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Do somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma? | Cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole-exome sequencing on pretreatment tumor and germline DNA from 50 patients with muscle-invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis "responders," 25 pT2+ "nonresponders") to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with nonresponders (q < 0.01). Expression of representative ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer, and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle-invasive urothelial carcinoma. | Many obese subjects show relevant psychological distress. The aims of this study were to assess the psychopathological and clinical features of a sample of overweight or obese subjects seeking weight loss treatment and to evaluate the possible, significant associations between the levels of overweight and the specific and general eating disorder psychopathology. A total of 397 consecutive overweight (body mass index > or =25 kg/m(2)) patients seeking treatment for weight loss at the Outpatient Clinic for Obesity of the University of Florence were studied. The prevalence of binge eating disorder was assessed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. All subjects were assessed through the self-report version of the Eating Disorder Examination Questionnaire, the Beck Depression Inventory, and the State-Trait Anxiety Inventory. The current prevalence of binge eating disorder was 24.2%; 35% of the subjects were overweight during childhood. High prevalence rates of clinical significant depressive (38%) and anxious (71.5%) symptoms were observed. Binge eating disorder, the severity of specific eating disorder psychopathology, and depressive and anxious symptoms were not associated with the severity of overweight. |
Are organ boundary NAC-domain transcription factors implicated in the evolution of petal fusion? | Research rationale: Evolution of fused petals (sympetaly) is considered to be an important innovation that has repeatedly led to increased pollination efficiency, resulting in accelerated rates of plant diversification. Although little is known about the underlying regulation of sympetaly, genetic pathways ancestrally involved in organ boundary establishment (e.g. CUP SHAPED COTYLEDON [CUC] 1-3 genes) are strong candidates. In sympetalous petunia, mutations in the CUC1/2-like orthologue NO APICAL MERISTEM (NAM) inhibit shoot apical meristem formation. Despite this, occasional 'escape shoots' develop flowers with extra petals and fused inter-floral whorl organs. Central methods: To To determine if petunia CUC-like genes regulate additional floral patterning, we used virus-induced silencing (VIGS) following establishment of healthy shoot apices to re-examine the role of NAM in petunia petal development, and uniquely characterise the CUC3 orthologue NH16. Confirming previous results, we found that reduced floral NAM/NH16 expression caused increased petal-stamen and stamen-carpel fusion, and often produced extra petals. However, further to previous results, all VIGS plants infected with NAM or NH16 constructs exhibited reduced fusion in the petal whorl compared to control plants. | To compare the efficacy of an enteric-coated buffered pancreatic enzyme (EC buffered PE) containing 1.5 mEq of bicarbonate per capsule with a conventional enteric-coated enzyme (EC-PE) capsule in cystic fibrosis patients with signs or symptoms of moderate to severe malabsorption. In a double-blind crossover study, subjects were randomly assigned to two consecutive, 2-week phases using an EC buffered PE product and conventional EC-PE product. Seventy-two hour stool collections from each phase were analyzed for energy, fat, and nitrogen content and expressed as percent of estimated intake. Twenty-one patients with cystic fibrosis and pancreatic insufficiency (14 female, mean age 20.6 +/- 11.5 years, range 8.8-41.9) completed the study. There was no significant difference in percent malabsorption of energy (19.4% vs. 19.0%), fat (20.7% vs. 20.2%), or nitrogen (10.4% vs. 10.7%) between the EC buffered PE product and the conventional EC-PE product. However, patients taking the EC buffered PE product received less enzyme based on actual enzyme activity measured in vitro (3,468 +/- 1,434 U lipase/g fat vs. 3,978 +/- 1,474 U lipase/g fat, P < 0.02). |
Does phase-contrast diffuse optical tomography pilot result in the breast? | We sought to investigate the utility of phase-contrast diffuse optical tomography (PCDOT) for differentiation of malignant and benign breast masses in humans and to compare PCDOT with conventional diffuse optical tomography (DOT) for analysis of breast masses in humans. Thirty-five breast masses were imaged in 33 patients (mean age, 51 years; range, 22-80) using PCDOT. Images characterizing the tissue refractive index, and absorption and scattering coefficients of breast masses were obtained with a finite element-based reconstruction algorithm. Theses images were then analyzed and compared with the biopsy/pathology results for all the cases examined. Malignant lesions tended to have a decreased refractive index, allowing them to be discriminated from benign lesions in most cases, whereas absorption and scattering images were unable to accurately discriminate benign from malignant lesions. The sensitivity, specificity, false-positive value, and overall accuracy for refractive index imaging were 81.8%, 70.8%, 29.2%, and 74.3%, respectively. The accuracy of refractive index imaging increases with increasing patient age. | Although excessive sympathetic activation in viral myocarditis and the protective effects of sympathetic inhibition with β-blockers are clear, the effects of enhancing vagal tone on viral myocarditis remain unclear. In several models, vagus nerve activation with the α7 nicotinic acetylcholine receptor (α7-nAChR) agonists has been demonstrated to ameliorate inflammation. This study was therefore designed to examine the effects of cholinergic stimulation with α7-nAChR agonist nicotine in a murine model of acute viral myocarditis. BALB/C mice were infected by an intraperitoneally injection with coxsackievirus B3. Nicotine and methyllycaconitine (an α7-nAChR antagonist) were administered at doses of 0.4mg/kg and 0.8mg/kg three times per day for 7 or 14 consecutive days, respectively. The effects of nicotine and methyllycaconitine on survival rate, myocardial histopathological changes, cardiac function, cytokine levels, viral RNA, malondialdehyde, and superoxide dismutase contents were investigated. Nicotine significantly increased survival rate of the infected mice, decreased myocardial inflammation, and improved the impairment of left ventricular function in murine coxsackievirus B3-induced myocarditis compared with methyllycaconitine. The proinflammatory cytokines TNF-α, IL-1β, IL-6 and IL-17A were significantly decreased in the infected mice treated with nicotine compared with methyllycaconitine. Nicotine had no significant anti-oxidative and antiviral effects in coxsackievirus B3-infected mice. |
Does activating PPARα prevent post-ischemic contractile dysfunction in hypertrophied neonatal hearts? | Post-ischemic contractile dysfunction is a contributor to morbidity and mortality after the surgical correction of congenital heart defects in neonatal patients. Pre-existing hypertrophy in the newborn heart can exacerbate these ischemic injuries, which may partly be due to a decreased energy supply to the heart resulting from low fatty acid β-oxidation rates. We determined whether stimulating fatty acid β-oxidation with GW7647, a peroxisome proliferator-activated receptor-α (PPARα) activator, would improve cardiac energy production and post-ischemic functional recovery in neonatal rabbit hearts subjected to volume overload-induced cardiac hypertrophy. Volume-overload cardiac hypertrophy was produced in 7-day-old rabbits via an aorto-caval shunt, after which, the rabbits were treated with or without GW7647 (3 mg/kg per day) for 14 days. Biventricular working hearts were subjected to 35 minutes of aerobic perfusion, 25 minutes of global no-flow ischemia, and 30 minutes of aerobic reperfusion. GW7647 treatment did not prevent the development of cardiac hypertrophy, but did prevent the decline in left ventricular ejection fraction in vivo. GW7647 treatment increased cardiac fatty acid β-oxidation rates before and after ischemia, which resulted in a significant increase in overall ATP production and an improved in vitro post-ischemic functional recovery. A decrease in post-ischemic proton production and endoplasmic reticulum stress, as well as an activation of sarcoplasmic reticulum calcium ATPase isoform 2 and citrate synthase, was evident in GW7647-treated hearts. | Previous studies have established that soluble interleukin-2 receptor alpha (sIL-2R alpha) levels are elevated in ascites and sera from individuals with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] Stage III/IV). This study was undertaken to evaluate sIL-2R alpha levels in individuals with benign ovarian neoplasms and early stage ovarian cancer (FIGO Stage I/II). Comparison with CA 125 levels was performed to assess screening potential. Sera from 92 healthy individuals, 61 with benign adnexal masses, 12 patients with FIGO Stage I/II ovarian cancers, and 27 patients with FIGO Stage III/IV ovarian cancers were assayed for sIL-2R alpha by enzyme-linked immunosorbent assay and CA 125 by radioimmunoassay. The mean serum sIL-2R alpha levels for benign pelvic masses, and Stage I/II and Stage III/IV epithelial ovarian cancer were 1507 +/- 82, 1631 +/- 274, and 2596 +/- 384 U/ml, respectively. The difference between mean serum sIL-2R alpha levels in individuals with benign adnexal masses and Stage III/IV epithelial ovarian cancer was statistically significant (P < 0.05). In addition, of the four individuals with FIGO Stage I/II ovarian cancer who had CA125 levels below 35 U/ml, the accepted upper limit of normal, three patients had elevated serum sIL-2R alpha levels. Eleven of 12 patients (92%) with potentially curable Stage I/II disease had elevated serum levels of either sIL-2R alpha or CA125 and 8 of 12 (67%) had elevations of both sIL-2R alpha and CA125. Sensitivity and specificity of a combination of CA 125 and soluble IL-2R alpha were 88.5% and 27.1%, respectively. |
Does cardiac-specific overexpression of diacylglycerol kinase zeta prevent Gq protein-coupled receptor agonist-induced cardiac hypertrophy in transgenic mice? | Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gqalpha protein-coupled receptor (GPCR) agonists such as angiotensin II, phenylephrine, and others. Diacylglycerol functions as a potent activator of protein kinase C (PKC) and is catalyzed by diacylglycerol kinase (DGK) to form phosphatidic acid and inactivated. However, the functional roles of DGK have not been previously examined in the heart. We hypothesized that DGK might prevent GPCR agonist-induced activation of diacylglycerol downstream signaling cascades and subsequent cardiac hypertrophy. To test this hypothesis, we generated transgenic (DGKzeta-TG) mice with cardiac-specific overexpression of DGKzeta. There were no differences in heart size and heart weight between DGKzeta-TG and wild-type littermate mice. The left ventricular function was normal in DGKzeta-TG mice. Continuous administration of subpressor doses of angiotensin II and phenylephrine caused PKC translocation, gene induction of atrial natriuretic factor, and subsequent cardiac hypertrophy in WT mice. However, in DGKzeta-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGKzeta-TG mice, angiotensin II and phenylephrine failed to increase cross-sectional cardiomyocyte areas and heart to body weight ratios. Phenylephrine-induced increases in myocardial diacylglycerol levels were completely blocked in DGKzeta-TG mouse hearts, suggesting that DGKzeta regulated PKC activity by controlling cellular diacylglycerol levels. | The present authors examined how patient hand contamination was associated with underlying disease and treatment environment in order to determine effective hand hygiene methods. Samples were collected from inpatients (45 with hematological malignancies, 48 postoperative), outpatients (48 undergoing hemodialysis, 55 on chemotherapy), and 44 individuals living in nursing homes. All participants provided informed consent for study participation. All subjects performed hand hygiene. Before and after hand hygiene, samples of bacteria were collected from the palm of the hand onto agar media. Bacteria were counted and bacterial strains were identified. The authors then collected smear samples from the contralateral palm and measured adenosine triphosphate (ATP) levels. Patient hand contamination was the highest in hemodialysis patients, followed by residents of nursing homes, postoperative patients, patients with cancer receiving chemotherapy, and patients of hematological malignancies. Regardless of the underlying disease and treatment environment, patients were able to reduce the number of bacterial colonies and ATP by proper hand hygiene. Compared with wet wipes, hand washing seemed to remove bacteria more effectively. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in 30 subjects, none of whom were patients of hematological malignancies. Of these, 19 tested negative for MRSA after performing proper hand hygiene. |
Does mRS show abnormalities before symptoms in familial Alzheimer disease? | Pathologic change in Alzheimer disease (AD) begins some years before symptoms. MRS has the potential to detect metabolic abnormalities reflecting this early pathologic change. Presenilin 1 (PS1) and amyloid precursor protein (APP) mutation carriers have a nearly 100% risk of developing AD and may be studied prior to symptom onset. Short echo time proton MR spectra were acquired from a midline posterior cingulate voxel in presymptomatic carriers of PS1 or APP mutations ("presymptomatic mutation carriers" [PMCs]; n = 7) and age- and sex-matched control subjects (n = 6). Ratios of N-acetyl aspartate (NAA), myo-inositol (MI), and choline-containing compounds (Cho) to creatine (Cr) were measured and NAA/MI calculated. Regression analyses and t tests were performed after log transformation. PMC and control subjects were matched for age and sex. PMC subjects were 1.7 to 21.6 years (mean 9.8 years) before expected symptom onset, predicted from family-specific mean age at onset. Age did not significantly affect metabolite ratios. Geometric mean ratios in control subjects were as follows: NAA/Cr = 1.75, MI/Cr = 0.59, and NAA/MI = 2.95. NAA/Cr and NAA/MI were significantly reduced in PMC relative to controls (NAA/Cr mean decrease 10% [95% CI 2 to 18%]; NAA/MI mean decrease 25% [95% CI 3 to 44%]). MI/Cr was increased in PMC, but the differences did not achieve significance (19% increase [95% CI 1% decrease to 41% increase]; p = 0.07)). In PMCs, reduction in NAA/MI (p = 0.001) and MI/Cr (p = 0.002) were related to proximity of expected age at onset. | To compare immunohistochemical findings in human donor corneas after successful laser in situ keratomileusis (LASIK) without clinical complications with a recently established human LASIK in vitro model. Donor corneas with prior LASIK treatment were investigated. Cryostat sections were stained immunohistochemically for collagen types I, III, and VI and laminin and fibronectin. With light microscopy, the interface of the LASIK flap could hardly be detected. In all samples, fibronectin was consistently detected along the entire extent of the surgical wound. In contrast, collagen type III and laminin only stained the superficial portion of the LASIK incision site. Staining for collagen types I and VI showed no changes after LASIK. |
Does perception of improvement in patients with rheumatoid arthritis vary with disease activity levels at baseline? | To analyze the minimum clinically important improvement (MCII) of disease activity measures in rheumatoid arthritis (RA) using patient-derived anchors, and to assess whether criteria for improvement differ with baseline disease activity. We used data from a Norwegian observational database comprising 1,050 patients (73% women, 65% rheumatoid factor-positive, mean duration of RA 7.7 years). At 3 months after initiation of therapy, patients indicated whether their condition had improved, had considerably improved, was unchanged, had worsened, or had considerably worsened. We used receiver operating characteristic curve analysis to determine the MCII for the Disease Activity Score based on the assessment of 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI), and analyzed the effects of different levels of baseline disease activity on the MCII. On average, patients started with high disease activity and improved significantly during treatment (American College of Rheumatology 20%, 50%, and 70% improvement criteria responses were 37%, 17%, and 5%, respectively). The overall mean (95% confidence interval [95% CI]) thresholds for MCII after 3 months for the DAS28, SDAI, and CDAI were 1.20 (95% CI 1.18-1.22), 10.95 (95% CI 10.69-11.20), and 10.76 (95% CI 10.49-11.04), respectively, and the mean (95% CI) thresholds for major responses were 1.82 (95% CI 1.80-1.83), 15.82 (95% CI 15.65-16.00), and 15.00 (95% CI 14.82-15.18), respectively. With increasing disease activity, much higher changes in disease activity were needed to achieve MCII according to patient judgment. | Sugar consumption affects insulin release and, in hypertension, may stimulate cardiac signaling mechanisms that accelerate left ventricular hypertrophy and the development of heart failure. We investigated the effects of high-fructose or sucrose diets on ventricular function and mortality in hypertensive Dahl salt-sensitive rats. Rats were fed chows that were either high starch (70% starch, 10% fat by energy), high fat (20% carbohydrates, 60% fat), high fructose (61% fructose, 9% starch, 10% fat), or high sucrose (61% sucrose, 9% starch, 10% fat). Hypertension was induced by adding 6% salt to the chow (n = 8-11/group). After 8 weeks of treatment, systolic blood pressure and left ventricular mass were similarly increased in all rats that were fed high-salt diets. Hypertension caused a switch in mRNA myosin heavy chain isoform from alpha to beta, and this effect was greater in the high-salt sucrose and fructose groups than in starch and fat groups. The cardiac mRNA for atrial natriuretic factor was also increased in all high-salt groups compared to respective controls, with the increase being significantly greater in the hypertensive sucrose fed group. Mortality was greater in the sucrose group (44%) compared to all the other hypertensive groups (12-18%), as was cardiomyocyte apoptosis. Left ventricular ejection fraction was lower in the high-salt sucrose group, which was due to an increase in end-systolic volume, and not increased end-diastolic volume. |
Do miRNAs affect the expression of innate and adaptive immunity proteins in celiac disease? | microRNAs (miRNAs) are short RNAs that regulate gene expression in various processes, including immune response. Altered immune response is a pivotal event in the pathogenesis of celiac disease (CD), and miRNAs could have a role in modulating both innate and adaptive response to gluten in celiac patients. We compared miRNA profiles in duodenal biopsies of controls and CD patients by miRNA array. Differentially expressed miRNAs were validated in controls, Marsh 3A-B, and Marsh 3C patients by quantitative PCR (qPCR). Target gene expression was assessed by qPCR, western blotting, and immunohistochemistry, and the effect of gliadin was evaluated by in vitro stimulation experiments on duodenal biopsies. Seven miRNAs were identified as significantly downregulated in the duodenum of adult CD patients as compared with controls. qPCR validated the decreased expression of miR-192-5p, miR-31-5p, miR-338-3p, and miR-197, in particular in patients with more severe histological lesions (Marsh 3C). In silico analysis of possible miRNA targets identified several genes involved in innate and adaptive immunity. Among these, chemokine C-X-C motif ligand 2 (CXCL2) and NOD2 showed significantly increased mRNA and protein level in Marsh 3C patients and a significant inverse correlation with the regulatory miR-192-5p. In addition, forkhead box P3 (FOXP3), Run-related transcription factor 1, and interleukin-18 (targets of miR-31-5p, miR-338-3p, and miR-197, respectively) showed upregulation in CD patients. Furthermore, alterations in CXCL2 and NOD2, FOXP3, miR-192-5p, and miR-31-5p expression were triggered by gliadin exposure in CD patients. | Right ventricular rupture, resulting in serious bleeding, is a life-threatening complication associated with negative-pressure wound therapy (NPWT) in cardiac surgery. The use of a rigid barrier between the heart and the sharp sternal edges has been successfully tested on pigs. In the present article, we demonstrate increased safety in NPWT through the use of the HeartShield device. Six patients were treated with a specially designed device in combination with NPWT. The device consists of a horizontally placed disk covered in foam. The back of the T-shaped device sticks up between the sternal edges and up above skin level. This part of the device is also covered in foam. Drainage is performed through two holes at the top of the device. The device and foam are changed every second to third day, and -120 mm Hg of continuous therapy is used. Six patients were treated with traditional NPWT, serving as control group. No signs of calluslike formation were seen on the right ventricle in the group treated with the HeartShield device. In the conventional NPWT control group, all six patients had calluslike formation (>1 × 2 cm2) on the anterior part of the right ventricle. All patients in the HeartShield group had grade 1 epicardial petechial bleeding (<0.5 cm2) on the right ventricle. In the control group, one patient had grade 1 (<0.5 cm2), three patients had grade 2 (0.5-2.0 cm2), and two patients had grade 3 (>2.0 cm2) epicardial petechial bleeding on the right ventricle. No major bleeding or mortality was observed in either group during the course of the study. |
Is respiratory function deterioration time-linked with upper-limb onset in amyotrophic lateral sclerosis? | In amyotrophic lateral sclerosis (ALS), symptoms apparently spread following regional rules, and depending on the site of onset. We examined if respiratory function deterioration appears earlier or is more severe in patients with upper-limb onset. We compared the results of various pulmonary function tests (PFT) obtained at diagnosis depending on the site of onset in 49 ALS patients. In a longitudinal study, we compared the deterioration of forced vital capacity (FVC) in relation to the site of onset, and analyzed the time elapsed to reach values below 80% of predicted according to site of onset, and we compared the survival depending on the site of onset. No significant differences in PFT were found in the upper-limb onset group in any of the analysis performed. No differences in survival were detected in any disease onset group. | Stem cells within the intestinal epithelium generate daughter cells that undergo lineage commitment and maturation through the combined action of the Wnt and Notch signaling cascades. Both pathways, in turn, regulate transcription factor networks that further define differentiation toward either enterocytes or 1 of 3 secretory cell lineages (Paneth, goblet, or enteroendocrine cells). In this study, we investigated the role of the Wnt-responsive, Ets-domain transcription factor Spdef in the differentiation of goblet and Paneth cells. The in vivo function of Spdef was examined by disrupting the Spdef gene in mice (Spdef(-/-) mice) and analyzing the intestinal phenotype using a range of histologic techniques and DNA microarray profiling. In accordance with expression data, we found that loss of Spdef severely impaired the maturation of goblet and Paneth cells and, conversely, led to an accumulation of immature secretory progenitors. Spdef appears to positively and negatively regulate a specific subset of goblet and Paneth cell genes, including Cryptdins, Mmp7, Ang4, Kallikreins, and Muc2. |
Does ets-1 mediate platelet-derived growth factor-BB-induced thrombomodulin expression in human vascular smooth muscle cells? | Thrombomodulin (TM), a potent anticoagulant, is not detected in quiescent vascular smooth muscle cells (VSMCs). In diseased vessels, VSMC expresses TM, but the mechanisms are unclear. This study examined molecular mechanisms for TM expression in VSMCs. Platelet-derived growth factor-BB (PDGF-BB) induced TM expression in cultured human aortic VSMCs. PDGF-induced TM is functional in activating protein C. TM induction was eliminated by inhibitors of Src kinase, phosphatidylinositol 3-kinase (PI3-kinase), and mammalian target of rapamycin (mTOR) and by expressing dominant-negative Akt while expressing active Akt-stimulated TM expression. PDGF-BB activated the TM promoter, and the deletion of a sequence segment -394/-255 drastically reduced TM promoter activity. Transcription factor E26 transformation-specific sequence-1 (Ets-1) was upregulated by PDGF-BB in a PI3-kinase- and mTOR-dependent manner. RNA interference of Ets-1 inhibited PDGF induction of TM, and overexpressing Ets-1 increased TM expression. Chromatin immunoprecipitation and electrophoretic mobility shift assay detected increased Ets-1 binding to the TM promoter after PDGF treatment. Following carotid artery ligation of C57/BL6 mice, PDGF-BB and TM were co-expressed in the media and neointima. | To study the effect of Cleistocalyx nervosum extract (CE) on diethylnitrosamine (DEN) and phenobarbital (PB) induced oxidative stress in early stages of rat hepatocarcinogenesis. Male Wistar rats were divided into 4 groups, with Group 1 as a negative control and Group 2 was a positive control receiving DEN injections once a week and PB in drinking water for 6 weeks. Two weeks before DEN initiation and PB treatment, Groups 3 and 4, were fed with 500 and 1000 mg/kg of CEs, respectively, for 8 weeks. A number of GST-P-positive foci, preneoplastic lesions, in the liver were markedly increased in carcinogen administered rats, but was comparatively decreased in rats treated with 1000 mg/kg of CE. The CE reduced malondialdehyde in serum and in the livers of rats treated with DEN and PB. Moreover, CE significantly increased the activities of glutathione peroxidase and catalase in rat liver. |
Does deletion of aquaporin-4 in APP/PS1 mice exacerbate brain Aβ accumulation and memory deficits? | Preventing or reducing amyloid-beta (Aβ) accumulation in the brain is an important therapeutic strategy for Alzheimer's disease (AD). Recent studies showed that the water channel aquaporin-4 (AQP4) mediates soluble Aβ clearance from the brain parenchyma along the paravascular pathway. However the direct evidence for roles of AQP4 in the pathophysiology of AD remains absent. Here, we reported that the deletion of AQP4 exacerbated cognitive deficits of 12-moth old APP/PS1 mice, with increases in Aβ accumulation, cerebral amyloid angiopathy and loss of synaptic protein and brain-derived neurotrophic factor in the hippocampus and cortex. Furthermore, AQP4 deficiency increased atrophy of astrocytes with significant decreases in interleukin-1 beta and nonsignificant decreases in interleukin-6 and tumor necrosis factor-alpha in hippocampal and cerebral samples. | Schatzki rings are found in the distal esophagus, are associated with hiatal hernias, and present with intermittent dysphagia to solid foods. They can be identified by radiology (GI series or barium swallow studies) or endoscopy. Rings are not always visualized during endoscopy in patients in whom they are suspected clinically. The Bolster technique involves application of epigastric abdominal pressure, which offers the potential to reveal a Schatzki ring that is otherwise obscured within a reduced hiatal hernia. The aim of this study was to determine whether the Bolster technique improves endoscopic detection of Schatzki rings. We reviewed 30 symptomatic patients with a history of a Schatzki ring in a tertiary care center. The Bolster technique was applied to patients in whom the ring was not visible during standard endoscopy. The main outcome measurement was identification of the Schatzki ring after the Bolster technique. A Schatzki ring was visible during standard endoscopy in 26 of the 30 patients. In the remaining 4, the ring was visible only after the application of the Bolster technique. |
Does executive Functioning predict Academic But Not Social Adjustment to University? | Adjusting well academically and socially has been associated with enhanced academic performance and student retention. The purpose of this study was to examine subthreshold levels of ADHD symptoms such as inattention, hyperactivity, and executive functioning as potential predictors of academic and social adjustment in a healthy sample of university students. Participants were 135 undergraduate university students who completed self-report questionnaires. Hierarchical regression analyses revealed that metacognition (an aspect of executive function), gender, and age were significant predictors of academic adjustment beyond hyperactivity, inattention, and depression. Depression was the only significant predictor of social adjustment. | Exogenously administered biglycan (core protein with high-molecular weight glycosaminoglycan chains) has been shown to protect neonatal cardiomyocytes against simulated ischemia/reperfusion injury (SI/R), however, the mechanism of action is not clear. In this study we aimed to investigate, which structural component of biglycan is responsible for its cardiocytoprotective effect and to further explore the molecular mechanisms involved in the cytoprotection. A pilot study was conducted to demonstrate that both native (glycanated) and deglycanated biglycan can attenuate cell death induced by SI/R in a dose-dependent manner in primary neonatal cardiomyocytes isolated from Wistar rats. In separate experiments, we have shown that similarly to glycanated biglycan, recombinant human biglycan core protein (rhBGNc) protects cardiomyocytes against SI/R injury. In contrast, the glycosaminoglycan component dermatan sulfate had no significant effect on cell viability, while chondroitin sulfate further enhanced cell death induced by SI/R. Treatment of cardiomyocytes with rhBGNc reverses the effect of SI/R upon markers of necrosis, apoptosis, mitochondrial membrane potential, and autophagy. We have also shown that pharmacological blockade of Toll-like receptor 4 (TLR4) signaling or its downstream mediators (IRAK1/4, ERK, JNK and p38 MAP kinases) abolished the cytoprotective effect of rhBGNc against SI/R injury. Pretreatment of cardiomyocytes with rhBGNc for 20h resulted in increased Akt phosphorylation and NO production without having significant effect on phosphorylation of ERK1/2, STAT3, and on the production of superoxide. Treatment over 10min and 1h with rhBGNc increased ERK1 phosphorylation, while the SI/R-induced increase in superoxide production was attenuated by rhBGNc. Blockade of NO synthesis also prevented the cardiocytoprotective effect of rhBGNc. |
Do tAp63 suppress metastasis via miR-133b in colon cancer cells? | TAp63 is a tumour-suppressor protein that is often underexpressed in various types of cancer. It has been shown to activate gene transcription depending on the transcription domain and to be closely related with metastasis. In this study, we demonstrate that TAp63 suppresses metastasis in colon cancer cells through microRNA-133b. We evaluated the correlation of TAp63 and miR-133b with HT-29 and SW-620 cells and investigated the roles of TAp63 in the expression of RhoA, E-cadherin and vimentin. We further investigated the roles of TAp63-mediated invasion and migration of colon cancer cells. TAp63 expression is downregulated in colon cancer, and microRNA-133b is a transcriptional target of TAp63. Furthermore, microRNA-133b is essential for the inhibitory effects of TAp63 on RhoA, E-cadherin and vimentin. Moreover, TAp63 inhibits cell migration and invasion through microRNA-133b. Correspondingly, the inhibitory effect of TAp63 on RhoA, E-cadherin, vimentin, migration and invasion can be blocked by the microRNA-133b inhibitor. | Anemia of chronic disease, a cytokine-mediated anemia, is a frequent complication of many chronic inflammatory conditions. The present case-control study was aimed to evaluate levels of systemic hematological markers indicative of anemia in patients with generalized, severe, chronic periodontitis. A convenience quota sample of 30 systemically-healthy, urban, male patients comprised two groups, based on full mouth periodontal examination: group A patients (n=15) were diagnosed with generalized, severe, chronic periodontitis, and group B patients comprised the control group (n=15), which included patients with a clinically-healthy periodontium. Laboratory blood investigations included hemoglobin (g%), total number of erythrocytes (red blood cells), hematocrit/packed cell volume, erythrocyte sedimentation rate, mean corpuscular volume of erythrocytes, and mean corpuscular hemoglobin concentration. An analysis of covariance using age as a covariate was done to compare the mean values of hematological parameters within groups. The mean values of hemoglobin, red blood cells, packed cell volume, and mean corpuscular hemoglobin concentration were significantly lower, while the mean corpuscular volume of erythrocytes and erythrocyte sedimentation rate were significantly higher in group A patients compared to those in group B, indicating mild anemia. |
Does nAP1 strain type predict outcomes from Clostridium difficile infection? | Studies are conflicting regarding the importance of the fluoroquinolone-resistant North American pulsed-field gel electrophoresis type 1 (NAP1) strain in Clostridium difficile infection (CDI) outcome. We describe strain types causing CDI and evaluate their association with patient outcomes. CDI cases were identified from population-based surveillance. Multivariate regression models were used to evaluate the associations of strain type with severe disease (ileus, toxic megacolon, or pseudomembranous colitis within 5 days; or white blood cell count ≥15 000 cells/µL within 1 day of positive test), severe outcome (intensive care unit admission after positive test, colectomy for C. difficile infection, or death within 30 days of positive test), and death within 14 days of positive test. Strain typing results were available for 2057 cases. Severe disease occurred in 363 (17.7%) cases, severe outcome in 100 (4.9%), and death within 14 days in 56 (2.7%). The most common strain types were NAP1 (28.4%), NAP4 (10.2%), and NAP11 (9.1%). In unadjusted analysis, NAP1 was associated with greater odds of severe disease than other strains. After controlling for patient risk factors, healthcare exposure, and antibiotic use, NAP1 was associated with severe disease (adjusted odds ratio [AOR], 1.74; 95% confidence interval [CI], 1.36-2.22), severe outcome (AOR, 1.66; 95% CI, 1.09-2.54), and death within 14 days (AOR, 2.12; 95% CI, 1.22-3.68). | The aim of this study was to investigate the response of the growth hormone (GH) in rat anterior pituitary to intermittent hypoxia (IH) and its modulation by hypothalamic somatostatin (SS). To observe the hypoxic response, rats were exposed to simulated altitude hypoxia (2 km or 5 km) in a hypobaric chamber for various days (4 h/d); to clarify SS-involvement, rats were pretreated with SS antagonist (cysteamine, CSH, 200 mg/kg/d, s.c.) then exposed to IH (5 km) for 2d. The GH mRNA and immunostaining GH in pituitary as well as immunostaining SS in median eminence (ME) of hypothalamus were assayed by RT-PCR and immuno-histochemistry, respectively. IH of 5 km altitude (IH5) markedly suppressed the body weight gain (BWG) of rats from 1d to 10d, and it was returned to control level henceforth, while no significant influence was showed in the group of IH of 2 km altitude (IH2). IH5 for 2 and 5d significantly decreased GH mRNA expression in the pituitary. The pituitary immunostaining GH was remarkably increased in groups of IH2 for 5, 10, and 15 d, and in groups of IH5 for 2, 5, and 10d. Immunostaining SS in ME was significantly reduced in group of IH2 for 5d, and in groups of IH5 for 2d and 5d. Pretreatments (s.c.) with SS antagonist (CSH) significantly reversed IH5-caused increase of immunostaining GH and reduction of mRNA levels in pituitary. |
Does a prehospital screening tool utilizing end-tidal carbon dioxide predict sepsis and severe sepsis? | To determine the utility of a prehospital sepsis screening protocol utilizing systemic inflammatory response syndrome (SIRS) criteria and end-tidal carbon dioxide (ETCO2). We conducted a prospective cohort study among sepsis alerts activated by emergency medical services during a 12 month period after the initiation of a new sepsis screening protocol utilizing ≥2 SIRS criteria and ETCO2 levels of ≤25 mmHg in patients with suspected infection. The outcomes of those that met all criteria of the protocol were compared to those that did not. The main outcome was the diagnosis of sepsis and severe sepsis. Secondary outcomes included mortality and in-hospital lactate levels. Of 330 sepsis alerts activated, 183 met all protocol criteria and 147 did not. Sepsis alerts that followed the protocol were more frequently diagnosed with sepsis (78% vs 43%, P < .001) and severe sepsis (47% vs 7%, P < .001), and had a higher mortality (11% vs 5%, P = .036). Low ETCO2 levels were the strongest predictor of sepsis (area under the ROC curve (AUC) of 0.99, 95% CI 0.99-1.00; P < .001), severe sepsis (AUC 0.80, 95% CI 0.73-0.86; P < .001), and mortality (AUC 0.70, 95% CI 0.57-0.83; P = .005) among all prehospital variables. Sepsis alerts that followed the protocol had a sensitivity of 90% (95% CI 81-95%), a specificity of 58% (95% CI 52-65%), and a negative predictive value of 93% (95% CI 87-97%) for severe sepsis. There were significant associations between prehospital ETCO2 and serum bicarbonate levels (r = 0.415, P < .001), anion gap (r = -0.322, P < .001), and lactate (r = -0.394, P < .001). | Chemoresistance of glioblastoma multiforme (GBM) has been attributed to the presence within the tumor of cancer stem cells (GSCs). The standard therapy for GBM consists of surgery followed by radiotherapy and the chemotherapeutic agent temozolomide (TMZ). However, TMZ efficacy is limited by O6-methylguanine-DNA-methyltransferase (MGMT) and Mismatch Repair (MMR) functions. Strategies to counteract TMZ resistance include its combination with poly(ADP-ribose) polymerase inhibitors (PARPi), which hamper the repair of N-methylpurines. PARPi are also investigated as monotherapy for tumors with deficiency of homologous recombination (HR). We have investigated whether PARPi may restore GSC sensitivity to TMZ or may be effective as monotherapy. Ten human GSC lines were assayed for MMR proteins, MGMT and PARP-1 expression/activity, MGMT promoter methylation and sensitivity to TMZ or PARPi, alone and in combination. Since PTEN defects are frequently detected in GBM and may cause HR dysfunction, PTEN expression was also analyzed. The statistical analysis of the differences in drug sensitivity among the cell lines was performed using the ANOVA and Bonferroni's post-test or the non-parametric Kruskal-Wallis analysis and Dunn's post-test for multiple comparisons. Synergism between TMZ and PARPi was analyzed by the median-effect method of Chou and Talalay. Correlation analyses were done using the Spearman's rank test. All GSCs were MMR-proficient and resistance to TMZ was mainly associated with high MGMT activity or low proliferation rate. MGMT promoter hypermethylation of GSCs correlated both with low MGMT activity/expression (Spearman's test, P = 0.004 and P = 0.01) and with longer overall survival of GBM patients (P = 0.02). Sensitivity of each GSC line to PARPi as single agent did not correlate with PARP-1 or PTEN expression. Notably, PARPi and TMZ combination exerted synergistic antitumor effects in eight out of ten GSC lines and the TMZ dose reduction achieved significantly correlated with the sensitivity of each cell line to PARPi as single agent (P = 0.01). |
Is perinucleolar compartment prevalence a phenotypic pancancer marker of malignancy? | The perinucleolar compartment (PNC) is a subnuclear structure localized at the nucleolar periphery. Previous studies using breast cancer as a model system demonstrated that PNC prevalence (the percentage of cells with 1 or more PNC) increased with disease progression and was associated with poor patient outcomes. To evaluate the validity of developing PNC prevalence as a novel pancancer prognostic marker, the authors investigated whether PNC prevalence was correlated with malignancy in a spectrum of tissue types and evaluated its selective association with malignancy under various experimental conditions. PNC prevalence was low in primary and immortalized cells and in cell lines derived from hematologic malignancies, but it was heterogeneous in cell lines derived from solid tumors, including those of epithelial and nonepithelial origins. Studies using human myometrial tissue and thyroid cancer cell lines with various levels of malignancy demonstrated a correlation between high PNC prevalence and malignant potential. Furthermore, PNC prevalence corresponded directly to metastatic capacities in a series of well characterized cell lines of the same origin that were selected for various levels of metastatic capacity in a mouse model. Conversely, PNC prevalence was reduced experimentally by over expressing an antimetastatic protein in breast cancer cells. However, PNC prevalence was not associated with traits that were shared by both cancer and normal cells, including proliferation, glycolysis, and differentiation. | The objective of this study was to determine whether 16 weeks of resistance training (RT) can reduce the blood pressure response and improve the cardiovascular function of men aged 70-80 years during submaximum aerobic exercise. Twenty-four men aged between 70 and 80 years were randomly assigned to an RT group (n = 12) and control group (n = 12). Training consisted of three sets of six to 10 repetitions at 70-90% of one repetition maximum, three times per week, on an incline squat machine for 16 weeks. Blood pressure and cardiovascular function were assessed during submaximum cycle exercise at 40 W, and 50 and 70% of maximum oxygen consumption (VO2max) before training and after 16 weeks of training. Leg strength and VO2max were assessed every 4 weeks of the 16-week study. At 40 W, heart rate, systolic blood pressure, and rate pressure product were lower and stroke volume was significantly higher after 16 weeks of training. At 50% VO2max, heart rate and rate pressure product were lower after 16 weeks of training and at 70% VO2max, cycle ergometry power, VO2, and arterio-venous oxygen difference were higher after 16 weeks of training. Leg strength significantly increased after 16 weeks of training. |
Do mKL1/2 and ELK4 co-regulate distinct serum response factor ( SRF ) transcription programs in macrophages? | Serum response factor (SRF) is a widely expressed transcription factor involved in multiple regulatory programs. It is believed that SRF can toggle between disparate programs of gene expression through association with different cofactors. However, the direct evidence as to how these factors function on a genome-wide level is still lacking. In the present study, I explored the functions of SRF and its representative cofactors, megakaryoblastic leukemia 1/2 (MKL1/2) and ETS-domain protein 4 (ELK4), during fungal infection challenge in macrophages. The knockdown study, combined with gene expression array analysis, revealed that MKL1/2 regulated SRF-dependent genes were related to actin cytoskeleton organization, while ELK4 regulated SRF-dependent genes were related to external stimulus responses. Subsequent chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) suggested that many of these regulations were mediated directly in cis. | Although meperidine is an effective treatment of postanesthetic shivering, its mechanism of action remains unknown. Investigation of other drugs might help clarify the mechanisms by which shivering can be controlled. Accordingly, we investigated the efficacy of clonidine, an alpha 2-adrenergic agonist, and ketanserin, a 5-hydroxytryptamine antagonist, in treating postanesthetic shivering. First, 54 patients shivering after general anesthesia were allocated randomly to receive an intravenous bolus of saline, 150 micrograms clonidine, or 10 mg ketanserin. A second study explored the dose-dependence of clonidine. Forty shivering patients were given saline or clonidine, 37.5, 75, or 150 micrograms. The duration of shivering was significantly shorter in those given clonidine (2.1 +/- 0.9 min) than in the other two groups and shorter in the ketanserin group (4.3 +/- 0.9 min) than in the saline group (12.0 +/- 1.6 min). Clonidine and ketanserin significantly decreased systolic arterial blood pressure when compared to saline. Core rewarming was significantly slower in the clonidine group. In the second study, 37.5 micrograms clonidine was no more effective than saline. Two minutes after treatment, 150 micrograms obliterated shivering in all patients. Five minutes after treatment, all patients given 75 micrograms had stopped shivering. Systolic arterial pressure and heart rate decreased significantly in patients given 75 and 150 micrograms clonidine. |
Is diastolic dysfunction associated with low urinary sodium excretion in patients with decompensated cirrhosis? | The pathogenesis and the clinical impact of diastolic dysfunction (DD) in cirrhosis remain unclear. Our aim was to investigate the factors significantly associated with the presence of DD in patients with decompensated cirrhosis on the waiting list for liver transplantation. consecutive patients with decompensated cirrhosis, who admitted for transplant assessment, were prospectively evaluated. We assessed the independent factors associated with the presence of DD, while their discriminative ability was evaluated by AUC curve. The diagnosis of DD was based on Doppler echocardiography and classified into three categories according to the current guidelines. we evaluated 115 consecutive patients. Sixty six patients (57.3%-group 1) had DD and 49 (42.7%-group 2) had not DD. The 2 groups had similar Child-Pugh/MELD scores and survival. In multivariable logistic regression analysis, pulse rate (OR: 1.082, 95% CI: 1.03-1.15, p = 0.004), and UNa24h (OR: 0.98, 95% CI: 0.97- 0.99, p = 0.004) were the only variables independently associated with the presence of DD. In the subgroup of consecutive patients (n = 31) with evaluation of cytokines, those (n = 22) with DD, compared to those (n = 9) without DD, had significantly higher levels of inteleukin-6 [145 (45-2000) vs. 56 (10-149)pg/mL, p = 0.043]. | An in vitro biomechanical study of halo-vest and odontoid screw fixation of Type II dens fracture. The objective were to determine upper cervical spine instability due to simulated dens fracture and investigate stability provided by the halo-vest and odontoid screw, applied individually and combined. Previous studies have evaluated posterior fixation techniques for stabilizing dens fracture. No previous biomechanical study has investigated the halo-vest and odontoid screw for stabilizing dens fracture. A biofidelic skull-neck-thorax model was used with 5 osteoligamentous whole cervical spine specimens. Three-dimensional flexibility tests were performed on the specimens while intact, following simulated dens fracture, and following application of the halo-vest alone, odontoid screw alone, and halo-vest and screw combined. Average total neutral zone and total ranges of motion at C0/1 and C1/2 were computed for each experimental condition and statistically compared with physiologic motion limits, obtained from the intact flexibility test. Significance was set at P < 0.05 with a trend toward significance at P < 0.1. Type II dens fracture caused trends toward increased sagittal neutral zone and lateral bending range of motion at C1/2. Spinal motions with the dens screw alone could not be differentiated from physiologic limits. Significant reductions in motion were observed at C0/1 and C1/2 in flexion-extension and axial rotation due to the halo-vest, applied individually or combined with the dens screw. At C1/2, the halo-vest combined with the dens screw generally allowed the smallest average percentages of intact motion: 3% in axial rotation, 17% in flexion-extension, and 18% in lateral bending. |
Does interleukin-6 trans-signaling induce VEGF synthesis partly via Janus kinases-STAT3 pathway in human mesothelial cells? | Interleukin-6 (IL-6) is a vital inflammatory factor in the peritoneal cavity of peritoneal dialysis (PD) patients. Because intraperitoneal inflammation is closely associated with angiogenesis, we sought to explore the effect of IL-6 on vascular endothelial growth factor (VEGF) synthesis and its transduction pathway in mesothelial cells. Human mesothelial cells (Met-5A) were incubated with different concentrations of glucose and mannitol, and the effect of glucose and mannitol on the expression of IL-6 was determined. Then, the cells were stimulated by IL-6 with or without two soluble receptors of IL-6 (sIL-6R or sgp130), and VEGF synthesis was detected. Finally, the cells were incubated with IL-6/sIL-6R combined with or without the inhibitor of Janus kinases (JAK) AG490. The phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and its intracellular translocation were examined. 1. High glucose and mannitol could up-regulate IL-6 mRNA expression and IL-6 secretion in mesothelial cells significantly, and there was no difference of its effect between high glucose and mannitol. 2. Met-5A was a cell line with a single IL-6 receptor. The IL-6/sIL-6R complex induced VEGF synthesis of mesothelial cells, which was alleviated by sgp130 or AG490. IL-6 trans-signaling could induce the phosphorylation of STAT3, which is recruited to the cellular nucleus of Met-5A cells. | Cortisone has been proposed as a useful additional biomarker for stress research. However, only very limited studies has investigated alterations of cortisone levels in stress-related mental disorder such as PTSD. The present study investigated the associations between PTSD symptomatology and hair cortisone levels which can reflect cumulative cortisone secretion over prolonged periods of time and is more robust to the influence of situational confounding. Participants included 201 females who experienced 2008 Wenchuan earthquake and lost their children during the disaster. PTSD symptoms were assessed with the PTSD Checklist (PCL), and depression symptoms with the Center for epidemiological studies depression scale (CES-D). Hair cortisone levels were quantified by liquid chromatography tandem mass spectrometer. The results indicated that although hair cortisone secretion could not distinguish traumatized individuals with and without PTSD, it was uniquely linked to dysphoric arousal symptoms, a key aspect of the complex PTSD phenotype |
Does improving search over Electronic Health Records using UMLS-based query expansion through random walk? | Most of the information in Electronic Health Records (EHRs) is represented in free textual form. Practitioners searching EHRs need to phrase their queries carefully, as the record might use synonyms or other related words. In this paper we show that an automatic query expansion method based on the Unified Medicine Language System (UMLS) Metathesaurus improves the results of a robust baseline when searching EHRs. The method uses a graph representation of the lexical units, concepts and relations in the UMLS Metathesaurus. It is based on random walks over the graph, which start on the query terms. Random walks are a well-studied discipline in both Web and Knowledge Base datasets. Our experiments over the TREC Medical Record track show improvements in both the 2011 and 2012 datasets over a strong baseline. | The purpose of this study was to explore the importance of local physical tissue support for homeostasis in the isolated retina. Full-thickness retinal sheets were isolated from adult porcine eyes. Retinas were cultured for 5 or 10 days using the previously established explant protocol with photoreceptors positioned against the culture membrane (porous polycarbonate) or the Müller cell endfeet and inner limiting membrane (ILM) apposed against the membrane. The explants were analyzed morphologically using hematoxylin and eosin staining, immunohistochemistry, TUNEL labeling, and transmission electron microscopy (TEM). Standard cultures displayed a progressive loss of retinal lamination and extensive cell death, with activated, hypertrophic Müller cells. In contrast, explants cultured with the ILM facing the membrane displayed a maintenance of the retinal laminar architecture, and a statistically significant attenuation of photoreceptor and ganglion cell death. Transmission electron microscopy revealed intact synapses as well as preservation of normal cellular membrane structures. Immunohistochemistry showed no signs of Müller cell activation (glial fibrillary acidic protein [GFAP]), with maintained expression of important metabolic markers (glutamine synthetae [GS], bFGF). |
Do diabetes treatments have differential effects on nontraditional cardiovascular risk factors? | The aim of this study was to determine the effect of basal insulin, alone or with a sensitizer, or a combination of oral agents on nontraditional risk factors for cardiovascular disease (CVD). We randomized 57 patients with T2DM to either (1) continuous subcutaneous basal Lispro insulin at a single rate using an insulin pump (basal insulin) or (2) basal insulin and oral pioglitazone 30 mg daily (basal insulin +Pio) or (3) a sulfonylurea and metformin (SU+M). We measured glycosylated hemoglobin (HbA1c), plasma high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1), 8-epi-prostaglandin F2 alpha (PGF2alpha), serum lipoprotein (a) [Lp (a)], and lipoprotein profile at baseline and after 20 weeks of treatment. HbA1c decreased by >or=2% (P<.001) and to comparable levels (P=NS) in all groups. Despite improved glycemia, hsCRP did not change in any group, whereas plasma PAI-1 fell with basal insulin +Pio (P<.02) and SU+M (P<.01). PGF2alpha declined with basal insulin (P<.02) and SU+M (P<.001). High-density lipoprotein cholesterol (HDL-C) increased only with basal insulin +Pio (18.2%, P<.05). Lp (a) increased with basal insulin therapy alone (P<.01). Data were pooled from all groups to determine the overall effect of glycemic control-there was a significant (P<.001) decline in HbA1c, PAI-1, and PGF2alpha and an increase in HDL-C (P<.001). There was no correlation between HbA1c reduction and changes in these parameters. | In human breast cancers, amplification of chromosome 11q13 correlates with lymph node metastasis and increased mortality. To date, two genes located within this amplicon, CCND1 and EMS1, were considered to act as oncogenes, because overexpression of both proteins, respectively cyclin D1 and cortactin, correlated well with 11q13 amplification. Cyclin D1 is involved in cell cycle regulation and the F-actin-binding protein cortactin in cytoskeletal dynamics and cell migration. To study the role of cortactin in mammary gland tumorigenesis, we examined mouse mammary tumor virus (MMTV)-cortactin transgenic mice and MMTV-cortactin/-MMTV-cyclin D1 bitransgenic mice. MMTV-cortactin transgenic mice were generated and intercrossed with previously described MMTV-cyclin D1 transgenic mice. Immunohistochemical, Northern and Western blot analyses were performed to study the expression of human transgene cortactin during mammary gland development and in mammary tumors. For tumor incidence studies, forced-bred, multiparous mice were used to enhance transgene expression in the mammary gland. Microscopical examination was performed using haematoxylin and eosin staining. Mammary gland tumors arose stochastically (incidence 21%) with a mean age of onset at 100 weeks. This incidence, however, did not exceed that of aged-matched control FVB/N mice (38%), which unexpectedly, also developed spontaneous mammary gland tumors. We mimicked 11q13 amplification by generating MMTV-cortactin/-MMTV-cyclin D1 bitransgenic mice but did not observe any synergistic effect of cortactin on cyclin D1-induced mammary hyperplasias or carcinomas, nor development of distant metastasis. |
Is sDF1 gene variation associated with circulating SDF1alpha level and endothelial progenitor cell number : the Bruneck Study? | Stromal cell-derived factor-1 (SDF1) and its receptor CXC chemokine receptor 4 (CXCR4) play a critical role in progenitor cell homing, mobilization and differentiation. It would be interesting to assess the predictive value of SDF-1alpha level for EPC number, and to ascertain whether there is a relationship between SDF1 gene variation, plasma SDF-1alpha level, and the number and function of circulating EPCs. We also tested whether EPC number and function was related to CXCR4 gene variation. We genotyped a cohort of individuals who participated in the Bruneck Study for single nucleotide polymorphisms (SNPs) in the SDF1 and CXCR4 genes, and measured blood SDF1alpha level as well as EPC number and function. SDF1alpha levels were correlated with age, gender, alcohol consumption, circulating reticulocyte numbers, and concentrations of matrix metalloproteinase-9, C-reactive protein, cystatin C, fibrinogen and homocytein. In blood samples taken in 2005, EPC number was inversely associated with SDF1alpha level (p<0.001). EPC number in 2005 was also inversely associated with SDF1alpha level in 2000 (p = 0.009), suggesting a predictive value of plasma SDF1alpha level for EPC number. There was an association between the SDF1 gene rs2297630 SNP A/A genotype, increased SDF1alpha level (p = 0.002) and lower EPC number (p = 0.006). | The study aimed to explore the alteration of autophagy in rat pancreas treated with exenatide. Normal Sprague-Dawley rats and diabetes-model rats induced by 2-month high-sugar and high-fat diet and streptozotocin injection were subcutaneously injected with exenatide, respectively, for 10 weeks, with homologous rats treated with saline as control. Meanwhile, AR42J cells, pancreatic acinar cell line, were cultured with exenatide at doses of 5 pM for 3 days. The pancreas was disposed, and several sections were stained with hematoxylin-eosin. Immunohistochemistry was used to measure the expressions of glucagon-like peptide 1 receptor (GLP-1R) and cysteinyl aspartate specific proteinase-3 in rat pancreas, and Western blot was used to test the expressions of GLP-1R, light chain 3B-I and -II, and p62 in rat pancreas and AR42J cells. The data were expressed as mean (standard deviation) and analyzed by unpaired Student t test using SPSS 18.0 statistics software (SPSS China, Shanghai, China). Exenatide can induce pathological changes in rat pancreas. The GLP-1R, p62, light chain 3B-II, and cysteinyl aspartate specific proteinase-3 in rat pancreas and AR42J cells treated with exenatide were significantly overexpressed. |
Does practice setting and physician influence on judgments of colon cancer treatment by community physicians? | This article compares judgments about the treatment of Dukes' B2 and C colon cancer made by general surgeons to those of internists and family practitioners. Physician and practice variables were specialty, affiliation with a Community Clinical Oncology Program (CCOP) hospital, time in practice, professional centrality (level of participation in cancer information networks), solo practice, and number of colon cancer patients. Data are combined from national probability samples of CCOP- and non-CCOP-affiliated physicians. This study focused on 1,138 internists, family physicians, and general surgeons who participated in decision making for patients diagnosed with Dukes' B2 or C stage colon cancer. Judgments were elicited using brief vignettes. Judgments of adjuvant therapy are classified as (a) consistent with the National Institutes of Health Consensus Conference recommendations (experimental for Dukes' B2, accepted for Dukes' C); (b) accepted treatment for both stages; or (c) experimental for both stages. Multinomial logit analyses were used to examine the association of practice setting and physician characteristics to judgments of treatment. Surgeons and CCOP-affiliated physicians were more likely to endorse the NIH consensus conference position. Surgeons, younger physicians, and those in group practice were more likely to approve of chemotherapy for both cancer stages. The most common position (chemotherapy experimental) was more likely from nonsurgeons, solo practitioners, and non-CCOP physicians. | In the nonobese diabetic (NOD) mouse model of Sjögren's syndrome, lymphocytic infiltration is preceded by an accumulation of dendritic cells in the submandibular glands (SMGs). NOD mice also exhibit an increased frequency of mature, fractalkine receptor (CX3C chemokine receptor [CX3CR]1) expressing monocytes, which are considered to be precursors for tissue dendritic cells. To unravel further the role played by fractalkine-CX3CR1 interactions in the salivary gland inflammation, we studied the expression of fractalkine in NOD SMGs. We studied protein expression using Western blot analysis of whole tissue lysates. Protease activity was measured in salivary gland tissue lysates using fluorimetric substrates. Digestive capacity of enzymes was determined by in vitro incubation of recombinant enzyme and fractalkine, followed by protein staining and Western blot. Fractalkine was detected in salivary glands of both NOD and control mice at all ages. Western blot analysis showed fractalkine cleavage with increasing age, which was more pronounced in NOD mice. This cleavage resulted in a decrease in the 31 kDa form of the protein, and the generation of an approximately 19 kDa band. Furthermore, in NOD animals older than 15 weeks, we noted the presence of a unique approximately 17 kDa fragment. This cleavage was organ specific, because it did not occur in brain or pancreas. Increased gelatinase and alpha-secretase activity were detected in NOD SMG and contributed to cleavage of the 31 kDa protein. Because aberrant cleavage products may induce autoimmunity, we studied the presence of autoantibodies against fractalkine. Indeed, NOD mice exhibited significantly more antibodies against fractalkine than did control animals. |
Does apolipoprotein A-I inhibit CD40 proinflammatory signaling via ATP-binding cassette transporter A1-mediated modulation of lipid raft in macrophages? | Apolipoprotein A-I (apoA-I), the major component of high-density lipoprotein (HDL), has been recently found to suppress inflammation. This study was to investigate the effects and potential mechanisms of apoA-I on the CD40/CD40 ligand (CD40L) proinflammatory signaling pathway. Human THP-1 macrophage-derived foam cells were treated with sCD40L alone or in the presence of apoA-I. Secretion of proinflammatory cytokines was performed by enzyme-linked immunosorbent assay(ELISA). The proteins and mRNA expression were examined by western-blot and real-time PCR analysis, respectly. Cholesterol efflux was assessed by liquid scintillation counting. Cholesterol depletion of macrophages was performed with methylated β-cyclodextrin. ApoA-I inhibits the inflammatory response stimulated by soluble CD40L (sCD40L) in macrophages. In addition, apoA-I inhibited the sCD40L-stimulated activation of nuclear factor-kB (NF-kB). The apoA-I-induced NF-kB deactivation was related to the decreased recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF-6), a crucial adapter protein for CD40 in macrophages, to lipid rafts after being treated by sCD40L. When interfering the expression of ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transporter for apoA-I in macrophages, it could significantly diminish the effect of apoA-I on the sCD40L-stimulated inflammatory response. | NI margins have to be chosen appropriately to control the risk of degradation of treatment effects in non-inferiority (NI) trials. We aimed to study whether the current choice of NI margins protects sufficiently against a degradation of treatment effect on an average. NI trials reflecting current practice were assembled and for each trial, the NI margin was translated into a likelihood of degradation. The likelihood of degradation was calculated as the conditional probability of a treatment being harmful given that it is declared non-inferior in the trial, using simulation. Its distribution among the NI trials was then studied to assess the potential risk of degradation. The median (lower/upper quartile) NI margin among 112 binary outcome NI trials corresponded to an odds ratio of 0.57(0.45, 0.66), while among 38 NI trials with continuous outcome, to a Cohen's d of -0.42(-0.54, -0.31) and a hazard ratio of 0.82(0.73, 0.86) among 24 survival outcome NI trials. Overall, the median likelihood of degradation was 56% (45%, 62%). |
Is endourological management better in early-onset ureteral stenosis in kidney transplantation? | The incidence of ureteral stenosis in kidney transplant recipients is 3%-8%. The treatment of ureteral stenosis has been traditionally operative reconstruction, although such intervention is associated with high rates of serious complications, including graft loss and even perioperative mortality. More recently, endourological treatment has been proposed due to its low morbidity. The objective of this study was to assess the usefulness of balloon percutaneous dilatation as a treatment technique for ureteral stenosis in kidney transplant recipients. Among 1000 kidney transplantations performed between 1980 and 2004, the coexistence of high creatinine values and urinary tract dilatation in the postoperative period, after discarding concomitant causes, was managed with a percutaneous nephrostomy. Once renal function recovered, antegrade pyelography was performed to confirm the presence and determine the location of ureteral stenosis. Ureteral dilatation was performed using a 5-French balloon-fitted angioplasty catheter. Fifty-six patients were diagnosed with ureteral stenosis during follow-up, an incidence of 5.6%. Transluminal balloon dilatation was the first therapeutic option in 45 cases, whereas surgery was performed directly on 11 patients. Disappearance of the stenosis as well as maintenance of an improved creatinine level was verified in 45% of cases (20 patients). Two patients experienced graft loss. Both a short time to diagnosis after transplantation (P = .06) and the presence of a previous acute rejection episode (P < .05) were good prognosis factors for the endourologic solution of a ureteral stricture. | Migraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine. We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS). We identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 × 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases. |
Is a novel trafficking-defective HCN4 mutation associated with early-onset atrial fibrillation? | Atrial fibrillation (AF) is the most common arrhythmia, and a recent genome-wide association study identified the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) as a novel AF susceptibility locus. HCN4 encodes for the cardiac pacemaker channel, and HCN4 mutations are associated with familial sinus bradycardia and AF. The purpose of this study was to determine whether novel variants in the coding region of HCN4 contribute to the susceptibility for AF. We sequenced the coding region of HCN4 for novel variants from 527 cases with early-onset AF from the Massachusetts General Hospital AF Study and 443 referents from the Framingham Heart Study. We used site-directed mutagenesis, cellular electrophysiology, immunocytochemistry, and confocal microscopy to functionally characterize novel variants. We found the frequency of novel coding HCN4 variants was 2-fold greater for individuals with AF (7 variants) compared to the referents (3 variants). We determined that of the 7 novel HCN4 variants in our AF cases, 1 (p.Pro257Ser, located in the amino-terminus adjacent to the first transmembrane spanning domain) did not traffic to cell membrane, whereas the remaining 6 were not functionally different from wild type. In addition, the 3 novel variants in our referents did not alter function compared to wild-type. Coexpression studies showed that the p.Pro257Ser mutant channel failed to colocalize with the wild-type HCN4 channel on the cell membrane. | This study examines the influence of surgical management (elimination of the infectious focus and abdominal lavage) on survival and the inflammatory response in the various compartments of the body: local (abdomen), systemic (blood) and distant organ (lungs). Peritonitis was established in mice by cecal ligation and puncture (CLP). After 24 h, a group was made in which the infected cecum was resected and the abdominal cavity was lavaged (RES), and another group that received no surgical resection (NoRES). Survival was examined over a period of 96 h. Mice were sacrificed at 24 (sham and CLP), 48 and 72 h after CLP to measure inflammatory parameters. Survival was significantly lower is NoRES compared to sham and RES (p = 0.006, p = 0.014, respectively). Intraperitoneal parameters were improved in the RES group compared to sham but results were not significantly different between groups. In plasma, levels of interleukin-6 (IL-6) were decreased in RES (p = 0.048). Accordingly, anti-inflammatory IL-10 in plasma was increased in this group (p = 0.031). In the lung, keratinocyte-derived chemokine (KC) and myeloperoxidase (MPO) was reduced indicating decreased granulocytes accumulation in the lung in the RES group (p = 0.012 and p = 0.004, respectively). |
Is arterial stiffness increased in patients with inflammatory bowel disease? | Recent studies have reported early atherosclerosis in patients with inflammatory bowel disease (IBD). In these patients, the chronic low-grade inflammation may predispose to vascular remodelling and arterial stiffening. We aimed at studying arterial stiffness in IBD patients. Thirty-two IBD patients without cardiovascular risk factors and 32 matched controls were enrolled (age 19-49 years). SphygmoCor device (AtCor Medical, Sydney, Australia) was used to measure carotid-femoral and carotid-radial (muscular artery) pulse wave velocity (PWV), augmentation index and central blood pressure. Carotid-femoral PWV was higher in IBD patients than in controls (6.6 ± 1.4 vs. 6.0 ± 0.8 m/s, respectively, P < 0.05), as well as carotid-radial PWV (8.5 ± 1.2 vs. 7.2 ± 1.0 m/s, P < 0.001). Central pulse pressure was higher in IBD than in controls (32 ± 6 vs. 28 ± 7 mmHg, P < 0.05). Aging was an important determinant of carotid-femoral PWV in both groups and carotid-radial PWV only in IBD patients. In fully adjusted model performed in both groups of patients considered as a whole, age was positively associated with carotid-femoral PWV [R(2) = 0.10; +0.05 m/s per 1 year of aging, 95% confidence interval (CI) 0.01-0.08 m/s, P < 0.05], as well as IBD (R(2) = 0.10; +0.72 m/s if IBD present, 95% CI 0.19-1.26 m/s, P < 0.05). In IBD patients, carotid-radial PWV was positively associated with the disease duration (R(2) = 0.20; +0.11 m/s per 1 year of aging, 95% CI 0.03-0.19 m/s, P < 0.05). | The stem of Marsdenia tenacissima (Roxb.) Wight et Arn. has long been used as a medicine to treat cancer in China. Our previous in vitro results showed that Marsdenia tenacissima extract (MTE) overcomes gefitinib resistance in non-small cell lung cancer (NSCLC) cells. However, it is unknown whether MTE could enhance gefitinib efficacy in vivo. The present study was intended to investigate the in vivo anti-tumour activity of MTE combined with gefitinib. Human NSCLC H460 (K-ras mutation) or H1975 cells (EGFR T790M mutation) were subcutaneously inoculated into nude mice. Tumour volume and body weight were measured regularly. Resected tumours were weighed after the animals were sacrificed. Immunoblotting or immunohistochemistry was used to assess the cellular proliferation and apoptosis in xenograft tumour tissue. Expression of the EGFR downstream pathways and c-Met were measured with western blot analysis to explore possible mechanisms. MTE (5, 10, 20 g/kg) dose-dependently reduced tumour growth and induced cell apoptosis. MTE suppressed EGFR related signals, and 20 g/kg was the most effective dose. Low-dose MTE (5 g/kg) significantly enhanced gefitinib efficacy in resistant H460 and H1975 xenografts. The combination inhibited tumour proliferation and induced cell apoptosis in both resistant NSCLC xenografts. Constitutive activation of the PI3K/Akt and MEK/ERK pathways is related to EGFR-TKI resistance. Accordingly, phosphorylation of PI3K/Akt/mTOR and ERK1/2 was suppressed after combination treatment. Simultaneously, cross-talked c-Met and EGFR were also prominently lowered in the presence of MTE combined with gefitinib. |
Does preservation of the rectus femoris origin during periacetabular osteotomy compromise acetabular reorientation? | The early recovery period after periacetabular osteotomy (PAO) can be limited by pain and activity restrictions. Modifications of the Bernese PAO, including sparing the rectus tendon and discontinuing routine arthrotomy, may accelerate early postoperative recovery compared with the standard approach. Does a modified approach for PAO (1) lead to improved pain control immediately after surgery; (2) lead to improved ambulation during the hospital stay; (3) lead to shorter stays, less blood loss, and shorter surgical times; and (4) compromise acetabular correction? We retrospectively reviewed all 75 patients who underwent PAO for developmental dysplasia of the hip between August 2009 and May 2013. The control group included 44 consecutive patients who underwent a standard Bernese PAO with rectus takedown (RT). The study group consisted of 31 consecutive patients who underwent PAO using a modified rectus-sparing (RS) approach without routine arthrotomy. The groups were similar in age, body mass index, and American Society of Anesthesiologists score, but the RT group was comprised of a greater percentage of men than the RS group. Outcome variables were collected from patient charts and included inpatient pain, inpatient ambulation as well as length of stay, estimated blood loss, surgical time, and postoperative radiographic measurements. Cohen's f(2) was used to calculate the effect size in the regression analysis and effects were considered small for values<0.15, moderate for 0.15 to 0.34, and large for values>0.35. Patients who underwent PAO with a RS approach had less overall pain (RT median 4 versus RS median 2); however, the difference may not have been perceptible to the typical patient (p=0.001, f2=0.059). Patients treated with the RS approach ambulated similar distances during the hospital stay with a median 11 feet (interquartile range [IQR], 0-72.5) for the RT group and a median 30 feet (IQR, 0-100) for the RS group (p=0.215, f2=0.095). Patients in the RT group had a median length of stay of 4 days (IQR, 4-5) compared with a median 3 days (IQR, 3-4) in the RS group (p<0.001). The median estimated blood loss was greater (p=0.010) in the RT group (median, 500 mL; IQR, 350-700) versus the RS group (median, 300; IQR, 250-500). The median surgical time was longer (p<0.001) in patients undergoing PAO with the RT approach (median, 159.5 minutes; IQR, 145.5-177) compared with the RS approach (median, 103 minutes; IQR, 75-114). Acetabular reorientation based on postoperative radiographs was not compromised by the modified approach. | Chronic idiopathic urticaria is a common skin disorder characterized by recurrent, transitory, itchy weals for more than 6 weeks. An autoimmune origin has been suggested based on the findings of auto-antibodies (Abs) directed against either the alpha subunit of the high-affinity IgE receptor or the IgE molecule in nearly half of the patients. To identify other autoantigen targets in patients with chronic idiopathic urticaria. We used pooled IgG derived from 133 patients with chronic idiopathic urticaria to screen a random peptide library to identify disease-relevant autoantigen peptides. Among the identified peptides, one was recognized by the vast majority of patients' sera. Abs against this peptide were affinity purified from the patients' sera and assayed for their ability to induce histamine release from basophils. We identified a peptide that showed similarity with the low-affinity IgE receptor (Fc epsilonRII/CD23) expressed on lymphomonocytes and eosinophils. Anti-peptide IgG Abs purified from the patients' sera bound cell surface CD23 and were able to induce histamine release from basophils. This effect appeared to be mediated by the release of major basic protein from eosinophils upon engagement of CD23. The same effects were obtained with the sera from mice immunized with the CD23 peptide. |
Is age-associated increase in salt sensitivity accompanied by a shift in the atrial natriuretic peptide modulation of the effect of marinobufagenin on renal and vascular sodium pump? | Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG. In younger (3-month-old) and older (12-month-old) Sprague-Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and α-ANP at baseline and following acute NaCl loading (20%, 2.5 ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by α-ANP in vitro. As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10 mmHg, P < 0.01) and greater inhibition of NKA in aorta (39 vs. 7%, P < 0.01), 30% less natriuresis, and less inhibition of renal NKA (25 vs. 42%, P < 0.05) in the presence of comparable responses of α-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and α-ANP failed to modulate MBG-induced NKA inhibition. | Many patients with psoriasis have developed acute promyelocytic leukemia (APL) whereas few reports on psoriasis-associated APL were found in the published literature. This study was aimed to study the etiology, clinical characteristics, and prognosis of psoriasis-associated APL and to map a suitable treatment regime for this condition. This study retrospectively analyzed the clinical data of 17 patients with psoriasis-associated APL diagnosed and treated in our hospital in the past decade. The 17 patients accounted for 8.3% of the total patients diagnosed with de novo APL during the same period in our hospital. Their clinical characteristics of APL were similar to those of general APL. Four patients had a definite history of taking bimolane. All patients received arsenic trioxide (ATO)-based remission induction and postremission treatment. After induction, 15 patients (88%) achieved hematologic complete remission. With a median follow-up of 27 months, the 3-year estimates of overall survival were 77.2% ± 12.4% and the 3-year estimates of event-free survival were 70.6% ± 13.5%. In addition, the ATO-based remission induction and postremission treatment significantly improved psoriasis symptoms in 83 and 85.7% of patients, respectively. Through the final follow-up, no chronic arsenicosis or secondary malignancy was observed. |
Does breast tumor specific mutation in GATA3 affect physiological mechanisms regulating transcription factor turnover? | The transcription factor GATA3 is a favorable prognostic indicator in estrogen receptor-α (ERα)-positive breast tumors in which it participates with ERα and FOXA1 in a complex transcriptional regulatory program driving tumor growth. GATA3 mutations are frequent in breast cancer and have been classified as driver mutations. To elucidate the contribution(s) of GATA3 alterations to cancer, we studied two breast cancer cell lines, MCF7, which carries a heterozygous frameshift mutation in the second zinc finger of GATA3, and T47D, wild-type at this locus. Immunofluorescence staining and subcellular fractionation were employed to verify cellular localization of GATA3 in T47D and MCF7 cells. To test protein stability, cells were treated with translation inhibitor, cycloheximide or proteasome inhibitor, MG132, and GATA3 abundance was measured over time using immunoblot. GATA3 turn-over in response to hormone was determined by treating the cells with estradiol or ERα agonist, ICI 182,780. DNA binding ability of recombinant GATA3 was evaluated using electrophoretic mobility shift assay and heparin chromatography. Genomic location of GATA3 in MCF7 and T47D cells was assessed by chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq). GATA3 localized in the nucleus in T47D and MCF7 cells, regardless of the mutation status. The truncated protein in MCF7 had impaired interaction with chromatin and was easily released from the nucleus. Recombinant mutant GATA3 was able to bind DNA to a lesser degree than the wild-type protein. Heterozygosity for the truncating mutation conferred protection from regulated turnover of GATA3, ERα and FOXA1 following estrogen stimulation in MCF7 cells. Thus, mutant GATA3 uncoupled protein-level regulation of master regulatory transcription factors from hormone action. Consistent with increased protein stability, ChIP-seq profiling identified greater genome-wide accumulation of GATA3 in MCF7 cells bearing the mutation, albeit with a similar distribution across the genome, comparing to T47D cells. | Reducing central line-associated bloodstream infections (CLABSIs) poses a set of unique challenges in long-term acute care hospitals (LTACHS). Patients are often admitted to LTACHs with central lines in place from the previous hospitalization; thus, LTACHs lack control over insertion techniques and respective central line care and maintenance. This study aimed to demonstrate the impact of a methodical bathing approach with 2% chlorhexidine gluconate (CHG) cloths and a correlation with a reduced prevalence of CLABSIs in our LTACH population. This retrospective observational quality initiative conducted in a 105-bed LTACH used plan-do-study-act methodology to assess the effects of a revised bathing approach using 2% CHG. Statistical significance demonstrated a 65% reduction in CLABSI on the pilot unit after the 6-month initial trial. The results of the quality initiative were evaluated through the end of 2012. |
Does expression microarray identify the unliganded glucocorticoid receptor as a regulator of gene expression in mammary epithelial cells? | While glucocorticoids and the liganded glucocorticoid receptor (GR) have a well-established role in the maintenance of differentiation and suppression of apoptosis in breast tissue, the involvement of unliganded GR in cellular processes is less clear. Our previous studies implicated unliganded GR as a positive regulator of the BRCA1 tumour suppressor gene in the absence of glucocorticoid hormone, which suggested it could play a similar role in the regulation of other genes. An shRNA vector directed against GR was used to create mouse mammary cell lines with depleted endogenous levels of this receptor in order to further characterize the role of GR in breast cells. An expression microarray screen for targets of unliganded GR was performed using our GR-depleted cell lines maintained in the absence of glucocorticoids. Candidate genes positively regulated by unliganded GR were identified, classified by Gene Ontology and Ingenuity Pathway Analysis, and validated using quantitative real-time reverse transcriptase PCR. Chromatin immunoprecipitation and dual luciferase expression assays were conducted to further investigate the mechanism through which unliganded GR regulates these genes. Expression microarray analysis revealed 260 targets negatively regulated and 343 targets positively regulated by unliganded GR. A number of the positively regulated targets were involved in pro-apoptotic networks, possibly opposing the activity of liganded GR targets. Validation and further analysis of five candidates from the microarray indicated that two of these, Hsd11b1 and Ch25h, were regulated by unliganded GR in a manner similar to Brca1 during glucocorticoid treatment. Furthermore, GR was shown to interact directly with and upregulate the Ch25h promoter in the absence, but not the presence, of hydrocortisone (HC), confirming our previously described model of gene regulation by unliganded GR. | emm types 12, 1, 28, 3, 4, 2 and 6 (in that order) are the types most commonly associated with uncomplicated group A streptococcal (GAS) pharyngitis in the United States, together accounting for approximately 78% of isolates. To determine whether the distribution of common pharyngeal group A streptococcal GAS types differs at various ages throughout childhood. We emm typed 3356 GAS isolates collected from the United States and Canada during 3 streptococcal seasons (2000-2003). Variations in prevalence by age for the 7 most prevalent emm types and the "uncommon" category (all types accounting for <5% of the total number of isolates) were analyzed and assessed for significance by chi2. The proportion of uncommon isolates increased significantly with increasing age from 18% in group 1 to 37% in group 4 (P = 0.001). We found a significant decrease in the proportion of the common pharyngeal emm types, specifically emm 12 and emm 4 type isolates, with increasing age (P = 0.001 and P = 0.003, respectively); there was no significant decline in the prevalence of other common pharyngeal types (emm 1, 2, 3, 6 and 28) with increasing age. |
Do dental Student Hand Hygiene Decreased With Increased Clinical Experience? | To investigate the effectiveness, related knowledge, attitudes, and practices of hand hygiene (HH) among dental students with different levels of clinical experience. This was a cross-sectional analytical study. Bacterial samples on the participants' hands were obtained using a swab technique before and after handwashing, for oral surgical procedures. After culturing, the colony-forming units were counted. Self-reported questionnaires reflecting the knowledge, attitudes, and practices related to HH were completed by the participants. This study was performed in a primary oral health care institution, Faculty of Dentistry, Chulalongkorn University (Bangkok, Thailand). Bacterial samples and self-reported questionnaires were collected in the Department of Oral and Maxillofacial Surgery. Bacterial culture was performed in the Department of Microbiology. The 120 participants comprised first, second, third-year clinical training students (CTs), and postgraduate dental students (PGs) (32, 34, 30, and 24 participants, respectively). More than 99% of the bacteria were eliminated from the participants' hands after handwashing. Significantly higher numbers of bacteria were recovered from the hands of the PGs compared with those of the CTs, and the hands of the third-year CTs compared with those of the first-year CTs (p < 0.001), after HH. The first-year CTs had the highest attitude scores, whereas the PGs had the lowest practice scores. The knowledge scores were similar in all groups. | Flightless I (FLII), member of the gelsolin superfamily of actin-remodeling proteins, functions as a transcriptional coregulator. We aim to evaluate a tumor-suppressive function of FLII in regulating androgen receptor (AR) in prostate cancer progression. We examined FLII protein and mRNA expression in clinical prostate cancer specimens by immunohistochemistry. Kaplan-Meier analysis was conducted to evaluate the difference in disease-overall survival associated with the expression levels of FLII and AR. Prostate cancer cells stably expressing FLII or shRNA knockdown were used for functional analyses. Immunoprecipitation, Luciferase reporter, and immunofluorescence staining assays were performed to examine the functional interaction between FLII and AR. Our analysis of the expression levels of FLII in a clinical gene expression array dataset showed that the expression of FLII was positively correlated with the overall survival of prostate cancer patients exhibiting high levels of AR expression. Examination of protein and mRNA levels of FLII showed a significant decrease of FLII expression in human prostate cancers. AR and FLII formed a complex in a ligand-dependent manner through the ligand-binding domain (LBD) of AR. Subsequently, we observed a competitive binding to AR between FLII and the ligand. FLII inhibited AR transactivation and decreased AR nuclear localization. Furthermore, FLII contributed to castration-sensitive and castration-resistant prostate cancer cell growth through AR-dependent signaling, and reintroduction of FLII in prostate cancer cells sensitized the cells to bicalutamide and enzalutamide treatment. |
Does human mesenteric adipose tissue play unique role versus subcutaneous and omental fat in obesity related diabetes? | Obesity is a common and rapidly growing health problem today. Obesity is characterized by the increase of body fat and an excess of total body fat and, in particular, visceral fat accumulation, is considered to be a risk factor for type 2 diabetes mellitus. To determine whether the malfunction of the mesenteric adipose tissue plays an important role in the diabetic related metabolic syndrome, in this study, lipolysis and gene expression in the subcutaneous, omental and mesenteric adipose tissue of the diabetic subjects were evaluated. Lipolysis and real time PCR were utilized to determine adipocyte function. Basal adipose tissue glycerol release is higher in diabetics than that of the non diabetics in all three fat depots. Isoproterenol (ISO) significantly increases glycerol release in subcutaneous, omental and mesenteric adipose tissues of non diabetic subjects but it stimulated glycerol release was significantly impaired in all three fat depots of the diabetic subjects. Gene expression studies indicate that leptin, Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), Fatty acid translocase (FAT/CD36) and 11beta-hydroysteroid dehydrogenase (HSD) gene expression were significantly up regulated in the mesenteric adipose tissue of the diabetic patients. | Since urinary nitric oxide synthase (NOS) activity correlates with certain disease process affecting the urinary tract and since nitric oxide increases cyclic GMP levels by activating guanylyl cyclase, urinary particulate NOS activity and cyclic GMP levels are evaluated in female patients with interstitial cystitis (IC) and compared with those from female controls and female patients with urinary tract infections (UTIs). Urinary NOS activity is measured as the formation of [(14)C]-L-citrulline from [(14)C]-L-arginine, and urinary cyclic GMP levels are measured by an [(125)I]-radioimmunoassay. Female patients with IC have significantly less NOS activity in their urine pellet particulate fractions than female control females UTIs, 2.3 +/- 1.0, 14 +/- 3.0, and 120 +/- 10 pmol. citrulline formed/min./mg. protein. Urinary cyclic GMP levels are significantly lower in IC patients than in female controls or females with UTIs: 0.50 +/- 0.06, 0.82 +/- 0.14. and 3.72 +/- 0.81 micromol. cyclic GMP/g. creatinine. |
Does tumor necrosis factor-alpha contribute to below-level neuropathic pain after spinal cord injury? | Our objective was to elucidate the mechanisms responsible for below-level pain after partial spinal cord injury (SCI). We used lateral hemisection to model central neuropathic pain and herpes simplex viral (HSV) vector-mediated transfer of the cleaved soluble receptor for tumor necrosis factor-alpha (TNF-alpha) to evaluate the role of TNF-alpha in the pathogenesis of below-level pain. We found activation of microglia and increased expression of TNF-alpha below the level of the lesion in the lumbar spinal cord after T13 lateral hemisection that correlated with emergence of mechanical allodynia in the hind limbs of rats. Lumbar TNF-alpha had an apparent molecular weight of 27 kDa, consistent with the full-length transmembrane form of the protein (mTNF-alpha). Expression of the p55 TNF soluble receptor (sTNFRs) by HSV-mediated gene transfer resulted in reduced pain behavior and a decreased number of ED1-positive cells, as well as decreased phosphorylation of the p38 MAP kinase (p-p38) and diminished expression of mTNF-alpha in the dorsal horn. | Microalbuminuria (MA) is related to cardiovascular disease both in diabetic patients and non-diabetic subjects. We investigated whether a polymorphism near the promoter region of the IGF-I gene was related to the development of MA. For this study, 1069 participants of the Rotterdam study were selected (440 participants with an abnormal glucose tolerance (AGT), 220 participants with type 2 diabetes and 254 subjects with pre-diabetes, and 595 subjects with a normal glucose tolerance (NGT). 787 subjects were carriers of the wild type IGF-I genotype (73.6%) and 282 subjects were variant carriers (26.4%) of this IGF-I gene polymorphism. Compared to subjects with NGT the risk for microalbuminuria was higher (Odds Ratio (OR): 3.1 (95% CI: 1.2-7.7); P = 0.02) in variant carriers with AGT than in carriers of the wild type of this IGF-I gene polymorphism (OR: 2.2 (95% CI: 1.2-4.0); P = 0.009). Compared with wild type carriers with AGT, the relative risk for MA was unadjusted and non-significantly increased in variant carriers with AGT (1.6; 95% CI: 0.8-2.9). However, after adjustment for possible confounding factors (age, gender, mean blood pressure, fasting insulin, fasting glucose and smoking) this risk became significant (OR: RR 2.1; 95% CI:1.1-4.4; P = 0.04). |
Does absence of chx10 cause neural progenitors to persist in the adult retina? | Mutation of the Chx10 homeobox gene in mice and humans causes congenital blindness and microphthalmia (small eyes). This study used Chx10-/- (ocular retardation) mice to investigate how lack of Chx10 affects progenitor/stem cell behavior in the retina and ciliary epithelium (CE). The distribution of mitotic retinal progenitor cells (RPCs) during embryonic development was analyzed using phosphohistone 3 (H3)-labeling. DNA flow cytometry was used to measure DNA content. The distribution and phenotype of dividing cells in the postnatal retina and CE was analyzed by incorporation of the thymidine analogue BrdU and immunohistochemistry. The Chx10-/- embryonic retina maintained a constantly sized population of mitotic RPCs during development, causing the mitotic index to increase markedly over time compared with the wild type. Also, the proportion of cells in the G1 phase of the cell cycle was increased compared with the wild type. Of interest, division of RPC-like cells with neurogenic properties persisted in the adult Chx10-/- retina. Colabeling for BrdU and the neural progenitor marker nestin or the neuronal markers beta3-tubulin, syntaxin, and VC1.1 showed that new amacrine-like neurons developed in the adult central retina. By contrast, cells with these characteristics were not observed in the mature wild-type retina. In the mature CE, BrdU-positive cells were observed in both wild-type and Chx10-/- mice. However, neurogenesis from this cell population was not evident. | Impaired cardiac function persists in the era of effective human immunodeficiency virus (HIV) therapy, although the etiology is unclear. We used magnetic resonance imaging (MRI) to measure intramyocardial lipid levels and fibrosis as possible contributors to HIV-associated myocardial dysfunction. A cross-sectional study of 95 HIV-infected and 30 matched-healthy adults, without known cardiovascular disease (CVD) was completed. Intramyocardial lipid levels, myocardial fibrosis, and cardiac function (measured on the basis of strain) were quantified by MRI. Systolic function was significantly decreased in HIV-infected subjects as compared to controls (mean radial strain [±SD], 21.7 ± 8.6% vs 30.5 ± 14.2%; P = .004). Intramyocardial lipid level and fibrosis index were both increased in HIV-infected subjects as compared to controls (P ≤ .04 for both) and correlated with the degree of myocardial dysfunction measured by strain parameters. Intramyocardial lipid levels correlated positively with antiretroviral therapy duration and visceral adiposity. Further, impaired myocardial function was strongly correlated with increased monocyte chemoattractant protein 1 levels (r = 0.396, P = .0002) and lipopolysaccharide binding protein levels (r = 0.25, P = .02). |
Does wireless EEG with individualized channel layout enable efficient motor imagery training? | The study compared two channel-reduction approaches in order to investigate the effects of systematic motor imagery (MI) neurofeedback practice in an everyday environment using a very user-friendly EEG system consisting of individualized caps and highly portable hardware. Sixteen BCI novices were trained over four consecutive days to imagine left and right hand movements while receiving feedback. The most informative bipolar channels for use on the subsequent days were identified on the first day for each individual based on a high-density online MI recording. Online classification accuracy on the first day was 85.1% on average (range: 64.7-97.7%). Offline an individually-selected bipolar channel pair based on common spatial patterns significantly outperformed a pair informed by independent component analysis and a standard 10-20 pair. From day 2 to day 4 online MI accuracy increased significantly (day 2: 69.1%; day 4: 73.3%), which was mostly caused by a reduction in ipsilateral event-related desynchronization of sensorimotor rhythms. | Lysophospholipids, particularly sphingosine 1-phosphate and lysophosphatidic acid, are known to be involved in the pathogenesis of atherosclerosis; however, the role of lysophosphatidylserine (LysoPS) in the onset of atherosclerotic diseases remains uncertain. We investigated the effects of LysoPS on the uptake of oxidized low-density lipoprotein (oxLDL) and the modulation of inflammatory mediators and ER stress utilizing RAW264.7 cells and mouse peritoneal macrophages (MPMs). We found that LysoPS augmented cholesterol accumulation in both models. Consistent with these findings, LysoPS increased the expression of scavenger receptors (CD36, MSR1, LOX1 and TLR4). Regarding the involvement of these lipids in inflammation, LysoPS significantly decreased the expression of inflammatory mediators in lipopolysaccharide (LPS)-treated RAW264.7 cells and MPMs. LysoPS also attenuated ER stress in LPS-untreated RAW264.7 cells. The expression patterns of LysoPS receptors differed considerably among the LPS-untreated RAW264.7 cells, LPS-treated RAW264.7 cells and MPMs. |
Does sexual activity predispose to reflux episodes in patients with gastroesophageal reflux disease? | The role of sexual activity on gastroesophageal reflux disease (GERD) is an under-recognized concern of patients, and one rarely assessed by physicians. The objective of this article is to determine the influence of sexual activity on the intraesophageal acid exposure and acid reflux events in GERD patients. Twenty-one patients with the diagnosis of GERD were prospectively enrolled. Intraesophageal pH monitoring was recorded for 48 hours with a Bravo capsule. All patients were instructed to have sexual intercourse or abstain in a random order two hours after the same refluxogenic dinner within two consecutive nights. Patients were requested to have sex in the standard "missionary position" and women were warned to avoid abdominal compression. The patients completed a diary reporting the time of the sexual intercourse and GERD symptoms. The percentage of reflux time and acid reflux events were compared in two ways: within 30 and 60 minutes prior to and after sexual intercourse on the day of sexual intercourse and in the same time frame of the day without sexual intercourse. Fifteen of 21 GERD patients were analyzed. The percentage of reflux time and number of acid reflux events did not show a significant difference within the 30- and 60-minute periods prior to and after sexual intercourse on the day of sexual intercourse and on the day without sexual intercourse, as well. | This study investigated whether mesenchymal stem cells (MSCs) combined with bone marrow transplantation (BMT), irradiation, or short-term immunosuppressant therapy could prolong composite tissue allotransplant survival in a swine hind-limb model. Heterotopic hind-limb transplantation was performed in outbred miniature swine. Group I (n=5) was the untreated control. Group II (n=3) received MSCs alone (given on days -1, +3, +7, +14, +21). Group III (n=6) received cyclosporine A (CsA days 0 to +28). Group IV (n=4) received preconditioning irradiation (day -1), BMT (day +1), and CsA (days 0 to +28). Group V (n=5) received irradiation (day -1), BMT (day +1), CsA (days 0 to +28), and MSCs (days +1, +7,+14). The expression and localization of CD4/CD25 T cells and MSCs were assessed using flow cytometry and immunohistochemistry. The allografts survival with MSCs alone revealed a significant prolongation, when compared with the controls (P=0.02). Allografts with CsA treatment exhibited delayed rejection. Irradiation and BMT-CsA treatment revealed no significant allograft survival benefit when compared with the CsA treatment group, but graft-versus-host disease (GVHD) was evident. However, combination of MSCs-BMT-CsA treatment demonstrated significant prolongation of allograft survival (>200 days, P<0.001) and no signs of GVHD with the lowest degree of rejection in the allo-skin and interstitial muscle layers. The CD4/CD25 regulatory-like T-cell expression in the circulating blood and allo-skin significantly increased in the MSC-BMT-CsA group. Examination of bromodeoxyuridine-labeled MSCs revealed donor MSC engraftment into the recipient and donor skin and the recipient liver parenchymal tissue. |
Is vitamin D deficiency at 16 to 20 weeks ' gestation associated with impaired lung function and asthma at 6 years of age? | Vitamin D deficiency is associated with chronic lung disease. We have previously shown in an in vivo mouse model that maternal vitamin D deficiency is associated with alterations in early life lung structure and function. However, there are limited data to support a relationship between maternal vitamin D deficiency during the early stages of lung development and postnatal lung function in human populations. To assess the association between maternal vitamin D deficiency, postnatal lung function, and asthmatic status in a longitudinal birth cohort. Serum was collected at 16 to 20 weeks' gestation at the time of recruitment in a community-based prospective birth cohort for measurement of vitamin D (25[OH]D). Lung function was assessed by spirometry according to American Thoracic Society guidelines in children at 6 and 14 years of age. Demographic and clinical history data were collected by questionnaire at recruitment and at the follow-up visits. FVC Z-scores in both sexes (β, 0.007 [95% confidence interval (CI), 0.001-0.013]; P = 0.02) and FEV1 Z-scores in girls (β, 0.007 [95% CI, 0.001-0.013]; P = 0.02) were positively associated with maternal serum 25(OH)D at 6 years of age. These associations were mostly absent at 14 years of age. Maternal vitamin D deficiency was positively associated with asthma at 6 years of age but only in boys (odds ratio, 3.03 [95% CI, 1.02-9.02]; P = 0.04). | Elevated glutamate levels within injured muscle play important roles in muscle pain and hyperalgesia. In this study, we hypothesized that protein kinase C (PKC)-dependent TRPV1 phosphorylation contributes to the muscle mechanical hyperalgesia following activation of Group I metabotropic glutamate receptors (mGlu1/5). Mechanical hyperalgesia induced by (R,S)-3,5-dihydroxyphenylglycine (DHPG), an mGlu1/5 agonist, in the masseter muscle was attenuated by AMG9810, a specific TRPV1 antagonist. AMG9810 also suppressed mechanical hyperalgesia evoked by pharmacologic activation of PKC. DHPG-induced mechanical hyperalgesia was suppressed by pretreatment with a decoy peptide that disrupted interactions between TRPV1 and A-kinase-anchoring protein (AKAP), which facilitates phosphorylation of TRPV1. In dissociated trigeminal ganglia, DHPG upregulated serine phosphorylation of TRPV1 (S800), during which DHPG-induced mechanical hyperalgesia was prominent. The TRPV1 phosphorylation at S800 was suppressed by a PKC inhibitor. Electrophysiologic measurements in trigeminal ganglion neurons demonstrated that TRPV1 sensitivity was enhanced by pretreatment with DHPG, and this was prevented by a PKC inhibitor, but not by a protein kinase A inhibitor. These results suggest that mGlu1/5 activation in masseter afferents invokes phosphorylation of TRPV1 serine residues including S800, and that phosphorylation-induced sensitization of TRPV1 is involved in masseter mechanical hyperalgesia. These data support a role of TRPV1 as an integrator of glutamate receptor signaling in muscle nociceptors. |
Is isatis canescens a rich source of glucobrassicin and other health-promoting compounds? | Glucobrassicin (GBS), a glucosinolate contained in many brassica vegetables, is the precursor of chemopreventive compounds such as indole-3-carbinol. Large amounts of GBS would be needed to perform studies aimed at elucidating its role in the diet. This study was mainly undertaken to evaluate the flower buds of Isatis canescens as a source for GBS purification. In order to investigate the health-promoting potential of this species, glucosinolate, phenol and flavonoid content as well as the whole antioxidant capacity were also determined. Flower bud samples were collected in four localities around Mount Etna in Sicily, Italy, where I. canescens is widespread, as they are locally traditionally eaten. I. canescens flower buds displayed high GBS concentrations, up to 60 µmol g(-1) dry weight. The purification method consisted of two chromatographic steps, which made it possible to obtain GBS with a purity of 92-95%, with a yield of 21 g kg(-1) . The total glucosinolates, phenols, flavonoids and antioxidant activity were considerable, with the southern locality showing the highest concentrations for all the phytochemicals. | Pulmonary embolism (PE) is common in patients with deep venous thrombosis (DVT). The outcome of DVT with concomitant symptomatic PE is worse than the outcome of isolated DVT. The risk factors for DVT and simultaneous asymptomatic PE have not been systematically studied yet. To evaluate the frequency and risk factors for asymptomatic PE in patients with DVT. In 155 consecutive patients with a first episode of DVT and no PE symptoms, a ventilation-perfusion lung scan was performed. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated and concentrations of D-dimer, high-sensitivity CRP (hsCRP), tissue plasminogen activator (t-PA) and troponin were measured. Laboratory tests for thrombophilia were performed. Asymptomatic PE was present in 36% of patients. No differences in gender, age, BMI and WHR were found between the patients with and without PE. PE was more common in patients with proximal DVT than in those with distal DVT (42% vs. 17%, p<0.01), and in patients with unprovoked DVT compared to patients with provoked DVT (51% vs. 28%, p<0.01). The risk of silent PE was the highest in patients with unprovoked proximal DVT (OR, 6.9; 95% CI, 2.3-21.0). Patients with asymptomatic PE had significantly higher values of D-dimer, hsCRP, t-PA and troponin than patients with isolated DVT. |
Is generalized joint hypermobility more common in chronic fatigue syndrome than in healthy control subjects? | This study aimed at (1) comparing the prevalence of generalized hypermobility in patients with chronic fatigue syndrome (CFS) and healthy volunteers, (2) examining the clinical importance of generalized hypermobility in patients with CFS, and (3) examining whether knee proprioception is associated with hypermobility in patients with CFS. Sixty-eight patients with CFS filled out two self-reported measures (for the assessment of symptom severity and disability), were questioned about muscle and joint pain, and were screened for generalized hypermobility. Afterward, the patients performed a knee repositioning test (assessment of knee proprioception), and it was examined whether or not they fulfilled the criteria for benign joint hypermobility syndrome (BJHS). Sixty-nine age- and sex-matched healthy volunteers were screened for generalized joint hypermobility and performed the same knee repositioning test. Compared with the healthy volunteers (4.3%, 3/68), significantly more patients with CFS (20.6%, 14/69) fulfilled the criteria for generalized joint hypermobility (Fisher exact test, P < .004). No associations were found between generalized joint hypermobility and the self-reported measures (including pain severity) or knee proprioception (Spearman correlation analysis). Knee proprioception was similar in both groups (Mann-Whitney U = 1961, z = -1.745, P = .81). Forty patients with CFS (58.8%) fulfilled the criteria for BJHS. | Successful cancer treatments still require more compounds to be isolated from natural sources. Thus, we have investigated anti-proliferative/apoptotic effects of methanolic extracts of lichen species Parmelia sulcata Taylor and Usnea filipendula Stirt on human lung cancer (A549, PC3), liver cancer (Hep3B) and rat glioma (C6) cells. Anti-proliferative effects were monitored by MTT and adenosine triphosphate viability assays, while genotoxic activity was studied using the comet assay. Additionally, cell death mode and apoptosis assays (fluorescence staining, caspase-cleaved cytokeratin 18, caspase-3 activity and PARP cleavage) were performed. Extracts produced anti-population growth effects in a dose-dependent manner (1.56-100 μg/ml) by inducing apoptosis-like cell death. This resulted in the lines having the presence of pyknotic cell nuclei. In addition, significant increase in genetic damage in the cell lines was seen, indicating that DNA damage may have been responsible for apoptotic cell death. |
Are connexin43 levels increased in mouse neural crest cells exposed to homocysteine? | Elevated homocysteine levels during embryonic development can result in neural tube and cardiovascular defects. The mechanisms that underlie the toxic effect of homocysteine are largely unknown. We cultured mouse neural tube explants to study the effects of homocysteine on the migratory behavior of neural crest cells and on the levels of the gap junction protein Connexin43 (Cx43) and the actin- and Cx43-interacting protein ZO-1. Homocysteine exposure resulted in a significantly augmented maximal migration distance (MMD). The level of Cx43 immunolabeling was 2 times higher in the cytoplasm and cell protrusions of neural crest cells in homocysteine-treated cultures than in control cultures. Furthermore, colocalization of Cx43 and ZO-1 was increased in neural crest cell protrusions by this treatment. | Medical emergency teams frequently implement do not resuscitate orders, but little is known about end-of-life care in this population. To examine resource utilization and end-of-life care following medical emergency team-implemented do not resuscitate orders. Retrospective review. Single, tertiary care center. Consecutive adult inpatients requiring a medical emergency team activation over 1 year. Changes to code status, time spent on medical emergency team activations, frequency of palliative care consultation, discharges with hospice care. None. We observed 1156 medical emergency team activations in 998 patients. Five percent (58/1156) resulted in do not resuscitate orders. The median time spent on activations with a change in code status was longer than activations without a change (66 vs 60 minutes, P = 0.05). Patients with a medical emergency team-implemented do not resuscitate order had a higher inpatient mortality (43 vs 27%, P = 0.04) and were less likely to be discharged with hospice at the end of life than patients with a preexisting do not resuscitate order (4 vs 29%, P = 0.01). There was no difference in palliative care consultation in patients with a preexisting do not resuscitate versus medical emergency team-implemented do not resuscitate order (20% vs 12%, P = 0.39). |
Does protease-modulating polyacrylate-based hydrogel stimulate wound bed preparation in venous leg ulcers -- a randomized controlled trial? | Stringent control of proteolytic activity represents a major therapeutic approach for wound-bed preparation. We tested whether a protease-modulating polyacrylate- (PA-) containing hydrogel resulted in a more efficient wound-bed preparation of venous leg ulcers when compared to an amorphous hydrogel without known protease-modulating properties. Patients were randomized to the polyacrylate-based hydrogel (n = 34) or to an amorphous hydrogel (n = 41). Wound beds were evaluated by three blinded experts using photographs taken on days 0, 7 and 14. After 14 days of treatment there was an absolute decrease in fibrin and necrotic tissue of 37.6 ± 29.9 percentage points in the PA-based hydrogel group and by 16.8 ± 23.0 percentage points in the amorphous hydrogel group. The absolute increase in the proportion of ulcer area covered by granulation tissue was 36.0 ± 27.4 percentage points in the PA-based hydrogel group and 14.5 ± 22.0 percentage points in the control group. The differences between the groups were significant (decrease in fibrin and necrotic tissue P = 0.004 and increase in granulation tissue P = 0.0005, respectively). | The aim of the present study was to explore the association of the functional single-nucleotide polymorphism (SNP) rs3746804 in C20orf54 with the susceptibility to esophageal squamous cell carcinoma (ESCC). SNP rs3746804 in C20orf54 was detected by direct sequencing in 434 ESCC patients and 554 healthy controls from Shanxi and Henan Provinces in China, geographically a high incidence area for ESCC. The frequencies and distribution of TT, CT, and CC genotypes of SNP rs3746804 between those 2 cohorts were compared and its association with ESCC was assessed. For SNP rs3746804 the genotype distribution of CT and CC in ESCC patients both significantly differed from those in healthy controls (p=0.002, 0.001, respectively), while the distribution of TT did not differ significantly between the groups (p=0.757). The ratio of T:C was high in healthy individuals and low in ESCC patients. Compared to genotype CC, both genotypes CT (odds ratio (OR)=0.63, 95% confidence interval (CI) 0.48l-0.826), and CT+TT (OR=0.654, 95% CI 0.507-0.844) were associated with significantly decreased risk for ESCC. |
Do comparison of serum folate species analyzed by LC-MS/MS with total folate measured by microbiologic assay and Bio-Rad radioassay? | The Bio-Rad QuantaPhase II radioassay (BR), used for 25 years to measure total folate (TFOL) concentrations for the National Health and Nutrition Examination Survey (NHANES), will be discontinued in 2007. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) or a microbiologic assay (MA) will be used in the future. We measured folate species by LC-MS/MS and TFOL by MA and BR in 327 serum samples. LC-MS/MS measured 5-methyltetrahydrofolic acid (5CH(3)THF; 82%), folic acid (FA; 8%), 5-formyltetrahydrofolic acid (5CHOTHF; 6%), tetrahydrofolic acid (THF; 4%), and 5,10-methenyltetrahydrofolic acid (5,10CH=THF; 0%). The sum of the folate species correlated well with TFOL measured by MA (R(2) = 0.97) and BR (R(2) = 0.91). Compared with LC-MS/MS results, MA and BR values were significantly lower (-6% and -29%, respectively); however, these differences were concentration dependent. The MA almost completely recovered folates added to serum samples except for FA [69% (3%)] and THF [36% (10%)]. The BR underrecovered 5CH(3)THF [61% (9%)] and 5CHOTHF [38% (14%)] and overrecovered 5,10CH=THF [234% (32%)]. Multiple linear regression models with log-transformed data yielded a good fit for converting BR data to MA or LC-MS/MS data and MA data to LC-MS/MS data. | Thermal angioplasty methods heat the arterial wall. We related platelet adhesion to the temperature to which subendothelium and purified adhesive proteins had been exposed. Cultured subendothelium, purified von Willebrand factor, collagen types I and III, or fibronectin was applied to glass coverslips. Coverslips were mounted on a heating device that applied a temperature gradient from 30 to 100 degrees C. De-endothelialized umbilical arteries were heated by immersion in phosphate-buffered saline. After cooling to room temperature, the surfaces were perfused with blood at 37 degrees C (shear rate, 1600 sec-1). Compared with 37 degrees C, platelet adhesion to endothelial cell matrix was significantly reduced by 25%, 50% or 75% after heating to 69 +/- 1 degree C (mean +/- SEM, P < .05), 72 +/- 1 degree C, or 75 +/- 1 degree C, respectively. Platelet coverage to umbilical artery subendothelium was in the same way significantly reduced after heating to 71 +/- 1 degree C, or 77 +/- 1 degree C, respectively. In contrast to endothelial cell matrix, however, heating to about 55 degrees C increased platelet coverage from 30 +/- 5% to 54 +/- 6% (P < .05). Both platelet adhesion to von Willebrand factor and monoclonal antibody binding against the GpIb binding site of von Willebrand factor showed a comparable temperature dependence as platelet adhesion to subendothelium, provided the proper von Willebrand factor concentration was used. Platelet adhesion to heated collagen types I and III was increased and maximal at 57 +/- 2 degrees C and 62 +/- 2 degrees C, respectively. Preincubation of collagen III with proteins resulted in decreased platelet adhesion with increasing temperatures. Heating did not affect the reactivity of fibronectin. |
Is cell phone use associated with an inflammatory cytokine profile of parotid gland saliva? | There is controversy on the effects of the non-ionizing radiation emitted by cell phones on cellular processes and the impact of such radiation exposure on health. The purpose of this study was to investigate whether cell phone use alters cytokine expression in the saliva produced by the parotid glands. Cytokine expression profile was determined by enzyme linked immuno sorbent assay (ELISA) in the saliva produced by the parotid glands in healthy volunteers, and correlated with self-reported cell phone use and laterality. The following parameters were determined, in 83 Brazilian individuals in saliva produced by the parotid glands comparing the saliva from the gland exposed to cell phone radiation (ipsilateral) to that from the contralateral parotid: salivary flow, total protein concentration, interleukin 1 β (IL-1 β), interleukin 6 (IL-6), interleukin 10 (IL-10), interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) salivary levels by ELISA. After multiple testing correction, decreased IL-10 and increased IL-1β salivary levels in the ipsilateral side compared with the contralateral side (P < 0.05) were detected. Subjects who used cell phones for more than 10 years presented higher differences between IL-10 levels in ipsilateral versus contralateral parotids (P = 0.0012). No difference was observed in any of the tested parameters in correlation with cell phone monthly usage in minutes. | Currently there is no reliable medical treatment for aortic regurgitation (AR). Thirty-nine Sprague-Dawley rats underwent creation of AR or sham operation. Treated rats were assigned to early or late institution of sildenafil therapy (100 mg/kg/day) for a total of 10 weeks. Treatment-effects were measured by serial echocardiography, invasive hemodynamic measurements, and tissue analysis. Rats assigned to early treatment developed less remodeling than untreated rats. Thus, left ventricular (LV) dilation was blunted by sildenafil with end-systolic diameter being significantly smaller (6.6 ± 0.4 vs. 7.7 ± 0.4 mm, respectively, p < 0.05). Also, LV wall thickness was significantly decreased in treated rats compared to controls (2.23 ± 0.08 vs. 2.16 ± 0.05 mm, p < 0.01). Fractional shortening was improved by treatment (p < 0.05). Myocardial fibrosis was borderline decreased by treatment (p = 0.09). Akt was increased in treated compared to controls (p < 0.05). |
Does temporo-parietal theta activity correlate with misery perfusion in arterial occlusive disease? | Temporo-parietal theta activity (TPTA), often detected in hemispheres with internal carotid (ICA) or middle cerebral artery (MCA) occlusive lesions, is more clearly separated from occipital alpha activity by magnetoencephalography (MEG) than electroencephalography. The present study investigated whether TPTA is correlated with misery perfusion, a surgically correctable type of hemodynamic impairment. Awake MEG was measured in 56 patients with ICA or MCA occlusive lesions. Regional cerebral blood flow (rCBF) and regional cerebrovascular reactivity (rCVR) to acetazolamide were measured in the MCA territory by xenon-133 single-photon emission computed tomography. MEG was repeated in 10 patients after vascular reconstruction surgery. Fourteen patients showed TPTA in the lesion hemisphere (n=13) or bilaterally (n=1). The presence of TPTA was significantly correlated with both reduced rCBF and reduced rCVR (P=0.0009). After surgery, TPTA disappeared in 7 of the 10 studied patients. | This study evaluated risk factors for acute wheeze in preschool children and investigated whether subnormal levels of vitamin D were associated with increased risk for acute wheeze, atopy or viral/bacterial respiratory infections. We recruited 130 children with acute wheeze, aged 6 months to 4 years, from paediatric emergency departments in Stockholm, Sweden, and 101 age-matched controls with no history of wheeze or sensitisation to airborne allergens. Parents answered standardised questionnaires, and blood samples were analysed for specific IgE to airborne and food allergens and levels of 25 hydroxyvitamin D (25(OH)D). Nasopharyngeal virus samples were collected during the emergency department visit in the group of children with wheeze, and a subset were also tested for bacteria. Vitamin D insufficiency (25(OH)D < 75 nmol/L (30 ng/mL)) was associated with an odds ratio of 2.7 (95% confidence interval 1.1-6.2) for acute wheeze. However, no association was found between vitamin D insufficiency and atopy, presence of virus or bacteria or recurrent infections. Children older than 24 months were particularly at risk of subnormal vitamin D levels, irrespective of wheezing history. |
Do igG antibodies to type II collagen reflect inflammatory activity in patients with rheumatoid arthritis? | To determine the clinical significance of IgG antibodies to type II collagen (CII) and to define any correlation of antibodies to CII with the inflammatory response in patients with rheumatoid arthritis (RA). IgG antibodies to native human type II collagen (IgG anti-CII) were measured in sera and synovial fluid (SF) from patients with RA, patients with osteoarthritis (OA), and healthy controls by an improved ELISA. Demographic, clinical, and laboratory data including tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) levels were also obtained at the time of sampling in patients with RA. The median level and positivity for circulating IgG anti-CII were higher in patients with RA (n = 297) than patients with OA (n = 34) and healthy controls (n = 50) (p < 0.001). The titers of IgG anti-CII in SF were also higher in RA (n = 45) than in OA (n = 16) (p < 0.001). In paired samples, the levels of IgG anti-CII were significantly higher in SF compared to the sera in patients with RA (n = 45) (p < 0.001), but levels were not different in patients with OA (n = 16). Circulating IgG anti-CII converted from positive to negative in 13 patients (10.7%) and from negative to positive in 18 patients (14.8%) among 122 patients with RA in whom IgG anti-CII were monitored sequentially at a mean interval of 12.2 months. IgG anti-CII positive patients (n = 98) had shorter disease duration (p = 0.04) and less frequent deformity (p = 0.013), and higher median erythrocyte sedimentation rate (ESR) (p = 0.001) and C-reactive protein (CRP) (p < 0.001) than IgG anti-CII negative patients (n = 120). The levels of IgG anti-CII correlated with CRP (r = 0.270) and ESR (r = 0.253). CRP decreased significantly in patients (n = 13) who converted from IgG anti-CII positive to negative (p = 0.013). IgG anti-CII positive patients (n = 40) had higher levels of TNF-alpha and IL-6 than negative patients (n = 40) (p < 0.001). Levels of IgG anti-CII correlated well with TNF-alpha (r = 0.617) and IL-6 (r = 0.347). | The majority of studies assessing executive function in attention deficit disorder (ADD) have shown deficits in attentional set shifting using either the Wisconsin card sorting task or the intra-dimensional/extra-dimensional set-shifting task (ID/ED). Damage to the prefrontal cortex in humans, primates, and rodents impairs extra-dimensional (ED) shifts. Noradrenergic depletion of the medial prefrontal cortex in rats is sufficient to impair attentional set shifting. Atomoxetine, a selective norepinephrine (NE) re-uptake inhibitor, is hypothesized to produce beneficial effects in patient with ADD by augmenting NE release in prefrontal cortex. We assessed the effects of systemic administration of atomoxetine (0.0, 0.1, 0.3, and 0.9 mg/kg/ml) in normal and noradrenergically lesioned (NE-LX) rats on attentional-set shifts. We replicated findings showing NE-LX rats are selectively impaired on the ED shifts but not reversals or other discriminations. Atomoxetine remediated the attentional set-shifting impairments in NE-LX rats but impaired ED performance of non-lesioned rats. |
Is age-related decline in mitral peak diastolic velocities unaffected in well-trained runners? | We examined whether diastolic left ventricular function in young and senior lifelong endurance runners was significantly different from that in sedentary age-matched controls, and whether lifelong endurance running appears to modify the age-related decline in diastolic left ventricular function. The study comprised 17 senior athletes (age: 59-75 years, running distance: 30-70 km/week), 10 young athletes (age: 20-36 years, matched for running distance), and 11 senior and 12 young weight-matched sedentary controls. Peak early (E) and late (A) mitral inflow and early (e') and late (a') diastolic and systolic (s') annular longitudinal tissue Doppler velocities were measured by echocardiography during four stages (rest, supine bike exercise at 30% and 60% of maximal workload, and recovery). The athletes had marked cardiac remodeling, while overall differences in mitral inflow and annular tissue Doppler velocities during rest and exercise were more associated with age than with training status. The senior participants had lower E/A at rest, overall lower E, e' and s', and greater E/e' compared to the young participants (all values of P < 0.05). The athletes had greater E/A (P = 0.004), but tissue Doppler velocities were not different from those of the controls. | To investigate the inhibitory effects of RNA interference (RNAi) on expression of matrix metalloproteinase-2 (MMP-2) gene and invasiveness and adhesion of human pancreatic cancer cell line, BxPC-3. RNAi was performed using the vector (pGPU6)-based small interference RNA (siRNA) plasmid gene silence system to specifically knock down MMP-2 expression in pancreatic cancer cell line, BxPC-3. Four groups of different specific target sequence in coding region of MMP-2 and one non-specific sequence were chosen to construct four experimental siRNA plasmids of pGPU6-1, pGPU6-2, pGPU6-3 and pGPU6-4, and one negative control siRNA plasmid of pGPU6 (-). MMP-2 expression was measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Cell proliferation and apoptosis were examined by methyl thiazolyl tetrazolium (MTT) and flow cytometry, respectively. The abilities of adhesion and invasion were detected by cell adhesion assay and cell invasion assay using Transwell chambers. The expression of MMP-2 was inhibited and the inhibitory effects of different sequence varied. pGPU6-1 group had the most efficient inhibitory effect, followed by pGPU6-2 and pGPU6-3 groups. Invasiveness and adhesion were more significantly reduced in pGPU6-1, pGPU6-2 and pGPU6-3 groups as compared with pGPU6 (-) and blank control groups. However, no difference concerning cell proliferation and apoptosis was observed after transfection between experiment groups and control groups. |
Is lamina Cribrosa Depth Associated With the Cup-to-Disc Ratio in Eyes With Large Optic Disc Cupping and Cup-to-Disc Ratio Asymmetry? | To investigate the lamina cribrosa (LC) depth and its relationship with the cup-to-disc ratio (CDR) in the eyes with generalized increased optic disc cupping and CDR asymmetry. Glaucoma suspect subjects with a CDR≥0.7, CDR asymmetry ≥0.2 in the absence of visual field (VF) loss, and normal control subjects were enrolled. The optic nerve head was imaged using the enhanced depth imaging modes of Spectralis optical coherence tomography. The LC depth was determined at the mid-horizontal, and the superior and inferior mid-peripheral regions of the optic nerve head. Disc area and CDRs were larger in the glaucoma suspect group compared with the control group (P<0.001). The mean LC depth was significantly greater in the disc area-matched glaucoma suspect group compared with the normal control group (P<0.001). The mean LC depth was positively correlated with the average and vertical CDRs (r=0.755 and 0.664, respectively; both P<0.001), which was maintained after controlling for the disc area (r=0.756 and 0.645, respectively; both P<0.001). In eyes with CDR asymmetry, the LC was located more posteriorly in eyes with a higher CDR compared with fellow eyes with a lower CDR (P<0.001). | To investigate the impact of thymopentin (Thy) on mortality and in vivo cytokine release in an animal model of gut-derived sepsis which includes different combinations of allogeneic blood transfusion (T) and burn injury plus bacterial gavage (BG). Randomly controlled experiments. Two hundred sixteen Balb/c (H-2d) and 50 C3H/HeJ (H-2k) mice. In the first study 60 Balb/c mice were given Thy (1 mg/kg). The same day of therapy onset, 40 mice were transfused with allogeneic blood (from C3H/HeJ mice). The remaining 20 mice received aliquots of saline. Five days post-T, 20 of the 40 transfused mice were subjected to a 20% TBSA thermal injury and simultaneous gavage with 1 x 10(9) Escherichia coli and the other 20 mice underwent a sham burn. The 20 nontransfused mice also received a 20% burn plus bacterial gavage. In all animals Thy was administered for 15 days. Three control groups (n = 20 each) entered the same protocol design, but they did not receive Thy. In the second study 96 animals were randomized to six groups (n = 16 each) according to the above experimental design. Animals were sacrificed by exsanguination after burn or 5 days post-T in nonburned mice to measure TNF-alpha, IL-2, and IL-4 plasma levels. The highest mortality (70%) occurred when T was combined with BG. Thy significantly reduced mortality in both groups that underwent BG, regardless of the association with T. TNF-alpha was detectable in 30% of the tested samples, IL-2 in 50%, and IL-4 in 70%. Thy significantly reduced the levels of IL-4 and increased the production of IL-2. |
Does disc arthroplasty design influence intervertebral kinematics and facet forces? | Total disc replacement is a novel approach for dynamically stabilizing a painful intervertebral segment. While this approach is gaining popularity, and several types of implants are used, the effect of disc arthroplasty on lumbar biomechanics has not been widely reported. Consequently, beneficial or adverse effects of this procedure may not be fully realized, and data for kinematic optimization are unavailable. To characterize kinematic and load transfer modifications at L5/S1 secondary to joint replacement. A human cadaveric biomechanical study in which the facet forces and instant axes of rotation (IAR) were measured for different spinal positions under simulated weightbearing conditions before and after total disc replacement at L5/S1 using semiconstrained (3 degrees of freedom [DOF]; Prodisc) and unconstrained (5 DOF; Charité) articulated implants. Twelve radiographically normal human cadaveric L5/S1 joints (age range 45-64 years) were tested before and after disc replacement using Prodisc II implants (Spine Solutions, Paoli, PA) in six specimens and SB Charité III (Johnson & Johnson, New Brunswick, NJ) in six other specimens. Semiconstrained fixtures in combination with a servo-hydraulic materials testing system subjected the test specimens to a physiologic combination of compression and anterior shear. Multiple intervertebral positions were studied and included up to 6 degrees of flexion, extension, and lateral bending. The IAR was calculated for every 3-degree intervals, and the force through the facet joints was simultaneously measured using flexible intra-articular sensors. Data were analyzed using repeated-measures analysis of variance. During flexion/extension, the average IAR positions and directions were not significantly modified by implantation with the exception that the IAR was higher relative to S1 end plate with the Charité (p=.028). The IAR had a vertically oriented centrode throughout flexion/extension with the Prodisc (p<.001) and the Charité (p<.016). The centrode tended to be greater with the Prodisc. There was a trend that the facet force was decreased throughout flexion/extension for the Prodisc; however, this was statistically significant only at 6 degrees extension (27%, p=.013). In lateral bending, the IAR was significantly modified by Prodisc replacement, with a decreased inclination relative to S1 end plate, (ie, increased coupled axial rotation). While the IAR moved in the horizontal plane toward the side of bending, this effect was more pronounced with the Prodisc. The ipsilateral facet force was significantly increased in 6 degrees lateral bending with the Charité (85%; p=.001). | It is well documented that hyperglycemia-induced oxidative stress is an important causative factor of endothelial dysfunction. Cinnamaldehyde (CA) is a key flavor compound in cinnamon essential oil that can enhance the antioxidant defense against reactive oxygen species (ROS) by activating NF-E2-related factor 2 (Nrf2), which has been shown to have a cardiovascular protective effect, but its role in endothelial dysfunction induced by high glucose is unknown. Dissected male C57BL/6J mouse aortic rings and HUVECs were cultured in normal glucose(NG 5.5 mM) or high glucose(HG 30.0 mM) DMEM treatment with or without CA (10 µM). Treatment with CA protected the endothelium relaxation, inhibited ROS generation and preserved nitric oxide (NO) levels in the endothelium of mouse aortas treated with high glucose . CA up-regulated Nrf2 expression, promoted its translocation to the nucleus'and increased HO-1, NQO1, Catalase and Gpx1 expression under high glucose condition. The increased level of nitrotyrosine in HUVECs under high glucose was also attenuated by treatment with CA. Dihydroethidium (DHE) and DAF-2DA staining indicated that CA inhibited the ROS generation and preserved the NO levels in HUVECs, but these effects were reversed by Nrf2-siRNA in high glucose conditions. |
Do fetal membranes from term vaginal deliveries have a zone of weakness exhibiting characteristics of apoptosis and remodeling? | Recently we identified a weak zone in term, pre-labor (repeat Cesarean section) human fetal membranes (FM) overlying the cervix with biochemical characteristics suggestive of apoptosis and collagen remodeling. We suggested that this weak zone is the FM rupture initiation site. Vaginally delivered patients have a weak zone in their FM overlying the cervix; a comparable weak zone lies adjacent to the tear line in FM after spontaneous rupture (SROM). FM from vaginally delivered patients with artificial rupture (AROM) and SROM were collected. FM of AROM patients were marked per vagina to identify the FM zone overlying the cervix. Postpartum FM were cut, strength tested, and piece strengths were remapped to their former location on a three-dimensional model. A 10-cm diameter zone centered on the marked area (AROM), or defined weak zone (SROM) was compared with the remaining FM. AROM FM exhibit a para-cervical weak zone. SROM FM exhibit a comparable zone on the tear line. The mean rupture strength within weak zones was 60% of the remaining membranes (P <.001). AROM and SROM FM weak zones both exhibit increased matrix metalloproteinase 9, increased poly (ADP-ribose) polymerase I cleavage, decreased tissue inhibitor of metalloproteinase 3 protein, and histology consistent with remodeling and apoptosis. | Vitamin A plays a major role in lipid metabolism. Previously, we reported that chronic vitamin A feeding (129 mg/kg) for two months normalized the abnormally high plasma HDL-cholesterol (HDL-C) levels in hypercholesterolemic obese rats by upregulating the hepatic scavenger receptor class B type 1 (SR-BI) expression. In this report, we hypothesize that the administration of a dose less than 129 mg of vitamin A/kg would also be effective in lowering the plasma HDL-C levels in these rats. Changes in the activity and expression of proteins related to RCT were analyzed together with blood parameters in five-month-old male lean and obese rats supplemented with 2.6 (control group), 26, 52 and 129 mg of vitamin A/kg as retinyl palmitate for 20 weeks. Vitamin A supplementation in the obese rats decreased the plasma HDL-C levels with a concomitant increase in the hepatic SR-BI expression and lipase activity compared to that observed in the control diet-fed obese rats treated with 2.6 mg of vitamin A/kg diet. Furthermore, vitamin A supplementation at doses of 52 and 129 mg/kg diet reduced the plasma lecithin cholesterol acyltransferase activity and increased the hepatic ATP-binding cassette transporter protein A1 expression in the obese rats. Interestingly, most of these changes were not observed in the lean rats fed a vitamin A-enriched diet. |
Do in chronic idiopathic urticaria autoantibodies against Fc epsilonRII/CD23 induce histamine release via eosinophil activation? | Chronic idiopathic urticaria is a common skin disorder characterized by recurrent, transitory, itchy weals for more than 6 weeks. An autoimmune origin has been suggested based on the findings of auto-antibodies (Abs) directed against either the alpha subunit of the high-affinity IgE receptor or the IgE molecule in nearly half of the patients. To identify other autoantigen targets in patients with chronic idiopathic urticaria. We used pooled IgG derived from 133 patients with chronic idiopathic urticaria to screen a random peptide library to identify disease-relevant autoantigen peptides. Among the identified peptides, one was recognized by the vast majority of patients' sera. Abs against this peptide were affinity purified from the patients' sera and assayed for their ability to induce histamine release from basophils. We identified a peptide that showed similarity with the low-affinity IgE receptor (Fc epsilonRII/CD23) expressed on lymphomonocytes and eosinophils. Anti-peptide IgG Abs purified from the patients' sera bound cell surface CD23 and were able to induce histamine release from basophils. This effect appeared to be mediated by the release of major basic protein from eosinophils upon engagement of CD23. The same effects were obtained with the sera from mice immunized with the CD23 peptide. | The purpose of this study was to evaluate the role of capsular closure after hip arthroscopy in reduction of the incidence of heterotopic ossification (HO). One hundred (50 study group, 50 control group) consecutive hip arthroscopy procedures with radiographic follow-up of more than 9 weeks were included in the study. The study group consisted of 50 patients in whom capsular closure with 2 No. 1 polydioxanone (PDS) sutures was performed, and a control group consisted of 50 patients in whom the capsule remained open after capsulotomy. HO was assessed by radiographs using the Brooker classification. Statistical analysis of the data was carried out with the χ-square or Fisher exact test and Student t test, when appropriate, at a significance level of .05. Thirty-six (36%) patients had radiographic evidence of postoperative HO (14 patients in the capsular closure group). No significant difference was found regarding sex, side of operation, age, or HO rate between the study and the control groups (P = .778, P = .123, P = .744, and P = .144, respectively). Furthermore, no significant difference was found in the rate of HO with potential clinical significance (Brooker classification > I) between the control and study groups (P = .764). |
Is autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA responsible for Treacher Collins syndrome? | Treacher Collins syndrome is a mandibulofacial dysostosis caused by mutations in genes involved in ribosome biogenesis and synthesis. TCOF1 mutations are observed in ~80% of the patients and are inherited in an autosomal dominant manner. Recently, two other genes have been reported in <2% of patients--POLR1D in patients with autosomal dominant inheritance, and POLR1C in patients with autosomal recessive inheritance. We performed direct sequencing of TCOF1, POLR1C, and POLR1D in two unrelated consanguineous families. The four affected children shared the same homozygous mutation in POLR1D (c.163C>G, p.Leu55Val). This mutation is localized in a region encoding the dimerization domain of the RNA polymerase. It is supposed that this mutation impairs RNA polymerase, resulting in a lower amount of mature dimeric ribosomes. A functional analysis of the transcripts of TCOF1 by real-time quantitative reverse transcription-polymerase chain reaction was performed in the first family, demonstrating a 50% reduction in the index case, compatible with this hypothesis. | Fibrinogen receptor antagonists block the fibrinogen-platelet interaction at the GPIIb/IIIa receptors and inhibit thrombus formation. SC-54701 is the active metabolite of SC-54684A, an orally fibrinogen receptor antagonist. We compared the efficacy of SC-54701A (SCa, hydrochloride salt) with that of aspirin (ASA) or heparin and with combination therapy in a canine model of continuous current injury. Sixty-six dogs were used (6 per treatment). SCa (15-minute loading dose followed by [//] infusion [microgram/kg per minute]: (0.87//0.39=1 X SCa; 0.52//0.23=0.6 X SCa; and 0.425//0.20= 0.5 X SCa), ASA (2.8 mg/kg), heparin (200 U/kg plus 1000 U/h), or saline (0.1 mL/kg) was administered intravenously. Experimental time was 180 minutes of current. Time to occlusion was increased (P < .05) by SCa (T=incidence of thrombosis) (1 X SCa, >180 minutes [T=0]; 0.6 X SCa, 158 +/- 15 minutes [T=2]; 0.5 X SCa, 130 +/- 22 minutes [T=4]), heparin (114 +/- 16 minutes [T=5]), and ASA plus heparin (130 +/- 11 minutes [T=5]) relative to saline (58 +/- 7 minutes [T=6]). Time to occlusion for the SCa treatments was increased compared with ASA (64 +/- 7 minutes [T=6]). When 0.5 X SCa was administered with ASA plus heparin, time to occlusion was >180 minutes [T=0]. SCa provided complete protection at > or = 90% inhibition of ex vivo collagen-induced platelet aggregation. Cyclic flow variations were minimal with SCa or any treatment involving 0.5 X SCa and ASA. |
Are multiple sodium channel isoforms and mitogen-activated protein kinases present in painful human neuromas? | Although axons within neuromas have been shown to produce inappropriate spontaneous ectopic discharges, the molecular basis for pain in patients with neuromas is still not fully understood. Because sodium channels are known to play critical roles in neuronal electrogenesis and hyperexcitability, we examined the expression of all the neuronal voltage-gated sodium channels (Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9) within human painful neuromas. We also examined the expression of two mitogen-activated protein (MAP) kinases, activated p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are known to contribute to chronic pain, within these human neuromas. We used immunocytochemical methods with specific antibodies to sodium channels Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9, and to activated MAP kinases p38 and ERK1/2 to study by confocal microscopy control and painful neuroma tissue from five patients with well-documented pain. We demonstrate upregulation of sodium channel Nav1.3, as well as Nav1.7 and Nav1.8, in blind-ending axons within human painful neuromas. We also demonstrate upregulation of activated p38 and ERK1/2 MAP kinases in axons within these neuromas. | Non-alcoholic steatohepatitis (NASH) is a metabolic disorder of the liver, which may evolve to fibrosis or cirrhosis. Pentoxifylline (PTX) has been postulated to act as an antifibrogenic agent able to inhibit hepatic stellate cell proliferation and collagen synthesis in vitro. Short-term studies suggest beneficial effects of PTX in experimental models of NASH. To study whether PTX can influence liver fibrogenesis in an animal model of NASH. To induce NASH, a choline-deficient diet (CDD) was given to Sprague- Dawley rats for 8 weeks. Rats were allocated to two experimental groups one receiving PTX (9 mg/kg/day) in drinking water. Control rats received a choline-supplemented diet. Biochemical and histological evaluation of fatty liver was performed by conventional techniques. In addition, mRNA levels of Pro-collagen I and transforming growth factor beta-1 were assessed by semi-quantitative RT-PCR and stellate cell activation by alpha-actin immunofluorescence stain. After 8 weeks CDD induced a marked elevation of serum aminotransferases, a marked decrease in both hepatic and biliary glutathione and a severe fatty liver infiltration with mild histological inflammation and fibrosis. A significant increase in mRNA levels of both Pro-collagen I and TGFbeta-1 was seen after CDD feeding. No differences were seen between rats receiving PTX and rats on CDD diet alone with regard to the biochemical, morphological or molecular alterations induced by the CDD. |
Does marker of Endothelial Dysfunction Asymmetric Dimethylarginine be Elevated in HIV Infection but Not Associated With Subclinical Atherosclerosis? | Cardiovascular disease contributes to excess morbidity and mortality in HIV infection, and endothelial dysfunction may contribute to this pattern. We aimed to determine the endothelial function in treated and untreated HIV-infected individuals and investigate potential associations with viral replication, immune activation, coagulation, platelet function, and subclinical atherosclerosis. Asymmetric dimethylarginine (ADMA, marker of endothelial dysfunction) and soluble CD14 (sCD14, marker of monocyte activation) were measured in plasma from two previously established cross-sectional cohorts: cohort A including 50 untreated and 50 antiretroviral therapy (ART)-treated HIV-infected individuals with previously assessed coagulation and platelet function and cohort B including 105 HIV-infected individuals on ART and 105 uninfected controls with previously assessed coronary artery calcium score, myocardial perfusion defects, and carotid intima-media thickness. Concentrations of ADMA were higher in HIV-infected individuals compared with uninfected controls, and higher ADMA was found in ART-treated compared with untreated HIV-infected individuals. ADMA was associated with viral load, sCD14, D-dimer, and low CD4 T-cell count in untreated HIV infection. Only viral load remained significant in multivariate analyses. In ART-treated HIV-infected individuals, ADMA was not associated with coronary artery calcium score, myocardial perfusion defects, or intima-media thickness. | The efficacy and feasibility of laparoscopic surgery (LAP) for gastric GISTs >5 cm has not been adequately assessed. Here we investigated the clinical outcomes of these patients. Twenty-seven consecutive patients who underwent resection for gastric GISTs >5 cm were enrolled in this retrospective study. We assessed the tumor characteristics, surgical outcomes, tumor recurrence, and patient survival in the open surgery (OPEN) group and in the LAP group. The tumor size in the OPEN group was larger than that in the LAP group, but there were no differences in the mitotic count. There were no differences in operative complications. Finally, there were no differences in the disease-free and no patients in the LAP group died. |
Does pancreatic T cell protein-tyrosine phosphatase deficiency ameliorate cerulein-induced acute pancreatitis? | Acute pancreatitis (AP) is a common clinical problem whose incidence has been progressively increasing in recent years. Onset of the disease is trigged by intra-acinar cell activation of digestive enzyme zymogens that induce autodigestion, release of pro-inflammatory cytokines and acinar cell injury. T-cell protein tyrosine phosphatase (TCPTP) is implicated in inflammatory signaling but its significance in AP remains unclear. In this study we assessed the role of pancreatic TCPTP in cerulein-induced AP. TCPTP expression was increased at the protein and messenger RNA levels in the early phase of AP in mice and rats. To directly determine whether TCPTP may have a causal role in AP we generated mice with pancreatic TCPTP deletion (panc-TCPTP KO) by crossing TCPTP floxed mice with Pdx1-Cre transgenic mice. Amylase and lipase levels were lower in cerulein-treated panc-TCPTP KO mice compared with controls. In addition, pancreatic mRNA and serum concentrations of the inflammatory cytokines TNFα and IL-6 were lower in panc-TCPTP KO mice. At the molecular level, panc-TCPTP KO mice exhibited enhanced cerulein-induced STAT3 Tyr705 phosphorylation accompanied by a decreased cerulein-induced NF-κB inflammatory response, and decreased ER stress and cell death. | GH acts through the GH receptor (GHR), whose polymorphisms might affect the growth response to recombinant human GH (rhGH). The objective of this study was to investigate possible influences of GHR polymorphisms on the growth response to rhGH in GH-deficient (GHD) children. This was a 2-yr study (first year, spontaneous growth; second year, growth during rhGH treatment). This study was performed at a referral center. Fifty-four prepubertal GHD children (11 females; mean age, 7.8 yr; sd, 3.96) were studied. Patients were treated with rhGH (0.2 mg/kg.wk) for at least 1 yr after diagnosis. Growth velocity (GV) was measured 1 yr before treatment and during the first treatment year. GHR exons were amplified by PCR using pairs of intronic primers. The presence of single or multiple mismatches in the PCR products was revealed by denaturing high-pressure liquid chromatography. For exons in which mismatches were found by denaturing high-pressure liquid chromatography, direct sequencing was performed by automatic sequencer. Before the start of treatment, the mean height (Ht) sd score was -1.93 (sd, 0.70), and the mean GV sd score was -1.49 (sd, 1.26). The posttreatment (first 12 months) mean GV sd score was 3.55 (sd, 3.27). Molecular analysis revealed a high frequency of GHR polymorphisms; in particular: exon 3 deletion (Del 3) in 26 subjects (48%), polymorphism 504 A>G at codon 168 of exon 6 in 44 (82%), and polymorphism 1576 A>C at codon 526 of exon 10 in 35 (65%). In most patients, these different polymorphisms recurred in association. We found no significant differences in GV between the groups of subjects defined by the polymorphic genotypes. |
Does overexpression of the PSMB5 gene contribute to bortezomib resistance in T-lymphoblastic lymphoma/leukemia cells derived from Jurkat line? | To study the mechanism of bortezomib resistance in JurkatB lines derived from T-lymphoblastic lymphoma/leukemia Jurkat line. Cytotoxicities of popular chemotherapeutic drugs to JurkatB cells were analyzed by trypan blue assay. Functional drug efflux in JurkatB cells was determined by flow cytometry utilizing daunorubicin and the expression of P-glycoprotein (P-gp) was detected by Western blot. mRNA expression levels of proteasome beta5 subunit (PSMB5) were measured by quantitation real-time reverse transcription polymerase chain reaction. In situ hybridization was performed to detect the amplification of PSMB5 gene. The chymotrypsin-like activities were assayed by measuring the release of the fluorescent 7-amido-4-methylcoumarin (AMC) from the substrate N-succinyl-Leu-Leu-Val-Tyr-AMC. Cytogenetic studies were performed using R-banded metaphases and fluorescence in situ hybridization (FISH) analysis. IkappaB-alpha levels were detected by Western blot. No cross-resistance to daunorubicin, adriamycin, vindesine, and etoposide was found in JurkatB cells. No evidence of drug efflux was found in JurkatB cells and the expression of P-gp was negative. The PSMB5 mRNA was overexpressed in highly resistant JurkatB5 and JurkatB1 lines compared with parental Jurkat, corresponding well with the increase of chymotrypsin-like activity and a karyotype of i(14q). Amplification of PSMB5 gene was demonstrated by in situ hybridization and FISH. The decreased IkappaB-alpha level in JurkatB5 cells after bortezomib treatment indicating an upregulation of nuclear factor-kappaB (NF-kappaB) activity. | Previous studies have reported an 11% to 75% incidence of postoperative cognitive decline among cardiac surgery patients. The INVOS Cerebral Oximeter (Somanetics Corp, Troy, MI) is a Food and Drug Administration approved device that measures regional cerebral oxygen (rSo(2)) saturation. The purpose of this study is to examine whether decreased rSo(2) predicts cognitive decline and prolonged hospital stay after coronary artery bypass grafting (CABG). The rSo(2) was monitored intraoperatively in a cohort of primary CABG patients. Patients were prospectively randomized to a blinded control group or an unblinded intervention group. Cognitive function was assessed preoperatively, postoperatively, and at 3 months using a battery of standardized neurocognitive tests. Cognitive decline was defined as a decrease of one standard deviation or more in performance on at least one neurocognitive measure. The rSo(2) desaturation score was calculated by multiplying rSo(2) below 50% by time (seconds). Multivariate logistic regression models were used to assess cognitive decline and hospital stay. The change in cognitive performance was also assessed using a multivariate linear regression model. Patients with rSo(2) desaturation score greater than 3,000%-second had a significantly higher risk of early postoperative cognitive decline [p = 0.024]. Patients with rSo(2) desaturation score greater than 3,000%-second also had a near threefold increased risk of prolonged hospital stay (>6 days) [p = 0.007]. |
Does monoclonal antibody against transforming growth factor Beta 1 influence liver regeneration after resection in large animal experiments? | Steatohepatitis is a type of histopathological liver injury that can be caused by chemotherapy [chemotherapy-associated steatohepatitis (CASH)] and can progress to liver fibrosis or cirrhosis. CASH impairs liver functions, including liver regeneration. Impaired liver regeneration reduces the number of patients who can undergo liver resection and reduces opportunities for curative therapies. Transforming growth factor-beta (TGFβ) is a potent mitotic inhibitor that participates during the last phase of liver regeneration. TGFβ has been studied as a potential solution to the development of liver fibrosis or hepatocellular carcinoma. The first aim of our study was to establish a large animal model of toxic liver injury and test the ability of a monoclonal antibody against TGFβ (MAB-TGFβ) to increase liver-regeneration capacity. The second aim was to evaluate the degree to which early preoperative administration of MAB-TGFβ influenced hepatic parenchyma regeneration following healthy liver resection in a swine experimental model. Toxic liver injury was induced by alcohol consumption and regular intraperitoneal administration of carbon tetrachloride (CCl4) to piglets for 10 weeks. After 10 weeks, the piglets underwent liver resection of the left lateral and left medial liver lobes. Twenty-four hours after liver resection, MAB-TGFβ was administered to the experimental group (10 piglets) and a physiological solution to the control group (10 piglets) through an implemented port-a-cath. In the second part of the study, either MAB-TGFβ or a saline solution control were administered at 12 and 4 days prior to resection of the right lobes of healthy liver (six experimental and 10 control group subjects). Observation and follow-up was performed throughout the entire experiment. Ultrasound and biochemical tests (for albumin, cholinesterase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, bilirubin, urea, creatinine and ammonia levels) were performed on postoperative days 1, 3, 7, 10 and 14. A histopathological examination was performed after sacrificing the animals on the 14th postoperative day. No significant differences were observed between groups when using ultrasound volumetry to assess the regenerative volume of the liver in both experiments. The only significant differences found when comparing biochemical parameters between groups were higher serum levels of both creatinine and γ-glutamyl transferase in the experimental group with preoperative administration of MAB-TGFβ. There were no differences in the histological analyses of hepatic lobule cross-sectional area nor in the proliferative index between animals receiving MAB-TGFβ and those treated with physiological saline solution before resection. Hepatocytic cross-sectional areas were larger in animals treated with physiological solution versus those treated with MAB-TGFβ on the operative day; however, these values were comparable between groups by 14 days following resection. | JC polyomavirus (JCPyV) is a widespread human polyomavirus that usually resides latently in its host. It can be reactivated under immunomodulating conditions and cause Progressive Multifocal Leukoencephalopathy (PML). Circulating microRNAs (miRNAs) are emerging as promising biomarkers for several pathologies. In this study, we have investigated whether circulating miRNAs exist that are differentially expressed between JCPyV seropositive and JCPyV seronegative on the one hand or between JCPyV shedders and JCPyV non-shedders on the other hand. Human miRNA expression profiling was performed in a small set of plasma samples obtained from seronegative subjects, seropositive shedders and seropositive non-shedders. A set of 10 miRNAs was selected for further analysis in a larger group of samples. Based on the plasma profiling experiment of 30 samples, 6 miRNAs were selected that were possibly differentially expressed between seropositive and seronegative subjects and 4 miRNAs were selected that were possibly differentially expressed between shedders and non-shedders. Subsequently, expression of these 10 selected miRNAs was assessed in an independent set of 100 plasma samples. Results indicated that none of them were differentially expressed. |
Is 3q26 amplification an effective negative triage test for LSIL : a historical prospective study? | Women with low grade squamous intraepithelial lesions (LSIL) at cervical cancer screening are currently referred for further diagnostic work up despite 80% having no precancerous lesion. The primary purpose of this study is to measure the test characteristics of 3q26 chromosome gain (3q26 gain) as a host marker of carcinogenesis in women with LSIL. A negative triage test may allow these women to be followed by cytology alone without immediate referral to colposcopy. A historical prospective study was designed to measure 3q26 gain from the archived liquid cytology specimens diagnosed as LSIL among women attending colposcopy between 2007 and 2009. 3q26 gain was assessed on the index liquid sample; and sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were measured at immediate triage and at 6-16 months after colposcopic biopsy. The sensitivity of 3q26 gain measured at immediate triage from automated and manually reviewed tests in 65 non-pregnant unique women was 70% (95% CI: 35, 93) with a NPV of 89% (95% CI: 78, 96). The sensitivity and NPV increased to 80% (95% CI: 28, 99) and 98% (95% CI: 87, 100), respectively, when only the automated method of detecting 3q26 gain was used. | In mammals, the temperature rhythm is regulated by the circadian pacemaker located in the suprachiasmatic nuclei, and is considered a "marker rhythm". Melatonin, the pineal gland hormone, is a major regulator of the endogenous rhythms including body temperature. Its production is influenced by many factors, such as type 1 diabetes mellitus. In rats, diabetes leads to hypothermia and reduced melatonin synthesis; insulin treatment reestablishes both. To study the body temperature daily rhythm of diabetic animals and the effects of insulin and/or melatonin treatment on its structure. We studied the effects of streptozotocin-induced diabetes (60 mg/kg) on the body temperature rhythm of Wistar rats and the possible modifications resulting from early and late treatments with insulin (6U/day) and/or melatonin (daily 0.5 mg/kg). We monitored the daily body temperature rhythm, its rhythmic parameters (MESOR, amplitude and acrophase), glycemia and body weight for 55 days. Data were classified by groups and expressed as mean ± SEM. One-way ANOVA analysis was performed followed by Bonferroni posttest. Statistical significance was set at p < 0.05. Diabetes led to complete disruption of the temperature rhythm and hypothermia, which were accentuated over time. All early treatments (insulin or/and melatonin) prevented the temperature rhythm disruption and hypothermia. Insulin plus melatonin restored the body temperature rhythm whereas insulin alone resulted less efficient; melatonin alone did not restore any of the parameters studied; however, when supplemented close to diabetes onset, it maintained the temperature rhythmicity. All these corrective effects of the early treatments were dependent on the continuous maintenance of the treatment. |
Do [ The sequencing analyze of 915 newborn with GJB2 heterozygous mutation in Beijing ]? | To determine GJB2 allelic mutant and estimate probability of hereditary hearing loss in newborn with GJB2 heterozygous mutation in Beijing. We performed genetic testing for sequencing of GJB2 gene for searching GJB2 allelic mutant in 915 newborn who received newborn deafness gene screening (GJB2 c. 235delC, GJB2 c. 299_300delAT, GJB2 c. 176191del16, GJB2 c. 35delG) in Beijing Tongren hospital, and the mutation were classified to pathogenic mutation,undefined variant and polymorphism. Four hundred (43.72%, 400/915) newborn were detected to carry at least one mutation allele in GJB2. 3 (0.33%, 3/915) newborn had pathogenic mutations (c. 94C>T, c. 380G>T, c. 344T>G); 62 (6.76%, 62/915) newborn carried 14 undefined variant, 36 newborn had c. 109G>A (58.06%, 36/62),13 newborn had c. 368C>A (20.97%,13/62), six (c. 268C>G, c. 282C>T, c. 294G>C, 456C>T, c. 501G>A, c. 587T>C) are novel; 335 (36.61%, 335/915) newborn were polymorphism. | The present study examined associations between psychological reactivity and hormonal responses to a standardized laboratory stressor (Trier Social Stress Test, TSST) in postmenopausal women. Postmenopausal women aged 50-74 years undertook anxiety and mood assessments prior to and following the TSST. Blood samples were drawn at multiple timepoints for assessment of cortisol, adrenocorticotrophic hormone (ACTH) and dehydroepiandrosterone (DHEA). Forty postmenopausal women completed the assessments. As expected, significant increases in anxiety and negative affect and decreases in positive affect were observed after the TSST; however, the magnitude of change in anxiety and mood varied considerably across individuals. Analyses indicated that greater increases in anxiety and negative affect after the TSST were associated with higher levels of cortisol, ACTH and DHEA after controlling for race, age, body mass index and smoking status. Changes in positive affect were not associated with cortisol, ACTH or DHEA. |
Do gene polymorphisms of stress hormone and cytokine receptors associate with immunomodulatory profile and psychological measurement? | We sought to identify whether stable single nucleotide polymorphisms (SNPs) of various endocrine and immune molecules could be used as biomarkers associated with specific immune alterations and chronic stress measures in normal humans. A total of 207 volunteer participants answered stress questionnaire and gave peripheral blood cells for identification of SNPs in genes coding for glucocorticoid receptor (GR), beta 2 adrenergic receptor (B2AR), interferon-gamma receptors (IFNGR1, IFNGR2), and interleukin-4 receptor (IL4R). Immunoregulatory profiles were measured by flow cytometry and genotyping assays were performed by allelic discrimination real-time PCR. Several significant differences were revealed in associations between stress marker and immune indicators based on SNP categories. For instance, Th1 levels of the minor alleles of GR TthIIII (AA) and IFNGR2 Q64R (Arg/Arg) groups were positively associated with chronic stress (PSS) (p = 0.024 and 0.005, respectively) compared with wild type (WT) and negatively associated with PSS in the heterozygous genotypes of GR BclI and IL4R Ile50Val (p = 0.040 and p = 0.052, respectively). Treg levels of the minor alleles of BclI (GG) and IFNGR1 T-56C (CC) groups were positively associated with PSS (p = 0.045 and p = 0.010, respectively) and negatively associated in the minor allele (Val/Val) of IL4R Ile50Va and the heterozygous genotype of IL4R Q576R (p = 0.041 and p = 0.017, respectively) compared to WT. | 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. |
Does infection with murine gammaherpesvirus 68 exacerbate inflammatory bowel disease in IL-10-deficient mice? | We questioned whether infection with murine gammaherpesvirus 68 (HV-68) might exacerbate inflammatory bowel disease using mice deficient in IL-10 (IL-10-/-) as a model of developing colitis. Groups of C57BL/6 mice and IL-10-/- mice were mock-treated or infected with HV-68. Two months following infection, mice were euthanized and a variety of parameters were measured to quantify the extent of inflammation and the presence of virus. Measurements included survival, body weight, splenomegaly, colonic disease scores, liver histopathology, viable bacteria in the liver, and splenic viral burden. IL-10-/- mice infected with HV-68 displayed reduced survival, lower body weights, increased splenomegaly, exacerbated colonic disease scores, increased numbers of viable bacteria in the liver, and increased leukocyte liver infiltration when compared to mock-treated IL-10-/- mice or HV-68 infected C57BL/6 mice. Surprisingly, levels of infectious or latent virus were not significantly different between the groups of mice exposed to HV-68. | Ischemic mitral regurgitation (MR) often persists after restrictive mitral valve annuloplasty, in which case it is associated with worse clinical outcomes. The goal of the present study was to determine whether persistence of MR and/or clinical outcome could be predicted from preoperative analysis of mitral valve configuration. In 51 consecutive patients undergoing restrictive annuloplasty for ischemic MR, posterior leaflet (PL) angle, anterior leaflet angle, coaptation distance, and tenting area were quantified by echocardiography before surgery (6+/-3 days), and MR severity was assessed before and early after surgery (9+/-4 days). Postoperatively, persistence of mild to moderate MR (vena contracta > 3 mm) was observed in 11 (22%) of the patients. The best predictor of postoperative persistence of MR was a PL angle > or = 45 degrees (sensitivity 100%, specificity 97%, positive predictive value 92%, negative predictive value 100%). Patients with persistent MR had markedly lower 3-year event-free survival (26+/-20%) compared with those with nonpersistent MR (75+/-12%, P=0.01). Preoperative presence of a PL angle > or = 45 degrees also was associated with a markedly lower 3-year event-free survival (22+/-17% versus 76+/-12%; P<0.001). |
Do higher vulnerable elders survey scores predict death and functional decline in vulnerable older people? | To examine whether the Vulnerable Elders Survey (VES-13) score predicts risk of death and functional decline in vulnerable older adults. Longitudinal evaluation with mean follow-up of 11 months (range 8-14 months). Two managed care organizations in the United States. Four hundred twenty community-dwelling older people identified as having moderate to high risk of death and functional decline based on a VES-13 score of 3 or higher. These older people were enrolled in the Assessing Care of Vulnerable Elders observational study. Baseline: VES-13 score, sex, income, cognitive score, and number of medical diagnoses. functional decline and death. VES-13 scores strongly predicted death and functional decline (P<.001, area under the receiver operating curve=0.66). The estimated combined risk of death and decline rose with VES-13 score, increasing from 23% for older people with a VES-13 score of 3 to 60% for those with a score of 10. Other measures (sex, comorbidity) were not significant predictors of death or decline over this period after controlling for VES-13 score. | Mast cells reside in most tissues and in close association with blood vessels and nerves, areas where lymphatic vessels are also present. Mast cells and lymphatic vessels are two important players in the development of the inflammatory process. This study was designed to examine the effects of mast cell degranulation on the contractile activity of mesenteric lymphatic vessels. Lymphatic vessel contractile activity was assessed in vitro by video microscopy of the mesentery of cow's milk-sensitized guinea pigs upon application of beta-lactoglobulin and compared to the response measured in sham animals. Application of 5-10 microM beta-lactoglobulin increased lymphatic vessel constriction frequency and decreased constriction amplitude (n = 12). This effect was not seen in sham-treated animals (n = 16) and was not due to an increased number of mast cells in the mesentery of the milk-sensitized animals, as revealed by histological examination. Two known mast cell-derived mediators, histamine and thromboxane A2, via stable mimetic U46619 also altered lymphatic pumping in a similar manner, but only pretreatment with the histamine H1 receptor antagonist pyrilamine (1 microM) could reduce the beta-lactoglobulin-induced response. The thromboxane A2 receptor antagonist, SQ 29548, and the 5-lipoxygenase inhibitor, caffeic acid, were without significant effect. |
Does opportunistic mammography screening provide effective detection rates in a limited resource healthcare system? | Breast cancer is the leading cause of cancer deaths in women world-wide. In low and middle income countries, where there are no population-based mammographic screening programmes, late presentation is common, and because of inadequate access to optimal treatment, survival rates are poor. Mammographic screening is well-studied in high-income countries in western populations, and because it has been shown to reduce breast cancer mortality, it has become part of the healthcare systems in such countries. However the performance of mammographic screening in a developing country is largely unknown. This study aims to evaluate the performance of mammographic screening in Malaysia, a middle income country, and to compare the stage and surgical treatment of screen-detected and symptomatic breast cancer. A retrospective review of 2510 mammograms performed from Jan to Dec 2010 in a tertiary medical centre is carried out. The three groups identified are the routine (opportunistic) screening group, the targeted (high risk) screening group and the diagnostic group. The performance indicators of each group is calculated, and stage at presentation and treatment between the screening and diagnostic group is analyzed. The cancer detection rate in the opportunistic screening group, targeted screening group, and the symptomatic group is 0.5 %, 1.25 % and 26 % respectively. The proportion of ductal carcinoma in situ is 23.1 % in the two screening groups compared to only 2.5 % in the diagnostic group. Among the opportunistic screening group, the cancer detection rate was 0.2 % in women below 50 years old compared to 0.65 % in women 50 years and above. The performance indicators are within international standards. Early-staged breast cancer (Stage 0-2) were 84.6 % in the screening groups compared to 61.1 % in the diagnostic group. | Indoleamine 2,3 dioxygenase (IDO) degrades the essential amino acid tryptophan and has been shown to minimize rejection in animal models of renal transplantation. Ischemia-reperfusion injury (IRI) is unavoidable in renal transplantation and correlates with shorter graft survival times. Despite its favorable effects on rejection, there is evidence that IDO may facilitate renal IRI. Differentiating the negative impact of IDO on IRI from its pro-tolerant effects in allograft rejection is of clinical relevance. In these studies we hypothesized that constitutive IDO activity may influence renal genes associated with recovery from IRI, and that IDO inhibition may unmask these effects. We examined the renal transcriptome in a rat model of IRI with and without IDO inhibition with 1-methyl-d-tryptophan (1-MT), and assessed for alterations in the gene expression signature. These studies demonstrated that during recovery from renal IRI, pre-treatment with 1-MT alleviated alterations in 105 coding sequences associated with IRI, and in turn triggered new changes in 66 non-coding transcripts, the majority of which were represented by small nucleolar RNA. |
Does aeromonas piscicola AH-3 express an extracellular collagenase with cytotoxic properties? | The aim of this study was to investigate the presence and the phenotypic expression of a gene coding for a putative collagenase. This gene (AHA_0517) was identified in Aeromonas hydrophila ATCC 7966 genome and named colAh. We constructed and characterized an Aeromonas piscicola AH-3::colAh knockout mutant. Collagenolytic activity of the wild-type and mutant strains was determined, demonstrating that colAh encodes for a collagenase. ColAh-collagen interaction was assayed by Far-Western blot, and cytopathic effects were investigated in Vero cells. We demonstrated that ColAh is a gluzincin metallopeptidase (approx. 100 kDa), able to cleave and physically interact with collagen, that contributes for Aeromonas collagenolytic activity and cytotoxicity. ColAh possess the consensus HEXXH sequence and a glutamic acid as the third zinc binding positioned downstream the HEXXH motif, but has low sequence similarity and distinct domain architecture to the well-known clostridial collagenases. In addition, these results highlight the importance of exploring new microbial collagenases that may have significant relevance for the health and biotechnological industries. | To investigate the pattern of perfusion abnormalities in ictal and interictal brain perfusion SPECT images (BSI) from patients with temporal lobe epilepsy (TLE). It was acquired interictal and ictal BSI from 24 patients with refractory TLE. BSIs were analyzed by visual inspection and statistical parametric mapping (SPM2). Statistical analysis compared the patients group to a control group of 50 volunteers. The images from patients with left-TLE were left-right flipped. It was not observed significant perfusional differences in interictal scans with SPM. Ictal BSI in SPM analysis revealed hyperperfusion within ipsilateral temporal lobe (epileptogenic focus) and also contralateral parieto-occipital region, ipsilateral posterior cingulate gyrus, occipital lobes and ipsilateral basal ganglia. Ictal BSI also showed areas of hypoperfusion. |
Is electronic endoscope insertion into a thoracic drainage tube a new technique in the treatment and diagnosis of pleural diseases? | Pleural disease remains a commonly encountered clinical problem for both physician and surgeon. This study describes a new way to better diagnose and treat pleural diseases (hemothorax, empyema, and pleural effusion) using an electronic endoscope (gastroscope or bronchoscope). We conducted a retrospective study of the use of an electronic endoscope in the treatment and diagnosis of pleural diseases. From November 2006 to February 2008, a total of 17 patients (3 women, 14 men; mean age = 41.8 years; range = 18-62 years) underwent procedures for thoracic empyema (13 patients), traumatic clotted hemothorax (3 patients), and undiagnosed pleural effusion (1 patient). The electronic endoscope was inserted via the thoracic drainage tube for the treatment or diagnosis of pleural diseases after regular treatments, including thoracentesis, tube thoracostomy, and biopsy, failed. All patients were cured and discharged from hospital and were followed up for 6 months. The patients recovered well and there was no recurrence. | We investigated parent-of-origin and allele-specific expression effects on obesity and hepatic gene expression in reciprocal crosses between the Berlin Fat Mouse Inbred line (BFMI) and C57Bl/6NCrl (B6N). We found that F1-males with a BFMI mother developed 1.8 times more fat mass on a high fat diet at 10 weeks than F1-males of a BFMI father. The phenotype was detectable from six weeks on and was preserved after cross-fostering. RNA-seq data of liver provided evidence for higher biosynthesis and elongation of fatty acids (p = 0.00635) in obese male offspring of a BFMI mother versus lean offspring of a BFMI father. Furthermore, fatty acid degradation (p = 0.00198) and the peroxisome pathway were impaired (p = 0.00094). The circadian rhythm was affected as well (p = 0.00087). Among the highest up-regulated protein coding genes in obese males were Acot4 (1.82 fold, p = 0.022), Cyp4a10 (1.35 fold, p = 0.026) and Cyp4a14 (1.32 fold, p = 0.012), which hydroxylize fatty acids and which are known to be increased in liver steatosis. Obese males showed lower expression of the genetically imprinted and paternally expressed 3 (Peg3) gene (0.31 fold, p = 0.046) and higher expression of the androgen receptor (Ar) gene (2.38 fold, p = 0.068). Allelic imbalance was found for expression of ATP-binding cassette transporter gene Abca8b. Several of the differentially expressed genes contain estrogen response elements. |
Do microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion? | 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). | While the incidence of inflammatory bowel disease (IBD) among African-Americans (AAs) is increasing, there is limited understanding of phenotypic differences and outcomes by race. To describe disease characteristics of AA patients compared to Caucasian (Ca) patients in a tertiary care population. We performed a cross-sectional review of the IBD registry at the University of Chicago from January 2008 to January 2013. Data regarding race, phenotype, disease onset, disease duration, medical therapy, and surgical treatment were abstracted from the database, then compared via Pearson's chi-square analysis, Kruskal-Wallis analysis, and logistic regression with a significance level of p < 0.05. A total of 1,235 patients with Crohn's disease (CD) and 541 patients with ulcerative colitis (UC) included 108 AA CD patients and 28 AA UC patients. AA CD patients had an increased rate of IBD-related arthralgias (36.5 vs. 23.9 %, p < 0.01) and surgery (p < 0.01), less ileal involvement (57.8 vs. 71.0 %, p < 0.01), and no differences for other extraintestinal manifestations or disease locations compared to Ca CD patients. AA UC patients were older at diagnosis, had an increased rate of arthralgias (28.6 vs. 14.6 %, p = 0.047) and ankylosing spondylitis/sacroiliitis (7.1 vs. 1.6 %, p = 0.035), with no differences for disease extent or rate of IBD-related surgeries compared to Ca UC patients. There were no differences in medication usage by race for CD and UC patients. |
Does total atrial conduction time evaluated with tissue Doppler imaging increase in hypertensive patients with hyperuricemia? | Serum uric acid (SUA) is an independent predictor of cardiovascular events in patients with hypertension. Total atrial conduction time (TACT) is a novel echocardiographic parameter used to identify the presence of electrical and structural atrial remodeling. We hypothesized that elevated SUA levels may be associated with prolonged TACT. A total of 50 consecutive hyperuricemic (defined as SUA>7 mg/dl for men and >6.0 mg/dl for women) patients who had hypertension were included in the study. A total of 42 normouricemic patients were also recruited consecutively as the control group. All patients were evaluated by two-dimensional echocardiography and TACT was estimated by measuring the time delay between the onset of the P-wave of ECG and peak A'-wave on the tissue Doppler imaging (TDI) of the left atrial lateral wall (PA-TDI duration). There were no significant differences between the two groups according to age, sex, left ventricular systolic function, left atrial diameter, and systolic and diastolic blood pressure values. PA-TDI duration was found to be significantly increased in the hyperuricemic group (112.3±14.7 vs. 92±12.7 ms; P<0.001) and positively correlated with the mean value of SUA levels (r=0.48, P<0.001). | The clinical significance of chemokine receptor CCR7 expression in pancreatic ductal cancer was investigated. Immunohistochemical staining of 89 pancreatic cancers treated macroscopically with curative resection without hematogenous metastases or peritoneal dissemination were analyzed in association with clinicopathological data. The positivity of CCR7 in pancreatic cancer was 32.6% (29/89). A significant correlation was detected between CCR7-positive expression and lymph node metastasis. Patients with CCR7-positive tumors had significantly shorter survival times than those with CCR7-negative tumors (median, 12.8 vs. 21.9 months, respectively; p = 0.0039). CCR7 expression was an independent prognostic factor (hazard ratio, 1.949; p = 0.0364) by multivariate survival analysis; however, it was not an indicator for any particular site of recurrence. |
Does the reversal of amphetamine-induced locomotor activation by a selective neurotensin-1 receptor agonist exhibit tolerance? | Neurotensin-1 (NT1) receptor agonists have been proposed as putative antipsychotic drugs. Recently, brain-penetrating NT analogs produced by stability-enhancing modification of the smallest NT fragment, NT(8-13), have demonstrated antipsychotic-like efficacy after acute systemic injection in several preclinical animal tests predictive for antipsychotic efficacy. However, the evidence regarding the persistence versus tolerance of these effects after repeated administration is ambiguous. Previous studies have used compounds that nonselectively activated both NT1 and NT2 receptors or used continuous slow, central infusion of doses rather than daily acute administration, both factors which may have contributed to the ambiguity in the literature regarding the emergence of tolerance. To determine if tolerance develops to the antipsychotic-like effects of NT1 receptor agonists, we investigated the effects of subchronic daily systemic administration of PD149163, a brain-penetrating NT analog with selectivity for the NT1 receptor, on amphetamine-induced locomotor activation, a classic preclinical test of antipsychotic efficacy. Sprague-Dawley rats were pretreated with eight consecutive daily subcutaneous (SC) injections of PD149163 or saline. On the ninth day, rats received a pair of SC injections consisting of PD149163 or saline, followed by amphetamine (0.5 mg/kg) or saline. Locomotor activity was then measured in photobeam-equipped cages. The results indicated that repeated daily administration of PD149163 was able to antagonize amphetamine's locomotor-activating effect comparable to that of the first dose, despite that repeated administration of PD149163 produced an increase in baseline locomotor activity not seen after the first dose. | To study E2F3a expression and its clinical significance in children with acute lymphoblastic leukemia (ALL). We quantified E2F3a expression at diagnosis in 148 children with ALL by real-time PCR. In the test cohort (n = 48), receiver operating characteristic (ROC) curve was used to find the best cut-off point to divide the patients into E2F3a low- and high-expression groups. The prognostic significance of E2F3a expression was investigated in the test cohort and confirmed in the validation cohort (n = 100). The correlations of E2F3a expression with the clinical features and treatment outcome of these patients were analyzed. ROC curve analysis indicated that the best cut-off point of E2F3a expression was 0.3780. In the test cohort, leukemia-free survival (LFS) and event-free survival (EFS) of the low-expression group were lower than those of the high-expression group (log rank: P = 0.026 for both). This finding was verified in the validation cohort. LFS, EFS, and overall survival were also lower in the low-expression group than in the high-expression group (log rank, P = 0.015, 0.008, and 0.002 respectively). E2F3a low expression was correlated with the existence of BCR-ABL fusion. An algorithm composed of E2F3a expression and minimal residual disease (MRD) could predict relapse or induction failure more precisely than current risk stratification. These results were still significant in the ALL patients without BCR-ABL fusion. |
Does negative pressure wound therapy decrease mortality in a murine model of burn-wound sepsis involving Pseudomonas aeruginosa infection? | The colonization of burn wounds by Pseudomonas aeruginosa can lead to septic shock, organ injuries, and high mortality rates. We hypothesized that negative pressure wound therapy (NPWT) would decrease invasion and proliferation of P. aeruginosa within the burn wound and reduce mortality. Thermal injuries were induced in anesthetized mice, and P. aeruginosa was applied to the wound surface for 24 h. After removing the burn eschar and debridement, the animals were subjected to either NPWT or wet-to-dry (WTD) treatment protocols. The bacterial loads on the wound surface were assessed during 7 d of treatment, as were the concentrations of inflammatory cytokines in the peripheral blood samples. Survival was monitored daily for 14 d after burn induction. Finally, samples of wounded skin, lung, liver, and kidney were collected and subjected to histopathological examination. Applying P. aeruginosa to the burn wound surface led to sepsis. During early stages of treatment, NPWT reduced the mortality of the septic animals and levels of P. aeruginosa within the burn wound compared with WTD-treated animals. Circulating levels of cytokines and cytoarchitectural abnormalities were also significantly reduced via NPWT. | To study the possible association of catechol-O-methyltransferase (COMT) Val158Met polymorphism with multiple and solitary uterine leiomyomas (ULs) and to check whether the COMT Val/Val genotype is associated with MED12 exon 2 mutations in fibroids. The COMT Val158Met allele and genotype frequencies were compared between age-matched women with ULs (n=104) and controls (n=59). Patients with UL were subcategorised by diagnosis of solitary (n=59) or multiple (n=45) fibroids and by the presence of somatic MED12 exon 2 mutations in at least one fibroid (n=32) or in neither fibroid (n=26). The association of COMT Val/Val genotype with the presence of any ULs, solitary/multiple ULs and ULs positive/negative for MED12 exon 2 mutations was evaluated by χ The COMT Val/Val genotype frequency did not differ between the patients with UL and the controls (28.8% vs 18.6%, p=0.149, OR 1.77; CI 0.81 to 3.86). However, it was significantly higher in the patients who had multiple UL compared with the solitary UL (40% vs 20.3%, p=0.028, OR 2.61; CI 1.09 to 6.24) and to the controls (40% vs 18.6%, p=0.016, OR 2.91; CI 1.20 to 7.06). No association of the COMT Val/Val genotype with UL-specific MED12 exon 2 mutations was found (p=0.662, OR 0.77; CI 0.23 to 2.53). |
Does sepsis impair microvascular autoregulation and delays capillary response within hypoxic capillaries? | The microcirculation supplies oxygen (O2) and nutrients to all cells with the red blood cell (RBC) acting as both a deliverer and sensor of O2. In sepsis, a proinflammatory disease with microvascular complications, small blood vessel alterations are associated with multi-organ dysfunction and poor septic patient outcome. We hypothesized that microvascular autoregulation-existing at three levels: over the entire capillary network, within a capillary and within the erythrocyte-was impaired during onset of sepsis. This study had three objectives: 1) measure capillary response time within hypoxic capillaries, 2) test the null hypothesis that RBC O2-dependent adenosine triphosphate (ATP) efflux was not altered by sepsis and 3) develop a framework of a pathophysiological model. This was an animal study, comparing sepsis with control, set in a university laboratory. Acute hypotensive sepsis was studied using cecal ligation and perforation (CLP) with a 6-hour end-point. Rat hindlimb skeletal muscle microcirculation was imaged, and capillary RBC supply rate (SR = RBC/s), RBC hemoglobin O2 saturation (SO2) and O2 supply rate (qO2 = pLO2/s) were quantified. Arterial NOx (nitrite + nitrate) and RBC O2-dependent ATP efflux were measured using a nitric oxide (NO) analyzer and gas exchanger, respectively. Sepsis increased capillary stopped-flow (p = 0.001) and increased plasma lactate (p < 0.001). Increased plasma NOx (p < 0.001) was related to increased capillary RBC supply rate (p = 0.027). Analysis of 30-second SR-SO2-qO2 profiles revealed a shift towards decreased (p < 0.05) O2 supply rates in some capillaries. Moreover, we detected a three- to fourfold increase (p < 0.05) in capillary response time within hypoxic capillaries (capillary flow states where RBC SO2 < 20 %). Additionally, sepsis decreased the erythrocyte's ability to respond to hypoxic environments, as normalized RBC O2-dependent ATP efflux decreased by 62.5 % (p < 0.001). | To test the relationships among particular motives for smoking cessation, stage of readiness to quit (preparation or contemplation), and sociodemographic characteristics. A cross-sectional study to examine attitudes toward and use of health promotion at the worksite, using a self-administered questionnaire. Two German metal companies. Of 1641 responding employees (response rate 65% in company A and 44% in company B), 360 smokers who intended to quit immediately (n = 105) or in the near future (n = 255) were analyzed. The questionnaire comprised of sociodemographic characteristics, smoking behavior, smoking history, readiness to quit smoking, motives to quit, such as coworkers' complaints and health-related or financial concerns. Chi-squared tests and multiple logistic regression analyses were performed. Health-related reasons (94%) predominated financial (27%) or image-related (14%) reasons for smoking cessation. Participants in the cessation preparation group were more likely to report an awareness of being addicted (79.6% vs. 58.2%; p < .001) and the negative public image (22.5% vs. 11.6%; p < .01) as reasons for quitting compared with those in the contemplation group. In multivariable regression models, the motives for smoking cessation, including reduced performance, family's and coworkers' complaints, pregnancy/children, and negative public image, but not health-related and financial concerns, differed significantly by gender, age, marital status, education, and occupational status. |
Is neonatal interleukin-12 capacity associated with variations in allergen-specific immune responses in the neonatal and postnatal periods? | A reduced capacity of antigen presenting cells (APC) to provide pro-T helper 1 (Th1) signals, such as IL-12, to T cells during early life may be implicated in the development of T helper 2 (Th2)-mediated allergic disease. In this study we examined the relationships between the capacity for IL-12 responses in the neonatal period and atopic risk (family allergy), in vitro T cell responses to allergens, and the subsequent development of allergic disease at 6 years. The capacity of circulating neonatal (and maternal) APC to produce IL-12 p70 in response to LPS (and IFN-gamma) stimulation was assessed in a group of 60 children with previously well-characterized immune responses to allergens and atopic outcomes. The IL-12 responses were compared with allergen-induced lymphoproliferation (to house dust mite (HDM) ovalbumin (OVA), cat and beta-lactoglobulin (BLG)) and IL-13 and IFN-gamma cytokine responses (to OVA, HDM and phytohaemaglutinin (PHA)) in the neonatal and postnatal periods. IL-12 responses were also compared according to atopic risk and atopic outcomes (doctor-diagnosed asthma, eczema, food allergies and sensitization as evidenced by skin prick testing) at 6 years clinical follow-up. Maternal peripheral blood mononuclear cells (PBMC) synthesized significantly greater amounts of IL-12 than neonatal PBMC, though within maternal-infant pairs IL-12 responses were significantly correlated (r = 0.4, P = 0.019). Moreover, neonatal IL-12 responses were positively correlated with neonatal allergen proliferation for HDM (r = 0.6, P < 0.0001), OVA (r = 0.55, P < 0.0001), cat (r = 0.5, P = 0.003) and BLG (r = 0.55, P = 0.001), but negatively correlated with neonatal IL-13 responses to both allergens tested (HDM: r = - 0.4, P = 0.03 and OVA: r = - 0.5, P = 0.001). Both neonatal and maternal IL-12 responses were positively correlated with postnatal IFN-gamma responses to HDM at 12, 18 and 24 months of age (responses after age of 2 years were not assessed). There was no relationship between atopic risk and IL-12 capacity in the neonatal period, but there was a (non-significant) trend for neonatal IL-12 responses to be lower in the high-risk children who developed clinical allergy at 6 years (compared with the low risk group) although the number in this analysis was small. | Arterial stiffness is used as an index of arteriosclerosis. The goal of this study was to clarify whether increased arterial stiffness, evaluated by measuring the brachial-ankle pulse wave velocity (baPWV), is a risk factor for the prognosis of heart failure (HF) patients. After examination of the baPWV, as well as the levels of neurohumoral factors, the 72 enrolled HF patients were followed up for a survival study, which had a primary endpoint of re-admission because of HF. The secondary endpoint was cardiac death. Results of Cox proportional hazards modeling revealed that baPWV, systolic blood pressure (BP) and brain natriuretic peptide level were factors that affected survival (P<0.05). The patients were divided into 2 groups according to the cutoff baPWV value (1,750 cm/s). Although hemodynamic factors were similar between the groups, the high-baPWV group had a lower event-free survival rate for the primary and secondary endpoints than the low-baPWV group (P<0.05). BP at re-admission was higher in the high-baPWV group (174+/-30 mmHg) than in the low-baPWV group (121+/-33 mmHg, P<0.01). |
Is ligand-dependent Notch signaling involved in tumor initiation and tumor maintenance in pancreatic cancer? | Aberrant activation of the Notch signaling pathway is commonly observed in human pancreatic cancer, although the mechanism(s) for this activation has not been elucidated. A panel of 20 human pancreatic cancer cell lines was profiled for the expression of Notch pathway-related ligands, receptors, and target genes. Disruption of intracellular Notch signaling, either genetically by RNA interference targeting NOTCH1 or pharmacologically by means of the gamma-secretase inhibitor GSI-18, was used for assessing requirement of Notch signaling in pancreatic cancer initiation and maintenance. Striking overexpression of Notch ligand transcripts was detectable in the vast majority of pancreatic cancer cell lines, most prominently JAGGED2 (18 of 20 cases, 90%) and DLL4 (10 of 20 cases, 50%). In two cell lines, genomic amplification of the DLL3 locus was observed, mirrored by overexpression of DLL3 transcripts. In contrast, coding region mutations of NOTCH1 or NOTCH2 were not observed. Genetic and pharmacologic inhibition of Notch signaling mitigated anchorage-independent growth in pancreatic cancer cells, confirming that sustained Notch activation is a requirement for pancreatic cancer maintenance. Further, transient pretreatment of pancreatic cancer cells with GSI-18 resulted in depletion in the proportion of tumor-initiating aldehyde dehydrogenase-expressing subpopulation and was associated with inhibition of colony formation in vitro and xenograft engraftment in vivo, underscoring a requirement for the Notch-dependent aldehyde dehydrogenase-expressing cells in pancreatic cancer initiation. | Polymorphonuclear leukocytes contain a large number of enzymes and bactericidal proteins stored in granules. Neutrophil activation induces degranulation and immediate release of these bioactive substances, including human neutrophil elastase (HNE) also known as elastase-2 (ELA2), which may contaminate whole blood units and blood components. The HNE concentration was determined in the supernatants of blood components with a commercial enzyme-linked immunosorbent assay (ELISA). The effect of leukocyte depletion and storage was evaluated by testing whole blood, buffy-coat-reduced, and leukocyte-depleted red cell units. Buffy-coat-derived platelets and plasma were also tested. HNE concentrations at day 1 were about 50 microg/l in all types of red cell components with the exception of leukocyte-depleted red cells (<0.26 microg/l). In leukocyte-depleted red cells, platelets and plasma, no significant increase was observed during storage. In whole-blood units and buffy-coat-reduced red cells, the HNE concentrations increased steadily and often exceeded 1,000 microg/l when the units expired. |
Are lactoferrin Levels in Tears Increased by the Topical Application of Diadenosine Tetraphosphate? | This study was undertaken to determine the effect of the topical application of diadenosine tetraphosphate on lactoferrin levels in rabbit tears. Diadenosine tetraphosphate was topically instilled in a single-dose, tear samples were collected by micropipette and lactoferrin was measured by Enzyme-Linked ImmunoSorbent Assay (ELISA). The concentration of lactoferrin in rabbit tears was significantly increased 1 h after diadenosine tetraphosphate application, remaining elevated for 3 h more. This effect was blocked by P2 receptors antagonists. | Epigenetic aberrations play a central role in the pathophysiology of acute myeloid leukemia (AML). It has been shown that molecular signatures based on DNA-methylation (DNAm) patterns can be used for classification of the disease. In this study, we followed the hypothesis that DNAm at a single CpG site might support risk stratification in AML. Using DNAm profiles of 194 patients from The Cancer Genome Atlas (TCGA), we identified a CpG site in complement component 1 subcomponent R (C1R) as best suited biomarker: patients with higher methylation at this CpG site (>27 % DNAm) reveal significantly longer overall survival (53 versus 11 months; P < 0.0001). This finding was validated in an independent set of 62 DNAm profiles of cytogenetically normal AML patients (P = 0.009) and with a region-specific pyrosequencing assay in 84 AML samples (P = 0.012). DNAm of C1R correlated with genomic DNAm and gene expression patterns, whereas there was only moderate association with gene expression levels of C1R. These results indicate that DNAm of C1R is a biomarker reflecting chromatin reorganization rather than being of pathophysiological relevance per se. Notably, DNAm of C1R was associated with occurrence of specific genomic mutations that are traditionally used for risk stratification in AML. Furthermore, DNAm of C1R correlates also with overall survival in several other types of cancer, but the prognostic relevance was less pronounced than in AML. |
Do associations of Heart Rate With Inflammatory Markers Are Modulated by Gender and Obesity in Older Adults? | Faster resting heart rate (HR), which is associated with inflammation and elevated cortisol levels, is a risk factor for excess cardiovascular morbidity and mortality. Obesity is associated with increased cardiovascular morbidity and mortality, inflammation, and elevated cortisol levels. The aim of the present study was to evaluate the interaction of Body Mass Index (BMI) with inflammation and cortisol in modulating HR in older subjects. We analyzed data of 895 participants aged 65+ enrolled in the "InCHIANTI" study, in sinus rhythm, and not taking beta blockers or digoxin. Linear regression was performed to assess the adjusted association between HR, IL-6, and cortisol levels. The model was also analyzed stratifying for BMI tertiles. Logistic regression was adopted for evaluating the association of HR exceeding the mean value with Il-6 and serum cortisol. According to multivariable linear regression, IL-6 and cortisol levels were associated with HR (B = 1.42, 95% CI = 0.43-2.42; p = .005 and B = .34, 95% CI = 0.17-.51; p < .0001, respectively). The association was significant only among women in the highest BMI tertile (B = 4.16, 95% CI = 1.40-6.91; p = .003 for IL-6 and B = .57, 95% CI = 0.14-1.01; p = .010 for cortisol). Logistic regression confirmed that IL-6 and cortisol levels were associated with HR above the mean value in the highest BMI tertile (OR = 2.13, 95% CI = 1.15-3.97; p = .009 and OR = 1.14, 95% CI = 1.03-1.25; p = .009, respectively). | Cytogenetic aberrations are of prognostic significance in childhood acute lymphoblastic leukaemias and a high detection rate could improve the biological understanding and classification of these diseases. Bone-marrow samples from 92 children with acute lymphoblastic leukaemia were studied by high-resolution comparative genomic hybridisation (HRCGH) using dynamic standard reference intervals that enhance both specificity and sensitivity in the detection of aberrations. In 80 patients (87%) HRCGH revealed a total of 405 aberrations, mostly whole chromosome gains (n = 265) and partial losses (n = 80). The 25 leukaemias with a gain of more than five whole chromosomes by HRCGH harboured only 7% of all losses. With G-band karyotyping 59 patients (64%) had aberrations. HRCGH revealed more aberrations per patient than did G-band karyotyping (median: 3 vs. 1, P = 0.005), revealed aberrations in 27 of the 34 patients for whom the G-band karyotyping failed or was found to be normal, and specifically revealed more 9p losses (21% vs. 5%, P < 0.005), 12p losses (12% vs. 2%, P < 0.05) and 17q gains (11% vs. 1%, P < 0.01). Compared to the present study, the frequency of patients with aberrant karyotypes was significantly lower in previous conventional CGH studies (64% vs. 87%, P < 0.0001), as was the rate of partial aberrations per patient (1.1% vs. 1.7, P < 0.001), particularly with fewer 6q losses, 9p losses and 17q gains detected. |
Does long-term NSAID treatment directly decrease COX-2 and mPGES-1 production in the articular cartilage of patients with osteoarthritis? | To simultaneously study the effect of a selective cyclooxygenase-2 (COX-2) inhibitor and that of a classic non-steroidal anti-inflammatory drug (NSAID) on the expression of pro-inflammatory genes in the cartilage of patients with severe knee osteoarthritis (OA) and in cultured human OA chondrocytes. A 3-month clinical trial was carried out on 30 patients with severe knee OA scheduled for knee replacement surgery. Patients were randomized into two groups: patients treated with celecoxib (CBX) and patients treated with aceclofenac (ACF). OA patients who did not want to be treated served as the control group. After surgery, cartilage was processed for molecular biology studies. We also employed cultured chondrocytes from different OA patients to examine NSAID effects on pro-inflammatory gene expression in cells stimulated with interleukin (IL)-1beta. Both CBX and ACF inhibited COX-2, microsomal prostaglandin E synthase-1 (mPGES-1) and inducible nitric oxide synthase (iNOS) synthesis in the articular cartilage of OA patients. In cultured chondrocytes, both NSAID decreased COX-2 and mPGES-1 synthesis and prostaglandin E2 (PGE2) release induced by IL-1beta, while no effect was observed on nitric oxide or iNOS synthesis. In OA patients, only CBX decreased tumor necrosis factor alpha and IL-1beta expression in the cartilage, while both NSAID diminished IL-1beta induced cytokine synthesis in cultured OA chondrocytes. | Left ventricular (LV) postero-lateral scar and total scar burden are factors responsible for a poor response to cardiac resynchronization therapy (CRT). Contrast-enhanced magnetic resonance imaging (CMR) and (99m)Tc-2-methoxy isobutyl isonitrile single photon emission computed tomography (SPECT) perfusion imaging are widely used to detect myocardial scar tissue; however, their ability to detect regional scars and predict a positive response to CRT has not been fully evaluated. CMR and SPECT were performed in 17 patients with dilated cardiomyopathy (DCM) and seven patients with ischemic cardiomyopathy (ICM) before CRT. All images were scored, using a 17-segment model. To analyze the LV scar regions by CMR, we assessed the transmural delayed enhancement extent as the transmural score in each segment (0 = no scar, 4 = transmural scar). Similarly, a perfusion defect score was assigned to each segment by SPECT (0 = normal uptake, 4 = defect). By both SPECT and CMR imaging, the total scar score was significantly higher in the ICM than in the DCM group. An LV postero-lateral wall scar region was detected using both imaging modes. By SPECT imaging, the percentage of regional scar score in the LV inferior wall was significantly higher in the DCM than in the ICM group. |
Does [ Analysis on 2011 quality control result on aerobic plate count of microbiology laboratories in China ]? | To test the aerobic plate count examining capability of microbiology laboratories, to ensure the accuracy and comparability of quantitative bacteria examination results, and to improve the quality of monitoring. The 4 different concentration aerobic plate count piece samples were prepared and noted as I, II, III and IV. After homogeneity and stability tests, the samples were delivered to monitoring institutions. The results of I, II, III samples were logarithmic transformed, and evaluated with Z-score method using the robust average and standard deviation. The results of IV samples were evaluated as "satisfactory" when reported as < 10 CFU/piece or as "not satisfactory" otherwise. Pearson χ2 test was used to analyze the ratio results. 309 monitoring institutions, which was 99.04% of the total number, reported their results. 271 institutions reported a satisfactory result, and the satisfactory rate was 87.70%. There was no statistical difference in satisfactory rates of I, II and III samples which were 81.52%, 88.30% and 91.40% respectively. The satisfactory rate of IV samples was 93.33%. There was no statistical difference in satisfactory rates between provincial and municipal CDC. | Although diverse functions of angiopoietin-2 (Ang2) have been revealed, little is known about upstream signaling molecules regulating Ang2 exocytosis. We therefore investigated the mechanism of Ang2 exocytosis in human blood and lymphatic endothelial cells (BECs and LECs) by stimulation with sphingosine-1-phosphate (S1P). By immunostaining and ELISA analyses using our newly developed human Ang2-specific antibodies, Ang2 exocytosis from human endothelial cells was examined. Both exogenous and endogenous S1P trigger rapid Ang2 exocytosis in time- and dose-dependent manners. Intriguingly, S1P-induced Ang2 exocytosis is higher in LECs than BECs. These effects of S1P are mainly mediated by the endothelial differentiation gene receptor 1, which subsequently activates its downstream phospholipase C and intracellular calcium mobilization to trigger Ang2 exocytosis. Consistently, S1P also dramatically stimulates Ang2 exocytosis from the ECs of ex vivo-incubated blood vessels. |
Is diurnal rhythmicity in glucose uptake mediated by temporal periodicity in the expression of the sodium-glucose cotransporter ( SGLT1 )? | Intestinal transport exhibits distinct diurnal rhythmicity. Understanding the mechanisms behind this may reveal new therapeutic strategies to modulate intestinal function in disease states such as diabetes and obesity, as well as short bowel syndrome. Although diurnal rhythms have been amply documented for several intestinal transporters, the complexity of transepithelial transport has precluded definitive attribution of rhythmicity in glucose uptake to a single transporter. To address this gap, we assessed temporal changes in glucose transport mediated by the Na(+)/glucose cotransporter SGLT1. SGLT1 expression was assessed at 4 times during the day: ZT3, ZT9, ZT15, and ZT21 (ZT, Zeitgeber time; lights on at ZT0; n = 8/ time). SGLT1 activity, which is defined as glucose uptake sensitive to the specific SGLT1 inhibitor phloridzin, was measured in everted intestinal sleeves. Changes in Sglt1 expression were assessed by real-time polymerase chain reaction (PCR) and immunoblotting. Glucose uptake was significantly higher at ZT15 in jejunum (P < 0.05 vs ZT3). Phloridzin significantly reduced glucose uptake and completely abolished its rhythmicity. Sglt1 mRNA levels were significantly greater at ZT9 and ZT15 in jejunum and ileum, respectively (P < 0.05 vs ZT3), whereas SGLT1 protein levels were significantly greater at ZT15 in jejunum (P < 0.05 vs ZT3). | Due to recent war situation in neighboring country we have witnessed large number of victims with post-traumatic false (pseudo) aneurysms of head and neck in roadside bomb blast victims in Pakistan. Thus through this observational retrospective study we aim to share our experience of managing these patients. 5 years patients' case records, from June 2008-June 2013, were reviewed from the hospital's records. 14 cases of roadside bomb blast victims, developing false aneurysms of major or minor vessels of head and neck, were studied. We excluded the post-traumatic pseudoaneurysms involving other sites and vessels of the body. We observed the mechanism, the duration of presentation, symptoms/signs, vessels involved, complications and the management done. All 14 cases presented with a localized pulsatile swelling with tenderness in the course of a known artery and with an overlying entry site wound from bomb blast sharp nails. Men were affected more as compared to women. All (14) cases had 2-12 weeks of duration between the injury and presentation. Temporal artery (4) was involved in most cases followed by common carotid artery (3). Open surgery was treatment of choice in 12 (85.7%) of cases; however 2 (14.3%) patients had endovascular intervention to correct the pathology. Post-operatively all patients recovered completely, without any major or minor complications. |
Are paternal depressive symptoms during pregnancy related to excessive infant crying? | Excessive infant crying, or infantile colic, is a common and often stress-inducing problem for parents that can ultimately result in child abuse. From previous research it is known that maternal depression is related to excessive crying, but so far little is known about the influence of paternal depression. In a prospective, population-based study, we obtained information on both maternal and paternal depressive symptoms at 20 weeks of pregnancy by using the Brief Symptom Inventory. Parental depressive symptoms were related to excessive crying in 4426 two-month-old infants. The definition of excessive crying was based on the widely used Wessel's criteria (ie, crying >3 hours for >3 days in the past week). After adjustment for depressive symptoms of the mother and relevant confounders, we found a 1.29 (95% confidence interval: 1.09-1.52) higher risk of excessive infant crying per SD of paternal depressive symptoms. | Dynamic contrast-enhanced (DCE) micro-computed tomography (micro-CT) has emerged as a valuable imaging tool to noninvasively obtain quantitative physiological biomarkers of drug effect in preclinical studies of antiangiogenic compounds. In this study, we explored the ability of DCE micro-CT to assess the antiangiogenic treatment response in breast cancer xenografts and correlated the results to the structural vessel response obtained from 3-dimensional (3D) fluorescence ultramicroscopy (UM). Two groups of tumor-bearing mice (KPL-4) underwent DCE micro-CT imaging using a fast preclinical dual-source micro-CT system (TomoScope Synergy Twin, CT Imaging GmbH, Erlangen, Germany). Mice were treated with either a monoclonal antibody against the vascular endothelial growth factor or an unspecific control antibody. Changes in vascular physiology were assessed measuring the mean value of the relative blood volume (rBV) and the permeability-surface area product (PS) in different tumor regions of interest (tumor center, tumor periphery, and total tumor tissue). Parametric maps of rBV were calculated of the tumor volume to assess the intratumoral vascular heterogeneity. Isotropic 3D UM vessel scans were performed from excised tumor tissue, and automated 3D segmentation algorithms were used to determine the microvessel density (MVD), relative vessel volume, and vessel diameters. In addition, the accumulation of coinjected fluorescence-labeled trastuzumab was quantified in the UM tissue scans to obtain an indirect measure of vessel permeability. Results of the DCE micro-CT were compared with corresponding results obtained by ex vivo UM. For validation, DCE micro-CT and UM parameters were compared with conventional histology and tumor volume. Examination of the parametric rBV maps revealed significantly different patterns of intratumoral blood supply between treated and control tumors. Whereas control tumors showed a characteristic vascular rim pattern with considerably elevated rBV values in the tumor periphery, treated tumors showed a widely homogeneous blood supply. Compared with UM, the physiological rBV maps showed excellent agreement with the spatial morphology of the intratumoral vascular architecture. Regional assessment of mean physiological values exhibited a significant decrease in rBV (P < 0.01) and PS (P < 0.05) in the tumor periphery after anti-vascular endothelial growth factor treatment. Structural validation with UM showed a significant reduction in reduction of relative vessel volume (rVV) (P < 0.01) and MVD (P < 0.01) in the corresponding tumor region. The reduction in rBV correlated well with the rVV (R = 0.73 for single values and R = 0.95 for mean values). Spatial maps of antibody penetration showed a significantly reduced antibody accumulation (P < 0.01) in the tumor tissue after treatment and agreed well with the physiological change of PS. Examination of vessel diameters revealed a size-dependent antiangiogenic treatment effect, which showed a significant reduction in MVD (P < 0.001) for vessels with diameters smaller than 25 μm. No treatment effect was observed by tumor volume. |
Does naringin protect against HIV-1 protease inhibitors-induced pancreatic β-cell dysfunction and apoptosis? | The protective effects of grapefruit-derived naringin against HIV-1 Protease Inhibitors (PIs)-associated oxidative damage to pancreatic β-cells and apoptosis were investigated in RIN-5F cells in culture. Cells in culture medium were challenged with 11-25 mM glucose with or without nelfinavir (1-10 μM), saquinavir (1-10 μM) and atazanavir (5-20 μM), respectively for 24 h to determine insulin secretion. The cells were further treated with nelfinavir (10 μM), saquinavir (10 μM), atazanavir (20 μM) with and without naringin or glibenclamide (10 μM) for 24 h to determine insulin secretion, lipid peroxidation, Superoxide Dismutase (SOD) activity, glutathione (GSH) levels, ATP production and caspase-3 and-9 activities, respectively. Glucose-dependent insulin secretion was significantly reduced by PIs in a concentration-dependent manner. Treatment with either naringin or glibenclamide significantly reduced lipid peroxidation, Superoxide Dismutase (SOD) activities and also increased glutathione (GSH) and ATP levels in the cells that were treated with PIs. Furthermore, naringin or glibenclamide significantly reduced caspase-3 and caspase-9 activities in cells that were treated with PIs. | To determine whether frontal white matter diffusion abnormalities can help predict acute executive function impairment after mild traumatic brain injury (mTBI). This study had institutional review board approval, included written informed consent, and complied with HIPAA. Diffusion-tensor imaging and standardized neuropsychologic assessments were performed in 20 patients with mTBI within 2 weeks of injury and 20 matched control subjects. Fractional anisotropy (FA) and mean diffusivity (MD) images (imaging parameters: 3.0 T, 25 directions, b = 1000 sec/mm(2)) were compared by using whole-brain voxelwise analysis. Spearman correlation analyses were performed to evaluate associations between diffusion measures and executive function. Multiple clusters of lower frontal white matter FA, including the dorsolateral prefrontal cortex (DLPFC), were present in patients (P < .005), with several clusters also demonstrating higher MD (P < .005). Patients performed worse on tests of executive function. Lower DLPFC FA was significantly correlated with worse executive function performance in patients (P < .05). |
Is suberoylanilide hydroxamic acid effective in preclinical studies of medulloblastoma? | Suberoylanilide hydroxamic acid (SAHA) has been studied in adult solid and hematologic malignancies. However, little information has been reported on the effects of SAHA on central nervous system (CNS) tumors including medulloblastoma, the most common malignant brain tumor in children. We investigated SAHA in preclinical medulloblastoma models to determine its anti-cancer efficacy as well as its ability to affect intracranial lesions when administered systemically. Tissue culture studies were performed treating primary human fibroblasts, established medulloblastoma cell lines, and primary human medulloblastoma tumors with SAHA. At 10 microM concentration, SAHA had little effect on normal fibroblasts but caused >90% apoptosis in cultured medulloblastoma cells. Primary medulloblastomas from patients were sensitive to SAHA compared to vehicle alone in ex vivo studies. In athymic mice with medulloblastoma xenograft tumors, oral SAHA resulted in apoptosis of tumor tissue and significantly slowed tumor growth. In the ND2:Smo transgenic mouse medulloblastoma model, SAHA treatment caused significant apoptosis in these cerebellar tumors. | C-reactive protein (CRP) elevated in inflammation is associated with atherosclerotic disease. We describe the distribution of CRP and its association with coronary heart disease (CHD) risk factors in a large CHD patient group. This analysis comprises 2,723 male and 256 female CHD patients, included in the Bezafibrate Infarction Prevention (BIP) study. High sensitive CRP levels were determined in frozen plasma samples. CRP distribution, was normalized upon log transformation. Levels among women were higher than in men in the entire group (4.4 vs. 3.5 mg/l) and in each age group. Co-morbidities, smoking, lower education level, and use of cardiovascular drugs, were associated with elevated CRP levels in both sexes. The correlation between CRP and body mass index (BMI), insulin and glucose was stronger among women. The explained variability in CRP level was larger in women (20%) compared to men (13%). Among women, BMI explained 10% of CRP variability, whereas the contribution of each variable among men was significantly smaller. |
Does transcriptomic analysis of wheat near-isogenic lines identify PM19-A1 and A2 as candidates for a major dormancy QTL? | Next-generation sequencing technologies provide new opportunities to identify the genetic components responsible for trait variation. However, in species with large polyploid genomes, such as bread wheat, the ability to rapidly identify genes underlying quantitative trait loci (QTL) remains non-trivial. To overcome this, we introduce a novel pipeline that analyses, by RNA-sequencing, multiple near-isogenic lines segregating for a targeted QTL. We use this approach to characterize a major and widely utilized seed dormancy QTL located on chromosome 4AL. It exploits the power and mapping resolution afforded by large multi-parent mapping populations, whilst reducing complexity by using multi-allelic contrasts at the targeted QTL region. Our approach identifies two adjacent candidate genes within the QTL region belonging to the ABA-induced Wheat Plasma Membrane 19 family. One of them, PM19-A1, is highly expressed during grain maturation in dormant genotypes. The second, PM19-A2, shows changes in sequence causing several amino acid alterations between dormant and non-dormant genotypes. We confirm that PM19 genes are positive regulators of seed dormancy. | This experimental study was undertaken to determine whether pretreatment with statins would enhance myocardial protection and minimize ischemic injury during revascularization of acutely ischemic myocardium. In 20 pigs the second and third diagonal arteries were occluded for 90 minutes, followed by 45 minutes of blood cardioplegic arrest and 180 minutes of reperfusion. Ten pigs received atorvastatin (40 mg orally every day) for 21 days before surgical intervention; 10 others received no statins. Ischemic damage was assessed on the basis of the need for cardioversions for ventricular arrhythmias, regional wall-motion scores (4 = normal to -1 = dyskinesia) were determined by means of 2-dimensional echocardiography, endothelial function was assessed on the basis of bradykinin-induced coronary artery relaxation, and infarct size was calculated by determining the area of necrosis to the area of risk by means of histochemical staining. Results are given as means +/- SE. Statin-treated animals required fewer cardioversions (0.11 +/- 0.01 vs 2.87 +/- 0.20, P =.0001), had improved wall-motion scores (2.81 +/- 0.10 vs 1.52 +/- 0.08, P =.01), had lower infarct size (21% +/- 2% vs 41% +/- 2%, P =.0001), and had more complete coronary artery relaxation (34% +/- 5% vs 8% +/- 4%, P =.01). Total serum cholesterol levels were similar between the groups (62 +/- 5 mg/dL for statin-treated animals vs 68 +/- 5 mg/dL for non-statin-treated animals, P =.30). |
Is combined bile acid therapy more effective on biliary lipids and dissolution rates than monotherapy after gallstone lithotripsy? | Accurate sampling of gallbladder bile for biliary analysis is essential for determining any potential difference between combined bile acid therapy and monotherapy in gallstone patients. In 104 gallstone patients undergoing extracorporeal shock wave lithotripsy with following bile acid therapy [either chenodeoxycholic acid (500 mg/day) and ursodeoxycholic acid (500 mg/day), group I (n = 53), or ursodeoxycholic acid alone (1000 mg/day), group II (n = 51)], bile samples, obtained by direct fine needle puncture of the gallbladder, were investigated for biliary lipids, total biliary protein concentration, and nucleation time before and after 12 months of bile acid therapy. Initially, a negative correlation was found between nucleation time and number of gallstones and between total biliary protein concentration and nucleation time (r = -0.52 and r = -0.49 in group I vs r = -0.56 and r = -0.51 in group II, p < 0.01 in each group). The correlation between total biliary protein concentration and nucleation time was also found after 12 months of bile acid treatment (r = -0.54 in group I vs r = -0.47 in group II, p < 0.01 in each group). In group I, the decrease in cholesterol saturation index, biliary cholesterol, cholic acid, deoxycholic acid, and total protein concentration was more pronounced than in group II (p < 0.01). The same effect was found concerning the prolongation of nucleation time (p < 0.01). Furthermore, dissolution rates were higher in group I compared with group II (80.4 vs 69.0%, p < 0.01). | Globally, heterosexual intercourse is the primary route of HIV-1 (HIV) transmission. It follows that mechanisms that protect against HIV infection are likely operative at the genital mucosa. In HIV-resistant Kenyan sex workers who are highly exposed to HIV infection yet remain uninfected, protection correlates with HIV-specific immune responses and genetic factors. However, these factors do not entirely explain this model of natural immunity to HIV. We hypothesized that protection may be mediated by innate immune proteins in the genital tract of HIV-resistant sex workers. The genital proteome of mucosal secretions from HIV-resistant women was examined using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Cervical lavage samples were collected from 315 HIV-resistant, HIV-uninfected and HIV-infected commercial sex workers. Univariate analysis identified a 6 kDa biomarker of HIV resistance in genital secretions from these women. This protein was identified by tandem mass spectrometry as elafin and was found to be overexpressed in HIV-resistant women compared with HIV-uninfected (P = 0.001) and infected (P = 0.002) women. The elevated levels of elafin/trappin-2 in HIV-resistant women were confirmed using ELISA. The prospective association of elevated cervicovaginal elafin/trappin-2 levels with protection from HIV acquisition was then confirmed in an independent cohort of high-risk female sex workers. |
Does richardson score predict short-term adverse respiratory outcomes in newborns > /=34 weeks gestation? | To develop a model to predict which newborns >/=34 weeks gestation with respiratory distress will die or will require prolonged (>3 days) assisted ventilation. Retrospective cohort study using data from Northern California newborns >/=34 weeks gestation who presented with respiratory distress. We split the cohort into derivation and validation datasets. Bivariate and multivariate data analyses were performed on the derivation dataset. After developing a simple score on the derivation dataset, we applied it to the original as well as to a second validation dataset from Massachusetts. Of 2276 babies who met our initial eligibility criteria, 203 (9.3%) had the primary study outcome (assisted ventilation >3 days or death). A simple score based on gestational age, the lowest PaO 2 /FIO 2 , a variable combining lowest pH and highest PaCO 2 , and the lowest mean arterial blood pressure had excellent performance, with a c-statistic of 0.85 in the derivation dataset, 0.80 in the validation dataset, and 0.80 in the secondary validation dataset. | Human gamma-delta (γδ) T cells are potent effector lymphocytes of innate immunity involved in anti-tumor immune surveillance. However, the Vδ1 γδ T-cell subset targeting multiple myeloma (MM) has not previously been investigated. Vδ1 T cells were purified from peripheral blood mononuclear cells of healthy donors and patients with MM by immunomagnetic sorting and expanded with phytohemagglutinin (PHA) together with interleukin (IL)-2 in the presence of allogeneic feeders. Vδ1 T cells were phenotyped by flow cytometry and used in a 4-h flow cytometric cytotoxicity assay. Cytokine release and blocking studies were performed. Primary myeloma cells were purified from MM patients' bone marrow aspirates. Vδ1 T cells expanded from healthy donors displayed prominent cytotoxicity by specific lysis against patients' CD38 (+) CD138 (+) bone marrow-derived plasma cells. Vδ1 T cells isolated from MM patients showed equally significant killing of myeloma cells as Vδ1 T cells from normal donors. Vδ1 T cells showed similarly potent cytotoxicity against myeloma cell lines U266 and RPMI8226 and plasma cell leukemia ARH77 in a dose-dependent manner. The interferon (IFN)-γ secretion and Vδ1 T-cell cytotoxicity against myeloma cells was mediated in part through the T-cell receptor (TCR) in addition to involvement of Natural killer-G2D molecule (NKG2D), DNAX accessory molecule-1 (DNAM-1), intracellular cell adhesion molecule (ICAM)-1, CD3 and CD2 receptors. In addition, Vδ1 T cells were shown to exert anti-myeloma activity equal to that of Vδ2 T cells. |
Does dietary Protein Intake be Protective Against Loss of Grip Strength Among Older Adults in the Framingham Offspring Cohort? | Age-related decline in muscle strength is an important public health issue for older adults. Dietary protein has been associated with maintenance of muscle mass, yet its relation to muscle strength remains unclear. We determined the association of dietary protein (total, animal, and plant) intake, measured by food frequency questionnaire, with change in grip strength over 6 years in 1,746 men and women from the Framingham Offspring cohort. Mean age at baseline was 58.7 years (range: 29-85), and mean total, animal, and plant protein intakes were 79, 57, and 22 g/d, respectively. Adjusted baseline mean grip strength did not differ across quartiles of energy-adjusted total, animal or protein intake. Greater protein intake, regardless of source, was associated with less decrease in grip strength (all p for trend ≤.05): participants in the lowest quartiles lost 0.17% to 0.27% per year while those in the highest quartiles gained 0.52% to 0.60% per year. In analyses stratified by age, participants aged 60 years or older (n = 646) had similar linear trends on loss of grip strength for total and animal (all p for trend <.03) but not plant protein, while the trends in participants younger than 60 years (n = 896) were not statistically significant. | The inadequacy of effector T-cell response in containment of tubercle bacilli is believed to result in the development of disseminated forms of tuberculosis (TB), such as miliary tuberculosis (MTB). Regulatory T cells (Treg) plausibly play a critical role in the immunopathogenesis of disseminated TB by suppression of effector immune response against Mycobacterium tuberculosis at the pathologic site(s). To understand the role of Treg cells in disseminated tuberculosis, we studied the frequency and function of Treg cells derived from the local disease site specimens (LDSS) of patients with TB pleural effusion and MTB as clinical models of contained and disseminated forms of disease, respectively. To (1) enumerate the frequency of Treg cells in bronchoalveolar lavage (BAL) fluid of patients with MTB and compare with that of peripheral blood, (2) study the role of Treg cells in suppression of local T-cell response, and (3) study the selective recruitment of Treg cells at the local disease site(s). Flow cytometry, reverse transcriptase polymerase chain reaction, and 3-(4,5-dimethylthythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)-based cell proliferation assay. Frequency of Treg cells (CD4(+)CD25(+)FoxP3(+)) was significantly higher in LDSS in MTB along with higher levels of FoxP3 mRNA. Importantly, FoxP3(+) Treg cells obtained from the BAL of patients with MTB predominantly produced IL-10 and could suppress the autologous T-cell proliferation in response to M. tuberculosis antigen. |
Does initial varus displacement of proximal humerus fractures result in similar function but higher complication rates? | To investigate the effect of initial varus or valgus surgical neck alignment on outcomes of patients who sustained proximal humerus fractures treated with open reduction and internal fixation (ORIF). An institutional review board approved database of proximal humerus fractures treated with locked plates was reviewed. Of 185 fractures in the database, 101 fractures were identified and met inclusion criteria. Initial varus displacement was seen in 47 fractures (OTA types 11.A2.2, A3.1, A3.3, B1.2, B2.2, C1.2, C2.2, or C2.3) and initial valgus displacement was observed in 54 fractures (OTA types 11.A2.3, B1.1, C1.1, or C2.1). All patients were treated in a similar manner and examined by the treating physician at standard intervals. Functional outcomes were quantified via the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and physical examination data at 12 months. Radiographs were reviewed for complications of healing. Additionally, complication rate and reoperation rate were investigated. Patients who presented with initial varus displacement had an average age of 59.3 years, while patients in the valgus group had an average age of 62.4 years. Overall, there was no statistically significant difference in age, sex distribution, BMI, fracture parts, screws used, or implant plate type between the two groups. At a minimum 12 months follow up, there was no significant difference in DASH scores between those presenting with varus versus valgus fracture patterns. In addition, no significant differences were seen in final shoulder range of motion in any plane. Overall, 30 patients included in this study developed a complication. A significantly greater number of patients in the initial varus cohort developed complications (40.4%), as compared to 20.3% of patients in the initial valgus cohort (P=0.03). Fourteen patients in this study underwent reoperation. Nine of these patients were in the varus cohort, while 5 were in the valgus cohort (P=0.15). | The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC α1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGCα1 allele [sGCα1 |
Are retinal adaptation responses revealed by global flash multifocal electroretinogram dependent on the degree of myopic refractive error? | There is evidence that the inner retina is involved in eye growth control processes and the development of myopia. We sought to investigate the response dynamics of the inner retina of adult emmetropes and myopes using the global flash multifocal electroretinogram (mfERG) paradigm. Fourteen myopes and 10 emmetropic subjects (mean age: 21.0+/-2.8 years) underwent mfERG testing using VERIS 5.1.5X. The global flash stimulus array consisted of 103-scaled hexagons which flickered according to a pseudorandom binary m-sequence (2(13)-1). The stimulation sequence was modified by inserting three frames, a dark frame, a global (full screen) flash, and another dark frame. The amplitude and implicit time of the two distinct waveform features, an early direct component (DC) and a later induced component (IC) of the first-order kernel were analyzed. Retinal responses were averaged over rings of increasing eccentricity, or into nasal and temporal hemifields. There was a significant correlation between the DC and IC response amplitude and myopic refractive error, i.e., the greater the myopic error, the greater the response amplitude. However, when comparing between the two refractive error groups, DC and IC response amplitudes of emmetropes and myopes were similar, even after compensating for the effect of axial length. There were no significant differences in implicit times of the DC and IC in emmetropes and myopes. | Interleukin-17A is a proinflammatory cytokine known to play a role in host defense and pathologic inflammation in murine models of lung injury. The relationship between interleukin-17A and inflammation in human lung injury is unknown. Our primary objective was to determine whether interleukin-17A levels are associated with alveolar measures of inflammation and injury in patients with acute respiratory distress syndrome. Our secondary objective was to test whether interleukin-17A levels are associated with acute respiratory distress syndrome-related outcomes. Observational study. Six North American medical centers. We studied two groups of patients with acute respiratory distress syndrome: 1) patients previously enrolled in a placebo-controlled clinical trial of omega-3 fatty acids performed at five North American medical centers (n = 86, acute respiratory distress syndrome 1), and 2) patients with systemic inflammatory response syndrome admitted to an ICU who developed acute respiratory distress syndrome (n = 140, acute respiratory distress syndrome 2). In acute respiratory distress syndrome 1, we used paired serum and bronchoalveolar lavage fluid samples obtained within 48 hours of acute respiratory distress syndrome onset, whereas in acute respiratory distress syndrome 2, we used plasma obtained within the first 24 hours of ICU admission. None. We measured circulating interleukin-17A in acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2. We also measured interleukin-17A, neutrophil counts, and total protein in bronchoalveolar lavage fluid from acute respiratory distress syndrome 1. We found that bronchoalveolar lavage interleukin-17A was strongly associated with higher bronchoalveolar lavage percent neutrophils (p < 0.001) and bronchoalveolar lavage total protein (p < 0.01) in acute respiratory distress syndrome1. In both acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2, elevated interleukin-17A was associated with higher Sequential Organ Failure Assessment scores (p < 0.05). |
Do paclitaxel-coated expanded polytetrafluoroethylene haemodialysis grafts inhibit neointimal hyperplasia in porcine model of graft stenosis? | The main pathology of haemodialysis graft stenosis is venous neointimal hyperplasia at graft-venous anastomoses. Neointimal hyperplasia is also observed in cases of coronary artery in-stent restenosis. Paclitaxel is a chemotherapeutic agent used to treat cancer, and has been proven to inhibit neointimal hyperplasia of coronary artery in-stent restenosis. In this study, we examined whether a paclitaxel-coated haemodialysis graft could inhibit neointimal hyperplasia and prevent stenosis. We dip-coated paclitaxel on expanded polytetrafluoroethylene (ePTFE) grafts at a dose density of 0.59 microg/mm(2). In vitro release tests showed an initial paclitaxel burst followed by a long-term slow release. Using ePTFE grafts with (coated group, n = 8) or without a paclitaxel coating (control group, n = 11), we constructed arteriovenous (AV) grafts connecting the common carotid artery and the external jugular vein in Landrace pigs. After excluding seven pigs for technical failure, cross-sections of graft-venous anastomoses obtained 6 weeks after placing the AV grafts were analysed. Percentage luminal stenosis, ratios of intima to media in whole cross-sections, areas of intima in the peri-junctional areas (within 2 mm above and 2 mm below the graft-venous junction), and the mean thickness of intima within venous sides of cross-sections, were 60.5% (range, 41.5-60.7), 13.0 (range, 8.6-20.4), 23.7 mm(2) (range, 10.8-32.1) and 2.1 mm (range, 1.1-3.0), respectively, in the control group, whereas corresponding median values in the coated group were 10.4% (range, 1.0-17.8), 1.0 (range, 0.7-5.1), 1.6 mm(2) (range, 0.2-8.0) and 0.3 mm (range, 0.1-2.2). All parameters were significantly different between the two groups (P<0.05 by Mann-Whitney test). | Corticotropin-releasing hormone receptor 1 (CRH-R1) in the amygdala and the stria terminalis plays an important role in the activation of central stress circuits. Genetic factors may contribute to the hyperresponsiveness of these circuits in irritable bowel syndrome (IBS). To determine if CRH-R1 SNPs are associated with: (1) a diagnosis of IBS, (2) gastrointestinal (GI) symptoms, and (3) acoustic startle response (ASR) to threat, which is mediated by the amygdala via CRH. Three CRH-R1 SNPS (rs110402, rs242924, and rs7209436) were genotyped using salivary DNA from IBS and healthy control subjects (HCs). Eye blink ASR was obtained during safe (no shock), anticipation (abdominal shock may soon occur) and threat (abdominal shock likely) conditions in a subset of subjects. Associations between each SNP with IBS status, clinical traits and ASR were measured. 235 IBS patients (mean age 37.5 yrs, 74% F) and 264 HCs (mean age 32.1 yrs, 70% F) were studied. Of these, 57 IBS and 41 HCs underwent the ASR protocol. The presence of IBS was associated with the major allele for all three CRH-R1 SNPs (p=0.009-0.025). Within IBS, the major allele for all three SNPs (p=0.017-0.065) was associated with GI symptom anxiety scores. Within subjects with at least one copy of the major allele for the CRH-R1 SNPs, IBS had significantly lower ASR compared to HCs during threat conditions (p=0.001-0.002). Within IBS, CRH-R1 SNPs were associated with a graded increase in ASR to threat (p=0.007-0.008). |
Does body weight correlate with mortality in early-stage breast cancer? | Body weight correlates with risk of breast cancer death. A retrospective cohort study using patient medical records, electronic cancer registry data, and archived tissue specimens. A 395-bed, comprehensive community hospital. One thousand three hundred seventy-six women, aged 24 to 81 years, who were diagnosed with breast cancer between January 1, 1988, and December 31, 1995, and for whom complete medical records and adequate tissue specimens existed. Body weight at the time of diagnosis and patient status (ie, alive and free of breast cancer, living with breast cancer, dead of breast cancer, or dead of other cause) at the time of longest follow-up. Additional data collected, including age at diagnosis, menopausal status, tumor size, tumor grade, lymph node status, stage at diagnosis, race, estrogen-receptor (ER) status, and treatment information, were used to create multivariate Cox proportional hazards models to estimate hazard rate (HR) ratios and 95% confidence intervals (CIs) for breast cancer death. We collected ER status from the patients' medical records, when available, and supplemented the information by using immunohistochemical techniques to determine ER status from archived paraffin-embedded tumor blocks. Patients were followed up for a median of 6.8 years after diagnosis. Two hundred forty-six patients died from breast cancer. Among patients with early-stage disease (I and IIA), we observed a dose-response relationship of increasing weight with increasing likelihood of dying of breast cancer. Compared with women in the lowest category of weight (< 133 lb [60 kg] at diagnosis), women in the highest category (> or = 175 lb [79 kg]) experienced a 2.5-fold increased risk of dying from breast cancer (HR ratio, 2.54 [95% CI, 1.08-6.00]; trend P = .02). Women with ER-negative cancer experienced an approximately 2-fold higher risk of dying from breast cancer compared with women with ER-positive cancer, regardless of stage at diagnosis. Women in the upper 50th percentile of weight with early-stage disease and with ER-negative tumors had a nearly 5-fold increased risk of dying (HR ratio, 4.99 [95% CI, 2.17-11.48]; P for interaction = .10) compared with women in the lower 50th percentile of weight and ER-positive tumors. The results were similar for body mass index, a measure of obesity in which weight is adjusted for height. | We investigated the pharmacological effect of TRPV1 antagonists in anesthetized rodent models of bladder function. The TRPV1 antagonists JNJ17203212 and JYL1421 were evaluated in the anesthetized rat volume induced micturition reflex model. JNJ17203212 was further evaluated in this model in capsaicin (Sigma) desensitized rats, and in rat capsaicin and mouse citric acid models of irritant induced detrusor overactivity. Systemic JNJ17203212 and JYL1421 administration in the anesthetized rat volume induced micturition reflex model resulted in an increased micturition threshold volume. JNJ17203212 also decreased bladder contraction amplitude but JYL1421 had no effect. Capsaicin desensitization significantly increased baseline micturition threshold volume and decreased bladder contraction amplitude in the volume induced micturition reflex model compared to those in sham treated controls and JNJ17203212 produced no further effect after capsaicin desensitization. JNJ17203212 was also effective in 2 models of irritant induced detrusor overactivity, preventing the decrease in micturition threshold volume and the increase in bladder contraction amplitude observed with intravesical instillation of 10 microM capsaicin, and the decreased voiding interval induced by intravesical citric acid. |
Does low anthropometric measures and mortality -- result from the Malmö Diet and Cancer Study? | To study the association between anthropometric measures: body mass index (BMI), percent body fat, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), waist-to-hip-to-height ratio (WHHR), and A Body Shape Index (ABSI); to see if individuals in the lowest 5 percentiles for these measures have an increased risk of mortality. A population-based prospective cohort study (10,304 men and 16,549 women), the Malmö Diet and Cancer study (MDC), aged 45-73 years. During a mean follow-up of 14 ± 3 years, 2,224 men and 1,983 women died. There was a significant increased mortality risk after adjustments for potential confounders in the group with the 5% lowest BMI (referent 25%-75%); hazard ratios (HR) with 95% confidence intervals were 1.33 (1.10-1.61) for women and 1.27 (1.07-1.52) for men. A similar significant increased mortality risk was seen with the 5% lowest percent body fat, HR 1.31 (1.07-1.60) for women and 1.25 (1.04-1.50) for men. Women with an ABSI in the lowest 5 percentiles had a lower mortality risk HR 0.64 (0.48-0.85). | This study was designed to evaluate the effects of a dorzolamide-timolol combination or dorzolamide on retinal ganglion cell (RGC) density and intraocular pressure (IOP) in glaucomatous eyes of adult rats. Glaucoma was induced in the right eye of adult Wistar rats by episcleral venous occlusion. One experimental group was administered dorzolamide 2%-timolol 0.5% combination eye drops, while the other experimental group was administered dorzolamide 2% eye drops. Control groups had surgery without drug administration. Drug application was initiated either 2 weeks before surgery (Group A), from the day of surgery (Group B), 2 weeks after surgery (Group C), or 4 weeks after surgery (Group D). RGCs were labeled by intratectal Fluorogold injections and counted from flat-mount preparations, and IOP was measured using Tonopen. Both dorzolamide-timolol combination and dorzolamide, when applied topically, significantly reduced IOP and improved RGC densities in experimental eyes when compared to control eyes. Earlier initiation, as well as longer duration of drug application, resulted in higher RGC densities. |
Does high-Speed Cycling Intervention improve Rate-Dependent Mobility in Older Adults? | The aim was to determine the feasibility of a six-week speed-based exercise program that could be used to initiate new exercise behaviors and improve rapid movement in older adults approaching frailty. The intervention group included 14 older adults (3 males, 11 females, mean (SD) age: 70 (7.6) years, height: 1.6 (.11) m, mass: 76.8 (12.0) kg, BMI: 27.7(4.7)). The control group included 12 older adults (6 males, 6 females, mean (SD) age: 69.2 (6.9) years, height: 1.7 (.09) m, mass: 78.2 (10.9) kg, BMI: 25.3 (2.7)). Subjects included active older adults, including regular exercisers, but none were engaged in sports or exercises with an emphasis on speed (e.g. cycling spin classes or tennis). Stationary recumbent cycling was selected to minimize fall risk and low pedaling resistance reduced musculoskeletal and cardiovascular load. Two weekly 30-minute exercise sessions consisted of interval training in which subjects pedaled at preferred cadence and performed ten 20-s fast cadence intervals separated by 40-s of active recovery at preferred cadence. Significant Group by Time interactions (p<.05) supported a 2-s improvement in the timed up and go test and a 34% improvement in rapid isometric knee extension contractions in the exercise group but not in controls. Central neural adaptations are suggested because this lower extremity exercise program also elicited significant improvements in the untrained upper extremities of the exercise group (elbow extension RFD-SF and 9-Hole Peg Test, p<.05). | Array-based comparative genomic hybridization (aCGH) is a new technique for detecting submicroscopic deletions and duplications, and can overcome many of the limitations associated with classic cytogenetic analysis. However, its clinical use in spontaneous abortion needs comprehensive evaluation. We used aCGH to investigate chromosomal imbalances in 100 spontaneous abortions and compared the results with G-banding karyotyping and fluorescence in situ hybridization (FISH). Inconsistent results were verified by quantitative fluorescence PCR. Abnormalities were detected in 61 cases. aCGH achieved the highest detection rate (93.4%, 57/61) compared with traditional karyotyping (77%, 47/61) and FISH analysis (68.9%, 42/61). aCGH identified all chromosome abnormalities reported by traditional karyotyping and interphase FISH analysis, with the exception of four triploids. It also detected three additional aneuploidy cases in 37 specimens with 'normal' karyotypes, one mosaicism and 10 abnormalities in 14 specimens that failed to grow in vitro. |
Is conservation of the glucan phosphatase laforin linked to rates of molecular evolution and the glucan metabolism of the organism? | Lafora disease (LD) is a fatal autosomal recessive neurodegenerative disease. A hallmark of LD is cytoplasmic accumulation of insoluble glucans, called Lafora bodies (LBs). Mutations in the gene encoding the phosphatase laforin account for approximately 50% of LD cases, and this gene is conserved in all vertebrates. We recently demonstrated that laforin is the founding member of a unique class of phosphatases that dephosphorylate glucans. Herein, we identify laforin orthologs in a protist and two invertebrate genomes, and report that laforin is absent in the vast majority of protozoan genomes and it is lacking in all other invertebrate genomes sequenced to date. We biochemically characterized recombinant proteins from the sea anemone Nematostella vectensis and the amphioxus Branchiostoma floridae to demonstrate that they are laforin orthologs. We demonstrate that the laforin gene has a unique evolutionary lineage; it is conserved in all vertebrates, a subclass of protists that metabolize insoluble glucans resembling LBs, and two invertebrates. We analyzed the intron-exon boundaries of the laforin genes in each organism and determine, based on recently published reports describing rates of molecular evolution in Branchiostoma and Nematostella, that the conservation of laforin is linked to the molecular rate of evolution and the glucan metabolism of an organism. | In the Microbicide Trial Network MTN-003 (VOICE) study, a Phase IIB pre-exposure prophylaxis trial of daily oral or vaginal tenofovir (TFV), product adherence was poor based on pharmacokinetic (PK) drug detection in a random subsample. Here, we sought to compare behavioural and PK measures of adherence and examined correlates of adherence misreporting. We included participants with PK and behavioural data from VOICE random subsample. Behavioural assessments included face-to-face interviews (FTFI), audio computer-assisted self-interviewing (ACASI) and pharmacy-returned product counts (PC). TFV concentrations < 0.31 ng/mL in plasma (oral group) and < 8.5 ng/swab in vaginal group were defined as "PK non-adherent." Logistic regression models were fit to calculate the combined predictive ability of the behavioural measures as summarized by area under the curve (AUC). Baseline characteristics associated with over-reporting daily product use relative to PK measures was assessed using a Generalized Linear Mixed Model. In this random adherence cohort of VOICE participants assigned to active products, (N = 472), PK non-adherence was 69% in the oral group (N = 314) and 65% in the vaginal group (N = 158). Behaviourally, ≤ 10% of the cohort reported low/none use with any behavioural measure and accuracy was low (≤ 43%). None of the regression models had an AUC > 0.65 for any single or combined behavioural measures. Significant (p < 0.05) correlates of over-reporting included being very worried about getting HIV and being unmarried for the oral group; whereas for the vaginal group, being somewhat worried about HIV was associated with lower risk of over-reporting. |
Do previous coronary stents increase early and long-term adverse outcomes in patients undergoing off-pump coronary artery bypass grafting : a propensity-matched comparison? | The aim of our study was to compare the early and long-term outcomes of patients undergoing off-pump coronary artery bypass grafting (CABG) with and without previous coronary stents. Between September 2004 and September 2011, 269 patients with previous stents underwent first-time isolated off-pump CABG. These patients were compared with 897 patients without previous stent. A propensity score-matching analysis was performed to compare early and late outcomes between the groups. Mean follow-up time was 43.4 months after surgery. Patients with previous stents were more likely to be men (85.9% in the stent group vs 79.4% in the no-stent group; P=.022) and more likely to have prior myocardial infarction (60.2% vs 36.8%; P<.001). Mean number of anastomoses was lower in patients with previous stents than in patients without previous stents (4.0 vs 4.2; P=.037). There was no difference in the use of bilateral internal thoracic artery graft between the groups (88.8% vs 89.1%; P>.999). After propensity adjustment for preoperative characteristics, both operative death (0.7% vs 1.5%; P=.414) and the major complications rates (7.8% vs 7.5%; P=.869) were similar between the groups. The actuarial survival rate at 7 years was not different between the groups (87.2%±3.2% vs 84.8%±2.9%; P=.470). Furthermore, freedom from major adverse cardiac and cerebrovascular events at 7 years were similar between the groups (78.9%±3.8% vs 77.6%±3.3%; P=.811). | To verify the effects of several 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) derivatives on LPS-induced NO production, cellular ROS levels and cytokine expression in BV-2 microglial cells. An MTT assay and FACS flow cytometry were performed to assess the cellular viability and apoptosis and cellular ROS levels, respectively. To examine the expression of pro-inflammatory cytokines and cellular signaling pathways, semi-quantitative RT-PCR and Western blotting were also used in this study. Among the six newly synthesized DMNQ derivatives, 2-cyclohexylamino-5,8-dimethoxy-1,4-naphthoquinone (R6) significantly inhibited the NO production, cellular ROS levels and the cytokines expression in BV-2 microglial cells, which stimulated by LPS. Signaling study showed that compound R6 treatment also significantly down-regulated the LPS-induced phosphorylation of MAPKs (ERK, JNK and p38) and decreased the degradation of IκB-α in BV2 microglial cells. |
Is broad spectrum psychiatric comorbidity associated with better executive functioning in an inpatient sample of individuals with schizophrenia? | Individuals with schizophrenia exhibit cognitive deficits but whether these deficits are exacerbated by broad spectrum psychiatric comorbidity (i.e., comorbidity that is inclusive of disorders from different diagnostic categories) is unclear. A broad spectrum approach to psychiatric comorbidity is an ecologically valid way to capture the diagnostic heterogeneity inherent in psychiatric presentations. This study compared the attention, working memory, processing speed, and executive functioning of individuals with schizophrenia only relative to individuals with schizophrenia and broad spectrum psychiatric comorbidity. Archival patient neuropsychological test data were obtained for a sample of patients with schizophrenia only (n=30) and a sample of patients with schizophrenia and psychiatric comorbidity (n=33). Relevant tests were used to form composite indices for the cognitive domains of attention, working memory, speed of processing, and executive functioning. Unexpectedly, individuals with schizophrenia and psychiatric comorbidity had significantly better executive functioning than individuals with schizophrenia only. There were no other significant differences. | Phenotypic switching of vascular smooth muscle cells (VSMCs) plays an initial role in neointimal hyperplasia, the main cause of many occlusive vascular diseases. The aim of this study was to measure the effects of resveratrol (RSV) on the phenotypic transformation of VSMCs and to investigate its mechanism of action. Cultured VSMCs isolated from rat thoracic aorta were prepared with serum starvation for 72 hours followed by RSV treatment (50-200 μmol/L) and 10% serum stimulation. Male Sprague-Dawley rats, subjected to carotid arteries injury from a balloon catheter, were exposed to intraperitoneal injection of RSV (1 mg/kg) or saline and were killed after 7 or 28 days. Compared with cells in the serum-induced group, VSMCs in the RSV or N-[N-(3, 5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) treatment group exhibited significant decreases of proliferation and migration. The total and cytoplasmic Notch-1 levels were declined by RSV, accompanied by a significant increase in smooth muscle α-actin and smooth muscle myosin heavy chain protein. The expression of Notch-1, Jagged-1, Hey-1, and Hey-2 mRNA in balloon-injured arteries at 7 days was decreased by RSV treatment. Arteries from RSV-treated rats showed less neointimal hyperplasia, lower collagen content, and a lower rate of cells positive for proliferating cell nuclear antigen 28 days after injury, compared with saline controls. |
Does insular lesion evoke autonomic effects of stroke in normotensive and hypertensive rats? | Increases in sympathetic activity and frequency of myocardial damage occur after middle cerebral artery occlusion (MCAO) in Wistar rats, while MCAO in the spontaneously hypertensive rat (SHR) decreases sympathoadrenal activity. Autonomic changes have been suggested to result from damage to the insular cortex (IC). A lesion of the IC was made using the excitotoxin D,L-homocysteic acid (DLH; 1 mol/L), in urethane-anesthetized Wistar rats and SHRs. Mean arterial pressure (MAP), heart rate, renal sympathetic nerve discharge (SND), ECG, and plasma catecholamines were measured in 14 SHRs and 14 Wistar male rats after a 500-nL injection of DLH or phosphate-buffered saline (PBS) into the IC. Histological examination showed that DLH resulted in neuronal damage throughout the IC. DLH injection initially elevated MAP (at approximately 10 minutes after injection) in Wistar rats but not in SHRs. At 4 hours after the DLH injection, there was a secondary, longer-term increase in MAP in the Wistar rats. MAP decreased in the SHRs after IC lesion such that at 6 hours, lesioned SHRs had a MAP that was significantly lower than that of sham-lesioned SHRs. SND initially increased (at 10 minutes) after DLH injection in Wistar rats. In the SHRs, SND decreased significantly from the initial values, by 3 hours after DLH injection. Plasma catecholamine levels were not significantly changed as a result of IC lesion in the Wistar rats or the SHRs. Heart rates increased in all animals, with no differences between groups. There were no changes in the ECG or in the frequency of cardiac myocytolysis in either strain (sham or lesioned animals). | The tumor suppressor p53 is known to be inactivated frequently in various cancers. In addition, germline polymorphisms in TP53 are known to affect protein function and influence risk of developing different types of cancers. In this study, we analyzed the association of TP53 Pro72Arg polymorphism with squamous cell carcinoma of oral tongue (SCCOT) and esophagus (ESCC) in India. We assessed the distribution of TP53 Pro72Arg polymorphism in one hundred and fifteen and eighty two SCCOT and ESCC patients, respectively, with respect to one hundred and ten healthy controls from the same population. In addition, we analyzed association of the polymorphism with several clinico-pathological and molecular parameters. Pro72 allele was significantly enriched in SCCOT patients compared to the healthy control group but neither allele was enriched in ESCC. Interestingly, Pro72 allele was preferentially mutated in ESCC which was confirmed by analysis of samples heterozygous for Pro72Arg. |
Does whole Genome Analysis of Injectional Anthrax identify Two Disease Clusters Spanning More Than 13 Years? | Anthrax is a rare disease in humans but elicits great public fear because of its past use as an agent of bioterrorism. Injectional anthrax has been occurring sporadically for more than ten years in heroin consumers across multiple European countries and this outbreak has been difficult to trace back to a source. We took a molecular epidemiological approach in understanding this disease outbreak, including whole genome sequencing of Bacillus anthracis isolates from the anthrax victims. We also screened two large strain repositories for closely related strains to provide context to the outbreak. Analyzing 60 Bacillus anthracis isolates associated with injectional anthrax cases and closely related reference strains, we identified 1071 Single Nucleotide Polymorphisms (SNPs). The synapomorphic SNPs (350) were used to reconstruct phylogenetic relationships, infer likely epidemiological sources and explore the dynamics of evolving pathogen populations. Injectional anthrax genomes separated into two tight clusters: one group was exclusively associated with the 2009-10 outbreak and located primarily in Scotland, whereas the second comprised more recent (2012-13) cases but also a single Norwegian case from 2000. | Fischer 344 (F344) rats display focal and diffuse glomerulosclerosis with aging postulated to result from loss of normal mesangial cell intrinsic function, e.g., vasoactive hormone signaling, or preservation of normal responsiveness to extrinsic growth factors. In 3-, 17-, and 24-month-old F344 male rats, glomerular structure, measured by PC-based morphometry, and function were compared. Immunoperoxidase staining of glomerular proliferating cell nuclear antigen (PCNA) detected cellular proliferation. Primary cultured mesangial cells from the 3 age groups were studied in parallel. Calcium (Ca2+) signaling, measured by Fura-2 fluorescence, contraction to vasopressin (AVP) 1 microM, measured by videomicroscopy, and proliferative response to platelet-derived growth factor-beta beta (PDGF) were compared. Proteinuria was 13 +/- 4, 38 +/- 17, and 110 +/- 35 mg/24 hours at 3, 17, and 24 months, respectively (n = 5, mean +/- SE, p < .01, 3 vs 24 months), with no change in 24-hour creatinine clearances. Glomerular volumes (n = 200/group) for 3, 17, and 24 months, respectively, were .30 +/- .01, .60 +/- .02, .74 +/- 0.2 x 10(6) micron3 (p < .001, 3 months vs 17 months, and 17 vs 24 months). Glomerular basement membrane (GBM) widths and fractional mesangial volumes increased significantly with aging. Glomerular cell PCNA staining remained positive at 24 months. Cultured mesangial cell Ca2+ signaling and contraction to AVP were unchanged with aging. Proliferation to PDGF, which was partially inhibited with verapamil, was similar at 3 and 24 months. |
Does effectiveness of hand hygiene depend on the patient 's health condition and care environment? | The present authors examined how patient hand contamination was associated with underlying disease and treatment environment in order to determine effective hand hygiene methods. Samples were collected from inpatients (45 with hematological malignancies, 48 postoperative), outpatients (48 undergoing hemodialysis, 55 on chemotherapy), and 44 individuals living in nursing homes. All participants provided informed consent for study participation. All subjects performed hand hygiene. Before and after hand hygiene, samples of bacteria were collected from the palm of the hand onto agar media. Bacteria were counted and bacterial strains were identified. The authors then collected smear samples from the contralateral palm and measured adenosine triphosphate (ATP) levels. Patient hand contamination was the highest in hemodialysis patients, followed by residents of nursing homes, postoperative patients, patients with cancer receiving chemotherapy, and patients of hematological malignancies. Regardless of the underlying disease and treatment environment, patients were able to reduce the number of bacterial colonies and ATP by proper hand hygiene. Compared with wet wipes, hand washing seemed to remove bacteria more effectively. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in 30 subjects, none of whom were patients of hematological malignancies. Of these, 19 tested negative for MRSA after performing proper hand hygiene. | To characterize the functional consequences of disease-associated mutations in the CNGB3 (B3) subunit of human cone photoreceptor cyclic nucleotide-gated channels in order to gain insight into disease mechanisms. Three separate disease-associated mutations were generated in CNGB3: F525N, R403Q, and T383fsX. These mutant subunits were then heterologously expressed in Xenopus oocytes in combination with wild type CNGA3 (A3) subunits, and characterized by patch-clamp recording in the inside-out configuration. Co-expression of A3 and B3F525N, A3 and B3R403Q, or A3 and B3R403Q and B3T383fsX subunits resulted in channels that exhibited an increase in ligand sensitivity without a reduction in current density compared to wild-type heteromeric channels. Each simulated disease state produced channels that exhibited greater sensitivity to block by L-cis-diltiazem than homomeric CNGA3 channels, confirming that the mutant CNGB3 subunits were competent to form functional heteromeric channels. Each combination of subunits displayed an increase in apparent affinity for cGMP relative to wild-type heteromeric channels. However, F525N enhanced cGMP apparent affinity to a significantly greater extent than the other two modeled disease states. |
Is gOLPH3 a novel marker of poor prognosis and a potential therapeutic target in human renal cell carcinoma? | Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development of several human cancers. The present study was conducted to investigate the expression of GOLPH3 and its prognostic significance in renal cell carcinoma (RCC). Meanwhile, the function of GOLPH3 in human RCC was further investigated in cell culture models. Expression of GOLPH3 was examined in 43 fresh RCC tissues and paired adjacent normal renal tissues by real-time quantitative PCR and western blotting. Immunohistochemistry for GOLPH3 was performed on additional 218 RCC tissues. The clinical significance of GOLPH3 expression was analysed. Downregulation of GOLPH3 was performed using small-interfering RNA (siRNA) in Caki-1 and 786-O cells with high abundance of GOLPH3, and the effects of GOLPH3 silencing on cell proliferation, migration, invasion in vitro, and tumour growth in vivo were evaluated. Expression of GOLPH3 was upregulated in the majority of the RCC clinical tissue specimens at both mRNA and protein levels. Clinicopathological analysis showed that GOLPH3 expression was significantly correlated with T stage (P<0.001), lymph-node status (P=0.003), distant metastasis (P<0.001), tumour-node-metastasis (TNM) stage (P<0.001), and Fuhman grade (P=0.001). Expression of GOLPH3 was inversely correlated with both overall and recurrence-free survival of RCC patients. Multivariate analysis showed that GOLPH3 expression was an independent prognostic indicator for patient's survival. Knockdown of the GOLPH3 expression reduced cell proliferation, anchorage-independent growth, migration, invasion, and tumour growth in xenograft model mice. | To determine whether treatment with corticosteroids decreases the incidence of postextubation airway obstruction in an adult intensive care unit. Clinical experiment. Adult medical and surgical intensive care unit of a teaching hospital. One hundred twenty-eight patients who were intubated for >24 hrs with a cuff leak volume <24% of tidal volume and met weaning criteria. : Patients were randomized into a placebo group (control, n = 43) receiving four injections of normal saline every 6 hrs, a 4INJ group (n = 42) receiving four injections of methylprednisolone sodium succinate, or a 1INJ group (n = 42) receiving one injection of the corticosteroid followed by three injections of normal saline. Cuff volume was assessed 1 hr after each injection, and extubation was performed 1 hr after the last injection. Postextubation stridor was confirmed by examination using bronchoscopy or laryngoscopy. The incidences of postextubation stridor were lower both in the 1INJ and the 4INJ groups than in the control group (11.6% and 7.1% vs. 30.2%, both p < .05), whereas there was no difference between the two treated groups (p = .46). The cuff leak volume increased after the second and fourth injection in the 4INJ group and after a second injection in the 1INJ group compared with the control group (both p < .05). |
Does yoga training improve quality of life in women with asthma? | Individuals with asthma frequently suffer with a decrease in quality of life. Yoga has been shown to improve autonomic function in the healthy population and has been used as an alternative therapy to help improve symptoms associated with various diseases. The purpose of this study was to assess whether 10 weeks of yoga training can improve quality of life and heart rate variability (HRV) in patients with asthma. Nineteen (19) females were randomly assigned to a yoga group or a control group for a 10-week intervention while still following guidelines established by their physician. All subjects answered the St. George's Respiratory Questionnaire (SGRQ) to assess quality of life and performed an isometric handgrip exercise test to assess HRV. Based on the SGRQ, significant improvements (45%, p < 0.05) in quality of life were observed with the yoga training, while no changes were found in the control group. Resting hemodynamic measures improved significantly in the yoga group compared to the control group (p < 0.05). The yoga group decreased parasympathetic modulation (HFnu [normalized units]) pre- to postintervention (0.45 ± 0.60 to 0.35 ± 0.06 nu, p<0.05, respectively) in response to the isometric forearm exercise (IFE), whereas the control group did not change. Additionally, the yoga group increased sympathetic (LFnu) (pre 0.47 ± 0.07 to post 0.60 ± 0.07 nu, p < 0.05) and sympathovagal modulation (logLF/HF) (pre 4.61 ± 0.39 to post 5.31 ± 0.44, p < 0.05, respectively) during IFE with no change in the control group. | The expression of tight junction-related transmembrane protein claudin-7 (CLDN7) and its regulatory mechanism were investigated in colorectal carcinomas (CRCs). Methylation-specific polymerase chain reaction and treatment with the demethylating agent 5-aza-2'-deoxycytidine were conducted to analyze the methylation status at the CLDN7 promoter region in the Colo320 CRC cell line. We used a total of 26 stage 0 CRCs with an adenoma component and 90 invasive CRCs (stage I-IV), as well as their corresponding lymph node metastases, in an immunohistochemical study. In Colo320 (CLDN7-negative) cells, hypermethylation at the CLDN7 promoter was detected and treatment with 5-aza-2'-deoxycytidine restored CLDN7 expression. In CRC tissues, decreased CLDN7 expression was detected in 62% of stage 0 CRCs and 80% of stage I-IV CRCs, compared with their adjacent adenoma lesions and nonneoplastic epithelia, which had a close correlation with the incidence of vessel infiltration and clinicopathologic stage. Hypermethylation at the CLDN7 promoter was detected in 20% of CRCs with low CLDN7 expression. However, CLDN7 expression tended to be re-expressed in their corresponding lymph node metastases. |
Are cytokine polymorphisms associated with poor sleep maintenance in adults living with human immunodeficiency virus/acquired immunodeficiency syndrome? | Cytokine activity and polymorphisms have been associated with sleep outcomes in prior animal and human research. The purpose of this study was to determine whether circulating plasma cytokines and cytokine polymorphisms are associated with the poor sleep maintenance commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Cross-sectional descriptive study. HIV clinics and community sites in the San Francisco Bay area. A convenience sample of 289 adults (193 men, 73 women, and 23 transgender) living with HIV/AIDS. None. A wrist actigraph was worn for 72 h to estimate the percentage of wake after sleep onset (WASO%) and total sleep time (TST), plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1B, IL1R2, IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor-alpha (TNFA). Controlling for demographic variables such as race and sex, and clinical variables such as CD4+ count and medications, higher WASO% was associated with single nucleotide polymorphisms (SNPs) of IL1R2 rs11674595 and TNFA rs1041981 and less WASO% was associated with IL2 rs2069776. IL1R2 rs11674595 and TNFA rs1041981 were also associated with short sleep duration. | Accurate sampling of gallbladder bile for biliary analysis is essential for determining any potential difference between combined bile acid therapy and monotherapy in gallstone patients. In 104 gallstone patients undergoing extracorporeal shock wave lithotripsy with following bile acid therapy [either chenodeoxycholic acid (500 mg/day) and ursodeoxycholic acid (500 mg/day), group I (n = 53), or ursodeoxycholic acid alone (1000 mg/day), group II (n = 51)], bile samples, obtained by direct fine needle puncture of the gallbladder, were investigated for biliary lipids, total biliary protein concentration, and nucleation time before and after 12 months of bile acid therapy. Initially, a negative correlation was found between nucleation time and number of gallstones and between total biliary protein concentration and nucleation time (r = -0.52 and r = -0.49 in group I vs r = -0.56 and r = -0.51 in group II, p < 0.01 in each group). The correlation between total biliary protein concentration and nucleation time was also found after 12 months of bile acid treatment (r = -0.54 in group I vs r = -0.47 in group II, p < 0.01 in each group). In group I, the decrease in cholesterol saturation index, biliary cholesterol, cholic acid, deoxycholic acid, and total protein concentration was more pronounced than in group II (p < 0.01). The same effect was found concerning the prolongation of nucleation time (p < 0.01). Furthermore, dissolution rates were higher in group I compared with group II (80.4 vs 69.0%, p < 0.01). |
Does implementation of the acute care surgery model provide benefits in the surgical treatment of the acute appendicitis? | Several reports have indicated the benefits of the acute care surgery (ACS) model in surgical outcomes. We tried to delineate the impact of the ACS model on surgical efficiency and quality. Before the ACS model was implemented, abdominal surgical emergencies were evaluated by an on-call nontrauma general surgeon (pre-ACS model). An in-house trauma surgeon treated all patients with trauma or nontrauma abdominal surgical emergencies after the ACS model. Patients with acute appendicitis who underwent appendectomies were included. We conducted a pre- and poststudy to compare the time patients were in the emergency department and surgical qualities. There were 146 and 159 patients enrolled in the pre-ACS model and ACS model, respectively. The overall ED length of stay in the ACS model was significantly shorter than that in the pre-ACS model (300.3 ± 61.7 vs 719.1 ± 339.0 minutes, P < .001). Hospital LOS was also significantly shorter in the ACS model than in the pre-ACS model (2.44 ± 1.39 vs 3.83 ± 2.21 days, P = .022). | A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain. Using antibodies to poly-GA, poly-GP, poly-GR, poly-AP and poly-PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR). Antibodies to poly-GA, poly-GP and poly-GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as 'star-burst' shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly-PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly-PR antibody did not identify any NCI but immunostained the nucleus of anterior horn cells, CA3/4 neurones and Purkinje cells, in patients with or without expansion in C9orf72, as well as in normal controls. Poly-GA antibody generally detected more DPR than poly-GP, which in turn was greater than poly-GR. All patients with bvFTD + MND or MND showed plentiful p62/TDP-43 positive inclusions in remaining anterior horn cells. |
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