [Adult Treatment Panel III (ATP III), International Diabetes Federation (IDF), or World Health Organization (WHO)], C-peptide and insulin were significantly higher in MetS subjects (P < 0.05). C-peptide and insulin correlated with all components of MetS; however, for waist circumference, waist-to-hip ratio, and fasting plasma glucose, C-peptide correlated better than insulin (P < 0.05). Moreover, C-peptide (AUC = 0.72-0.78) was a better marker than insulin (AUC = 0.62-0.72) for MetS (P < 0.05). Finally, HOMA2-IR calculated with C-peptide (AUC = 0.80-0.84) was more accurate than HOMA2-IR calculated with insulin (AUC = 0.68-0.75, P < 0.05) at determining MetS. |
Do divergent growth strategies between red algae and kelps influence biomechanical properties? | Morphology and material properties are the main components of the mechanical design of organisms, with species groups developing different optimization strategies in the context of their physical environment. For intertidal and subtidal seaweeds, possessing highly flexible and extensible tissues allows individuals to bend and reconfigure in flow, thereby reducing drag. Previous research has shown that aging may compromise these qualities. Tissue age increases with distance from the blade's meristem, which differs in its position on kelps and red algae. Here, we assess whether longitudinal patterns of blade material properties differ between these two algal groups according to tissue age. We performed tensile tests on tissues samples excised from various positions along the extent of blades in nine kelp species (basal growth) and 15 species of red algae (apical growth). We found that older tissues were less flexible and extensible than younger tissues in all species tested. As predicted, tissue near the basal meristem in kelp was more flexible and extensible than older tissue at the blade's distal end. The opposite pattern was observed for red algae, with the most flexible and extensible tissues found near the apical meristem at the distal ends of blades. | Carbamazepine is a commonly used anticonvulsant agent; however, it has been linked with various blood cell abnormalities. This study evaluated the effect of low-dose folic acid supplementation on the prevention of carbamazepine-induced hematological derangements in children. This randomized clinical trial was conducted in children with epilepsy who received carbamazepine monotherapy. Group 1 received carbamazepine alone, and group 2 received carbamazepine plus folic acid. The two groups were age- and sex-matched. Each group comprised 41 children with epilepsy. Complete blood counts were obtained before starting medication (baseline) and then serially. The patients were followed for at least 1 year. In group 1, 31.4% of the patients developed leukopenia and 17.1% neutropenia, but in group 2, these figures were 14.6 and 9.8% (P = 0.067 and P = 0.331, respectively). At the end of the first year of follow up, white blood cell and polymorphonuclear cell counts were significantly higher in group 2 (P = 0.007 and P = 0.001, respectively). Hemoglobin concentration dropped in group 1, but rose slightly in group 2; these changes were significant. Platelet, lymphocyte, and monocyte counts and changes in serial blood tests did not differ significantly between the two groups. |
Is human cathelicidin LL-37 a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors? | Inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by the presence of eosinophils and neutrophils. However, the mechanisms that mediate the influx of these cells are incompletely understood. Neutrophil products, including neutrophil elastase and antimicrobial peptides such as neutrophil defensins and LL-37, have been demonstrated to display chemotactic activity towards cells from both innate and adaptive immunity. However, chemotactic activity of LL-37 towards eosinophils has not been reported. Therefore, the aim of the present study was to investigate the chemotactic activity of LL-37 for eosinophils and to explore the mechanisms involved in LL-37-mediated attraction of neutrophils and eosinophils. Neutrophils and eosinophils were obtained from venous blood of healthy donors. Chemotaxis was studied using a modified Boyden chamber technique. Involvement of formyl-peptide receptors (FPRs) was studied using the antagonistic peptide tBoc-MLP. Activation of the mitogen-activated protein kinase (MAPK) ERK1/2 was studied by Western blotting using antibodies directed against phosphorylated ERK1/2. Our results show that LL-37 chemoattracts both eosinophils and neutrophils. The FPR antagonistic peptide tBoc-MLP inhibited LL-37-induced chemotaxis. Whereas the FPR agonist fMLP activated ERK1/2 in neutrophils, LL-37 did not, indicating that fMLP and LL-37 deliver different signals through FPRs. | Currently, surgical resection is considered the first-line treatment for early stage hepatocellular carcinoma (HCC). Radiofrequency ablation (RFA) has been an alternative choice for unresectable HCC. However, RFA is expected to have similar therapeutic efficacy for early stage HCC with fewer invasions. The authors retrospectively analyzed 199 patients who underwent surgery and 209 patients who underwent RFA for HCC with a maximum diameter of < or = 3 cm and tumors numbering < or = 3. All patients were complicated with Child-Pugh A cirrhosis. The 3- and 5-year survival rates of the resection (90.3%, 79.0%, respectively) and RFA groups were similar (87.4%, 74.8). The 1- and 3-year tumor recurrence-free survival rates of the resection group (83.1%, 51.0%, respectively) were higher than in the RFA group (82.7%, 41.8%; P = .011). Multivariate analysis identified prothrombin time > or = 80% (hazard ratio [HR], 2.72; 95% confidence interval [CI], 1.56-4.74; P < .001) as an independent prognostic factor for survival in the resection group. Des-gamma-carboxy prothrombin (DCP) <100 arbitrary units (AU)/L (HR, 5.49; CI, 2.23-13.5; P < .001) and platelet count > or = 1.0 x 10(5) (HR, 2.70; CI, 1.24-5.88; P = .012) were significant markers in the RFA group. Among patients with DCP > or = 100 AU/L, treatment procedure (HR, 1.26; CI, 1.04-1.53; P = .020) was a significant prognostic factor for survival. |
Do obese first-degree relatives of patients with type 2 diabetes with elevated triglyceride levels exhibit increased β-cell function? | Type 2 diabetes mellitus (T2DM) is characterized as a disease continuum that is marked by metabolic changes that are present for several years, sometimes well before frank diagnosis of T2DM. Genetic predisposition, ethnicity, geography, alterations in BMI, and lipid profile are considered important markers for the pathogenesis of T2DM through mechanisms that remain unresolved and controversial. The aim of this study was to investigate the relationship between triglycerides (TGs) and β-cell function, insulin resistance (IR), and insulin sensitivity (IS) in obese first-degree relatives of patients with T2DM (FDR-T2DM) among subjects from central Mexico with normal glucose tolerance (NGT). We studied 372 FDR-T2DM subjects (ages,18-65) and determined body mass index (BMI), fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), insulin, and TGs levels. Subjects were categorized based on glycemic control [NGT, prediabetes (PT2DM), or T2DM]. NGT subjects were further categorized by BMI [normal weight (Ob-) or obese (Ob+)] and TGs levels (TG-, <150 mg/dL, or TG+, ≥150 mg/dL). β-cell function, IR, and IS were determined by the homeostasis model assessment of β-cell function (HOMA2-β), homeostasis model assessment of insulin resistance (HOMA2-IR), and Quantitative Insulin Sensitivity Check Index (QUICKI) indices, respectively. The obese subjects with elevated TGs levels had 21%-60% increased β-cell function when compared to all groups (P<0.05). In addition, this group had insulin levels, IS, and IR similar to PT2DM. Furthermore, only in obese subjects did TGs correlate with β-cell function (ρ=0.502, P<0.001). | To analyze the safety and efficacy of a short course of granulocyte colony-stimulating factor (G-CSF) to maintain dose-intensity of subsequent cycles of chemotherapy after a prior episode of prolonged neutropenia, without febrile complications, in patients receiving adjuvant treatment for breast cancer. Thirty-two patients undergoing adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) or doxorubicin-CMF for stages I to II breast cancer were included after having chemotherapy delays due to neutropenia (absolute neutrophil count [ANC] < 1.5 x 10(9)/L) on day 22. G-CSF was administered subcutaneously on days 15 to 19 of each subsequent cycle. None of the patients included in this study had to be admitted to the hospital for fever and neutropenia. The median percentage of the projected dose-intensity for CMF or doxorubicin-CMF on an intent-to-treat basis was 0.994, which was significantly higher than the delivered dose-intensity before the start of G-CSF treatment (P < .0001). Patients who received concomitant G-CSF and radiotherapy achieved a similar dose-intensity as patients who did not undergo radiotherapy. Seven patients discontinued G-CSF treatment due to musculoskeletal pain. These patients had more subsequent cycle delays because of day 22 neutropenia than the 25 patients who followed the G-CSF schedule (P = .0028). |
Is dietary magnesium intake related to metabolic syndrome in older Americans? | Magnesium (Mg) is an essential cofactor for enzymes involved in glucose and insulin metabolism. Low intakes of dietary magnesium may be linked to greater risk of metabolic syndrome (MS) in older adults. The objective of this study was to examine the cross-sectional relationship between dietary Mg intake, metabolic risk factors and MS in elderly adults. This study was conducted in a sample of 535 (179 men and 356 women) community-living adults aged 60 years and in Boston Massachusetts between the years 1981 and 1984. Dietary Mg intake was assessed by a 3-day food record and categorized by quartiles of dietary intake. The MS was defined based on criteria set by the Third Report of the National Cholesterol Education Program except that body mass index was used in place of waist circumference. Logistic regression analysis was used to examine the association between quartile categories of Mg intake, prevalence of MS and components of the MS. Models were adjusted for age, gender, BMI, race, educational attainment, marital status, smoking status, alcohol intake, exercise, energy intake, percentage of calories from saturated fat, use of antihypertensive or lipid medication. Mg intake was inversely associated with the MS; those with the highest intake of Mg had significantly lower risk of having MS compared to the lowest quartile of intake (OR: 0.36, 95% CI 0.19-0.69, P for trend 0.002). Significant inverse relationships were observed between Mg intake and BMI (OR: 0.47, 95% CI: 0.22-1.00, P trend = 0.03), and fasting glucose (OR: 0.41, 95% CI 0.22-0.77, P trend = 0.005). | Decortication for thoracic empyema is associated with significant blood loss and prolonged postoperative air leak. We sought to assess the potential application of an irrigated-tip radiofrequency (RF) sealing device, in an attempt to reduce this morbidity. Data for all patients undergoing open decortication (OD) for stage II thoracic empyema, using either conventional approach or facilitated by use of the Aquamantys(®) device, at a single thoracic surgical unit between April 2010 and July 2014, were retrospectively analysed. Unpaired t-test and Fisher's exact test were used for statistical analysis. Thirty-three patients, aged 54±15 years (mean ± SD), and with a Charlson comorbidity index of 2.5±1.9 were included. Preoperative and intraoperative characteristics, including surgical time, were similar in the conventional and Aquamantys(®) groups. Patients in the Aquamantys group were less likely to require red cell transfusion (9/22 vs. 10/11 patients, P=0.024) and received lower volume transfusions [0.0 (2.0) vs. 3.0 (1.6) units (median, IQR), P<0.0001]; chest drain duration was shorter [3.0 (1.0) vs. 6.5 (6.8) days, P=0.006], as was length of postoperative hospital stay [6.0 (8.7) vs. 10.0 (4.6) days, P=0.031]. There was no demonstrable difference in mortality. |
Is elevated serum interleukin-18 level associated with all-cause mortality in stable hemodialysis patients independently of cardiac dysfunction? | High circulating interleukin (IL)-18 level predicts a higher hospitalization rate among dialysis patients, possibly through cardiovascular mechanisms; however, whether higher IL-18 level is associated with mortality in dialysis patients is less clear. In addition, its impacts on left ventricular (LV) function are also unknown. We conducted a cohort study to examine the impacts of IL-18 level on LV function and prognosis among clinically stable hemodialysis patients. Clinically stable patients undergoing maintenance hemodialysis (≥ 3 months) were prospectively enrolled from December 2008 to January 2009, and were followed up for 31 months. The enrolled patients (41% male, 66.4 ± 10.9 years of age) received 2-dimensional echocardiography and myocardial deformation (strain) analysis, including LV peak systolic longitudinal strain (GLS) and circumferential strain (CS). Laboratory measurements were also performed. Cox regression analysis was used to investigate prognostic factors. Seventy-five patients were stratified into 2 groups by the median value of IL-18 (654.2 pg/ml). Between these 2 groups, there was no significant difference in baseline characteristics including LV ejection fraction. The high IL-18 group had a worse LV systolic function as demonstrated by reduced GLS and CS. Seventeen patients (22.7%) died during the follow-up period. Multivariate Cox regression analysis showed that low serum albumin, the presence of hypertension, high serum IL-18, and less negative GLS (>-15%) were independently associated with all-cause mortality. No significant interaction between IL-18 and less negative GLS was noted in the final Cox model. | To determine whether repeat administration of an adenovector (Ad) into the eye results in efficient gene delivery and to test whether transgenes can be expressed from an adenovector expression system in the presence of preexisting, neutralizing anti-Ad antibodies. To assess the efficiency of repeated gene delivery of an adenovector expression system, C57Bl/6 mice received one, two, or three injections (intravitreal [IVT] or periocular [PO]) of AdNull.11D (empty cassette) at 2-week intervals, followed by a single AdLuciferase (AdL.11D) IVT or PO injection. Mice were killed approximately 24 hours after AdL.11D injection and the eyes were enucleated and stored until assayed. Serum samples were also analyzed to determine whether repeated IVT or PO injections lead to induction of neutralizing antibodies directed against an adenovector delivery system. To determine whether preexisting neutralizing anti-Ad antibodies would block transgene expression, mice were preimmunized with one, two, or three intramuscular (IM) injection(s) of AdNull.11D (1 x 10(9) particle units [pu]). Fourteen days later, when systemic anti-Ad antibody titers were expected to exist, mice were given a single AdL.11D injection (IVT or PO) and killed, and the eyes and serum collected. These studies show that multiple injections at 2-week intervals with adenovectors (IM, IVT, or PO) did not prevent transgene expression in the eye. Moreover, measurement of neutralizing anti-Ad antibody titers revealed that measurable anti-Ad antibody titers in mice did not ablate transgene expression. |
Does over-expression of PTEN sensitize human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner? | Resistance to cisplatin-centered chemotherapy is a major cause of treatment failure in human ovarian cancer. Whereas PTEN, a tumor suppressor gene product, is believed to promote apoptosis primarily via inactivation of the PI3K/Akt cell survival pathway, recent evidence suggests that PTEN may function independently of this pathway. Activation of p53 is a key determinant of sensitivity to cisplatin-induced apoptosis. Whether PTEN can facilitate cisplatin sensitivity, and this involves the activation of p53, remains unclear. In this study, we determined whether and how PTEN over-expression sensitizes ovarian cancer cells to CDDP-induced apoptosis. Using pairs of chemosensitive and chemoresistant ovarian cancer cell lines (OV20028 vs. C13* and A2780-s vs. A2780-cp) as an in vitro model, we have examined the influence of PTEN over-expression in regulation of cisplatin-induced apoptosis. Apoptosis was assessed morphologically by Hoechst staining and confirmed by the detection of cleaved products of caspase-3 and PARP by Western blot. Over-expression of PTEN by PTEN cDNA transfection up-regulates p53 content and increases the sensitivity of chemoresistant cells to cisplatin-induced apoptosis without detectable changes in the levels of phosphorylated Akt and FKHR as well as FasL mRNA abundance as determined by Western blot and RT-PCR, respectively. PTEN-mediated chemosensitization was attenuated by p53 down-regulation by siRNA in C13*, a chemoresistant wild-type p53 cell. Moreover, PTEN over-expression failed to sensitize the chemoresistant p53 mutant ovarian cancer cell line A2780-cp to cisplatin-induced apoptosis, unless wild-type p53 was reconstituted by adenoviral p53 infection. | The purpose of the present study was to evaluate the extent of the ventricular epicardial fat and its relationship with the underlying myocardium, neither of which is still completely understood. A total of 117 autoptic human hearts was subdivided into four groups: normals (N), ischemics (I), hypertrophics (H) and hypertrophic-ischemics (HI). In each heart, the ventricular myocardial and epicardial fat weights were measured. On the basis of these data, the epicardial fat percentage within the ventricles was calculated. The left, right and total ventricular fat weights were greater in H and HI than in N and I (P<.05, P<.05, P<.01, respectively). No differences were detected in the epicardial fat weights in comparing H versus HI and N versus I. Moreover, the fat percentage in each ventricle did not vary between the four groups. However, if compared with the right ventricle, the left ventricle showed an epicardial fat percentage consistently lower (P<.0001). In nonhypertrophied hearts (N and I), the body mass index and the total epicardial fat weight were correlated (P<.05), whereas in hypertrophied hearts (H and HI), they were not. |
Are phospholipase C epsilon 1 ( PLCE1 ) haplotypes associated with increased risk of gastric cancer in Kashmir Valley? | Phospholipase C epsilon 1 (PLCE1) plays a crucial role in carcinogenesis and progression of several types of cancers. A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus. The aim of the present study was to investigate the role of three potentially functional SNPs (rs2274223A > G, rs3765524C > T, and rs7922612C > T) of PLCE1 in gastric cancer patients from Kashmir Valley. The study was conducted in 108 GC cases and 195 healthy controls from Kashmir Valley. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism method. Data were statistically analyzed using c2 test and logistic regression models. A P value of less than 0.05 was regarded as statistically significant. The frequency of PLCE1 A2274223C3765524T7922612, G2274223C3765524T7922612 , and G2274223T3765524C7922612 haplotypes were higher in patients compared with controls, conferred high risk for GC [odds ratio (OR) =6.29; P = 0.001; Pcorr = 0.003], (OR = 3.23; P = 0.011; Pcorr = 0.033), and (OR = 5.14; P = 0.011; Pcorr = 0.033), respectively. Smoking and salted tea are independent risk factors for GC, but we did not find any significant modulation of cancer risk by PLCE1 variants with smoking or excessive consumption of salted tea. | Two-stage revision surgery for infected total hip arthroplasty (THA) is commonly advocated, but substantial morbidity and expense are associated with this technique. In certain cases of infected THA, treatment with one-stage revision surgery and intraarticular infusion of antibiotics may offer a reasonable alternative with the distinct advantage of providing a means of delivering the drug in high concentrations. We describe a protocol for intraarticular delivery of antibiotics to the hip through an indwelling catheter combined with one-stage revision surgery and examine (1) the success as judged by eradication of infection at 1 year when treating chronically infected cemented stems; (2) success in treating late-onset acute infections in well-ingrown cementless stems; and (3) what complications were associated with this approach in a small case series. Between January 2002 and July 2013, 30 patients (30 hips) presented to the senior author for treatment of infected THA. Of those, 21 patients (21 hips) with infected cemented THAs underwent débridement and single-stage revision to cementless total hip implants followed by catheter infusion of intraarticular antibiotics. Nine patients (nine hips) with late-onset acute infections in cementless THA had bone-ingrown implants. These patients were all more than 2 years from their original surgery and had acute symptoms of infection for 4 to 9 days. Seven had their original THA elsewhere, and two were the author's patients. All were symptom-free until the onset of their infection, and none had postoperative wound complications, fever, or prolonged pain suggestive of a more chronic process. They were treated with débridement and head and liner exchange, again followed by catheter infusion of intraarticular antibiotics. During this time period, this represented all infected THAs treated by the senior author, and all were treated with this protocol; no patient underwent two-stage exchange during this time, and no patients were lost to followup. At the time of the surgery, two Hickman catheters were placed in each hip to begin intraarticular delivery of antibiotics in the early postoperative period. Antibiotics were infused daily into the hip for 6 weeks with the tubes used for infusion only. Eleven of the single-stage revisions and four of the hips treated with débridement had methicillin-resistant Staphylococcus aureus. Patients were considered free of infection if they had no clinical signs of infection and had a normal C-reactive protein and erythrocyte sedimentation rate at 1 year. Complications were ascertained by chart review. Twenty of 21 (95%) infections in patients who had single-stage revision for chronically infected cemented THA were apparently free from infection and remained so at a mean followup of 63 months (range, 25-157 months). One case grew Candida albicans in the operative cultures and remained free of signs of infection after rerevision followed by infusion of fluconazole. The nine cementless THAs treated with débridement and head/liner exchange all remained free of signs of infection at a mean followup of 74 months (range, 62-121 months). Few complications were associated with the technique. Four patients had elevated serum levels of vancomycin without renal function changes and two patients had transient blood urea nitrogen/creatinine elevations with normal vancomycin levels that resolved with dosage adjustments. No patient had evidence of permanent renal damage. None of the patients in this study developed a chronic fistula or had significant drainage from the catheter site. |
Does magnetic resonance imaging correlate of transient cerebral ischemic attacks? | MRI of patients with a transient ischemic attack (TIA) may provide more detailed morphological insights than CT. We therefore studied the frequency and type of TIA-related infarcts shown by MRI, examined the utility of intravenous contrast material, and searched for potential predictors of infarct occurrence. We performed 1.5-T MRI of the brain of 52 patients (age range, 28 to 93 years; mean, 61 years) with a hemispheric TIA. Contrast material (Gd-DTPA) was given to 45 individuals. We recorded type, number, size, and location of ischemic brain lesions and related the presence of acute infarction to features of clinical presentation and probable causes for the TIA. MRI showed focal ischemic lesions in 50 patients (81%), but an acute TIA-associated infarct was seen in only 19 subjects (31%). In patients with an acute lesion, the infarcts were smaller than 1.5 cm in 13 (68%), purely cortical in 11 (58%), and multiple in 7 (37%) individuals. Contrast enhancement contributed to the delineation of an acute lesion in only 2 of 45 patients (4%). Acute infarction was unpredictable by clinical TIA features, but the frequency of identifiable vascular or cardiac causes was significantly higher in those patients with TIA-related morphological damage (odds ratio, 5.2 [95% confidence interval, 1.6 to 17.3]). | The polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance predisposing to diabetes mellitus type 2 and atherosclerosis. Adiponectin is a recently discovered adipocytokine with insulin-sensitizing and putative antiatherosclerotic properties. The aim of the study was to elucidate determinants of circulating adiponectin levels and to investigate the potential role of adiponectin in insulin resistance in PCOS women. Plasma adiponectin and parameters of obesity, insulin resistance and hyperandrogenism were measured In 62 women with PCOS and in 35 healthy female controls. Both in PCOS and controls, adiponectin levels were lower in overweight or obese women than in normal-weight women, without any difference between PCOS and controls after adjustment for body mass index (BMI). In PCOS and in controls there was a significant correlation of adiponectin with BMI (r = -0.516, P < 0.001), fasting insulin (r = -0.404, P < 0.001), homeostasis model sensitivity (HOMA %S) (r = -0.424, P < 0.001) and testosterone (r = -0.279, P < 0.01), but no correlation with androstenedione (r = -0.112, P = 0.325), 17-OH-progesterone (r =-0.031, P = 0.784) or the LH/FSH ratio (r =-0.033, P = 0.753). Multiple linear regression analysis revealed that BMI and HOMA %S but not testosterone were independently associated with adiponectin plasma levels, explaining 16% (BMI) and 13% (HOMA %S) of the variability of adiponectin, respectively. In PCOS patients insulin sensitivity, as indicated by continuous infusion of glucose with model assessment (CIGMA %S) was significantly correlated with adiponectin (r = 0.55; P < 0.001), BMI (r =-0.575; P < 0.001), waist-to-hip ratio (WHR) (r =-0.48; P = 0.001), body fat mass assessed by dual-energy X-ray-absorptiometry (DEXA) [Dexa-fat (total) (r = -0.61; P < 0.001) and Dexa-fat (trunk) (r = -0.59; P < 0.001)] and with testosterone (r = -0.42; P = 0.001). Multiple linear regression analysis demonstrated that markers of obesity such as BMI, total or truncal fat mass, age and adiponectin were independently associated with CIGMA %S, and that circulating adiponectin accounted for about 18% of the degree of insulin resistance in PCOS. By contrast, testosterone was not a significant factor, suggesting that PCOS per se did not affect insulin sensitivity independent from obesity, age and adiponectin. Metformin treatment for 6 months in insulin-resistant PCOS women (n = 9) had no effect on plasma adiponectin (P = 0.59) despite significant loss of weight and fat mass and improvement in hyperandrogenaemia. |
Does automated quantification with BRASS reduce equivocal reporting of DaTSCAN ( 123I-FP-CIT ) SPECT studies? | ¹²³I-FP-CIT (DaTSCAN) SPECT studies of the nigrostriatal pathway are a valuable tool in the diagnosis of movement disorders. However some scans are reported as equivocal with potential adverse consequences. We investigated whether the use of quantification of tracer uptake within the striatum can be used to reduce the number of equivocal reports. BRASS software (Hermes, Sweden) was used to quantify striatal tracer uptake in DaTSCAN studies of patients referred to our institution. Scans were quantified and numerical limits were determined to distinguish between normal and abnormal scans. Scans were then re-reported both with, and without, the use of quantification. Number of equivocal reports and accuracy of reporting between the two types of reporting were compared. Scan reporting using quantification led to a significant reduction in the number of equivocal reports with no significant change in reporting accuracy. | Honey has been familiar to possess antimicrobial potential to clear infection against burn wound infecting bacteria since ancient times. The objective of the study was to evaluate the efficacy of the newly formulated honey ointment during the treatment of burn wound infections. The Experimental (Non comparative) study was conducted at outpatient department of Dermatology, Fauji Foundation Hospital, Rawalpindi from November 2009 to October 2010. The antimicrobial activity of different Pakistani floral sources (Acacia nilotica species indica, Zizyphus, Helianthus annuus and Carisa opaca) honey samples were investigated by disc diffusion method against freshly isolated burn wounds infecting bacteria. Ointment containing 20% active antimicrobial honey was formulated as a sovereign remedy. A total number of twenty patients with second degree of burn wounds on different parts of the body were studied. A thin layer of honey ointment on gauze was applied to the wounds two to three times a day up to the complete healing. During microbiological study, Pakistani honey samples were discovered to exhibit a very promising antimicrobial activity against all the wound infecting microorganisms tested. Clinical trials demonstrated that the topical application of honey ointment have significant control of infections arising form pathogenic bacteria and up to 100% healing results were observed in all burn wound cases within mean healing time for the duration of 8.15 (3-18) days time period. |
Is expression of KLF5 a prognostic factor for disease-free survival and overall survival in patients with breast cancer? | Kruppel-like factor (KLF5) is a cell growth mediator in various epithelial cells. Higher KLF5 increases cell growth rate and leads to transformed phenotypes. Because tumor cell proliferation is tightly associated with tumor progression, and consequently, with survival of cancer patients, we wanted to examine the prognostic value of KLF5 gene expression for patients with breast cancer. The gene expression levels of KLF5, ER, PR, HER2, and MKI67 were quantified in the tumor tissues of 90 patients with breast cancer and correlated with disease-free survival and overall survival of the patients. The correlations of gene expression between KLF5 and ER, PR, HER2, and MKI67 were analyzed. In addition, KLF5 expression was also compared with clinical data and age of patients. Statistically significant correlations were found between gene expression of KLF5 and both disease-free survival (univariate analysis) and overall survival (univariate and multivariate analysis). Patients with higher KLF5 expression had shorter disease-free survival and overall survival time, whereas patients with lower KLF5 expression had better survival. Moreover, KLF5 was also found to be positively correlated with HER2 and MKI67, and negatively correlated with age of the patients at diagnosis. | Our aim was to investigate mechanisms of inflammation-induced endothelial dysfunction in humans. Endothelial function in twenty-one healthy human volunteers was measured using forearm venous plethysmography before and 8 h after administration of typhoid vaccination to generate an inflammatory response. Basal and stimulated endothelial nitric oxide (NO) bioavailability was assessed by measurement of the responses to intra-arterial N(G)-monomethyl-l-arginine (l-NMMA) and bradykinin, respectively. The effects of supplementation with l-arginine or ascorbic acid were assessed to probe the effects of substrate deficiency and oxidative stress, respectively. Systemic effects were determined by measuring cytokine response, total anti-oxidant status (TAOS) and urinary protein excretion. Vaccination induced a cytokine response, a fall in total anti-oxidant status and increased urinary albumin excretion (UAE). There was a reduction in the response to bradykinin (BK, P<0.005) and l-NMMA (P<0.0001) with no effect on the response to glyceryl trinitrate (GTN) and norepinephrine (NE). Following vaccination blood flow response to BK (but not GTN) was partially returned to pre-vaccine levels by infusion of ascorbic acid (P=0.01). Supplementation with l-arginine had no effect. |
Does metabolic control analysis of the Trypanosoma cruzi peroxide detoxification pathway identify tryparedoxin as a suitable drug target? | The principal oxidative-stress defense in the human parasite Trypanosoma cruzi is the tryparedoxin-dependent peroxide detoxification pathway, constituted by trypanothione reductase (TryR), tryparedoxin (TXN), tryparedoxin peroxidase (TXNPx) and tryparedoxin-dependent glutathione peroxidase A (GPxA). Here, Metabolic Control Analysis (MCA) was applied to quantitatively prioritize drug target(s) within the pathway by identifying its flux-controlling enzymes. The recombinant enzymes were kinetically characterized at physiological pH/temperature. Further, the pathway was in vitro reconstituted using enzyme activity ratios and fluxes similar to those observed in the parasites; then, enzyme and substrate titrations were performed to determine their degree of control on flux. Also, kinetic characterization of the whole pathway was performed. Analyses of the kinetic properties indicated that TXN is the less efficient pathway enzyme derived from its high Kmapp for trypanothione and low Vmax values within the cell. MCA established that the TXN-TXNPx and TXN-GPxA redox pairs controlled by 90-100% the pathway flux, whereas 10% control was attained by TryR. The Kmapp values of the complete pathway for substrates suggested that the pathway flux was determined by the peroxide availability, whereas at high peroxide concentrations, flux may be limited by NADPH. | When medical students move from the classroom into clinical practice environments, their roles and learning challenges shift dramatically from a formal curricular approach to a workplace learning model. Continuity among peers during clinical clerkships may play an important role in this different mode of learning. We explored students' perceptions about how they achieved workplace learning in the context of intentionally formed or ad hoc peer groups. We invited students in clerkship program models with continuity (CMCs) and in traditional block clerkships (BCs) to complete a survey about peer relationships with open-ended questions based on a workplace learning framework, including themes of workplace-based relationships, the nature of work practices, and selection of tasks and activities. We conducted qualitative content analysis to characterize students' experiences. In both BCs and CMCs, peer groups provided rich resources, including anticipatory guidance about clinical expectations of students, best practices in interacting with patients and supervisors, helpful advice in transitioning between rotations, and information about implicit rules of clerkships. Students also used each other as benchmarks for gauging strengths and deficits in their own knowledge and skills. |
Does family need at a post-acute rehabilitation setting and suggestions for supports? | To explore the perceived needs, obstacles to services, psychological distress and social problem-solving abilities of family members of persons with ABI at a post-acute community-based brain injury rehabilitation facility and offer suggestions for methods of assessment and providing support. Twenty-nine family members who did not provide daily care, but were involved in the care process. Participants completed self-report questionnaires including the FNQ:R, SOS, DASS-21, WHO-QOL BREF and SPSI:R-S. Participants reported informational and professional needs as most met and involvement in care, instrumental support and emotional support as most unmet. Most were satisfied with the amount of professional help and services and had confidence in the quality of care. Nearly half of the family members felt there were few ABI-related resources in the community and one third were unaware of good ABI treatment resources in their community. Psychosocial functioning was generally average. | A functional vacuolar adenosine triphosphatase (v-ATPase) complex regulates canonical Wnt/β-catenin signaling. The goal of this study was to identify the distribution of the v-ATPase in human and murine models of pancreatic intraepithelial neoplasms (PanINs) and assess its role in Wnt/β-catenin signaling. We evaluated the immunolabeling pattern of the v-ATPase in human PanIN specimens and murine PanIN-1 and PanIN-2 lesions obtained from Ptf1a(Cre/+); LSL-Kras(G12D) mice. Wnt/β-catenin signaling was interrogated in primary PanIN cells by examining the phosphorylated levels of its surface coreceptor, low-density lipoprotein receptor-related protein-6 (LRP6), and its intracellular effector, nonphosphorylated β-catenin. The response of primary PanIN cells to epidermal growth factor (EGF) was assessed in the absence and presence of the v-ATPase inhibitor, concanamycin. In advanced (PanIN-2), but not early (PanIN-1), lesions, the v-ATPase assumed a polarized phenotype. Blocking the v-ATPase disrupted Wnt/β-catenin signaling in primary PanIN cells despite significantly higher levels of the total and activated Wnt cell surface coreceptor, LRP6. Vacuolar adenosine triphosphatase blockade significantly decreased the total and activated levels of EGF receptor, a determinant of PanIN progression. The activation of EGF receptor and its intracellular mediator, p44/42 mitogen-activated protein kinase, was also reduced by v-ATPase blockade. This led to diminished proliferation in response to EGF ligand. |
Do impaired post-tetanic potentiation of muscle twitch in myasthenia gravis? | The aim of this study was to evaluate post-tetanic potentiation of muscle twitch in myasthenia gravis (MG). Post-tetanic potentiation was evaluated by recording the compound muscle action potential (CMAP) of abductor pollicis brevis and movement-related potential (MRP) of the thumb using an accelerometer after tetanic stimulation of the median nerve at the wrist. After baseline recording, tetanic stimulation was delivered to the median nerve at a frequency of 10 Hz for 10s. The CMAP and MRP were successively recorded at baseline and at 5, 10, 30, 60, 90 and 120 s after tetanic stimulation. The chronological changes of CMAPs and MRPs were recorded bilaterally in 11 patients with MG, 9 patients with myopathies (disease controls), and 25 healthy control subjects. Maximal acceleration of MRP was significantly elevated during 10s after tetanic stimulation without any CMAP changes in all groups. However, statistical analysis detected a significant decrease in post-tetanic potentiation of maximal acceleration of MRP in MG patients only compared to healthy controls, but not in myopathy patients, which may imply impairment of excitation-contraction coupling in MG. | The B cell leukemia 11A (BCL11A) gene was identified as a proto-oncogene in hematopoietic cell malignancies and breast cancer. Alternative RNA splicing generates three main transcripts designated as Extra-long (XL; 5.9 kb/125 kD), Long (L; 3.8 kb/100 kD) and Short (S; 2.4 kb/35 kD). Our previous study results demonstrated that BCL11A expression levels were specifically upregulated in non-small cell lung cancer (NSCLC) tissues, especially in squamous cell carcinoma (SCC) and large cell carcinoma (LCC). In this study, we detected the BCL11A protein isoforms with immunohistochemistry (IHC) method in NSCLC with in a cohort (n=40) of BCL11A overexpression NSCLC patients. All 40 cases were BCL11A overexpression including 27 SCCs, 8 LCCs and 5 adenocarcinomas (ACs). Relationship between BCL11A isoforms and the clinicopathological parameters were also analyzed. Compare to the BCL11A-L and S isoforms, the BCL11A-XL isoform was specifically expressed in SCC and LCC (P=0.006). There were 19 (19/40, 47.5%) cases positive for BCL11A-XL expression, SCC accounted for 63.2% (12/19) and LCC accounted for 36.8% (7/19). The survival analysis indicated that BCL11A-XL expression was an independent prognostic factor for disease-free survival (DFS) [hazards ratio (HR) 0.246; 95% confidence interval (CI), 0.065-0.939, P=0.040] but not for overall survival (OS) in patients with SCC and LCC. |
Does ursodeoxycholic acid reduce expression of heat shock proteins in primary biliary cirrhosis? | To identify injured cells in the liver of patients with primary biliary cirrhosis (PBC) and to determine the effects of ursodeoxycholic acid (UDCA) on these cells, we examined the cellular expression of heat shock proteins (HSPs) in PBC both before and after treatment with UDCA. Expression of HSP70 and ubiquitin in PBC livers (n=34) was evaluated immunohistochemically as well as by immunoblot analysis, and compared with chronic viral hepatitis type C (n= 9), primary sclerosing cholangitis (n=8), and controls (n=7). Immunoblot analysis demonstrated a marked expression of HSP70 and ubiquitin in PBC. Immunohistochemical staining for both HSP70 and ubiquitin was observed to be strong in biliary epithelial cells (BECs) and moderate in both hepatocytes and arteries in PBC. Cellular labelling rates for HSP70 and ubiquitin of bile ducts in PBC were significantly higher (p<0.01) than those in chronic viral hepatitis type C, primary sclerosing cholangitis, or controls. The labelling rates for HSP70 and ubiquitin in bile ducts and in hepatocytes were significantly decreased (p<0.01) after treatment with UDCA in PBC. | To evaluate pedestrian behavior, including reaction time, impulsivity, risk-taking, attention, and decision-making, in children with obstructive sleep apnea syndrome (OSAS) compared with healthy controls. Using a case control design, 8- to 16-year-olds (n = 60) with newly diagnosed and untreated OSAS engaged in a virtual reality pedestrian environment. Sixty-one healthy children matched using a yoke-control procedure by age, race, sex, and household income served as controls. Children with OSAS were riskier pedestrians than healthy children of the same age, race, and sex. Children with OSAS waited less time to cross (P < .01). The groups did not differ in looking at oncoming traffic or taking longer to decide to cross. |
Are blood biomarkers helpful in the prediction of response to chemoradiation in rectal cancer : a prospective , hypothesis driven study on patients with locally advanced rectal cancer? | Chemoradiation (CRT) has been shown to lead to downsizing of an important portion of rectal cancers. In order to tailor treatment at an earlier stage during treatment, predictive models are being developed. Adding blood biomarkers may be attractive for prediction, as they can be collected very easily and determined with excellent reproducibility in clinical practice. The hypothesis of this study was that blood biomarkers related to tumor load, hypoxia and inflammation can help to predict response to CRT in rectal cancer. 295 patients with locally advanced rectal cancer who were planned to undergo CRT were prospectively entered into a biobank protocol (NCT01067872). Blood samples were drawn before start of CRT. Nine biomarkers were selected, based on a previously defined hypothesis, and measured in a standardized way by a certified lab: CEA, CA19-9, LDH, CRP, IL-6, IL-8, CA IX, osteopontin and 25-OH-vitamin D. Outcome was analyzed in two ways: pCR vs. non-pCR and responders (defined as ypT0-2N0) vs. non-responders (all other ypTN stages). 276 patients could be analyzed. 20.7% developed a pCR and 47.1% were classified as responders. In univariate analysis CEA (p=0.001) and osteopontin (p=0.012) were significant predictors for pCR. Taking response as outcome CEA (p<0.001), IL-8 (p<0.001) and osteopontin (p=0.004) were significant predictors. In multivariate analysis CEA was the strongest predictor for pCR (OR 0.92, p=0.019) and CEA and IL-8 predicted for response (OR 0.97, p=0.029 and OR 0.94, p=0.036). The model based on biomarkers only had an AUC of 0.65 for pCR and 0.68 for response; the strongest model included clinical data, PET-data and biomarkers and had an AUC of 0.81 for pCR and 0.78 for response. | Parenting practices can reduce how much television (TV) children watch. This study evaluated the longitudinal association between maternal regulation of TV content and the amount of TV watched by low-income ethnic minority children. This was a secondary data analysis of the Welfare, Children & Families: A Three City Study. Data were used from ethnic minority mothers with a child from birth to 4 years old, collected over two waves approximately 16 months apart. The dependent variable was the amount of TV watched by the child (wave two). The main independent variable was the maternal regulation of TV content (wave one). Using multiple linear regression, we evaluated the relationship between maternal regulation of TV content and the amount of TV watched by the child, adjusting for covariates. Of the 835 mothers, 71% were high content regulators and 8% reported no content regulation. Children whose mothers reported no regulation watched more TV approximately 16 months later than those whose mothers reported high regulation of content (β = 0.91, 95% CI: 0.09-1.73). |
Is urinary dysfunction after rectal cancer treatment mainly caused by surgery? | Urinary dysfunction (UD) is common after rectal cancer treatment, but the contribution of each treatment component (surgery and radiotherapy) to its development remains unclear. This study aimed to evaluate UD during 5 years after total mesorectal excision (TME) and to investigate the influence of preoperative radiotherapy (PRT) and surgical factors. Patients with operable rectal cancer were randomized to TME with or without PRT. Questionnaires concerning UD were completed by 785 patients before and at several time points after surgery. Possible risk factors, including PRT, demographics, tumour location, and type and extent of resection, were investigated by multivariable regression analysis. Long-term incontinence was reported by 38.1 per cent of patients, of whom 72.0 per cent had normal preoperative function. Preoperative incontinence (relative risk (RR) 2.75, P = 0.001) and female sex (RR 2.77, P < 0.001) were independent risk factors. Long-term difficulty in bladder emptying was reported by 30.6 per cent of patients, of whom 65.0 per cent had normal preoperative function. Preoperative difficulty in bladder emptying (RR 2.94, P < 0.001), peroperative blood loss (RR 1.73, P = 0.028) and autonomic nerve damage (RR 2.82, P = 0.024) were independent risk factors. PRT was not associated with UD. | Accumulating evidence suggests that the balance between pathogenic effector T cells (Teffs) and regulatory T cells (Tregs) may be important for controlling atherosclerotic disease. We hypothesized that a combination therapy with anti-CD3 antibody (CD3-Ab) and IL-2/anti-IL-2 monoclonal antibody complex (IL-2 complex) aimed at increasing the ratio of Tregs to Teffs would effectively inhibit atherosclerosis in mice. We treated apolipoprotein E-deficient mice fed a high-cholesterol diet with vehicle, CD3-Ab, IL-2 complex, or their combination. Mice receiving the combination therapy had markedly reduced atherosclerotic lesions than mice treated with CD3-Ab or IL-2 complex alone. In addition, a striking increase in the Treg/Teff ratio of lymphoid organs and atherosclerotic lesions, along with plaque stabilization characterized by decreased macrophage content and increased collagen content was observed. The combination treatment also markedly reduced splenic Ly6C(high) inflammatory monocytes and might induce a favorable macrophage phenotype change in atherosclerotic lesions. |
Does vacuum-assisted closure therapy increase local interleukin-8 and vascular endothelial growth factor levels in traumatic wounds? | Clinical observations are suggesting accelerated granulation tissue formation in traumatic wounds treated with vacuum-assisted closure (VAC). Aim of this study was to determine the impact of VAC therapy versus alternative Epigard application on local inflammation and neovascularization in traumatic soft tissue wounds. Thirty-two patients with traumatic wounds requiring temporary coverage (VAC n = 16; Epigard n = 16) were included. At each change of dressing, samples of wound fluid and serum were collected (n = 80). The cytokines interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), and fibroblast growth factor-2 were measured by ELISA. Wound biopsies were examined histologically for inflammatory cells and degree of neovascularization present. All cytokines were found to be elevated in wound fluids during both VAC and Epigard treatment, whereas serum concentrations were negligible or not detectable. In wound fluids, significantly higher IL-8 (p < 0.001) and VEGF (p < 0.05) levels were detected during VAC therapy. Furthermore, histologic examination revealed increased neovascularization (p < 0.05) illustrated by CD31 and von Willebrand factor immunohistochemistry in wound biopsies of VAC treatment. In addition, there was an accumulation of neutrophils as well as an augmented expression of VEGF (p < 0.005) in VAC wound biopsies. | Diabetic patients commonly suffer from disturbances in production and clearance of plasma lipoproteins, known as diabetic dyslipidemia, resulting in an increased risk of coronary heart disease. The study aimed to examine the cause of hypobetalipoproteinemia in two patients with type 1 diabetes. The Diabetes Control and Complications Trial (DCCT) is a study demonstrating that intensive blood glucose control delays the onset and progression of type 1 diabetes complications. Hypobetalipoproteinemia was present in two DCCT subjects, IDs 1427 and 1078, whose LDL-C levels were 36 and 28 mg/dL, respectively, and triglyceride levels were 20 and 28 mg/dL, respectively. We performed exome sequencing on genomic DNA from the two patients with hypobetalipoproteinemia. The subjects 1427 and 1078 had heterozygous loss-of-function mutations in the gene apolipoprotein B (ApoB), and these mutations resulted in premature stop codons at amino acid 1333 (ApoB-29) and 3680 (ApoB-81), respectively. Indeed, the plasma ApoB level of subject 1427 (19 mg/dL) was the lowest and that of subject 1078 (26 mg/dL) was the second to the lowest among all the 1,441 DCCT participants. Sequencing genomic DNA of family members showed that probands 1427 and 1078 inherited the mutations from the father and the mother, respectively. |
Is galectin-1 a local but not systemic immunomodulatory factor in mesenchymal stromal cells? | Mesenchymal stromal cells (MSCs) have powerful immunosuppressive activity. This function of MSCs is attributed to plethora of the expressed immunosuppressive factors, such as galectin-1 (Gal-1), a pleiotropic lectin with robust anti-inflammatory effect. Nevertheless, whether Gal-1 renders or contributes to the immunosuppressive effect of MSCs has not been clearly established. Therefore, this question was the focus of a complex study. MSCs were isolated from bone marrows of wild-type and Gal-1 knockout mice and their in vitro anti-proliferative and apoptosis-inducing effects on activated T cells were examined. The in vivo immunosuppressive activity was tested in murine models of type I diabetes and delayed-type hypersensitivity. Both Gal-1-expressing and -deficient MSCs inhibited T-cell proliferation. Inhibition of T-cell proliferation by MSCs was mediated by nitric oxide but not PD-L1 or Gal-1. In contrast, MSC-derived Gal-1 triggered apoptosis in activated T cells that were directly coupled to MSCs, representing a low proportion of the T-cell population. Furthermore, absence of Gal-1 in MSCs did not affect their in vivo immunosuppressive effect. | Analgesia and sedation, routinely used as adjunct medications for regional anesthesia, are rarely used in the pregnant patient because of concerns about adverse neonatal effects. In an effort to obtain more information about maternal analgesia and sedation we studied neonatal and maternal effects of iv fentanyl and midazolam prior to spinal anesthesia for elective Cesarean section. In this double-blinded, randomized, placebo-controlled trial, 60 healthy women received either a combination of 1 microg x kg(-1) fentanyl and 0.02 mg x kg(-1) midazolam intravenously or an equal volume of iv saline at the time of their skin preparation for a bupivacaine spinal anesthetic. Sample size was based on a non-parametric power analysis (power > 0.80 and alpha = 0.05) for clinically important differences in Apgar scores. Fetal outcome measures included Apgar scores, continuous pulse oximetry for three hours, and neurobehavioural scores. Maternal outcomes included catecholamine levels, and recall of anesthesia and delivery. There were no between-group differences of neonatal outcome variables (Apgar score, neurobehavioural scores, continuous oxygen saturation). Mothers in both groups showed no difference in their ability to recall the birth of their babies. |
Does suicidal ideation and behavior and some psychological correlate in physically disabled motor-vehicle accident survivors? | Previous research has shown some maladaptive psychological reactions and even increased incidence of various mental disorders in patients with spinal cord injury during their rehabilitation. Self-concept and suicidal risk in particular have not been studied often in these samples. Our principal goal was to explore suicidal ideation and behavior, self-concept, posttraumatic stress disorder (PTSD) symptoms, and correlations among these traits, in subjects after a motor vehicle accident (MVA) resulting in permanent physical disability. Our sample consisted of 50 individuals with paraplegia, tetraplegia, or significant amputation, of whom eight had a family history of suicidal behavior. The following assessment instruments were used: an anamnestic data questionnaire; the Tennessee Self-Concept Scale; the Impact of Event Scale-Revised; and the Suicidal Ideations and Behaviour Questionnaire. Rehabilitating patients with spinal cord injury were characterized by low total self-concept, presence of PTSD symptoms, and suicidal ideation and behavior. PTSD symptoms were correlated with low self-concept and suicidal tendencies. | Angiotensin II (AngII), a vasoconstrictive peptide of the renin-angiotensin system (RAS), promotes hepatic fibrogenesis and induces microRNA-21(mir-21) expression. Angiotensin-(1-7) [Ang-(1-7)] is a peptide of the RAS, which attenuates liver fibrosis. Recently, it was reported that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome participated in liver fibrosis. However, it remains unclear how mir-21 mediates AngII-induced NLRP3 inflammasome activation. We investigate the role of AngII-induced mir-21 in the regulation of NLRP3 inflammasome/IL-1β axis in liver fibrosis. In vivo, circulating mir-21 was upregulated in patients with liver fibrosis and was positively correlated with liver fibrosis and oxidation. Treatment with Ang-(1-7) inhibited mir-21, NLRP3 inflammasome, and liver fibrosis after bile duct ligation (BDL) or AngII infusion. Inhibition of mir-21 suppressed the Smad7/Smad2/3/NOX4, Spry1/ERK/NF-κB pathway, NLRP3 inflammasome, and liver fibrosis induced by AngII infusion. In vitro, AngII upregulated mir-21 expression via targeting Smad7 and Spry1 in primary hepatic stellate cells (HSCs). In contrast, Ang-(1-7) suppressed mir-21 expression and oxidation induced by AngII. Overexpression of mir-21 promoted oxidation, and collagen production enhanced the effect of AngII on NLRP3 inflammasome activation via the Spry1/ERK/NF-κB, Smad7/Smad2/3/NOX4 pathways. However, downregulation of mir-21 exerted the opposite effects. |
Does aganglionosis with the absence of hypertrophied nerve fibres predict disease proximal to rectosigmoid colon? | The gold standard for the diagnosis of Hirschsprung's disease (HSCR) is the pathologic evaluation of a rectal biopsy that demonstrates the absence of ganglion cells and nerve fibre hypertrophy. However, it has been frequently reported that hypertrophic nerves may not be present in some variants like long-segment HSCR, total colonic aganglionosis, premature and very young infants. The aim of this study was to determine this association. We performed a retrospective review of the HSCR database at our tertiary care children's hospital from 2000 to 2013. In order to analyse the relationship between the diameter of the nerve fibres and the level of aganglionosis, we classified the patient sample into two groups-fibres ≤40 and >40 μm. The groups were statistically compared with P < 0.05 being significant. Rectal biopsies of 92 patients confirmed as HSCR with definitive operation performed at the same institution were reviewed. The mean nerve diameter was 50.1 μm (range 20-87.5 μm). Nerve fibre diameter ≤40 μm was predictive of transition zone above the sigmoid colon. A specificity of 77.3 % and a likelihood ratio of 2.03 supported this perception. No correlation was noted between nerve fibre diameter and gestational age at birth, birth weight or age at biopsy. | It is well known that cardiac rehabilitation (CR) including regular exercise training (ET) is cardioprotective with respect to clinical events in patients with acute myocardial infarction (AMI). However, it is not known whether the regular ET may affect coronary restenosis after percutaneous coronary intervention (PCI) with stenting in AMI. The aim of this study was to evaluate the effect of regular ET on a stented coronary segment and its association with inflammatory markers in AMI. Consecutively 74 AMI patients who underwent PCI with implantation of a drug-eluting stent and 9 month follow-up angiography were included. Thirty seven patients who received CR with ET were assigned to the ET group. Another 37 patients who did not participate in ET, of similar age to those of participants, were assigned to the control group. At 9 months, angiographic restenosis measured as in-segment late luminal loss of the stented coronary artery was analyzed via quantitative coronary angiography using CAAS 5.9. There were no significant differences in baseline characteristics including age, sex, body mass index, smoking, DM, hypertension, lipid profile, use of statin, and complete blood cell between two groups. On 9 month follow-up angiography, late luminal loss per stent was significantly smaller in the ET group compared to the control group (0.14 ± 0.57 vs. 0.54 ± 0.88 mm, p=0.02). Maximal oxygen consumption (VO2max) significantly improved in the ET group after 9months (27.9 ± 6.4 vs. 30.8 ± 5.2 mL/kg/min, p<0.001). Increment in high density lipoprotein-cholesterol (HDL-C) was significantly larger in the ET group at 9 months (0.15 ± 0.12 vs. 0.04 ± 0.24 mg/dL, p=0.03). |
Are bronchiolitis : age and previous wheezing episodes linked to viral etiology and atopic characteristics? | : Diagnostic criteria for bronchiolitis are variable. : To study how the risk factors for recurrent wheezing and asthma vary by different definitions of bronchiolitis. : Viral etiology and atopic characteristics were studied in 259 hospitalized wheezing children (median age, 14 months; range, 0-36 months). The data were analyzed according to age (<6, <12, <24 and <36 months) and whether they had a history or no history of a previous wheezing episode. Sixteen viruses were detected by conventional and molecular methods. Atopic characteristics included the presence of eczema, specific and total IgE responses, blood eosinophil count, and modified asthma predictive index. : Evidence of respiratory virus infection was found in 93% of the cases and allergic sensitization in 26% of the cases. Rhinovirus infections and atopic characteristics (sensitization, blood eosinophil count, and modified asthma predictive index) increased by age and were significantly more common in children with recurrent wheezing episodes than in first-time wheezers in age categories of <24 and <36 months (P < 0.05 for all). | Large-scale epidemiological studies support a correlation between obesity and breast cancer in postmenopausal women. Circulating leptin levels are increased in obese and it has been suggested to play a significant role in mammary tumor formation and progression. Moreover, regulation of oxidative stress is another important factor in both tumor development and responses to anticancer therapies. The aim of this study was to examine the relationship between oxidative stress and chronic leptin exposure. We treated MCF-7 breast cancer cells with 100 ng/mL leptin for 10 days and analyzed cell growth, ROS production and oxidative damage, as well as, some of the main antioxidant systems. Furthermore, since the hyperleptinemia has been associated with a worse pathology prognosis, we decided to test the influence of leptin in response to cisplatin anticancer treatment. Leptin signalling increased cell proliferation but reduced ROS production, as well as, oxidative damage. We observed an upregulation of SIRT1 after leptin exposure, a key regulator of stress response and metabolism. Additionally, leptin counteracted cisplatin-induced cytotoxicity in tumor cells, showing a decrease in cell death. |
Does umbilical cord gene expression reveal the molecular architecture of the fetal inflammatory response in extremely preterm newborns? | The fetal inflammatory response (FIR) in placental membranes to an intrauterine infection often precedes premature birth raising neonatal mortality and morbidity. However, the precise molecular events behind FIR still remain largely unknown, and little has been investigated at gene expression level. We collected publicly available microarray expression data profiling umbilical cord (UC) tissue derived from the cohort of extremely low gestational age newborns (ELGANs) and interrogate them for differentially expressed (DE) genes between FIR and non-FIR-affected ELGANs. We found a broad and complex FIR UC gene expression signature, changing up to 19% (3,896/20,155) of all human genes at 1% false discovery rate. Significant changes of a minimum 50% magnitude (1,097/3,896) affect the upregulation of many inflammatory pathways and molecules, such as cytokines, toll-like receptors, and calgranulins. Remarkably, they also include the downregulation of neurodevelopmental pathways and genes, such as Fragile-X mental retardation 1 (FMR1), contactin 1 (CNTN1), and adenomatous polyposis coli (APC). | Thyroid hormone has important effects on the cardiovascular system. The consequences of episodes of acute hypothyroidism on cardiac function have been investigated in only a few studies, and their results are inconclusive. Our objective was to investigate the effects of acute hypothyroidism on cardiac function in patients with iatrogenically induced subclinical hyperthyroidism after treatment for differentiated thyroid carcinoma. Fourteen patients with a history of differentiated thyroid carcinoma on thyroid-stimulating hormone (TSH)-suppressive thyroxine replacement therapy were studied. We assessed cardiac function before, and 1 and 4 weeks after withdrawal of thyroxine substitution. We measured serum levels of free thyroxine, triiodothyronine and TSH and used a new sophisticated Doppler echocardiography technique, tissue Doppler imaging (TDI), to assess detailed and quantitative assessment of systolic and diastolic cardiac function. Echocardiographic parameters in patients were compared to controls. Compared to controls, patients had higher left ventricular mass and wall thickness and decreased diastolic function during TSH-suppressive l-thyroxine substitution therapy. Thyroxine withdrawal resulted in a decrease in both early (E) and late (A) diastolic mitral inflow velocities, without impact on E/A ratio. Using TDI, late diastolic velocity (A') decreased without impact on E'/A' ratio. Left ventricular dimensions, wall thickness and mass did not change during thyroxine withdrawal. |
Does erythropoietin-induced phosphorylation/degradation of BIM contribute to survival of erythroid cells? | A proapoptotic BH3-only protein BIM (BCL-2 interacting mediator of cell death) can link cytokine receptor signaling with the apoptotic machinery in hematopoietic cells. We investigated here the role of BIM in erythropoietin (EPO)-mediated survival in erythroid cells. We downregulated BIM in EPO-dependent HCD57 erythroid cells with short hairpin RNA (shRNA), and used real-time polymerase chain reaction, Western blots, and flow cytometry to characterize BIM expression and apoptosis. Hematologic analyses of BIM-deficient (Bim(-/-)) mice were conducted. BIM expression increases in primary murine erythroid cells and HCD57 cells deprived of EPO. Whereas Bim mRNA increased less than twofold, BIM protein increased more than 10-fold after EPO withdrawal, suggesting posttranscriptional regulation of BIM. EPO treatment resulted in rapid phosphorylation of BIM at Serine 65 and phosphorylation correlated with degradation of BIM. Inhibition of extracellular signal-regulated kinase (ERK) by a MEK/ERK inhibitor, U0126, blocked both phosphorylation and degradation of BIM, resulting in apoptosis. Treatment with a proteasome inhibitor, MG-132, also blocked degradation of phosphorylated BIM. Downregulation of BIM with the shRNA resulted in HCD57 cells more resistant to apoptosis induced by either EPO withdrawal or ERK inhibition. Although we observed no significant changes in the number of erythrocytes or reticulocytes in the circulation of Bim(-/-) mice, erythroid progenitors from bone marrow in Bim(-/-) mice were reduced in number and more resistant to apoptosis induced by U0126 MEK/ERK inhibitor. | Endothelial dysfunction is defined by reduced bioavailability of nitric oxide and has been shown to be associated with cardiovascular risk. The global arginine bioavailability ratio and the arginine to ornithine ratio have recently been shown to be associated with cardiovascular outcome in patients with coronary artery disease. The aim of our study was to investigate the impact of a multifactorial risk factor intervention in subjects with Type 2 diabetes on these two potential new cardiovascular surrogate parameters. In a single-centre and prospective study, we investigated 41 patients with Type 2 diabetes not reaching treatment targets according to current local diabetes guidelines in two out of three of the following measurements: HbA(1c) LDL cholesterol 2.6 or blood pressure. Within 3 months, therapy was intensified according to current guidelines aiming to reach the treatment targets. At baseline and 3 months, arginine, ornithine and citrulline were chromatographically determined after pre-column-derivatization followed by fluorescent detection, and arginine bioavailability ratios were calculated. Intensified risk factor management significantly improved the global arginine bioavailability ratio (0.33 ± 0.12 at baseline vs. 0.38 ± 0.14 after 3 months; P = 0.018). A significant improvement was only seen in patients with short diabetes duration (< 5 years), whereas in patients with longer diabetes duration improvement did not reach statistical significance. |
Is daily physical activity in patients with chronic obstructive pulmonary disease mainly associated with dynamic hyperinflation? | Although the major limitation to exercise performance in patients with COPD is dynamic hyperinflation, little is known about its relation to daily physical activity. To analyze the contribution of dynamic hyperinflation, exercise tolerance, and airway oxidative stress to physical activity in patients with COPD. In a cross-sectional study, we included 110 patients with moderate to very severe COPD. Daily physical activity was measured using a triaxial accelerometer providing a mean of 1-minute movement epochs as vector magnitude units (VMU). Patients performed the 6-minute walk test, incremental exercise test with measurement of breathing pattern and operating lung volumes, and constant-work rate test at 75% of maximal work rate. Using the GOLD stage and BODE index, we determined arterial blood gases, lung volumes, diffusing capacity, and biomarkers in exhaled breath condensate. Daily physical activity was lower in the 89 patients who developed dynamic hyperinflation than in the 21 who did not (n =161 [SD 70] vs. n = 288 [SD 85] VMU; P = 0.001). Physical activity was mainly related to distance walked in 6 minutes (r = 0.72; P = 0.001), Vo(2) (r = 0.63; P = 0.001), change in end-expiratory lung volume during exercise (r = -0.73; P = 0.001), endurance time (r = 0.61; P = 0.001), and 8-isoprostane in exhaled breath condensate (r = -0.67; P = 0.001). In a multivariate linear regression analysis using VMU as a dependent variable, dynamic hyperinflation, change in end-expiratory lung volume, and distance walked in 6 minutes were retained in the prediction model (r(2) = 0.84; P = 0.001). | Using sonography, the bicornate and septate uterus as causes of failure of quinacrine sterilization (QS) are explored. Whether QS can be effectively performed on women with a bicornate or septate uterus is a question answered by a presentation of three such cases. Three cases presented were part of a prospective nonrandomized study of QS in 205 women requesting sterilization at the Family Planning Clinic, School of Medicine of the Federal University of Minas Gerais, Belo Horizonte, Brazil. Sonography was performed on all patients before, during and after QS. Quinacrine was packaged as seven pellets in a modified Copper-T IUD inserter (Sipharm, Sisseln, Switzerland). Each woman received the first transcervical insertion of 252 mg of quinacrine during the follicular phase of the menstrual cycle, usually immediately after menses. One month later, a second insertion was similarly performed. Patients were advised to use an alternate method of birth control for 12 weeks to allow time for scarring of the oviducts. A blood pregnancy test was done before the QS procedure. The diagnosis of a septate or bicornuate uterus was made by sonography in three of the 205 patients in the study. It was obvious that quinacrine had to be inserted into the two horns of such an anomalous uterus if the dissolved drug was to enter both fallopian tubes. Quinacrine dissolved into "lakes of quinacrine," and sonographically could be seen at the top of the uterine fundus. For this clinical trial of 205 patients, there were 546 woman-years of follow-up, and the Pearl index was 0.73 per 100 woman-years (95% confidence limits: 0.02, 1.4). |
Is minimally invasive colon resection for malignant colonic conditions associated with a transient early increase in plasma sVEGFR1 and a decrease in sVEGFR2 levels after surgery? | Plasma VEGF levels increase after minimally invasive colorectal resection (MICR) and remain elevated for 2-4 weeks. VEGF induces physiologic and pathologic angiogenesis by binding to endothelial cell (EC) bound VEGF-Receptor-1 (VEGFR1) and VEGFR2. Soluble forms of these receptors sequester plasma VEGF, decreasing the amount available to bind to EC-bound receptors. Ramifications of surgery-related plasma VEGF changes partially depend on plasma levels of sVEGFR1 and sVEGFR2. This study assessed perioperative sVEGFR1 and sVEGFR2 levels after MICR in patients with colorectal cancer. Forty-five patients were studied; blood samples were taken from all patients preoperatively (preop) and on postoperative days (POD) 1 and 3; in most a fourth sample was drawn between POD 7-30. Late samples were bundled into two time points: POD 7-13 and POD 14-30. sVEGFR1 and sVEGFR2 levels were measured via ELISA. sVEGFR2 data are reported as mean +/- SD and were assessed with the paired samples t test. sVEGFR1 data were not normally distributed. They are reported as median and 95% confidence interval (CI) and were assessed with the Wilcoxon signed-Rank test (p < 0.05). Preoperatively, the mean plasma sVEGFR2 level (7583.9 pg/ml) was greater than the sVEGFR1 result (98.3 pg/ml). Compared with preop levels, sVEGFR2 levels were significantly lower on POD 1 (6068.2 pg/ml, +/-2034.5) and POD 3 (6227.6 pg/ml, +/-2007.0), whereas sVEGFR1 levels were significantly greater on POD 1 (237.5 pg/ml; 95% CI, 89.6-103.5), POD 3 (200.2 pg/ml; 95% CI, 159-253), and POD 7-13 (102.9 pg/ml; 95% CI, 189.7-253). No differences were found on POD 7-13 for sVEGFR2 or POD 14-30 for either protein. | The lengthy competition transition phases commonly experienced by competitive swimmers may mitigate the benefits of the pool warm-up. To combat this, we examined the impact of additional passive and active warm-up strategies on sprint swimming performance. Counterbalanced, repeated-measures cross-over study. Sixteen junior competitive swimmers completed a standardised pool warm-up followed by a 30min transition and 100m freestyle time-trial. Swimmers completed four different warm-up strategies during transition: remained seated wearing a conventional tracksuit top and pants (Control), wore an insulated top with integrated heating elements (Passive), performed a 5min dryland-based exercise circuit (Dryland), or a combination of Passive and Dryland (Combo). Swimming time-trial performance, core and skin temperature and perceptual variables were monitored. Time variables were normalised relative to Control. Both Combo (-1.05±0.26%; mean±90% confidence limits, p=0.00) and Dryland (-0.68±0.34%; p=0.02) yielded faster overall time-trial performances, with start times also faster for Combo (-0.37±0.07%; p=0.00) compared to Control. Core temperature declined less during transition with Combo (-0.13±0.25°C; p=0.01) and possibly with Dryland (-0.24±0.13°C; p=0.09) compared to Control (-0.64±0.16°C), with a smaller reduction in core temperature related to better time-trial performance (R(2)=0.91; p=0.04). |
Do obese children and adolescents need increased gastric volumes in order to perceive satiety? | In order to develop effective weight management strategies, it is important to identify factors that influence energy intake. Portion size has been discussed as one such factor. To date, most studies focusing on the relationship between portion size, energy intake, and weight have analyzed questionnaire data and 24-h records. In this study, we assessed the onset of satiety using the water-load test in normal-weight and obese children and adolescents. 60 obese and 27 normal-weight children and adolescents aged between 9 and 17 years participated in the water load test which involved drinking water for 3 min or until feeling full. The amount of water consumed was recorded. Obese children and adolescents drank 20% more water until the onset of satiety when compared with normal-weight participants (478 ± 222 ml vs. 385 ± 115 ml, P < 0.05). | The outcome of cardiac surgical patients with clinically diagnosed heparin-induced thrombocytopenia (HIT) was studied. Retrospective, observational study. University hospital. All cardiac surgical patients with diagnosed HIT after cardiac surgery between January 2002 and December 2004, and concurrently, consecutive patients without HIT. None Measurements and Main Results: 3465 patients were treated postoperatively in the cardiac surgical intensive care unit during the study period. Clinical suspicion of HIT arose when platelet count markedly fell several days after surgery and HIT was proven by a positive enzyme immunoassay in 20 patients. Thrombocytopenia (35.5 [22] x 10(9)/L, median [interquartile range]) developed within 7 (6) days. HIT patients received significantly more platelet transfusions perioperatively than controls (p < 0.001). Thromboembolic complications occurred in 70% of HIT patients, but in none of non-HIT patients (14/20 v 0/20, p = 0.001). Intensive care unit stay was longer in HIT patients than in controls (16.5 [11.0] v 1.0 [3.0] days, p < 0.001). Nine HIT patients died (45%), while all control patients survived. Mortality was related to thrombotic complications in seven HIT patients (35%). |
Does release of endogenous opioids from duodenal enteroendocrine cells require Trpm5? | Enteroendocrine cells, the largest and most diverse population of mammalian endocrine cells, comprise a number of different cell types in the gut mucosa that produce, store, and secrete small molecules, peptides, and/or larger proteins that regulate many aspects of gut physiology. Little is known about less typical endocrine cells in the intestinal mucosa that do not contain secretory granules, such as brush or caveolated cells. We studied a subset of these enteroendocrine cells in duodenum that produce several peptides, including endogenous opioids, and that also express the Trpm5 cation channel. We studied expression patterns of Trpm5 and other molecules by immunohistochemical and enzyme-linked immunosorbent assay analyses of intestinal tissues from transgenic mice that express green fluorescent protein from the Trpm5 promoter, as well as wild-type and Trpm5-null mice. We describe a type of enteroendocrine cell in mouse duodenum that is defined by the presence of Trpm5 and that does not contain typical secretory granules yet expresses endogenous opioids (beta-endorphin and Met-enkephalin) and uroguanylin in apical compartments close to the lumen of the gut. | Increasing evidence points to the inflammatory character of atherosclerosis and several parameters of inflammation have been proposed as cerebrovascular risk markers. The objective of the research was to examine the connection of serum inflammatory parameters and ultrasound (US) characteristics of the structure and size of carotid plaque. We assumed that the number of leukocytes (Le) was an indicator of carotid plaque instability and an increased risk of stroke. Serum inflammatory parameters: erythrocyte sedimentation rate in the first (ESR I) and second hour (ESR II), the number of Le, high sensitivity C-reactive protein (hsCRP) and fibrinogen were measured by standard methods. All the subjects (n = 75) were divided into 3 groups (symptomatic, asymptomatic and control). US evaluation of extracranial carotid arteries was performed in a duplex system. Plaques were classified into categories according to stenosis percentage (≥ 50%, < 50%) and pursuant to echomorphological characteristics (Gray-Weale classification). In the subjects with stroke an ischemic lesion was confirmed by computed tomography. The average values of biochemical parameters in the symptomatic group were: ESR I 29.57 ± 29.87 cm, ESR II 51.60 ± 36.87 cm, the number of Le 10.10 ± 3.20 x 10⁹ U/L, hsCRP 8.15 ± 5.50 mg/L and fibrinogen 4.03 ± 0.70 g/L. The average values of all testing biochemical parameters in symptomatic patients were significantly higher than in the asymptomatic ones and the control group: for ESR I (p < 0.05) and ESR II (p < 0.05); for the number of Le (p < 0.001); for hsCRP (p < 0.001) and fibrinogen (p < 0.001). Category I of echomorphological characteristics in the symptomatic group was present in 66.7% of the cases and it was significantly higher than in the asymptomatic (40.0%; p < 0.05) and the control group (20.0%; p < 0.01). Univariate logistic regression analysis confirmed that all testing biochemical parameters are indicators of stroke risk. Multivariate logistic regression analysis confirmed a statistically significant correlation of the number of Le and stroke risk, while the increase in the value by a unit of measurement was associated with the growth of risk by 3.22 times (from 1.67 to 6.22). |
Are oncolytic herpes simplex virus mutants more efficacious than wild-type adenovirus Type 5 for the treatment of high-risk neuroblastomas in preclinical models? | High-risk neuroblastoma (Nb) is incurable using current treatment regimens in the majority of patients. Oncolytic virotherapy is a novel approach being tested for several types of adult cancers. To compare the susceptibility of Nb tumor models to oncolytic adenovirus and HSV mutants and delineate the mechanisms of resistance or sensitivity. Human Nb cell lines were used to determine susceptibility to adenovirus type 5 wild-type and HSV1 mutant (NV1066) infection, adenovirus receptor expression, support of NV1066 replication, and induction of apoptosis. Human xenograft tumors in immunodeficient mice were evaluated for histological effects and tumor response to intratumoral injection of an oncolytic HSV mutant. All eight Nb cell lines tested in culture were relatively resistant to infection with wild type and attenuated adenoviruses. Cells expressed the cocksackie-adenovirus attachment receptor (CAR) but had low or absent expression of the internalization receptors (alphavbeta3, alphavbeta5 integrins). In contrast, all cells were uniformly sensitive to infection with the attenuated HSV mutant, NV1066. Productive virus replication and induction of apoptosis were observed in HSV-infected cells. CHLA-20 and LAN-5 xenograft tumors injected with a single dose of NV1066 showed a significant antitumor response, and the animals had a prolonged survival post infection in comparison to the PBS-treated control group. HSV injected tumors showed extensive areas of necrosis and morphologic evidence of apoptosis. | We sought to prospectively examine whether childbearing is associated with higher incidence of the metabolic syndrome (MetS) after delivery among women of reproductive age. In 1451 nulliparas who were aged 18-30 years and free of the MetS at baseline (1985-1986) and reexamined up to 4 times during 20 years, we ascertained incident MetS defined by the National Cholesterol Education Program Adult Treatment Panel III criteria among time-dependent interim birth groups by gestational diabetes mellitus (GDM): (0 [referent], 1 non-GDM, 2+ non-GDM, 1+ GDM births). Complementary log-log models estimated relative hazards of the MetS among birth groups adjusted for race, age, and baseline and follow-up covariates. We identified 259 incident MetS cases in 25,246 person-years (10.3/1000 person-years). Compared with 0 births, adjusted relative hazards (95% confidence interval [CI]) were 1.33 (95% CI, 0.93-1.90) for 1 non-GDM, 1.62 (95% CI, 1.16-2.26) for 2+ non-GDM (P trend = .02), and 2.43 (95% CI, 1.53-3.86) for 1+ GDM births. |
Is late onset spinal motor neuronopathy caused by mutation in CHCHD10? | A study was undertaken to identify the responsible gene defect underlying late onset spinal motor neuronopathy (LOSMoN/SMAJ; Online Mendelian Inheritance in Man #615048), an autosomal dominant disease mapped to chromosome 22q11.2. The previous genetic linkage approach by microsatellite haplotyping was continued in new families. A whole genome sequencing was performed to find all possibly pathogenic mutations in the linked area. The detected variations were verified by Sanger sequencing. Six new SMAJ families were identified based on the unique founder haplotype. A critical recombination in 1 family restricted the linked area to 727kb between markers SHGC-106816 and D22S345. In whole genome sequencing a previously unknown mutation c.197G>T p.G66V in CHCHD10 was identified. The mutation was shown to segregate with the disease in 55 patients from 17 families. | Allogeneic red blood cell transfusions may exert immunomodulatory effects in recipients including an increased rate of postoperative bacterial infection. It is controversial whether allogeneic transfusion is an independent predictor for the development of postoperative bacterial infection. We analysed a prospectively collected database of 1,349 patients undergoing colorectal surgery in 11 centres across Canada. The primary outcome was the development of either a postoperative wound infection or intra-abdominal sepsis in transfused and nontransfused patients. The effect of allogeneic transfusion on postoperative infection was evaluated with adjustment for all the confounding factors in a multiple regression analysis. The 282 patients who received a total of 832 allogeneic units had a significantly higher frequency of wound infections and intra-abdominal sepsis than the patients who were not transfused (25. 9 vs. 14.2%, p = 0.001). A significant dose-response relationship between transfusion and infection rate was demonstrated. Multiple regression analysis identified allogeneic transfusion as a statistically significant independent predictor for postoperative bacterial infection (OR 1.18, 95% CI 1.05-1.33, p = 0.007). Other independent predictors were anastomotic leak, repeat operation, patient age and preoperative haemoglobin level. The mortality rate was also significantly higher in the transfused group. |
Does periodontitis in rats induce systemic oxidative stress that is controlled by bone-targeted antiresorptives? | Periodontitis is a chronic, polymicrobial inflammatory disease that degrades connective tissue and alveolar bone and results in tooth loss. Oxidative stress has been linked to the onset of periodontal tissue breakdown and systemic inflammation, and the success of antiresorptive treatments will rely on how effectively they can ameliorate periodontal disease-induced oxidative stress during oral infection. Rats were infected with polybacterial inoculum consisting of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, as an oral lavage every other week for 12 weeks. Daily subcutaneous injections of enoxacin, bis-enoxacin, alendronate, or doxycycline were administered for 6 weeks after 6 weeks of polybacterial infection in rats. The serum levels of oxidative stress parameters and antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase, were evaluated in each of the infected, treated, and sham-infected rats. Rats infected with the periodontal pathogens displayed a five-fold increase in the oxidative stress index compared with controls as a result of increased levels of serum oxidants and decreases in total antioxidant activity. The overall decrease in antioxidant activity occurred despite increases in three important antioxidant enzymes, suggesting an imbalance between antioxidant macromolecules/small molecules production and antioxidant enzyme levels. Surprisingly, the bone-targeted antiresorptives bis-enoxacin and alendronate inhibited increases in oxidative stress caused by periodontitis. Bis-enoxacin, which has both antiresorptive and antibiotic activities, was more effective than alendronate, which acts only as an antiresorptive. | Social influence is prominent across the lifespan, but sensitivity to influence is especially high during adolescence and is often associated with increased risk taking. Such risk taking can have dire consequences. For example, in American adolescents, traffic-related crashes are leading causes of nonfatal injury and death. Neural measures may be especially useful in understanding the basic mechanisms of adolescents' vulnerability to peer influence. We examined neural responses to social exclusion as potential predictors of risk taking in the presence of peers in recently licensed adolescent drivers. Risk taking was assessed in a driving simulator session occurring approximately 1 week after the neuroimaging session. Increased activity in neural systems associated with the distress of social exclusion and mentalizing during an exclusion episode predicted increased risk taking in the presence of a peer (controlling for solo risk behavior) during a driving simulator session outside the neuroimaging laboratory 1 week later. These neural measures predicted risky driving behavior above and beyond self-reports of susceptibility to peer pressure and distress during exclusion. |
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