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Does acute weight loss followed by an aggressive nutritional recovery strategy have little impact on on-water rowing performance? | To assess the influence of moderate, acute weight loss on on-water rowing performance when aggressive nutritional recovery strategies were used in the two hours between weigh in and racing. Competitive rowers (n = 17) undertook three on-water 1800 m time trials under cool conditions (mean (SD) temperature 8.4 (2.0) degrees C), each separated by 48 hours. No weight limit was imposed for the first time trial--that is, unrestricted body mass (UNR1). However, one of the remaining two trials followed a 4% loss in body mass in the previous 24 hours (WT(-4%)). No weight limit was imposed for the other trial (UNR2). Aggressive nutritional recovery strategies (WT(-4%), 2.3 g/kg carbohydrate, 34 mg/kg Na+, and 28.4 ml/kg fluid; UNR, ad libitum) were used in the first 90 minutes of the two hours between weigh in and performance trials. WT(-4%) had only a small and statistically non-significant effect on the on-water time trial performance (mean 1.0 second, 95% confidence interval (CI) -0.9 to 2.8; p = 0.29) compared with UNR. This was despite a significant decrease in plasma volume at the time of weigh in for WT(-4%) compared with UNR (-9.2%, 95% CI -12.8% to -5.6%; p<0.001). | To investigate whether programmed death ligand 1 (PD-L1) expressed in the periodontal tissue of chronic periodontitis and the correlativity of PD-L1 and different degrees of chronic periodontitis, provide experience for immunoregulation mechanism, clinical treatment and prognosis of chronic periodontitis. Gingiva and periodontal tissue of healthy people and chronic periodontitis patients were collected. Based on clinical probing, periodontal tissue were classified into three groups: periodontal tissues of healthy people, periodontal tissue of mild chronic periodontitis, periodontal tissue of severe chronic periodontitis. Fluorescent quantitation polymerase chain reaction was applied to explore the expression of PD-L1 mRNA in the periodontal tissue of the different groups. Western blot and immunohistochemistry method were utilized to test the expression of PD-L1 protein in the periodontal tissue of the different groups. Combining with clinical image data, the relationship between differentially expressions of PD-L1 and different degrees of chronic periodontitis was analyzed. The relative expression quantity of PD-L1 in the periodontal tissue of the mild chronic periodontitis was significantly higher that of the severe chronic periodontitis (P<0.01). The relative expression quantity of PD-L1 in the periodontal tissue of healthy subjects and severe chronic periodontitis had no statistical significance (P>0.05). |
Does benzodiazepine-induced reduction in activity mirror decrements in cognitive and psychomotor performance? | To assess whether actigraphy is sensitive to benzodiazepine-induced changes in cognitive and psychomotor performance and sleep. Healthy young volunteers (n = 23; 11 males), were randomised to a double-blind, placebo-controlled, crossover trial. Actigraphy was used to record motor activity continuously. Following dosing at 18.00 h with 2.5 mg lorazepam (LZP), psychomotor and cognitive assessments were made at hourly intervals post-dose for 4 h and after sleep at 14.5 h post-dose. Activity levels were significantly reduced after LZP for 5 h post-dose (p = 0.0104), during sleep (5-13 h) (p < 0.02) and the following morning, 13-14.5 h post-dose (p < 0.02). At the same time cognitive and psychomotor performance was also significantly impaired (p < 0.05). LZP also significantly increased actigraphic sleep efficiency and sleep per cent (p < 0.02). | In order to determine the synergistic effects of human placental mesenchymal stem cells (PMSCs) on hematopoiesis in vivo, we compared the intrabone marrow injection (IBMI) with the conventional intravenous injection (IVI). C57BL/6 recipient mice conditioned with lethal doses of irradiation were transplanted with bone marrow mononuclear cells (MNCs) and bone marrow-derived mesenchymal stem cells (BMSCs) from BALB/c mice by IBMI or IVI. NOD/SCID recipient mice conditioned with sublethal doses of irradiation were transplanted with human umbilical cord blood MNCs (UCB-MNCs) and PMSCs by IBMI or IVI. The number of hematopoietic cells was significantly higher in mice transplanted with BMSCs by IBMI than in those transplanted by IVI in a murine transplantation model (BALB/c→C57BL/6). Moreover, the percentage of human hematopoietic cells in the tibiae of the NOD/SCID mice that were transplanted with PMSCs plus UCB-MNCs was higher than that in mice transplanted with UCB-MNCs alone. In addition, in mice that were transplanted with PMSCs, PMSCs injected by IBMI were more efficient than those injected by IVI. |
Do intramucosal bacterial microcolonies exist in chronic rhinosinusitis without inducing a local immune response? | Although chronic rhinosinusitis (CRS) causes very significant morbidity, much about its pathogenesis remains uncertain. Recent studies have identified polymicrobial biofilms on the surface of sinus mucosa and Staphylococcus aureus within the sinus mucosa of patients with CRS, both with and without nasal polyps. The pathogenic implications of intramucosal bacteria in CRS are unknown. This study was designed to determine the prevalence and species of bacterial colonies within the sinus mucosa of adult patients with and without CRS and to describe the relationship of these bacterial colonies to the host immune response. Sinus mucosa from patients with and without CRS was examined using Gram and Giemsa staining, immunohistochemistry, bacterial culture, and fluorescence in situ hybridization techniques. Bacterial microcolonies were observed within the mucosa in 14 of 18 patients with CRS. In 10 of these patients colonies were positively identified as S. aureus. Staphylococcal microcolonies were observed at a lower level (1 of 8 patients) in normal sinus mucosa. There was no correlation between detection of S. aureus on the mucosal surface and microcolonization of the mucosa. Surprisingly, there was no evidence of an immune reaction to microcolonies. Indeed, fewer T lymphocytes (p = 0.03) and eosinophils (p = 0.03) were counted immediately surrounding the microcolonies compared with uninfected areas of the same tissue. | Cannabinoid type 1 receptor (CB1R) antagonists such as rimonabant (Rim) represent a novel approach to treat obesity and related metabolic disorders. Recent data suggest that endocannabinoids are also produced by human adipocytes. Here we studied the potential involvement of endocannabinoids in the negative crosstalk between fat and muscle. The protein level of CB1R in human skeletal muscle cells (SkM) during differentiation was analysed using western blotting. SkM were treated with adipocyte-conditioned medium (CM) or anandamide (AEA) in combination with the CB1R antagonists Rim or AM251, and insulin-stimulated Akt phosphorylation and glucose uptake were determined. Furthermore, signalling pathways of CB1R were investigated. We revealed an increase of CB1R protein in SkM during differentiation. Twenty-four hour incubation of SkM with CM or AEA impaired insulin-stimulated Akt(Ser473) phosphorylation by 60% and up to 40%, respectively. Pretreatment of cells with Rim or AM251 reduced the effect of CM by about one-half, while the effect of AEA could be prevented completely. The reduction of insulin-stimulated glucose uptake by CM was completely prevented by Rim. Short-time incubation with AEA activated extracellular regulated kinase 1/2 and p38 mitogen-activated protein kinase, and impaired insulin-stimulated Akt(Ser473) phosphorylation, but had no effect on Akt(Thr308) and glycogen synthase kinase 3alpha/beta phosphorylation. In addition, enhanced IRS-1 (Ser307) phosphorylation was observed. |
Do helicobacter pylori infection and administration of non-steroidal anti-inflammatory drugs down-regulate the expression of gastrokine-1 in gastric mucosa? | Gastrokine-1 is a novel protein that plays an important role in the maintenance of the integrity of the gastric mucosa. However, whether Helicobacter pylori infection and non-steroidal anti-inflammatory drugs, which are known to cause gastric mucosal injuries, affect gastrokine-1 expression in the gastric mucosa is unknown. The aim of the present study was to determine gastric mucosal expression of gastrokine-1 in patients with Helicobacter pylori infection or long-term non-steroidal anti-inflammatory drug administration. A total of 40 patients with functional dyspepsia (20 with Helicobacter pylori-negative chronic gastritis, and 20 with Helicobacter pylori-positive chronic gastritis), and 37 Helicobacter pylori-negative long-term non-steroidal anti-inflammatory drug users (26 with aspirin, 11 with selective cyclooxygenase-2 inhibitors) were selected. In addition, 20 Helicobacter pylori-negative healthy volunteers were recruited as controls. All subjects underwent endoscopies with biopsies taken from the antrum and the sites with lesions. Gastric mucosal changes were detected endoscopically and histologically, and gastrokine-1 protein expression in the antral mucosa was analyzed by immunohistochemistry. Expression of gastrokine-1 protein was decreased in Helicobacter pylori-positive chronic gastritis compared with Helicobacter pylori-negative subjects and the healthy controls. Similarly, gastrokine-1 expression in non-steroidal anti-inflammatory drug users was also decreased, compared with the healthy controls, but there was no significant difference in gastrokine-1 expression between the aspirin group and selective cyclooxygenase-2 inhibitor group. Moreover, gastrokine-1 expression levels tended to be associated with the severity of chronic gastritis. | We sought to determine whether mitral annular calcification (MAC) predicts mortality and cardiac disease in a group of renal transplant candidates. Hundred and forty patients were prospectively studied. All had echocardiography and coronary angiography. Significant coronary artery disease (CAD) was defined as luminal stenosis >70% by visual estimation in at least one coronary artery. There were 21 deaths over a follow-up period of 2.2+/-0.7 years. MAC occurred in 56 patients (40%) and was associated with higher mortality (p=0.04). Patients with MAC were older (p=or<0.001), had larger left ventricular (LV) end systolic (p=0.005) and LV end diastolic (p=0.04) diameter, larger left atrial diameter (p=0.001), lower LV fractional shortening (p=0.003), larger LV mass index (p=0.04) and higher mitral E/Ea ratio (p=0.03) compared to those without. Plasma calcium (p=0.002), phosphate (p=0.004), cardiac troponin T (p=0.03), N-terminal Pro-B-type natriuretic peptide (p=0.004) concentrations were higher in those with MAC but gender, total cholesterol, haemoglobin and creatinine were similar in the two groups. The proportion diabetic (p=0.03), on dialysis (p=0.05), with significant CAD (p=or<0.001), taking calcium containing phosphate binders (p=0.02) and Vitamin D3 (p=0.04) was significantly higher in those with MAC. Significant CAD (OR 12, 95% CI 3.25, p=0.001) was the only independent associate of MAC. |
Are globally , CYP1B1 mutations in primary congenital glaucoma strongly structured by geographic and haplotype backgrounds? | To obtain a global perspective on the distribution and evolution of CYP1B1 mutations in primary congenital glaucoma (PCG) worldwide. Five intragenic single-nucleotide polymorphisms in CYP1B1-R48G, A119S, V432L, D449D, and N453S-were used to generate haplotype data from 138 Indian patients with PCG and 132 ethnically matched normal controls, which were then analyzed in conjunction with data from other populations. Maximum-likelihood estimates of haplotype frequencies were estimated from the genotype data. Subsets of patients and normal control subjects were also genotyped with respect to eight short tandem repeat (STR) markers around the CYP1B1 locus (D2S305, D2S165, D2S367, D2S2259, D2S391, D2S3337, D2S23678, and D2S286), to gain evolutionary insights. Common mutations in CYP1B1 that are causal of PCG occurred on a uniform haplotype background among Indian patients, which is completely distinct from the modal haplotype background found among unaffected control subjects. Comparison of these data with data from other global regions reveals strong clustering of CYP1B1 mutations by geographic and haplotype backgrounds. The two distinct modal haplotypes found among Indian patients with PCG and control subjects are both ancient with ages of similar magnitudes, as indicated by large variances in the number of repeats at eight STR loci. Together with data from chimpanzee and normal control subjects from India and other global regions, it was possible to make a parsimonious reconstruction of the evolution of these haplotypes. | The furosemide drip (FD), in addition to improving volume overload respiratory failure, has been used to decrease fluid in attempts to decrease intra-abdominal and abdominal wall volumes to facilitate fascial closure. The purpose of this study is to evaluate the FD and the associated rate of primary fascial closure following trauma damage control laparotomy (DCL). From January 2004 to September 2008, a retrospective review from a single institution Trauma Registry of the American College of Surgeons dataset was performed. All DCLs greater than 24 h who had a length of stay for 3 or more days were identified. The study group (FD+) and control group (FD-) were compared. Demographic data including age, sex, probability of survival, red blood cell transfusions, initial lactate, and mortality were collected. Primary outcomes included primary fascial closure and primary fascial closure within 7 days. Secondary outcomes included total ventilator days and LOS. A total of 139 patients met inclusion criteria: 25 FD+ and 114 FD-. The 25 FD+ patients received the drug at a median 4 days post DCL. Demographic differences between the groups were not significantly different, except that initial lactate was higher for FD- (1.7 vs 4.0; P=0.03). No differences were noted between groups regarding successful primary fascial closure (FD+ 68.4% vs FD- 64.0%; P=0.669), or closure within 7 days (FD+13.2% vs FD- 28.0%; P=0.066) of original DCL. FD+ patients suffered more open abdomen days (4 [2-7] vs 2 [1-4]; P=0.001). FD+ did not demonstrate an association with primary fascial closure [Odds ratio (OR) 1.5, 95% confidence interval (CI) 0.260-8.307; P=0.663]. FD+ patients had more ventilator days and longer Intensive Care Unit (ICU)/hospital LOS (P<0.01). |
Is disagreement in preference for residential care between family caregivers and elders greater among cognitively impaired elders group than cognitively intact elders group? | This study examined the predictive factors of preference for residential care in cognitively intact and impaired elders and their family caregivers. It was hypothesized that disagreement in preference for residential care between the elders and their caregivers was greater in the cognitively impaired. A cross-sectional survey was conducted during June 2007 to March 2008 in Hong Kong, and 707 community-dwelling elders aged 65 and above and 705 family caregivers were interviewed. Cognitively impaired elders were over-sampled to give reliable estimates for that sub-group. A structural questionnaire was used to collect data on preference for residential care and potential factors. Logistic regression was used to identify the predictors. More cognitively impaired elder-caregiver dyads (37.4%) had disagreement in preference for residential care than cognitively intact elder-caregiver dyads (20.5%) (p < .001). From the elders' perspective, less preference for residential care was associated with cognitive impairment, whereas greater preference was associated with depression (for cognitively intact elders), more usage of community service and functional impairment. From the caregivers' perspective, greater preference for residential care was associated with greater caregiver burden, or care-recipients having cognitive or functional impairment, or more usage of community services. | The mainstay of toxoplasmosis treatment targets the folate biosynthetic pathways and has not changed for the last 50 years. The activity of these chemotherapeutic agents is restricted to one lifecycle stage of Toxoplasma gondii, they have significant toxicity, and the impending threat of emerging resistance to these agents makes the discovery of new therapies a priority. We now demonstrate that auranofin, an orally administered gold containing compound that was FDA approved for treatment of rheumatoid arthritis, has activity against Toxoplasma gondii in vitro (IC50 = 0.28 µM) and in vivo (1 mg/kg). Replication within human foreskin fibroblasts of RH tachyzoites was inhibited by auranofin. At 0.4 µM, auranofin inhibited replication, as measured by percent infected fibroblasts at 24 hrs, (10.94% vs. 24.66% of controls; p = 0.0003) with no effect on parasite invasion (16.95% vs. 12.91% p = 0.4331). After 18 hrs, 62% of extracellular parasites treated with auranofin were non-viable compared to control using an ATP viability assay (p = 0.0003). In vivo, a previously standardized chicken embryo model of acute toxoplasmosis was used. Fourteen day old chicken embryos were injected through the chorioallantoic vein with 1×104 tachyzoites of the virulent RH strain. The treatment group received one dose of auranofin at the time of inoculation (1 mg/kg estimated body weight). On day 5, auranofin-treated chicken embryos were 100% protected against death (p = 0.0002) and had a significantly reduced parasite load as determined by histopathology, immunohistochemistry and by the number of parasites quantified by real-time PCR. |
Does foxO3 inactivation promote human cholangiocarcinoma tumorigenesis and chemoresistance through Keap1-Nrf2 signaling? | FoxO transcription factors have been reported to play pivotal roles in tumorigenesis and drug resistance. The mechanisms underlying the tumor suppression function of FoxOs in human cancers remain largely unknown. Aberrant expression and activation of Nrf2 often correlate with chemoresistance and poor prognosis. Here, we report that FoxO3 directs the basal transcription of Kelch-like ECH-associated protein 1 (Keap1), an adaptor protein that bridges Nrf2 to Cul3 for degradation. FoxO3 depletion resulted in Keap1 down-regulation, thereby activating Nrf2 signaling. We further demonstrated that inhibition of the FoxO3-Keap1 axis accounts for Nrf2 induction and activation induced by constitutively active AKT signaling or tumor necrosis factor α treatment. Unlike previous findings, FoxO3 silencing led to decreased reactive oxygen species production, therefore protecting cells from oxidative stress-induced killing in an Nrf2-dependent manner. Importantly, FoxO3 deficiency strongly potentiated tumor formation in nude mice and rendered cholangiocarcinoma xenografts resistant to cisplatin-induced cell death by activating Nrf2. Additionally, we found that clinical cholangiocarcinoma samples displayed FoxO3-Keap1 down-regulation and Nrf2 hyperactivation, underscoring the essential roles of these proteins in cholangiocarcinoma development. | A recurrent finding of trials on renal sympathetic denervation is a certain percentage of non-responders. The aim of this study was to examine the influence of arterial stiffness to predict response. Eighty-eight patients were included in the study. Arterial stiffness was measured by invasive pulse wave velocity. Antihypertensive medication had to be unchanged during follow-up. Ambulatory blood pressure measurement (ABPM) was used to record blood pressure before and six months after denervation. Fifty-eight patients without changes in medication were included in the final analysis. Responders (n=37; blood pressure reduction -12.8±6.4 mmHg) had a significantly lower pulse wave velocity (14.4±4.4 m/s versus 17.7±4.5 m/s; p=0.009) compared to non-responders (n=21; blood pressure reduction +3.0±4.5 mmHg; p<0.001 for comparison with responders). In multivariate analysis, invasive pulse wave velocity was the only significant predictor of blood pressure reduction after denervation (odds ratio 1.15, 95% confidence interval [CI] 1.014-1.327; p=0.03). Patients with increased stiffness were older (p=0.001), had a higher prevalence of diabetes (p=0.008), more often had isolated systolic hypertension (p=0.007), and had a higher invasive pulse pressure (p<0.001). |
Does choline supplementation reduce oxidative stress in mouse model of allergic airway disease? | Asthma is a multi-factorial inflammatory disease associated with increased oxidative stress and altered antioxidant defences. We have evaluated the effect of choline on oxidative stress in a mouse model of airway disease. Balb/c mice were sensitised with 100 microg of ovalbumin on days 0 and 14, and challenged with aerosolized ovalbumin on days 25-27. Mice were administered 1 mg kg(-1) of choline via oral gavage or intranasal route on days 14-27. Mice were also administered 100 mg kg(-1) of alpha-lipoic acid as standard antioxidant. Total cell counts, eosinophils and eosinophil peroxidase (EPO) activity were determined in bronchoalveolar lavage (BAL) fluid. Reactive oxygen species (ROS), lipid peroxidation and isoprostanes levels were measured in BAL fluid. IL-13 and tumour necrosis factor-alpha (TNF-alpha) levels were also measured in BAL fluid and spleen cell culture supernatant. Nuclear factor kappaB (NFkappaB) p65 protein expression was measured after last ovalbumin challenge in nuclear and cytosolic extracts of lungs. Compared with ovalbumin-challenged mice, choline and alpha-lipoic acid treated mice had significantly reduced eosinophilic infiltration and EPO activity in BAL fluid. Choline and alpha-lipoic acid treatment reduced ROS production and isoprostanes level significantly in BAL fluid and thus suppressed oxidative stress. Choline and alpha-lipoic acid administration by either route decreased lipid peroxidation levels and down regulated NFkappaB activity. Further, choline and/or alpha-lipoic acid treatment suppressed TNF-alpha level significantly as compared with that of ovalbumin-challenged mice. | Current staging for renal cancer (RC) does not directly rely on tumor size. We examined the increment in accuracy related to inclusion of pathologically determined tumor size in prediction of nodal metastases (N+), distant metastases (M+), and cancer-specific survival (CSS). Partial or radical nephrectomy was performed in 2245 patients with clear cell histology. Pathologic stages were T1a in 566, T1b in 490, T2 in 303, T3 in 831, and T4 in 55 patients. Tumor size was 0.5-25 cm (mean, 6.8). Multivariate models relied on 1997 and 2002 TNM variables and addressed N+, M+ disease, and CCS. Their accuracy was compared according to either the presence or absence of tumor size. In all univariate and multivariate models, tumor size was a statistically significant predictor of all outcomes (p< or =0.001). In all multivariate models, tumor size added between 3.7% and 0.8% to predictive accuracy of either 1997 or 2002 TNM categories. |
Are non-insulin-dependent diabetes mellitus and fasting glucose and insulin concentrations associated with arterial stiffness indexes . The ARIC Study . Atherosclerosis Risk in Communities Study? | Cardiovascular diseases are the most common cause of disability and death among subjects with non-insulin-dependent diabetes mellitus (NIDDM). The atherosclerotic process begins during the prediabetic phase characterized by impaired glucose tolerance, hyperinsulinemia, and insulin resistance. In vitro studies have suggested that glucose and insulin can substantially alter the structure and function of the arterial wall and affect the development of atherosclerosis. We performed a cross-sectional study of the relation of arterial stiffness indexes with glucose tolerance and serum insulin concentrations. Several indexes of common carotid artery stiffness were assessed with noninvasive ultrasound methods in a biracial sample of 4701 men and women 45 to 64 years of age in the Atherosclerosis Risk in Communities (ARIC) Study. Arterial compliance (AC), stiffness index (SI), pressure-strain elastic modulus (Ep), and Young's elastic modulus (YEM) were calculated. YEM includes wall (intima-media) thickness and thus gives an estimate of arterial stiffness controlling for wall thickness. All indexes of arterial stiffness were higher with increasing concentrations of fasting glucose. This finding was consistent in both black and white examines and in both sexes. A 25% increase in fasting glucose (approximately 1 SD) was associated in nondiabetic white men with a 5.8% (95% CI, -9.6% to -1.9%; P = .004) decrease in AC and increases of 5.8% (95% CI, 2.0% to 9.7%; P = .002) in SI, 11.3% (95% CI, 6.9% to 15.9%; P < .001) in Ep, and 11.2% (95% CI, 6.2% to 16.6%; P < .001) in YEM. In nondiabetic white women, the corresponding predicted changes were a decrease of 15.0% (95% CI, -18.2% to -11.7%; P < .001) in AC and increases of 16.6% (95% CI, 12.5% to 20.8%; P < .001) in SI, 23.2% (95% CI, 18.4% to 28.2%; P < .001) in Ep, and 19.2% (95% CI, 14.0% to 24.7%; P < .001) in YEM. Glucose and insulin contributed synergistically to the increase in stiffness indexes. Insulin and triglycerides also had a synergistic association with stiffness indexes. | Recurrence and subsequent acquired chemoresistance to platinum-based treatments constitute major hurdles to ovarian carcinoma therapy. Our objective was to examine the involvement of Bcl-xL anti-apoptotic protein in resistance to cisplatin. We described the effect of cisplatin on cell cycle and apoptosis induction in sensitive (IGROV1 and OAW42) and resistant (IGROV1-R10 and SKOV3) ovarian carcinoma cell lines. We correlated it with Bcl-xL mRNA and protein expression after exposure to cisplatin. We then used bcl-xS gene transfer to impede Bcl-xL activity. Our study showed that Bcl-xL basal expression was high in both sensitive and resistant cell lines, as well as in all the studied ovarian tumor samples. Thus, Bcl-xL basal expression could not allow to predict sensitivity. Wondering whether variation of Bcl-xL level in response to cisplatin could be a better determinant of sensitivity, we investigated the expression of this protein in the cell lines after treatment. Cisplatin-induced down-regulation of Bcl-xL was strictly associated with apoptosis and absence of recurrence in vitro. Conversely, the maintenance of Bcl-xL expression in response to cisplatin appeared as a sine qua non condition to escape to treatment. To try to sensitize SKOV3 cells by impeding anti-apoptotic activity of Bcl-xL, we transfected bcl-xS gene in these cells. Bcl-xS exogenous expression was only slightly cytotoxic on its own, but highly sensitized SKOV3 resistant cells to cisplatin-induced apoptosis, and delayed recurrence. |
Does hypothermic acid-base management affect cerebral metabolic rate for oxygen at 27 degrees C. A study during cardiopulmonary bypass in rabbits? | It has been contended that, during cardiopulmonary bypass at 27 degrees C, pH-stat management decreases cerebral metabolic rate for oxygen (CMRO2) more than alpha-stat management. In contrast, other studies have not found CMRO2 to differ between techniques. Using each animal as its own control, the authors assessed the effect of alpha-stat versus pH-stat management of CMRO2, cerebral blood flow (CBF), and brain oxygen extraction during cardiopulmonary bypass at 27 degrees C. Fourteen New Zealand White rabbits, anesthetized with fentanyl and diazepam, underwent cardiopulmonary bypass at 27 degrees C (membrane oxygenator, centrifugal pump, and bifemoral arterial perfusion). Group 1 animals (n = 7) had alpha-stat management for the initial 65-70 min of bypass, and were then changed to pH-stat management for the remaining 30 min of bypass. Group 2 animals (n = 7) had pH-stat management for the initial 65-70 min of bypass, and were then changed to alpha-stat management for the remaining 30 min. Measurement of CBF (radiolabeled microspheres), CMRO2 (CBF x brain arterial-venous oxygen content difference), brain temperature, systemic hemodynamics, and arterial blood gases were made in each animal under both alpha-stat and pH-stat conditions. CMRO2 did not differ between alpha-stat and pH-stat conditions (1.4 +/- 0.3 ml.100 g-1.min-1; median +/- quartile deviation), and was independent of order of determination. Changes in CBF between alpha-stat and pH-stat conditions were associated with proportional opposite changes in cerebral oxygen extraction. Cerebral blood flow was significantly greater with pH-stat management than with alpha-stat management (37 +/- 5 vs. 30 +/- 3 ml.100 g-1.min-1, respectively). The CBF response to changing PaCO2 was significantly greater when going from alpha-stat to pH-stat conditions (group 1) than in the reverse order (group 2). | Matrix metalloproteinases (MMPs) play an important role in modeling and remodeling the extracellular matrix in leiomyomas. Hence, we investigated whether associations exist between leiomyomas and promoter polymorphisms in the MMP-1 and MMP-9 genes in a Japanese population. We compared the distribution of polymorphisms in the promoter regions of MMP-1 (-1607 1G/2G) and MMP-9 (-1562 C/T) in 267 leiomyoma patients and 184 control patients using polymerase chain reaction-fragment-length polymorphism (PCR-RFLP) analysis. The allele frequencies of the MMP-1 -1607 2G and MMP-9 -1562 T polymorphisms were 74.6% and 18.6% in leiomyoma patients, and 71.3% and 18.6% in control patients, respectively. No significant differences in allele frequencies or genotype distributions were found between leiomyoma and control patients. Moreover, no associations were found between MMP-1 and MMP-9 genotypes and leiomyoma size or a family history of the condition. |
Does alcohol consumption during gestation reduce the histamine and triiodothyronine content of rat immune cells? | Different factors acting during pregnancy can cause non-morphological alterations of cells which are manifested later, in adulthood. We studied the effect of maternal alcohol consumption for one day in early pregnancy on the hormone content of immune cells in the adult rat. Lactating dams were given 15% ethanol in the drinking water for 24 h on the 3rd day post partum, exposing their pups to ethanol in the breast milk. Some of the same dams had been successfully mated on the day of delivery, so that they were also 3 days pregnant on the treatment day, exposing embryos to alcohol on the third day of pregnancy. In 4 month old pups histamine and triiodothyronine (T(3)) content of citrate elicited peritoneal immune cells (lymphocytes, monocyte-macrophage-granulocyte group, mast cells) as well as thymic cells were determined by flow cytometry and confocal microscopy using specific antibodies. Alcohol treatment during pregnancy decreased highly significantly the content of both hormones in peritoneal cells of the 4 month old adult animals while it was ineffective by breast feeding after birth. Thymic cells did not show any changes. | The prognosis of patients with severe aortic stenosis, low aortic gradient and preserved ejection fraction is controversial. Our study analyzed the prognosis of these patients and its relation to pressure gradient and aortic valve flow. We performed a retrospective cohort study of 363 consecutive patients with severe aortic stenosis and preserved ejection fraction, divided into 4 groups, based on the presence of a systolic volume index greater or lower than 35 mL/m(2) and the presence of a mean aortic gradient greater or lower than 40 mmHg. Group I: normal flow, high gradient (n=169, 47%); group II: normal flow, low gradient (n=98, 27%); group III: low flow, high gradient (n=54, 15%), and group IV: low flow, low gradient (n=42, 12%). The primary endpoint was overall mortality. Independent risk factors for mortality were age (hazard ratio=1.04; 95% confidence interval, 1.01-1.08) and atrial fibrillation (hazard ratio=2.21; 95% confidence interval, 1.24-3.94). Surgical treatment was associated with longer survival in all groups (hazard ratio=0.25; 95% confidence interval: 0.13-0.49). Mortality was higher in patients with low flow than in those with with normal flow (26.6% vs 13.6%; P=.004). The most favorable mean prognosis was found in group II (hazard ratio=0.4; 95% confidence interval, 0.2-0.9). |
Is serum cystatin C a suitable marker for routine monitoring of renal function in pediatric cancer patients , especially of very young age? | Monitoring renal function is crucial in children undergoing chemotherapy. To date, a combination of routine serum creatinine (SCR) monitoring with occasional determination of creatinine clearance ratio (CCR) is widely used as clinical standard for this purpose. Both methods have their limitations regarding diagnostic value (SCR) or practicability (CCR), especially in young children. Diagnostic alternatives, such as glomerular filtration rate (GFR) estimation formulas have not been proved to be superior. The aim of the study was to evaluate whether serum cystatin C (CysC) may have a diagnostic impact on pediatric patients. CysC, SCR, several GFR estimation formulas (Counahan-Barratt, Ghazali-Barratt, Schwartz, Shull, Traub), and CCR were studied in 80 pediatric cancer patients (age range: 0.17-17.9 years) during their chemotherapy. Special attention was given to children under the age of 3 in whom accurate urine collection for CCR is difficult. All parameters correlated similarly well with CCR. Total accuracy was 66% and 67% for CysC and SCR, respectively. In very young children (<3 years), correlation with CCR was for CysC r = -0.74 with an area under the curve (AUC) of 0.646, and for SCR r = -0.27 with AUC = 0.594. Total accuracy was 60% for CysC, 50% for SCR. | High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein and is released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. To test the hypothesis that HMGB1 enhances angiogenesis and restores cardiac function after myocardial infarction (MI), we generated transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) using alpha-myosin heavy chain promoter. The left anterior descending coronary artery was ligated in HMGB1-Tg and wild-type littermate (Wt) mice. After coronary artery ligation, HMGB1 was released into circulation from the necrotic cardiomyocytes of HMGB1-overexpressing hearts. The size of MI was smaller in HMGB1-Tg than in Wt mice. Echocardiography and cardiac catheterization demonstrated that cardiac remodelling and dysfunction after MI were prevented in HMGB1-Tg mice compared with Wt mice. Furthermore, the survival rate after MI of HMGB1-Tg mice was higher than that of Wt mice. Immunohistochemical staining revealed that capillary and arteriole formation after MI was enhanced in HMGB1-Tg mice. |
Do cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle? | Cannabinoid type 1 receptor (CB1R) antagonists such as rimonabant (Rim) represent a novel approach to treat obesity and related metabolic disorders. Recent data suggest that endocannabinoids are also produced by human adipocytes. Here we studied the potential involvement of endocannabinoids in the negative crosstalk between fat and muscle. The protein level of CB1R in human skeletal muscle cells (SkM) during differentiation was analysed using western blotting. SkM were treated with adipocyte-conditioned medium (CM) or anandamide (AEA) in combination with the CB1R antagonists Rim or AM251, and insulin-stimulated Akt phosphorylation and glucose uptake were determined. Furthermore, signalling pathways of CB1R were investigated. We revealed an increase of CB1R protein in SkM during differentiation. Twenty-four hour incubation of SkM with CM or AEA impaired insulin-stimulated Akt(Ser473) phosphorylation by 60% and up to 40%, respectively. Pretreatment of cells with Rim or AM251 reduced the effect of CM by about one-half, while the effect of AEA could be prevented completely. The reduction of insulin-stimulated glucose uptake by CM was completely prevented by Rim. Short-time incubation with AEA activated extracellular regulated kinase 1/2 and p38 mitogen-activated protein kinase, and impaired insulin-stimulated Akt(Ser473) phosphorylation, but had no effect on Akt(Thr308) and glycogen synthase kinase 3alpha/beta phosphorylation. In addition, enhanced IRS-1 (Ser307) phosphorylation was observed. | In NcoI restriction fragment length polymorphism analysis of tumor necrosis factor-beta (TNF-beta) gene, the frequency of 10.5-kb homozygote is low in patients with lung cancer and is associated with a better prognosis. These results should be examined in other malignancies. Using polymerase chain reaction, the authors performed NcoI restriction fragment length polymorphism analysis in 152 patients with gastric cancer, in 69 patients with benign gastric lesion, and in 141 healthy volunteers. In 3-year survival, the 10.5-kb homozygote showed a better prognosis (87.1%) than other alleles (5.5-kb homozygote, 52.5%; heterozygote, 79.1%), and there was a statistically significant difference between the 10.5-kb homozygote and the 5.5-kb homozygote. In 3-year survival for Stages III and IV, the 10.5-kb homozygote also showed a better prognosis (64.9%) than other alleles (5.5-kb homozygote, 16.7%; heterozygote, 41.4%). There were statistically significant differences (10.5-kb homozygote vs. 5.5-kb homozygote, P < 0.01; heterozygote vs. 5.5-kb homozygote, P < 0.05). There was a statistical difference between all patients and Stages III and IV (P < 0.05). |
Is nerve Growth Factor Expression Associated with Perineural Invasion in Extrahepatic Cholangiocarcinoma? | Although the presence of perineural invasion has been recognized as a poor prognostic factor in extrahepatic cholangiocarcinoma, the molecular mechanisms of perineural invasion in extrahepatic cholangiocarcinoma remain unclear. Nerve growth factor has been reported to be a candidate predictive biomarker of perineural invasion in some cancers. To investigate the impact of intratumoral nerve growth factor expression in resected extrahepatic cholangiocarcinoma on survival. Intratumoral nerve growth factor expression was investigated immunohistochemically in 112 patients with resected extrahepatic cholangiocarcinoma. Associations between nerve growth factor expression and clinicopathological factors were statistically evaluated, and risk factors for poor survival were analyzed using univariate and multivariate analyses. High and low nerve growth factor expression was observed in 62 (55%) and 50 (45%) patients, respectively. For all 112 patients, no significant correlation was found between nerve growth factor expression and presence of perineural invasion (P = 0.942). Moreover, nerve growth factor expression was not associated with recurrence-free survival (P = 0.861) and overall survival (P = 0.973). In multivariate analysis, lymph node metastasis (P = 0.004) was identified as an independent risk factor for early recurrence and the presence of perineural invasion (P = 0.002) and lymph node metastasis (P < 0.001) was identified as independent risk factors for poor survival. | All 4 dengue virus (DENV) serotypes are now simultaneously circulating worldwide and responsible for up to 400 million human infections each year. Previous studies of CD8(+) T-cell responses in HLA-transgenic mice and human vaccinees demonstrated that the hierarchy of immunodominance among structural versus nonstructural proteins differs as a function of the infecting serotype. This led to the hypothesis that there are intrinsic differences in the serotype-specific reactivity of CD8(+) T-cell responses. We tested this hypothesis by analyzing serotype-specific CD8(+) T-cell reactivity in naturally infected human donors from Sri Lanka and Nicaragua, using ex vivo interferon γ-specific enzyme-linked immunosorbent spot assays. Remarkably similar and clear serotype-specific patterns of immunodominance in both cohorts were identified. Pooling of epitopes that accounted for 90% of the interferon γ response in both cohorts resulted in a global epitope pool. Its reactivity was confirmed in naturally infected donors from Brazil, demonstrating its global applicability. |
Is desert dust a risk factor for the incidence of acute myocardial infarction in Western Japan? | Recently, there has been increasing concern about adverse health effects of exposure to desert dust events. However, the association between dust and the incidence of ischemic heart diseases is unknown. The aim of the present study was to elucidate whether Asian dust (AD), a windblown sand dust originating from mineral soil in China and Mongolia, is associated with the incidence of acute myocardial infarction (AMI). We investigated the data regarding hospitalization because of AMI among 3068 consecutive patients from 4 AMI centers in Fukuoka, Japan, and data for AD from April 2003 to December 2010. We applied a time-stratified case-crossover design to examine the association between AD and the incidence of AMI. Using a conditional logistic regression analysis, we estimated the odds ratios of AMI associated with AD after controlling for ambient temperature and relative humidity. The occurrence of AD events 0 to 4 days before the day of admission was significantly associated with the incidence of AMI. In particular, the occurrence of AD 4 days before admission was significantly associated with the onset of AMI. | During endoscopic or open carpal tunnel release, a palmar fat pad is visualized immediately proximal to the distal end of the transverse carpal ligament (TCL). Visualization of the fat pad allows anticipation of complete release of the TCL without unnecessary distal dissection that could risk iatrogenic injury. This study defines the anatomic relationship of the distal edge of the TCL to the fat pad, the superficial palmar arch, and the motor branch of the median nerve. Eighteen fresh-frozen cadaver hands were dissected, and the proximal aspect of the palmar fat pad, the distal edge of the TCL, the superficial palmar arch, and the motor branch of the median nerve were identified. An electronic caliper was used to measure distances between each structure along the axis of the radial border of the ring finger. A subset of 8 hands was radiographically imaged with fingers flexed and extended (wrist neutral) to determine if finger positioning influenced measurements between marked structures. The proximal aspect of the palmar fat pad is 2.0 mm proximal to the distal edge of the TCL. The distal end of the TCL, as measured along the axis of the radial border of the ring finger is 12.7 mm from the most proximal aspect of the palmar arch and 6.5 mm from the nearest aspect of the motor branch. Flexing the fingers decreases the distance between the distal end of the TCL and the fat pad while not markedly affecting the distance between the TCL and the palmar arch or the motor branch. |
Do influence of the Number of Predicted Words on Text Input Speed in Participants With Cervical Spinal Cord Injury? | To determine whether the number of words displayed in the word prediction software (WPS) list affects text input speed (TIS) in people with cervical spinal cord injury (SCI), and whether any influence is dependent on the level of the lesion. A cross-sectional trial. A rehabilitation center. Persons with cervical SCI (N=45). Lesion level was high (C4 and C5, American Spinal Injury Association [ASIA] grade A or B) for 15 participants (high-lesion group) and low (between C6 and C8, ASIA grade A or B) for 30 participants (low-lesion group). TIS was evaluated during four 10-minute copying tasks: (1) without WPS (Without); (2) with a display of 3 predicted words (3Words); (3) with a display of 6 predicted words (6Words); and (4) with a display of 8 predicted words (8Words). During the 4 copying tasks, TIS was measured objectively (characters per minute, number of errors) and subjectively through subject report (fatigue, perception of speed, cognitive load, satisfaction). For participants with low-cervical SCI, TIS without WPS was faster than with WPS, regardless of the number of words displayed (P<.001). For participants with high-cervical SCI, the use of WPS did not influence TIS (P=.99). There was no influence of the number of words displayed in a word prediction list on TIS; however, perception of TIS differed according to lesion level. | Of the numerous adhesion molecules expressed by eosinophils, the alpha4-integrin has been identified as critically involved in eosinophil trafficking in the lung. Most studies have focused on the role of the alpha4beta1-adhesion complex, but eosinophils also express the alpha4beta7-integrin complex. To investigate the role of alpha4beta7, by assessing its membrane expression on eosinophils from different compartments using allergen-challenged mice and IL-4/IL-5 bi-transgenic mice. In addition, we aim to determine the impact of beta7-integrin deficiency on eosinophil recruitment to the lungs and intestine in specific experimental allergic models. Evaluation of alpha4beta7 expression on bronchoalveolar lavage fluid (BALF) and lung tissue eosinophils revealed a down-regulation of this integrin as eosinophils migrate through the lungs. Indeed eosinophils isolated from the BALF and lung of allergic mice had low expression of the alpha4beta7-complex. While expression of the alpha4-chain remained unchanged, a significant decrease in beta7-surface expression was observed. Intestinal eosinophils, isolated from Peyer's patches, also displayed a down-regulation of the alpha4beta7-integrin, albeit only modest. In contrast, circulating eosinophils, isolated from the blood and spleen, expressed high levels of the alpha4beta7-integrin. However, eosinophil trafficking into the lungs of beta7-integrin-deficient mice was not significantly impaired in response to respiratory allergen challenges. In contrast, beta7-deficient mice had impaired eosinophil recruitment to the intestine. |
Does gAB2 gene modify the risk of Alzheimer 's disease in Spanish APOE 4 carriers? | The genetic basis of Alzheimer's disease (AD) is being analyzed in multiple whole genome association studies (WGAS). The GAB2 gene has been proposed as a modifying factor of APOE epsilon 4 allele in a recent case-control WGAS conducted in the US. Given the potential application of these novel results in AD diagnostics, we decided to make an independent replication to examine the GAB2 gene effect in our series. We are conducting a multicenter population-based study of AD in Spain. We analyzed a total of 1116 Spanish individuals. Specifically, 521 AD patients, 475 controls from the general population and 120 neurologically-normal elderly controls (NNE controls). We have genotyped GAB2 (rs2373115 G/T) and APOE rs429358 (SNP112)/rs7412 (SNP158) polymorphisms using real time-PCR technologies. As previously reported in Spain, APOE epsilon 4 allele was strongly associated with AD in our series (OR=2.88 [95% C.I. 2.16- 3.84], p=7.38E-11). Moreover, a large effect for epsilone 4/epsilone 4 genotype was also observed (OR=14.45 [95% C.I., 3.34-125.2], p=1.8E-6). No difference between the general population and the NNE controls series were observed for APOE genotypes (P > 0.61). Next, we explored GAB2 rs2373115 SNP singlelocus association using different genetic models and comparing AD versus controls or NNE controls. No evidence of association with AD was observed for this GAB2 marker (p > 0.17). To evaluate GAB2-APOE genegene interactions, we stratified our series according to APOE genotype and case-control status, in accordance with the original studies. Again, no evidence of genetic association with AD was observed in any strata of GAB2-APOE loci pair (p > 0.34). | Peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane. However, the (ir)reversibility of these pathological changes of the peritoneum is not understood fully. In an experimental PD model, rats (n = 15) received daily 10 ml conventional glucose containing PD fluid, via peritoneal catheters connected to implanted subcutaneous mini vascular access ports. After 5 weeks of treatment, the first group of animals (PDF; n = 10) was sacrificed, while peritoneal catheters of the remaining group of rats (PD-rest; n = 5) were removed 1 week later. The latter group (PD-rest) was sacrificed 12 weeks after removing catheters. At both time points, untreated rats were included as controls. Cellular and morphological parameters were analysed by light and electron microscopy. Rats exposed to PD fluid for 5 weeks showed a severe angiogenesis in various peritoneal tissues. Peritoneal rest resulted in a significant reduction in blood vessel density in visceral (mesentery, P<0.05), but not in parietal peritoneum. Five weeks' exposure to PD fluid resulted in a profound fibrosis in the parietal peritoneum, whereas the degree of fibrosis was significantly reduced in the PD-rest group (P<0.02). Daily exposure to PD fluid induced a higher number of mast cells in the omentum compared with untreated rats, whereas peritoneal rest normalized the increased mast cell density completely (P<0.03). Likewise, continued PD fluid instillation evoked a strong omental milky spot response, which was returned to the control level after peritoneal rest (P<0.009). Furthermore, the number of mesothelial cells on the liver was significantly increased in rats treated with PD fluid, whereas animals from the PD-rest group had a lower number of mesothelial cells, although this was not statistically significant (P = 0.08). Finally, as evidenced by electron microscopy, daily exposure to PD fluid resulted in severe damage to the mesothelial cell layer covering the peritoneum, whereas this cell layer was completely recovered after peritoneal rest. |
Is elevated preoperative plasma D-dimer level a useful predictor of chemoresistance and poor disease outcome for serous ovarian cancer patients? | To examine whether the elevated preoperative plasma D-dimer levels show correlation with chemoresistance and poor prognosis in serous ovarian cancer patients. Preoperative plasma D-dimer levels were measured in 125 patients with primary serous ovarian cancer (SOC).The correlations of plasma D-dimer levels with clinicopathological features, chemotherapeutic response, and survival outcome were further analyzed. Kaplan-Meier estimates were used to compute the survival functions and were compared using log-rank tests. Cox proportional-hazard regression analysis was used to evaluate the effects of D-dimer on progression-free survival (PFS) and overall survival (OS), controlling for potential confounding factors. The median follow-up period was 49 (range 5-85) months. Elevated plasma D-dimer levels were positively associated with advanced FIGO stage (P = 0.010), residual tumor size (P = 0.017), the presence of malignant ascites (P = 0.028), increased serum CA125 level (P = 0.014), and neo-adjuvant chemotherapy (P = 0.008). The patients with elevated plasma D-dimer levels had significantly higher chemoresistance rates (56.41 %) compared to the normal plasma D-dimer levels (20.93 %). Additionally, it was found by the univariate analysis that elevated plasma D-dimer levels were closely related with a low 5-year PFS rate (28.21 vs 52.33 %, P = 0.002) and a poor 5-year OS (30.77 vs 63.95 %, P < 0.001). However, after adjustment for other factors, high plasma D-dimer levels were only closely correlated with a poor 5-year OS (HR 1.901, 95 % CI 1.021-3.540; P = 0.043). | Priming a high level construal has been shown to enhance self-control and reduce preference for indulgent food. Subtle visual cues have been shown to enhance the effects of a priming procedure. The current study therefore examined the combined impact of construal level and a visual cue reminder on the consumption of energy-dense snacks. A student and community-based adult sample with a wide age and body mass index (BMI) range (N = 176) were randomly assigned to a high or low construal condition in which a novel symbol was embedded. Afterward participants completed a taste test of ad libitum snack foods in the presence or absence of the symbol. The high (vs. the low) construal level prime successfully generated more abstract responses (p < .0001) and reduced intake when the cue-reminder was present (p = .02) but not when it was absent (p = .40). |
Is fast activity at seizure onset mediated by inhibitory circuits in the entorhinal cortex in vitro? | Network mechanisms responsible for focal seizure initiation are still largely unknown. One of the prevalent seizure patterns observed during diagnostic intracranial recordings performed in patients with mesial temporal lobe epilepsy is characterized by fast activity at 20 to 30 Hz. We reproduced 20 to 30 Hz oscillations at seizure onset in the temporal lobe of the in vitro isolated guinea pig brain to study cellular and network mechanisms involved in its generation. Seizure-like activity was induced in the isolated brain by 3-minute arterial perfusion of 50 microM bicuculline. Intracellular, extracellular, and ion-selective electrophysiological recordings were performed simultaneously in the entorhinal cortex (EC) during interictal-ictal transition. Principal neurons in deep and superficial layers of the EC did not generate action potentials during fast activity at ictal onset, whereas sustained firing was observed in putative interneurons. Within 5 to 10 seconds from seizure initiation, principal neurons generated a prominent firing that correlated with the appearance of extracellular hypersynchronous bursting discharges. In superficial neurons, fast activity correlated with rhythmic IPSPs that progressively decreased in amplitude during the development of a slow depolarization associated with an increase in extracellular potassium. | Inflammation plays a pathogenic role in the development of heart failure (HF). The aim of this study was to examine the effect of treatment with the immunomodulating drug thalidomide in a rat model for post-myocardial infarction (MI) HF. Rats were subjected to MI by left coronary artery ligation or sham-operated. Seven days after surgical intervention rats were randomised to treatment with thalidomide or vehicle for 8 weeks. Our main findings were: (i) thalidomide treatment did not affect cardiac function or the hypertrophic response, as determined by haemodynamic measurements and heart chamber weights, respectively. (ii) HF rats treated with thalidomide had a minor reduction in septum and relative wall thickness (p<0.05), indicating an anti-remodelling effect. (iii) Thalidomide appeared to have immunostimulatory effects on the myocardium as evident by increased MIP-1alpha gene expression (p<0.05). (iv) Treating HF rats with thalidomide reduced myocardial collagen content, as assessed by markedly decreased levels of hydroxyproline ( approximately 40% reduction; p<0.05), accompanied by lower TGF-beta(1) gene expression (p<0.05). |
Does the dihydropyridine calcium channel blocker benidipine prevent lysophosphatidylcholine-induced endothelial dysfunction in rat aorta? | Lysophosphatidylcholine (LPC), an atherogenic component of oxidized low-density lipoprotein, has been shown to induce the attenuation of endothelium-dependent vascular relaxation. Although benidipine, a dihydropyridine-calcium channel blocker, is known to have endothelial protective effects, the effects of benidipine on LPC-induced endothelial dysfunction remain unknown. We examined the effects of benidipine on the impairment of endothelium-dependent relaxation induced by LPC. Benidipine was administered orally to rats and aortas were then isolated. Aortic rings were treated with LPC and endothelial functions were then evaluated. Additionally, the effects of benidipine on intracellular calcium concentration ([Ca2+]i) and membrane fluidity altered by LPC in primary cultured rat aortic endothelial cells were examined. [Ca2+]i was measured using the fluorescent calcium indicator fura-2. Membrane fluidity was monitored by measuring fluorescence recovery after photobleaching. Treatment with LPC impaired endothelial function. Benidipine prevents the impairment of relaxation induced by LPC. Acetylcholine elicited an increase in [Ca2+]i in fura-2 loaded endothelial cells. The increase in [Ca2+]i was suppressed after exposure to LPC. Plasma membrane fluidity increased following incubation with LPC. Benidipine inhibited the LPC-induced increase in membrane fluidity and impairment of increase in [Ca2+]i. | There remains a controversy between unreamed intramedullary nailing and external fixation to treat Gustilo grade IIIB tibial fractures. To evaluate the comparative effectiveness and safeness of both methods for this type of fracture, we performed this meta-analysis. Relevant original studies were searched in MEDLINE, EMBASE, China National Knowledge Infrastructure, and Cochrane Central Database (all through February 2014). Studies included in this meta-analysis had to compare the effectiveness or complications and provided sufficient data of interest. The patients treated by both methods were similar statistically in demography and injury mechanism. The Stata 11.0 was used to analyze all data. Six studies involving 163 participants were included. Unreamed intramedullary nailing was associated with reduced time to union (standardized mean difference, -1.14; 95% confidence interval, -2.04 to -0.24) and lower rates of superficial infection (odds ratio: 0.39; 95% confidence interval: 0.17-0.87) and malunion (odds ratio: 0.27; 95% confidence interval: 0.09-0.78). However, there were no significant differences in other adverse events including delayed union, non-union, deep infection, and fixation failure. |
Does [ Electroretinogram `` b '' wave vary with the posology of the antimalarial treatment ]? | The electroretinogram (ERG) is currently, together with the central visual field test, color vision test and electroculogram (EOG), an examination dedicated to prevent retinopathy due to hydroxychloroquine (HCQ) or chloroquine (CQ) intoxication. Thirty-two patients on treatment with HCQ were studied. Each patient had underwent a complete clinical ophthalmological examination and a set of paraclinical examinations including at least an ERG. All the patients were requested to decrease or stop their HCQ treatment. Following this change, a second ERG was recorded for each patient. The ERGs before and after stopping HCQ treatment were compared. We noted a statistically significant increase in the amplitude of "b" wave of the ERG, following after decrease or discontinuation of HCQ treatment. | SMAD4 loss is associated with the development of metastases and poor prognosis. We evaluated expression of SMAD4 protein and its association with tumor characteristics, including biomarkers and outcome in terms of relapse-free survival and overall survival. We used 1,564 stage II/III colon cancer samples from PETACC-3 to evaluate SMAD4 expression by immunohistochemistry. SMAD4 protein expression was validated by assessing mRNA expression using available expression array data. SMAD4 expression was also studied on 34 adenomas and 10 colon cancer liver metastases with their primaries. Loss of SMAD4 immunoreactivity was defined as focal or diffuse. Cases without SMAD4 loss were subdivided into those with strong and weak expression. SMAD4 protein expression was informative in 1,381/1,564 cases. SMAD4 loss was found in 293/1,381 (21%) cases. Of 1,088 cases without SMAD4 loss (79%), 530 showed weak and 558 strong expression. SMAD4 loss occurred also in adenomas, but less extensively than in carcinomas. Liver metastases followed mostly the expression pattern of the primary tumor. SMAD4 loss, including weak expression, identified patients with poor survival in stage II as well as III and in both treatment arms. SMAD4 loss was less frequent in tumors with microsatellite instability and more frequent in those with loss of heterozygosity of 18q. |
Does defect in potentiation of adenylyl cyclase correlate with bronchial hyperreactivity? | Adenylyl cyclase is a transmembrane signaling system involved in the inhibition of cellular responses. Recently, we showed that the activity of adenylyl cyclase may be potentiated by stimuli that induce an increase of cellular responses but that do not activate adenylyl cyclase. This is probably an important physiologic feedback mechanism that prevents cells from becoming "overstimulated." Because increased cellular activities are frequently observed in persons with asthma, we hypothesized that a defect in potentiation of adenylyl cyclase might be involved. Potentiation of isoprenaline-induced adenosine cyclic monophosphate (cAMP) production with the mitogen phytohemagglutin (PHA; 45 micrograms/ml) or the calcium ionophore A23187 (1 mumol/L) was studied in peripheral blood mononuclear cells taken from patients with asthma (n = 8) and healthy control subjects (n = 11). Isoprenaline-induced cAMP production was potentiated significantly in the healthy control subjects (PHA, 110% +/- 15%; A23187, 92% +/- 25%). In contrast, potentiation was not seen with PHA or A23187 in the total group of patients with asthma. However, some patients showed weak potentiation, whereas in others PHA decreased isoprenaline-induced cAMP production. Moreover, the effect of PHA on isoprenaline-induced cAMP production correlated significantly with the degree of bronchial hyperreactivity in patients with asthma (r = 0.96; p = 0.0001). | State-supported trauma systems have a proven association with improved mortality, but to date, there are no data reported on what mechanism leads to this benefit. Our hypothesis is that trauma systems with funding support are associated with increased number of trauma centers (TCs). A retrospective population study: data for the number of American College of Surgeons-verified adult TCs in 2010 were obtained from the American College of Surgeons and for state-designated TCs from state departments of health. Population and gross domestic product (GDP) were obtained from the US Census. The main outcome measure was the number of TCs per population and per GDP. Statistical analysis was carried out using the Mann-Whitney U-test and Poisson regression. There was no association between a trauma system and the numbers of level 1 or 2 centers. In states with funded trauma systems, the numbers of level 3 centers per GDP and per million state population were 4.76 ± 2.37/$100 billion and 1.77 ± 0.51/million people compared with 0.72 ± 1.72/$100 billion and 0.28 ± 0.60/million people for unfunded states (P < 0.05). Poisson multivariate regression identified system funding as an independent predictor of number of level 3 centers. |
Does triglyceride predict cardiovascular mortality and its relationship with glycaemia and obesity in Chinese type 2 diabetic patients? | To examine the lipid profile in Chinese type 2 diabetic patients and their relationship with anthropometric parameters, glycaemic control and cardiovascular mortality. A consecutive cohort of 562 newly referred patients with type 2 diabetes to a hospital-based diabetes centre were examined in 1996. Subjects treated with lipid lowering drugs at the time of referral were excluded. A total of 517 subjects were followed up over a mean (+/-SD) period of 4.6 +/- 0.9 years. Glycated haemoglobin (HbA1c), fasting insulin and lipid profile and anthropometric parameters were documented at the time of recruitment. Cardiovascular mortality, mainly due to coronary heart disease and stroke, was ascertained using death registry and review of hospital case notes in 2001. Of the 517 subjects (mean age of 54.0 +/- 14.0 years), 42.6% were men. In this cohort, 63.3% of subjects were either overweight (BMI > or = 23 kg/m2) or obese (BMI > or = 25 kg/m2) using Asian criteria. The mean (+/-SD) total cholesterol (TC), LDL-Cholesterol (LDL-C), HDL-Cholesterol (HDL-C) and geometric mean (x// antilog SD) of triglycerides (TG) were 5.6 +/- 1.3 mmol/L, 3.6 +/- 1.1 mmol/L, 1.3 +/- 0.3 mmol/L and 1.46x//1.90 mmol/L respectively. TC and LDL-C correlated positively with HbA1c, HDL-C negatively with BMI and WC (waist circumference), while TG positively with HbA1c, BMI, WC and HOMA (insulin resistance estimated using the homeostasis model assessment). During the 4.6 years follow-up period, there were 61 deaths giving a total mortality rate of 11.4%, of which 15 (25%) were because of cardiovascular events. Apart from age and disease duration, logarithm of TG was significantly associated with increased risk of cardiovascular mortality (p = 0.049, relative risk = 2.97, 95% CI 1.00-8.77). | Intact myelin, which normally surrounds axons, breaks down in Wallerian degeneration following axonal injury and during neurodegenerative diseases such as multiple sclerosis. Clearance of degenerated myelin by phagocytosis is essential since myelin impedes repair and exacerbates damage. CR3 (complement receptor-3) is a principal phagocytic receptor in myelin phagocytosis. We studied how tyrosine kinase Syk (spleen tyrosine kinase) and cofilin control phagocytosis of degenerated myelin by CR3 in microglia and macrophages. Syk is a non-receptor tyrosine kinase that CR3 recruits to convey cellular functions. Cofilin is an actin-depolymerizing protein that controls F-actin (filamentous actin) remodeling (i.e., disassembly and reassembly) by shifting between active unphosphorylated and inactive phosphorylated states. Syk was continuously activated during prolonged phagocytosis. Phagocytosis increased when Syk activity and expression were reduced, suggesting that normally Syk down regulates CR3-mediated myelin phagocytosis. Levels of inactive p-cofilin (phosphorylated cofilin) decreased transiently during prolonged phagocytosis. In contrast, p-cofilin levels decreased continuously when Syk activity and expression were continuously reduced, suggesting that normally Syk advances the inactive state of cofilin. Observations also revealed inverse relationships between levels of phagocytosis and levels of inactive p-cofilin, suggesting that active unphosphorylated cofilin advances phagocytosis. Active cofilin could advance phagocytosis by promoting F-actin remodeling, which supports the production of membrane protrusions (e.g., filopodia), which, as we also revealed, are instrumental in myelin phagocytosis. |
Are the personality domains and styles of the five-factor model related to incident depression in Medicare recipients aged 65 to 100? | Few prospective studies have examined personality and depression in older adults. The authors investigated whether the Five-Factor Model of personality traits-Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness-and trait combinations (styles) are related to incident major or minor depression. Prospective data were gathered on a community sample of 512 older adults with disability and a history of significant health care utilization who were enrolled in a Medicare Demonstration Project. Depression and personality traits and styles were assessed at baseline; depression was assessed again at approximately 12 and 22 months. Participants who developed incident major depression were compared with those free of depression at all three assessments. Similar analyses were done for minor depression. High Neuroticism and low Conscientiousness were risk factors for both major and minor depression. Combinations of high Neuroticism with low or high Extraversion or high Openness conferred risk for major depression. Other novel findings for major depression revealed new trait combinations of low Conscientiousness with low or high Extraversion, high Openness, or low Agreeableness. Three trait combinations, all involving low Conscientiousness, predicted risk for minor depression: high Neuroticism, high Agreeableness, and low Openness. | Pancreatic hypoxia/ischemia, as a consequence of shock-induced microcirculatory failure, is considered a causative factor in the initiation and/or progression of pancreatic tissue injury. The aim of this study was to compare the effects of "small volume resuscitation" with conventional isovolemic colloid and hypervolemic crystalloid resuscitation on pancreatic microcirculation after hemorrhagic shock. Randomized, controlled intervention trial. University laboratory. Twenty-three male Sprague-Dawley rats anesthetized with á-chloralose mechanically and ventilated. Rats subjected to 1 hr of hemorrhagic shock (mean arterial pressure of 40 mm Hg) were resuscitated with lactated Ringer's solution (four-fold shed volume/20 mins), 10% hydroxyethyl starch (shed volume/5 mins), or 7.2% sodium chloride-10% hydroxyethyl starch (10% shed volume/2 mins). The microcirculation of pancreatic acinar tissue was studied by means of intravital fluorescence microscopy and laser Doppler flowmetry. At 1 hr after resuscitation, mean arterial pressure, pancreatic capillary erythrocyte velocity, and erythrocyte flux were found to be significantly increased when compared with those values in the shock state. However, mean arterial pressure, pancreatic capillary erythrocyte velocity, and erythrocyte flux did not completely return to preshock values, regardless of the type of fluid used for resuscitation. At 15 mins and 1 hr after resuscitation, shock-induced capillary perfusion failure (reduction of functional capillary density) was restored to 91% to 94% of baseline values in all groups. Pancreatic capillary narrowing, indicating microvascular endothelial cell swelling, was abolished by resuscitation with both isotonic hydroxyethyl starch and hypertonic hydroxyethyl starch (p<.05 vs. lactated Ringer's solution). |
Are activating FLT3 mutations rare in children with juvenile myelomonocytic leukemia? | Activating mutations of FLT3 have been identified in multiple myeloid malignancies. Two types of activating mutations have been described: (1) the internal tandem duplication (FLT3-ITD) and (2) point mutations within the activating loop (FLT3-ALM). Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder of early childhood. Mutations and other genetic abnormalities of RAS, NF1, and PTPN11 have been implicated as causative events in JMML, but approximately 25% of JMML patients harbor none of these abnormalities. We investigated whether FLT3 mutations might also contribute to JMML pathogenesis, and if present, whether FLT3 status would correlate with disease natural history and prognosis. Genomic DNA was isolated from peripheral blood and bone marrow samples of 60 patients meeting international JMML diagnostic criteria. Samples were analyzed for FLT3-ITD and FLT3-ALM using polymerase chain reaction and restriction endonuclease digestion. FLT3-ALM was found in 1/60 (1.7%) patients analyzed. Direct sequencing confirmed a C836G mutation. Clinical and laboratory characteristics of the JMML patient with the FLT3-ALM did not differ from the remainder of the cohort. No FLT3-ITD mutations were detected. | Dietary silicon has been positively linked with vascular health and protection against atherosclerotic plaque formation, but the mechanism of action is unclear. We investigated the effect of dietary silicon on 1) serum and aorta silicon concentrations, 2) the development of aortic lesions and serum lipid concentrations, and 3) the structural and biomechanic properties of the aorta. Two studies, of the same design, were conducted to address the above objectives. Female mice, lacking the apolipoprotein E (apoE) gene, and therefore susceptible to atherosclerosis, were separated into 3 groups of 10-15 mice, each exposed to a high-fat diet (21% wt milk fat and 1.5% wt cholesterol) but with differing concentrations of dietary silicon, namely: silicon-deprived (-Si; <3-μg silicon/g feed), silicon-replete in feed (+Si-feed; 100-μg silicon/g feed), and silicon-replete in drinking water (+Si-water; 115-μg silicon/mL) for 15-19 wk. Silicon supplementation was in the form of sodium metasilicate (feed) or monomethylsilanetriol (drinking water). The serum silicon concentration in the -Si group was significantly lower than in the +Si-feed (by up to 78%; P < 0.003) and the +Si-water (by up to 84%; P < 0.006) groups. The aorta silicon concentration was also lower in the -Si group than in the +Si-feed group (by 65%; P = 0.025), but not compared with the +Si-water group. There were no differences in serum and aorta silicon concentrations between the silicon-replete groups. Body weights, tissue wet weights at necropsy, and structural, biomechanic, and morphologic properties of the aorta were not affected by dietary silicon; nor were the development of fatty lesions and serum lipid concentrations. |
Does counselor-assisted problem solving improve caregiver efficacy following adolescent brain injury? | The purpose of the current study is to examine the efficacy of Counselor-Assisted Problem Solving (CAPS) in improving caregiver adaptation following traumatic brain injury (TBI). In a randomized clinical trial comparing CAPS (n = 65), an online problem-solving intervention with accompanying Web-based counseling sessions, with an information-based Internet Resource Comparison (IRC; n = 67) program, participants included families of 12- to 17-year-olds who had sustained a TBI in the past 6 months. Linear regression analyses were used to identify main effects and to examine whether caregiver education, race, or prior computer use moderated treatment efficacy. Computer experience moderated postintervention improvements in caregiving self-efficacy following CAPS, Specifically, parents in CAPS with low levels of prior use reporting the greatest improvements. CAPS participants who completed 5 or more sessions reported greater reductions in depression than did the IRC; however, the groups did not differ on global distress. | Fight or flight heart rate (HR) increases depend on protein kinase A (PKA)- and calmodulin kinase II (CaMKII)-mediated enhancement of Ca(2+) uptake and release from sarcoplasmic reticulum (SR) in sinoatrial nodal cells (SANC). However, the impact of specific PKA and CaMKII phosphorylation sites on HR is unknown. We systematically evaluated validated PKA and CaMKII target sites on phospholamban and the ryanodine receptor using genetically modified mice. We found that knockin alanine replacement of ryanodine receptor PKA (S2808) or CaMKII (S2814) target sites failed to affect HR responses to isoproterenol or spontaneous activity in vivo or in SANC. Similarly, selective mutation of phospholamban amino acids critical for enhancing SR Ca(2+) uptake by PKA (S16) or CaMKII (T17) to alanines did not affect HR in vivo or in SANC. In contrast, CaMKII inhibition by expression of AC3-I has been shown to slow SANC rate responses to isoproterenol and decrease SR Ca(2+) content. Phospholamban deficiency rescued SR Ca(2+) content and SANC rate responses to isoproterenol in mice with AC3-I expression, suggesting that CaMKII affects HR by modulation of SR Ca(2+) content. Consistent with this, mice expressing a superinhibitory phospholamban mutant had low SR Ca(2+) content and slow HR in vivo and in SANC. |
Does cholinesterase inhibitor use significantly influence the ability of 123I-FP-CIT imaging to distinguish Alzheimer 's disease from dementia with Lewy bodies? | 123I-labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) imaging is a diagnostic tool to help differentiate dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). However, in animals, cholinesterase inhibitors (ChEi) have been reported to reduce radioligand binding to the striatal dopamine transporter. As ChEi are frequently used in people with dementia, it is important to determine whether their use affects 123I-FP-CIT uptake in the striatum. To clarify whether chronic ChEi therapy modulates striatal dopamine transporter binding measured by 123I-FP-CIT in patients with AD, DLB and Parkinson's disease with dementia (PDD). Cross sectional study in 99 patients with AD (nine on ChEi, 25 not on ChEi), DLB (nine on ChEi, 19 not on ChEi) and PDD (six on ChEi, 31 not on ChEi) comparing 123I-FP-CIT striatal binding (caudate, anterior and posterior putamen) in patients receiving compared with those not receiving ChEi, correcting for key clinical variables including diagnosis, age, sex, Mini-Mental State Examination score, severity of parkinsonism and concurrent antidepressant use. As previously described, 123I-FP-CIT striatal uptake was lower in DLB and PDD subjects compared with those with AD. Median duration of ChEi use was 180 days. 123I-FP-CIT uptake was not significantly reduced in subjects receiving ChEi compared those not receiving ChEi (mean percentage reduction: AD 4.3%; DLB 0.7%; PDD 6.1%; p = 0.40). ChEi use did not differentially affect striatal 123FP-CIT uptake between patient groups (p = 0.83). | Immunosuppression is the therapeutic alternative for patients with aplastic anemia who are ineligible for allogeneic transplant. We aimed to assess the benefit of the combination of antithymocyte globulin (ATG) and cyclosporine (CsA). We performed a systematic review and meta-analysis of all randomized controlled trials that compared ATG and CsA to ATG alone as first-line treatment for patients with severe and nonsevere aplastic anemia. The Cochrane Library, Medline, conference proceedings and references were searched until 2008. Relative risks (RR) with 95% confidence intervals (CIs) were estimated for each trial and pooled. Our search yielded 4 trials. For patients with severe aplastic anemia, there was a significant reduction in mortality in the ATG and CsA arm, which began at 3 months (RR = 0.50, 95% CI 0.29-0.85) and was maintained over a long follow-up of 5 years (RR = 0.58, 95 % CI 0.36-0.93). Conversely, in patients with nonsevere aplastic anemia, there was no difference in mortality. |
Are changes in hydration of the stratum corneum the most suitable indicator to evaluate the irritation of surfactants on the skin? | Irritancy levels of surfactants on human skin have not been clarified completely. The relationships between skin damage and changes of skin properties caused by various surfactants were investigated using non-invasive measurements. Aqueous solutions of seven kinds of anionic, non-ionic, and amphoteric surfactants were exposed to the inside of forearm skin of 20 human subjects in two separate studies using the cup method. Hydration of the stratum corneum (SC), transepidermal water loss (TEWL), pH, skin surface roughness, and contents of the SC were measured before and after one exposure and after five and nine consecutive exposures to various surfactants. The discontinuation ratio of subjects for testing in each surfactant was determined by skin irritation symptoms and was defined as the degree of skin damage. Significant changes were observed only in hydration, TEWL, and natural moisturizing factors (NMF) content in the SC following surfactant exposure. A significant correlation was observed between the discontinuation ratio of each surfactant and the changes of hydration, TEWL, and NMF. Especially, the change of SC hydration showed an excellent correlation with the discontinuation ratio both for single (r = 0.942, P < 0.001) and for chronic exposures (r = 0.934, P < 0.001). | In 38 patients with myelodysplastic syndromes (MDS) the values of serum erythropoietin were measured at diagnosis and compared with the haemoglobin level. A highly significant inverse relationship was found between these two parameters, suggesting that the physiologic mechanism of erythroid progenitor cell recruitment is preserved in MDS. Fourteen transfusion-dependent patients were treated with recombinant human erythropoietin at the dose of 150 U/Kg three times weekly for at least 2 months. |
Is tissue inhibitor of metalloproteinases II ( TIMP-2 ) an osteoanabolic factor in vitro and in vivo? | Critical size defects (CSDs) of bone are defined as defects that do not heal spontaneously to new bone during the lifetime of an adult individual. In contrast, immature animals are capable to heal defects of identical size. It was our hypothesis that age-related paracrine effects are relevant for this difference in regeneration. The pooled supernatant of primary rat calvarial osteoblast-like cell cultures (POBC) derived from prenatal or postnatal donors was concentrated and applied into CSDs of adult recipient organisms (n = 10). In addition, the supernatant of POBC derived from prenatal donors was pooled and purified by reverse-phase chromatography. Each pre-purified fraction was tested in a proliferation indicating bioassay. Peptide fractions containing proliferative activities were re-chromatographed and re-tested in a bioassay. Finally, a proliferative activity was purified, identified by sequence analysis and applied into CSDs of adult recipients. The application of POBC derived from prenatal donors resulted in osseous regeneration of a CSD in adult recipients, while the supernatant of postnatal donors had much smaller effects. The morphologic features resembled the spontaneous osseous healing of calvarial defects of the same size in immature organisms. The polypeptide "tissue inhibitor of metalloproteinases type II"(TIMP-2) was isolated from the supernatant of cultures of POBC derived from prenatal donors by measuring the induction of their proliferation. Additionally, the application of human TIMP-2 injected into calvarial CSDs of adult organisms resulted in osseous healing. | To assess the ability of an adult risk screening questionnaire (RSQ), previously shown to predict attendance at hospital emergency departments, to identify impaired quality of life in adult patients with asthma in general practice. Baseline data from an RCT of asthma clinics in general practice, using the St. George Respiratory Questionnaire (SGRQ) to measure quality of life. Twelve general practices in Adelaide, Australia. A total of 184 adult asthmatics were recruited, with a mean (standard deviation) age of 50.3 years (16.6 years). Age, gender, weight, number of comorbidities, smoking status, FEV1 and percent predicted FEV1 (pre-and post-bronchodilator), peak flow (pre and post), and RSQ were independently related to SGRQ scores. After adjusting for potential confounders, an RSQ score predictive of hospital attendance was also associated with an average increase (worsening) in SGRQ total score of 11.9 (95% CI: 7.6, 16.3), an average increase in activity score of 9.0 (2.5, 15.5), symptom score of 14.8 (8.6, 21.0), and impact score of 13.1 (8.6, 17.6). These represent clinically significant differences. |
Do the most frequent ED patients carry insurance and a significant burden of disease? | The objective of this study was to determine factors that impact emergency department (ED) utilization among the most frequent ED users. This prospective observational study consisting of questionnaires was conducted in an urban ED with an annual census of 95000 patients. A convenience sample of the top 1% of adult frequent users (≥9 ED visits in the previous 12 months) was enrolled from February 2009 to March 2010. Patients were excluded because of intoxication, altered mental status, or acute psychosis. A total of 115 patients were enrolled, with an average age of 44 years and median number of 22 ±13 ED visits in the preceding 12 months. Seventy-eight percent of frequent users reported adequate health insurance coverage, and 75% reported one or more chronic medical conditions. Despite the high rates of insured patients, 75% identified the ED as their primary health care site. Half of the cohort had 2 or more hospital admissions over the past 12 months, of which 24% were patients with end-stage renal disease. | To investigate the effects of resveratrol on the proliferation, apoptosis, mitochondrial membrane potential and cell morphology of human liver cancer cell line HepG2. The changes in HepG2 cell growth and proliferation in response to resveratrol treatment were evaluated by MTT assay, and resveratrol-induced apoptosis of HepG2 cells was investigated by flow cytometry. Inverted microscope and electron microscope were employed for observing morphological changes of the treated cells. The whole-cell mitochondrial membrane potential was measured in separate experiments using two fluorimetric probes, rhodamine123 and TMRE, respectively. HepG2 cells treated with rhodamine123 were analyzed by flow cytometry and cells treated with TMRE by confocal microscope. MTT assay showed that low concentrations of resveratrol produced no significant effect on the growth of HepG2 cells, whereas at high concentrations, resveratrol could obviously inhibit the cell growth in a time- and dose-dependent manner. Resveratrol also induced apoptosis of HepG2 cells, and after a 24-hour treatment, resveratrol caused sharp increment of the mitochondria membrane potential. |
Does lactobacillus fermentum BCS87 express mucus- and mucin-binding proteins on the cell surface? | To identify and characterize adhesion-associated proteins in the potential probiotic Lactobacillus fermentum BCS87. Protein suspensions obtained from the treatment of Lact. fermentum BCS87 with 1 mol 1(-1) LiCl were analysed by Western blotting using HRP-labelled porcine mucus and mucin. Two adhesion-associated proteins with relative molecular weight of 29 and 32 kDa were identified. The N-terminal and internal peptides of the 32 kDa protein (32-Mmubp) were sequenced, and the corresponding gene (32-mmub) was found by inverse polymerase chain reaction. The complete nucleotide sequence of 32-mmub revealed an open reading frame of 903 bp encoding a primary protein of 300 amino acids and a mature protein of 272 residues. A basic local alignment search showed 47-99% identity to solute-binding components of ATP binding cassette transporter proteins in Lactobacillus, Streptococcus and Clostridium. An OpuAC-conserved domain was identified and phylogenetic relationship analysis confirmed that 32-Mmubp belongs to the OpuAC family. | the study was aimed at assessment of the efficacy of percutaneous high frequency selective rhizotomy (PHFSR) after failure of conservative treatment of trigeminal neuralgia (TN) in multiple sclerosis (MS). A retrospective analysis of 28 patients with TN associated with MS who underwent percutaneous rhizotomy in the period from 2000 to 2014 was performed. All patients were definitely diagnosed with MS according to the McDonald criteria (version of 2001, 2005, and 2010). The patients were divided by age, gender, and the trigeminal nerve branches involved in the process. The patients' condition was evaluated at different times after surgery. Good outcomes in the form of pain syndrome regression were achieved in 100% of the patients. A disease recurrence was observed in 6 (21%) patients during a follow-up period of 3 months to 14 years. Dysesthesia complications occurred in 4 (14%) patients. There were no deaths and severe complications. The percentage of minor complications was low. |
Does the phospholipase A ( 2 ) inhibitor methyl indoxam suppress diet-induced obesity and glucose intolerance in mice? | Previous results have shown that mice lacking in the group 1B phospholipase A(2) (Pla2g1b) are resistant to obesity and diabetes induced by feeding a diabetogenic high-fat/high-carbohydrate diet. This study examined the potential of using the Pla2g1b inhibitor methyl indoxam as therapy to suppress diet-induced obesity and diabetes. Male C57BL/6 mice were fed the diabetogenic diet with or without methyl indoxam supplementation. Body weight gain, fasting plasma glucose levels, glucose tolerance and postprandial lysophospholipid absorption were compared. Wild-type C57BL/6 mice fed the diabetogenic diet without Pla2g1b inhibitor showed 31 and 69% body weight gain after 4 and 10 weeks respectively. These animals also showed elevated plasma glucose levels and were glucose intolerant. In contrast, C57BL/6 mice fed the diabetogenic diet with 90 mg.kg(-1) of methyl indoxam gained only 5% body weight after 10 weeks. These animals were also euglycaemic and displayed normal glucose excursion rates in glucose tolerance test. Methyl indoxam suppression of diet-induced body weight gain and glucose intolerance was correlated with the inhibition of Pla2g1b-mediated postprandial lysophospholipid absorption. | Clinically, constant severe trachoma predicts an increased risk of scarring in children. There are no data on the risk of scarring associated with constant infection with Chlamydia trachomatis, regardless of clinical manifestation. We propose to determine the 5-year incidence of scarring in children with a history of constant severe trachoma, constant infection, or both compared with children who had a history of neither. A 5-year, longitudinal observational study. Children aged less than 10 years with data on trachoma and infection for 3 of the 5 visits in the first 18 months, and follow-up 5-year data on scarring. Data were collected on clinical trachoma, and ocular swabs were taken to determine the presence of C. trachomatis in children in a hyperendemic village in Tanzania. Images were graded for scarring. Data were collected at baseline; 2, 6, 12, and 18 months; and 5 years from baseline. Severe trachoma was defined as the presence of 10 or more follicles, or trachoma intense. A child had constant infection (severe trachoma) if infection (severe trachoma) was present on at least 3 visits before the 5-year survey. Five-year risk of scarring. Of the 189 children, 22 (11.6%) had constant severe trachoma, but not constant infection. Nine children (4.8%) had constant infection but not constant severe trachoma. Both constant severe trachoma and constant infection were present in 16 children (8.5%). The 5-year incidence of scarring was similar in all 3 groups; children with constant severe trachoma only, with constant infection only, and with both were most likely to develop scars (35.0%, 44.4%, 31.2%, respectively) compared with those with sporadic trachoma or infection (15.2%) or neither (6.8%) (P = 0.0002). |
Does intracoronary verapamil rapidly terminate reperfusion tachyarrhythmias in acute myocardial infarction? | The restoration of coronary flow after transient ischemia immediately induces life-threatening ventricular tachyarrhythmias. Although most of these arrhythmias disappear spontaneously, some of them induce serious hemodynamic changes. This retrospective study investigates the efficacy of therapy with intracoronary verapamil to terminate reperfusion-induced ventricular tachyarrhythmias in patients with acute myocardial infarction (AMI). Between February 1992 and February 2003, 390 patients with a diagnosis of AMI were enrolled into the study. All patients received mechanical revascularization therapy within 6 h of onset of symptoms, and 109 patients experienced reperfusion-induced tachyarrhythmias. A subset of these patients was treated with intracoronary verapamil (0.25 to 1.0 mg) to terminate the reperfusion-induced tachyarrhythmia. They were evaluated for immediate termination of the tachyarrhythmias, hemodynamic changes, resumption rates, and major complications. Thirty-one patients (28%) were treated with intracoronary verapamil for the immediate termination of reperfusion-induced ventricular tachyarrhythmias. These tachyarrhythmias included 6 premature ventricular contractions, 19 accelerated idioventricular rhythms, 3 ventricular tachycardias, 2 ventricular fibrillations (VFs), and 1 torsades de pointes. Intracoronary verapamil was effective in rapidly terminating all reperfusion-induced arrhythmias except for VFs. The side effects of treatment included temporary hypotension (two patients) and bradycardia (one patient), although all patients recovered spontaneously. No major complications were induced by the intracoronary use of verapamil, and no resumptions of arrhythmias were documented. | White adipose tissue (WAT) consists of various depots with different adipocyte functionality and immune cell composition. Knowledge of WAT-depot-specific differences in expandability and immune cell influx during the development of obesity is limited, therefore we aimed to characterise different WAT depots during the development of obesity in mice. Gonadal WAT (gWAT), subcutaneous WAT (sWAT) and mesenteric WAT (mWAT) were isolated from male C57Bl/6J mice with different body weights (approximately 25-60 g) and analysed. Linear and non-linear regression models were used to describe the extent of WAT depot expandability and immune cell composition as a function of body weight. Whereas mouse sWAT and mWAT continued to expand with body weight, gWAT expanded mainly during the initial phase of body weight gain. The expansion diminished after the mice reached a body weight of around 40 g. From this point on, gWAT crown-like structure formation, liver steatosis and insulin resistance occurred. Mouse WAT depots showed major differences in immune cell composition: gWAT consisted mainly of macrophages, whereas sWAT and mWAT primarily contained lymphocytes. |
Is thyroid function associated with non-alcoholic fatty liver disease in chronic hepatitis B-infected subjects? | Associations between thyroid function and non-alcoholic fatty liver disease (NAFLD) are unknown in chronic hepatitis B (CHB)-infected patients. Thus, the aim of the study was to investigate the prevalence of thyroid dysfunction and its relationship with NAFLD in CHB. Consecutive naive CHB infected patients that had undergone liver biopsy and serum thyroid function tests between January 2007 and December 2011 were retrospective analyzed. NAFLD was diagnosed as at least 5% biopsy-proven hepatic steatosis without significant alcohol consumption. A total of 1154 non-alcoholics with CHB were included, 270 (23.39%) patients were found to have NAFLD, most of them (88.5%) with mild steatosis. The prevalence of hyperthyroidism and hypothyroidism (including subclinical and overt) was 1.56% and 1.64%, respectively, both with similar rates in patients with and without NAFLD (1.85% vs 1.47%, 1.48% vs 1.69%, respectively, both P > 0.05). The serum thyroid-stimulating hormone (TSH) level in NAFLD patients was significantly higher than that in patients without NAFLD (2.22 ± 2.13 vs 1.61 ± 1.20 mIU/L, P < 0.05). After adjustment for age and gender, the elevated TSH level was associated with increased odds of having steatosis (odds ratio1.54, 95% confidence interval 1.049-2.271) instead of viral factors and hepatic inflammation and fibrosis. | Platelets are believed to play an important role in atherogenesis and the vessel response to vascular injury. The P2Y(12) receptor (P2Y(12)) plays a central role in amplifying platelet aggregation, dense granule and alpha-granule secretion, P-selectin expression, microparticle formation, and procoagulant membrane changes, regardless of the activating stimulus. We hypothesized that P2Y(12) deficiency might reduce the vessel wall response to vascular injury as well as thrombosis in murine vascular injury models. P2Y(12)-deficient (-/-) mice and littermate controls (+/+) were bred on a C57 BL/6 background. In vivo murine models of arterial injury were employed alone and in combination with bone marrow transplantation to investigate the role of P2Y(12) in the vessel wall response to arterial injury and thrombosis. At 21 days after ferric chloride injury, neointima formation in P2Y(12)(-/-) arteries was significantly less than that observed in control strain arteries (P<0.025). In agreement with this, the intima-media ratio was significantly greater in femoral wire-injured arteries from P2Y(12)(+/+) compared with P2Y(12)(-/-) animals (P<0.05). Bone marrow transplantation was used to examine the importance of vessel wall P2Y(12) versus platelet P2Y(12). Analysis of arterial sections from chimeric animals at 21 days after injury revealed a smaller intima-media ratio in -/- to +/+ animals than in the positive (+/+ to +/+) control group (P<0.01). |
Is childhood caries still in force : a 15-year follow-up? | To examine changes in caries prevalence among 3 to 15-year-old adolescents. Of 1582 eligible mothers, 1443 gave informed consent. Participating children and their parents were followed up continuously from 3 to 15 years of age in a pre-planned fashion and at regular intervals. Data on dental health status were obtained from 1066/1287 adolescents (82%) during regular clinical dental examinations. Dentinal untreated caries (D) was seen among more than 26% of the adolescents at 15 years of age. Altogether, 4.9 carious teeth surfaces were affected in each case (mean). Close to 18% of the adolescents (186/1066) had poor dental health (DMFT was 5 or more) and 26% (271/1066) had DMFS 5 or more. | B-type natriuretic peptide (BNP) and N-terminal-pro-BNP (NT-pro-BNP) are important diagnostic tools for patients with suspected cardiac disorders. The aim of this study was to evaluate the predictive value of plasma NT-pro-BNP in identifying cardiac metastases in patients with non-small cell lung cancer (NSCLC) and dyspnoea. A total of 120 patients, median age 62 years (range 46-83), with NSCLC and dyspnoea were studied. Patients with heart failure or documented coronary artery disease were excluded. Echocardiographic imaging was used to detect cardiac metastases and estimate global left ventricular function. Ejection fraction and E/A ratio from transmitral inflow pattern were calculated. Plasma NT-pro-BNP was also measured. 72 patients (72/120, 60%) with cardiac metastases were identified. NT-pro-BNP was significantly higher in patients with metastases (1347.5 +/- 1004.30 pg/ml vs. 159.02 +/- 93.29 pg/ml; p = 0.001). No differences between groups, regarding s-creatinine (p = 0.45), haemoglobin (p = 0.71), left ventricular hypertrophy (p = 0.91), and diastolic dysfunction (p = 0.79), were observed. |
Is the neuroprotective effects of oxaloacetate in closed head injury in rats mediated by its blood glutamate scavenging activity : evidence from the use of maleate? | Treatment with oxaloacetate after traumatic brain injury has been shown to decrease blood glutamate levels and protect against the neurotoxic effects of glutamate on the brain. A number of potential mechanisms have been suggested to explain oxaloacetate-induced neuroprotection. We hypothesize that the primary mechanism by which intravenous oxaloacetate provides neuroprotection is by activation of the blood glutamate-scavenging enzyme glutamate-oxaloacetate transaminase, increasing thereby the driving force for the efflux of excess glutamate from brain interstitial fluids into blood. If so, coadministration of maleate, a glutamate-oxaloacetate transaminase-blocker is expected to prevent the neuroprotective effects of oxaloacetate. A neurological severity score (NSS) was measured 1 hour after closed head injury (CHI) in rats. Then, rats received 30 microL/min/100 g infusion of saline, or 1 mmol/100 g solution of oxaloacetate, maleate, or a mixture of oxaloacetate and maleate. NSS was reassessed at 24 and 48 hour after CHI. Blood glutamate and glucose levels were measured at 0, 60, 90, and 120 minutes. NSS improved significantly at 24 hour (P<0.001) and 48 hour (P<0.001) only in the rats treated with oxaloacetate. Blood glutamate decreased significantly in the oxaloacetate-treated group at 90 minute (at the conclusion of oxaloacetate administration) (P<0.00001), but not in the control, maleate or oxaloacetate+maleate groups. A strong correlation r2=0.86 was found to exist between the percent decrease in blood glutamate levels and percent improvement in NSS. | A consensus for which patients with thin melanomas (≤1 mm) should undergo sentinel lymph node biopsy (SLNB) is not established. We describe a large single institution experience with SLNB for thin melanomas to determine factors predictive of nodal metastases. Retrospective review from 2005 to 2010 identified 271 patients with thin melanomas who underwent SLNB, along with 13 additional patients not treated with SLNB who developed a nodal recurrence as first site of recurrence. Clinicopathologic characteristics were correlated with nodal status and outcome. Median age was 55 years, and 53% of patients were male. Median Breslow thickness was 0.85 mm. Overall, a positive sentinel lymph node (SLN) was found in 22 (8.1%) of 271 cases; 8.4% of melanomas ≥0.76 mm were SLN positive with 5% of T1a melanomas ≥0.76 mm and 13% of T1b melanomas ≥0.76 mm having SLN metastases. Only two of 33 highly selected patients with melanomas <0.76 mm (both T1b) had a positive SLN. Logistic regression analysis demonstrated that mitotic rate ≥1/mm(2) significantly correlated with nodal disease (p < 0.05) and ulceration correlated with SLN metastases (p < 0.05). Median follow-up was 2.1 years. Overall survival did not differ between positive and negative SLN patients (p = 0.53) but was worse for patients presenting with a nodal recurrence (p < 0.01). |
Does corneal thickness result in the Menicon Z 30-day continuous wear and ACUVUE 7-day extended-wear contact lens clinical trial? | This study was conducted to measure the corneal thickness changes associated with wearing 30-day tisilfocon A (Dk = 163) and 6-day etafilcon A (Dk = 28) contact lenses. The probable cause of the outcomes is discussed. Thirty subjects were fitted with Menicon Z rigid gas-permeable (RGP) contact lenses and a control group (n = 30) was fitted with ACUVUE hydrogel lenses, at two study sites. After a 2-week period of daily wear, subjects began prolonged wear. Measurements were performed at the dispensing visit, and then at the 2-week daily wear, the 1-week, 6-month, and 12-month extended- and continuous-wear visits. Repeated measures analysis of covariance was performed on mean corneal thickness. There was a significant increase in corneal thickness in the hydrogel lens extended-wear group compared to the RGP group (P = 0.03). The mean corneal thickness in the ACUVUE group was 2.58% higher at the 2-week daily wear visit, 2.38% higher at the 1-week extended-wear visit, 2.96% higher at the 6-month, and 2.97% higher at the 1-year visit compared to the RGP continuous-wear patients. | Protein kinase B (Akt) and the mitogen-activated protein kinases (MAPKs) mediate hypertrophy in the adult heart, although their importance in the developing heart is poorly understood. The goal of the current study was to determine if volume loading the fetal heart resulting from chronic anemia affects regulation of Akt and the MAPKs and if this response is developmentally regulated. Anemia was created by 7 days of isovolumic hemorrhage beginning at 101 days (early GA) or 129 days (late GA) gestational age (GA) in fetal sheep (term = 145 days), following which protein levels of total and active Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK), and p38 were determined in the right and left ventricle (RV and LV). RV protein-to-DNA ratios were also assessed. At both GAs, ventricular (RV + LV + septum) weight normalized to body weight was significantly increased in anemic fetuses. Anemia had no effect on expression of myocardial total or active Akt, JNK, or p38 at either GA. Levels of total ERK1/2 were also unchanged, although active ERK1/2 was significantly decreased in the late but not early GA anemic fetuses. Total JNK and total and active ERK1/2 and Akt were significantly greater in early versus late GA anemic fetuses. Protein-to-DNA ratios were unchanged in response to anemia at both GAs, but were greater in late GA compared to early GA anemic fetuses. |
Does boron-deficiency-responsive microRNAs and their targets in Citrus sinensis leave? | MicroRNAs play important roles in the adaptive responses of plants to nutrient deficiencies. Most research, however, has focused on nitrogen (N), phosphorus (P), sulfur (S), copper (Cu) and iron (Fe) deficiencies, limited data are available on the differential expression of miRNAs and their target genes in response to deficiencies of other nutrient elements. In this study, we identified the known and novel miRNAs as well as the boron (B)-deficiency-responsive miRNAs from citrus leaves in order to obtain the potential miRNAs related to the tolerance of citrus to B-deficiency. Seedlings of 'Xuegan' [Citrus sinensis (L.) Osbeck] were supplied every other day with B-deficient (0 μM H3BO3) or -sufficient (10 μM H3BO3) nutrient solution for 15 weeks. Thereafter, we sequenced two small RNA libraries from B-deficient and -sufficient (control) citrus leaves, respectively, using Illumina sequencing. Ninety one (83 known and 8 novel) up- and 81 (75 known and 6 novel) down-regulated miRNAs were isolated from B-deficient leaves. The great alteration of miRNA expression might contribute to the tolerance of citrus to B-deficiency. The adaptive responses of miRNAs to B-deficiency might related to several aspects: (a) attenuation of plant growth and development by repressing auxin signaling due to decreased TIR1 level and ARF-mediated gene expression by altering the expression of miR393, miR160 and miR3946; (b) maintaining leaf phenotype and enhancing the stress tolerance by up-regulating NACs targeted by miR159, miR782, miR3946 and miR7539; (c) activation of the stress responses and antioxidant system through down-regulating the expression of miR164, miR6260, miR5929, miR6214, miR3946 and miR3446; (d) decreasing the expression of major facilitator superfamily protein genes targeted by miR5037, thus lowering B export from plants. Also, B-deficiency-induced down-regulation of miR408 might play a role in plant tolerance to B-deficiency by regulating Cu homeostasis and enhancing superoxide dismutase activity. | While it is well-known that there is 18F-FDG uptake in breast tumors, clinical impact of (18)F-FDG PET in managing breast cancer patients is not well-studied. One hundred and thirty-three consecutive breast cancer patients from May 1996 to June 2000 were studied. All patients were treated and being followed. Reasons of referral included equivocal conventional studies, staging/re-staging, clinical suspicion of recurrence, and elevated serum tumor markers. Clinical status at 6 months postPET is used as the gold standard in lesions of worsening versus stable or improving. PET was 69% sensitive and 80% specific in predicting clinical stage at 6 months. This 69% of the patients who got worse at 6 months was PET positive and 80% of the patients who were stable or improving at 6 months were PET negative. There was a significant association between PET results and clinical outcome, after adjusting for stage of disease (P=0.04), or for the treatment patients received (P<0.01). Negative PET results changed therapy as often as positive ones did. PET influenced treatment decisions in 74% of the patients referred for study. |
Does living in rural New England amplify the risk of depression in patients with HIV? | The importance of depression as a complication of HIV infection is increasingly understood, and people living in rural areas are at increased risk for depression. However, it is not known whether living in rural areas amplifies the risk of depression in patients with HIV. We compared the prevalence of depression between rural and metropolitan HIV patients seen at the Dartmouth-Hitchcock HIV Program in a retrospective cohort study. Using the validated Rural-Urban Commuting Area Score, we categorized patients as living in small town/rural areas, micropolitan or metropolitan towns. Then, using a multivariate logistic regression model to adjust for demographic factors that differed between rural and metropolitan patients, we estimated the impact of living in rural areas on the odds of depression. Among 646 patients with HIV (185 small town/rural, 145 micropolitan, 316 metropolitan), rural patients were older, white, male, and men who have sex with men (ANOVA, F-statistic < 0.05). The prevalence of depression was highest in rural patients (59.5 vs. 51.7 vs. 41.2%, F statistic < 0.001), particularly rural patients on antiretroviral therapy (72.4 vs. 53.5 vs. 38.2%, F-statistic < 0.001. A multivariate logistic regression model showed that the odds of depression in rural patients with HIV were 1.34 (P < 0.001). | Scleroderma (SSc) is characterized by excess production and deposition of extracellular matrix (ECM) proteins. Activated fibroblasts play a key role in fibrosis in SSc and are resistant to Fas-mediated apoptosis. Acid sphingomyelinase (ASMase), a major sphingolipid enzyme, plays an important role in the Fas-mediated apoptosis. We investigated whether dysregulation of ASMase contributes to Fas-mediated apoptosis resistance in SSc fibroblasts. Fibroblasts were isolated from SSc patients and healthy controls. Western blot was performed to analyze protein levels and quantitative real time RT-PCR was used to determine mRNA expression. Cells were transiently transfected with siRNA oligos against ASMase or transduced with adenoviruses overexpressing ASMase. Apoptosis was induced using anti-Fas antibody (1 μg/mL) and analyzed using caspase-3 antibody or Cell Death Detection ELISA. SSc fibroblasts showed increased resistance to Fas-mediated apoptosis. ASMase expression was decreased in SSc fibroblasts and Transforming Growth Factor beta (TGFβ), the major fibrogenic cytokine involved in the pathogenesis of SSc, downregulated ASMase in normal fibroblasts. Forced expression of ASMase in SSc fibroblasts restored sensitivity of these cells to Fas-mediated apoptosis while blockade of ASMase was sufficient to induce partial resistance to Fas-induced apoptosis in normal fibroblasts. In addition, ASMase blockade decreased activity of protein phosphatase 2A (PP2A) through phosphorylation on Tyr(307) and resulted in activation of extracellular regulated kinase 1/2 (Erk1/2) and protein kinase B (Akt/PKB). |
Does reduced physical activity increase intermuscular adipose tissue in healthy young adults? | Recent findings suggest that higher levels of intermuscular adipose tissue (IMAT) are associated with glucose dysregulation, lower levels of muscle strength, and a heightened risk of disability. Although several studies have described adaptations in muscle after reduced physical activity, the change in IMAT in healthy young adults is unknown. The objective was to determine whether reduced lower limb activity alters IMAT in healthy young adults and to assess whether this change affects muscle strength loss. The subjects (6 men and 12 women aged 19-28 y) underwent a 4-wk control period, which was followed by 4 wk of unilateral lower limb suspension. Volumes of whole muscle, subcutaneous adipose tissue, and IMAT were assessed by using magnetic resonance imaging in the thigh and calf. Muscle strength was assessed during maximal voluntary isometric contractions. No changes were observed in the control period. Reduced physical activity decreased thigh and calf muscle volumes by 7.4% and 7.9% (P < 0.001), respectively; no significant change in subcutaneous adipose tissue was observed. Additionally, IMAT increased in both regions; the increase was larger in the calf (20%) than in the thigh (14.5%) (P <or= 0.005) and was partially explained by the loss in muscle (R(2) = 26%). The loss in strength was greater in the thigh (20.4%) than in the calf (15%). Strength loss was associated with increases in IMAT (P = 0.039) after adjustment for the loss in muscle, initial strength, initial IMAT, and initial muscle volume. | Aberrant expression of the cell cycle kinase inhibitors p16, p21, and p27 has been associated with poor prognosis in a variety of human malignancies. Little is known, however, about their clinical impact in vulvar carcinoma patients. Thus, we analyzed a larger series of vulvar squamous cell carcinomas and compared the results with clinical outcome. A total of 224 vulvar squamous cell carcinomas were immunohistochemically investigated for expression of p16, p21, and p27 using the biotin-streptavidin-peroxidase method and the OptiMax Plus automated cell staining system. High p16 (> or =5%) positive nuclear immunostaining was found in 69 (31%) cases, high p21 (any staining) protein levels was detected in 95 (42%) cases, and low p27 (< or =50% positive nuclei) staining was seen in 170 (76%) cases. High expression of p16 was related to lower patient age and low expression of p53. High expression of p16 indicated a better prognosis in the multivariate analysis (RR = 0.5, 95% CI = 0.2-1.0) and less risk of developing lymph node metastasis (OR = 0.3, 95% CI = 0.2-0.7). High level of p21 was significantly associated with shorter survival in patients staged FIGO I and II (RR = 3.4, 95% CI = 1.3-9.3). We found no significant correlation between the expression of p27 and any of the clinicopathological variables. |
Does miR-138 suppress Cell Proliferation by Targeting Bag-1 in Gallbladder Carcinoma? | MiR-138 is frequently downregulated in different cancer types and is thought to be involved in the progression of tumorigenesis. However, the molecular mechanism of miR-138 involvement in gallbladder carcinoma still remains unknown. The expression of miR-138 in 49 gallbladder carcinoma samples and paired normal gallbladder samples was analyzed using quantitative reverse transcription-polymerase chain reaction. The biological functions of miR-138 and Bag-1 (Bcl-2-associated athanogene-1) on cell proliferation were examined using 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide and apoptosis assays. Targets of miR-138 were predicted using bioinformatics and validated using luciferase reporter and Western blot analyses. The in vivo effects of miR-138 were examined using subcutaneous inoculation of gallbladder carcinoma cells in Balb/c nude mice. Compared with their paired normal gallbladder samples, the gallbladder carcinoma samples had decreased expression of miR-138 and increased expression of Bag-1. Overexpression of miR-138 inhibited the proliferation of gallbladder carcinoma cells. Bag-1 was defined as a novel target of miR-138. Both the inhibition of Bag-1 by miR-138 and the silencing of Bag-1 by siRNA led to alterations of apoptosis-related proteins such as Bcl-2 and Bax. Restoring expression of Bag-1 eliminates the effects of miR-138 on cell proliferation and apoptosis. Furthermore, overexpression of miR-138 markedly inhibited the growth of tumors in the gallbladder carcinoma xenograft model in nude mice. | The purpose of this randomized controlled cross-over study was to determine the acute effects of high doses of alcoholic beverages on circulating markers related to atherosclerosis and fibrinolysis. Twenty-two healthy men consumed a high dose (8.1+/-0.9 dl) of alcohol-containing red wine and dealcoholized red wine, and an equal ethanol dose of cognac (2.4+/-0.3 dl). Blood samples were taken before and shortly after interventions. Red wine, unlike dealcoholized red wine and cognac, increased tissue plasminogen activator inhibitor-1 levels significantly, indicating an acute inhibition of fibrinolysis after a high dose. |
Does high urinary albumin/creatinine ratio at admission predict poor functional outcome in patients with acute ischemic stroke? | Albuminuria and a low estimated glomerular filtration rate (eGFR) are widely recognised indices of kidney dysfunction and have been linked to cardiovascular events, including stroke. We evaluated albuminuria, measured using the urinary albumin/creatinine ratio (UACR), and the eGFR in the acute phase of ischemic stroke, and investigated the clinical characteristics of ischemic stroke patients with and those without kidney dysfunction. The study included 422 consecutive patients admitted between June 2010 and May 2012. General blood and urine examinations were performed at admission. Kidney dysfunction was defined as a low eGFR (<60 mL/min/1.73 m Kidney dysfunction was diagnosed in 278 of the 422 patients (65.9%). The eGFR was significantly lower and UACR was significantly higher in patients with a poor outcome than in those with a good outcome. In multivariate analyses performed after adjusting for confounding factors, UACR >31.2 mg/g creatinine (OR, 2.58; 95% CI, 1.52-4.43; P = 0.0005) was independently associated with a poor outcome, while a low eGFR was not associated. | This study was conducted to test the efficacy of a new cancer vaccine, composed of dendritic cells (DCs) pulsed with an interleukin-2 gene-encoded vaccinia virus tumor oncolysate (DC-IL-2VCO) in a CC-36 murine colon adenocarcinoma model. CC-36 tumor cells were injected subcutaneously into the left flank of four- to six-week old male BALB/c mice. The mice were divided into three groups, each of which received one of the following treatments: (1) DCs pulsed with the IL-2 gene-encoded vaccinia oncolysate (DC-IL-2VCO), (2) DCs pulsed with the tumor oncolysate alone (DC-CO), or (3) no treatment (control). Tumor incidence was measured, and survival rates were compared using a paired Student's t-test. Cytolytic T cell activity was measured in peripheral blood lymphocytes (PBL) and splenic lymphocytes using a (51)Cr-release assay. Lastly, mice were depleted of either CD4+ or CD8+ lymphocytes prior to receiving the vaccine to test the mechanism of tumor immunity in these mice. Mice treated with DC-IL-2VCO demonstrated decreased tumor burden, increased survival, and greater cytolytic activity compared with control mice and mice receiving DC-CO. In addition, mice depleted of CD8+ T cells prior to immunization with IL-2VV + DC-IL-2VCO had a significant increase in the incidence of tumor, similar to the untreated control mice. |
Does lRP1-dependent endocytic mechanism govern the signaling output of the bmp system in endothelial cells and in angiogenesis? | Among the extracellular modulators of Bmp (bone morphogenetic protein) signaling, Bmper (Bmp endothelial cell precursor-derived regulator) both enhances and inhibits Bmp signaling. Recently we found that Bmper modulates Bmp4 activity via a concentration-dependent, endocytic trap-and-sink mechanism. To investigate the molecular mechanisms required for endocytosis of the Bmper/Bmp4 and signaling complex and determine the mechanism of Bmper's differential effects on Bmp4 signaling. Using an array of biochemical and cell biology techniques, we report that LRP1 (LDL receptor-related protein 1), a member of the LDL receptor family, acts as an endocytic receptor for Bmper and a coreceptor of Bmp4 to mediate the endocytosis of the Bmper/Bmp4 signaling complex. Furthermore, we demonstrate that LRP1-dependent Bmper/Bmp4 endocytosis is essential for Bmp4 signaling, as evidenced by the phenotype of lrp1-deficient zebrafish, which have abnormal cardiovascular development and decreased Smad1/5/8 activity in key vasculogenic structures. | To identify pre-therapeutic predictors of sustained virological response (SVR) in Taiwanese patients with chronic hepatitis C. One hundred and ninety-eight consecutive patients receiving interferon plus ribavirin combination therapy were included. Stepwise logistic regression model was performed to estimate the SVR on the presence of various pre-therapeutic clinical parameters. The difference of alanine aminotransferase and aspartate aminotransferase levels (beta = 0.0080, P=0.0151), the presence of genotype 1b (beta = -1.9225, P<0.0001), the presence of dense packing of inflammatory cells in portal tract (beta = 1.5239, P=0.0354), age (beta = -0.0441, P=0.0179) and pre-therapeutic HCV-RNA concentration (beta = -0.0682, P=0.0411) were identified as independent predictors in the regression analysis. Patients with dense packing of inflammatory cells in portal tract (n=21) had significantly higher aspartate aminotransferase concentration, higher histology activity index, higher fibrosis score, and more histologically cirrhosis (P=0.032, 0.0001, 0.034, and 0.020, respectively). Paradoxically, they had a higher chance to achieve SVR (18/21 (85.7%) versus 99/177 (55.9%); P=0.017). |
Does prostaglandin E ( 2 ) suppress CCL27 production through EP2 and EP3 receptors in human keratinocytes? | The chemokine CCL27 attracts skin-homing T cells. CCL27 production by keratinocytes is enhanced in skin lesions from patients with atopic dermatitis or psoriasis vulgaris. It is suggested that prostaglandin E(2) (PGE(2)) regulates skin inflammation. We examined the in vitro effects of PGE(2) on CCL27 production in human keratinocytes. Keratinocytes were incubated with TNF-alpha in the presence or absence of PGE(2) . CCL27 secretion and mRNA level were analyzed by means of ELISA and RT-PCR, respectively. Nuclear factor kappaB (NF-kappaB)-dependent transcriptional activity was analyzed by using luciferase assays. TNF-alpha increased CCL27 secretion and mRNA levels in parallel to NF-kappaB activity in keratinocytes. NF-kappaB p50 or p65 antisense oligonucleotides suppressed TNF-alpha-induced CCL27 production, indicating the requirement of NF-kappaB for CCL27 production. PGE(2) , EP2, or EP3 agonists reduced TNF-alpha-induced CCL27 secretion and mRNA levels in parallel to NF-kappaB activity and CCL2, CCL5, CXCL8, and CXCL10 mRNA levels. Either EP3-specific or dual EP1-EP2 antagonist partially blocked the inhibitory effects of PGE(2) on CCL27 production and NF-kappaB activity, and the addition of both completely abrogated the inhibition, whereas EP1 or EP4 antagonists were ineffective. Intracellular Ca(2+) chelator BAPTA/AM or cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor H-89 partially blocked the inhibitory effects of PGE(2) on CCL27 production and NF-kappaB activity, and the addition of both completely abrogated the inhibition. PGE(2) or EP3 agonist increased intracellular Ca(2+) concentrations. PGE(2) or EP2 agonist increased intracellular cAMP concentrations. | Anemia is an established adverse risk factor in cardiovascular disease. However, the effect of preoperative anemia is not well defined in heart surgery. This study evaluates the effect of preoperative anemia on early clinical outcomes in patients undergoing cardiac surgery. A retrospective, observational, cohort study of prospectively collected data was undertaken on 7,738 consecutive patients undergoing heart surgery between April 2003 and February 2009. Of these, 1,856 patients with preoperative anemia were compared to 5,882 patients without anemia (control group). According to the World Health Organization, anemia was defined as hemoglobin level < 13 g/dl for men and <12 g/dl for women. Selection bias not controlled by multivariable methods was assessed with propensity-adjustment method. Overall mortality was 2.1%. Preoperative anemia was associated with tripling in the risk of death (4.6% vs 1.5%, p < 0.0001) and postoperative renal dysfunction (18.5% vs 6.5%, p < 0.0001). There was also a significant difference between the anemic and non-anemic group in the risk of postoperative stroke (1.9% vs 1.1%, p = 0.008), atrial fibrillation (36.7% vs 33%, p = 0.003) and length of hospital stay > 7 days (54% vs 36.7%, p < 0.0001). In propensity-adjusted, multivariable logistic regression, preoperative anemia was an independent predictor of mortality (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.02 to 2.03), postoperative renal dysfunction (OR 1.73, 95% CI 1.43 to 2.1) and length of hospital stay > 7 days (OR 1.3, 95% CI 1.15 to 1.47). |
Do importance of time-window overlap in the detection and analysis of embolic signals? | The detection of asymptomatic embolic signals by Doppler ultrasound may offer a powerful investigational tool in the management of cerebrovascular disease. However, early studies, particularly in patients with carotid artery disease, have reported very different frequencies of embolic signals. While this may reflect differences in patient groups and the criteria used for embolic signal identification, the degree of time-window overlap may be important. If this is insufficient, some embolic signals may fall between two time windows and not appear on the spectral display. Furthermore, the use of nonrectangular time windows, such as the Hanning window, may result in variation of the intensity of an embolic signal depending on where it is detected within the time window. To test the importance of this potential problem, the same 25 embolic signals recorded as the audio signal on digital audiotape were each played repeatedly through a transcranial Doppler ultrasound (TCD) system using fast Fourier transform analysis. An older system with no time-window overlap was used, and a more modern system was also used in which three different degrees of overlap were used: -9%, 27%, and 57%. The number of signals audible but not appearing on the spectral display was recorded. The variability in the relative intensity increase for the same embolic signal played repeatedly was estimated by calculating the coefficient of variation of the relative intensity increase. With the older system, 39/500 (7.8%) of embolic signals were missed. With the newer system, the number of embolic signals missed was fewer and decreased with increasing degrees of overlap (10/500 for -9% overlap, 1/500 for 27% overlap, and 0/500 for 57% overlap). For those setups in which embolic signals were missed, there was a highly significant relationship between duration of embolic signal and number of signals missed. In parallel with these results, the coefficient of variation of the relative intensity increase became progressively less with increasing degrees of time-window overlap. For all processing setups, the coefficient of variation was greater for the less intense and shorter duration signals, but this dependence, as estimated by the slope of the regression line, became less strong with higher degrees of overlap. | Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin-independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function. Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters--including time until insulin independence, insulin independence at one year, and C-peptide levels over one year--remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome. |
Does multicomponent Fitness Training improve Walking Economy in Older Adults? | Walking economy declines with increasing age, possibly leading to mobility limitation in older adults. Multicomponent fitness training could delay the decline in walking economy. This study aimed to determine the effect of multicomponent fitness training on walking economy in older adults. Participants were untrained adults, age 50 to 83 yr (N = 26, 10 males, age = 63 ± 6 yr, BMI = 25.6 ± 2.1 kg·m, mean ± SD). A control group was also recruited (N = 16, 9 males, age = 66 ± 10 yr, BMI = 25.4 ± 3.0 kg·m), matching the intervention group for age, weight, body composition, and fitness. The intervention group followed a multicomponent fitness program of 1 h, twice per week during 1 yr. The control group did not take part in any physical training. Fat-free mass, walking economy, and maximal oxygen uptake (V˙O2max) were measured in both groups before and after the year. Walking economy was measured with indirect calorimetry as the lowest energy needed to displace 1 kg of body mass for 1 m while walking on a treadmill. The data were compared between the two groups with repeated-measures ANOVA. Thirty-two subjects completed all measurements. There was an interaction between the effects of time and group on V˙O2max (P < 0.05) and walking economy (P < 0.05), whereas fat-free mass did not change significantly (P = 0.06). V˙O2max decreased by 1.8 mL·kg·min in the control group and increased by 1.3 mL·kg·min in the intervention group. The lowest energy needed to walk increased by 0.12 J·kg·m in the control group and decreased in the intervention group by 0.13 J·kg·m. | Sequential events of endometrial tumorigenesis can be studied by comparison of genetic lesions seen in normal, premalignant, and malignant tissues. The distribution of k-ras mutations in microsatellite stable and unstable premalignant lesions was studied to determine whether this gene is implicated in both tumorigenic pathways. K-ras mutations were analysed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing in matched endometrial normal, premalignant (atypical hyperplasias), and adenocarcinoma tissues from individual patients. Identification of precancers solely by their appearance as atypical endometrial hyperplasias is very subjective; therefore, in addition to histopathological assessment, we performed molecular testing (non-random X inactivation or clonal altered microsatellites) for an expected feature of precancers--that is, monoclonality. Equivalent K-ras mutation frequencies were seen in microsatellite stable (six of 33) and unstable (three of 23) cancers. In both types, K-ras mutation in monoclonal precancers usually corresponded to a change from normal to an equivocal (two of 12) or hyperplastic (10 of 12) histology. Divergent K-ras genotypes among multiple neoplastic tissues of individual patients (two of six patients) are exceptions explained either by multicentric premalignant disease, or acquisition of K-ras mutation late in neoplastic progression. |
Does chronic aerobic exercise improve blood pressure dipping status in African American nondippers? | The effects of exercise training on nocturnal blood pressure (BP) dipping status remain unclear. African Americans have the highest prevalence of nondippers compared with other racial/ethnic populations. In this 6-month study we tested the hypothesis that long-term aerobic exercise training would increase the levels of nocturnal BP dipping in African American nondippers. We recruited African Americans who were nondiabetic, nonsmoking, and free from cardiovascular and renal disease. For this analysis, only African Americans with a nondipping profile, defined as those with the absence of a nocturnal decline in systolic or diastolic BP (<10% of daytime values), which was determined by ambulatory BP monitoring, were chosen. A pre-post design was used, with baseline and final evaluation including office blood pressure measurement, 24-h ambulatory blood pressure monitoring, fasted blood sampling, and graded exercise testing. Participants engaged in 6 months of supervised aerobic exercise training (AEXT). Following the AEXT intervention, there were significant increases in systolic BP dipping (baseline: 5.8±3.9% vs. final: 9.4±6.1%, P=0.0055) and pulse pressure dipping (baseline: -3.1±6.6% vs. final: 5.0±12.8%, P=0.0109). Of the 18 participants with a nondipping profile at baseline, eight were nonclassified as nondippers after the AEXT intervention. There were no significant changes in office systolic BP/diastolic BP values following the AEXT intervention. | Throughout Asia, there is an unprecedented link between cholangiocarcinoma and infection with the liver fluke Opisthorchis viverrini. Multiple processes, including chronic inflammation and secretion of parasite proteins into the biliary epithelium, drive infection toward cancer. Until now, the mechanism and effects of parasite protein entry into cholangiocytes was unknown. Various microscopy techniques were used to identify O. viverrini extracellular vesicles (EVs) and their internalization by human cholangiocytes. Using mass spectrometry we characterized the EV proteome and associated changes in cholangiocytes after EV uptake, and we detected EV proteins in bile of infected hamsters and humans. Cholangiocyte proliferation and interleukin 6 (IL-6) secretion was measured to assess the impact of EV internalization. EVs were identified in fluke culture medium and bile specimens from infected hosts. EVs internalized by cholangiocytes drove cell proliferation and IL-6 secretion and induced changes in protein expression associated with endocytosis, wound repair, and cancer. Antibodies to an O. viverrini tetraspanin blocked EV uptake and IL-6 secretion by cholangiocytes. |
Is cD56 expression in T-cell acute lymphoblastic leukemia associated with non-thymic phenotype and resistance to induction therapy but no inferior survival after risk-adapted therapy? | Expression of CD56 has been associated with poor prognosis in acute myeloid leukemia and aggressive lymphoma. We analyzed the impact of CD56 expression in a cohort of 452 newly diagnosed adult T-cell acute lymphoblastic leukemia (T-ALL) patients; clinical data were available for 306 patients. Treatment was according to the GMALL study protocols 06/99 and 07/03 stipulating stratification into standard (thymic T-ALL) and high risk (pre- and mature T-ALL) groups. CD56 expression was detected in 63/452 (13.9%) patients. CD56(+) T-ALL were predominantly of non-thymic (pre-T 35%, mature 41%) immunophenotypic subtypes, whereas 53% of the CD56(-) cases were thymic T-ALL (p=0.00002). CD13, CD33, CD34 and HLA-DR were significantly more frequently expressed. A clonal T-cell receptor rearrangement was detected in 22/23 CD56(+) ALL. No major clinical differences were observed at presentation. Treatment of CD56(+) ALL resulted in a lower rate of complete remissions (70% vs. 88%) (p=0.001) and a higher rate of resistant disease (21% vs. 8%) (p=0.004). CD56 expression had no significant influence on overall (48% vs. 59%) and disease free survival (67% vs. 57%) at three years. | Tubuloglomerular feedback (TGF) is an important mechanism in control of signal nephron glomerular filtration rate. The oxidative stress in the macula densa, primarily determined by the interactions between nitric oxide (NO) and superoxide (O2-), is essential in maintaining the TGF responsiveness. However, few studies examining the interactions between and amount of NO and O2- generated by the macula densa during normal and hypertensive states. In this study, we used isolated perfused juxtaglomerular apparatus to directly measure the amount and also studied the interactions between NO and O2- in macula densa in both physiological and slow pressor Angiotensin II (Ang II)-induced hypertensive mice. We found that slow pressor Ang II at a dose of 600 ng kg(-1) min(-1) for two weeks increased mean arterial pressure by 26.1 ± 5.7 mmHg. TGF response increased from 3.4 ± 0.2 μm in control to 5.2 ± 0.2 μm in hypertensive mice. We first measured O2- generation by the macula densa and found it was undetectable in control mice. However, O2- generation by the macula densa increased to 21.4 ± 2.5 unit min(-1) in Ang II-induced hypertensive mice. We then measured NO generation and found that NO generation by the macula densa was 138.5 ± 9.3 unit min(-1) in control mice. The NO was undetectable in the macula densa in hypertensive mice infused with Ang II. |
Do perivascular cells along venules upregulate NG2 expression during microvascular remodeling? | Recently the authors have shown that neuron-glial antigen 2 (NG2) is expressed by perivascular cells along arterioles and capillaries, but not along venules in quiescent rat mesenteric microvascular networks. To investigate how the spatial distribution of this proteoglycan changes during microvascular remodeling, the objective of this study was to characterize the expression of NG2 in adult rat mesenteric microvascular networks undergoing active remodeling. The distribution of NG2 expression was evaluated in adult rat mesenteric microvascular networks. Tissues were harvested from 250 g, female, Sprague-Dawley rats at 1, 3, and 5 days poststimulation and double immunolabeled for NG2 and CD31 (endothelial cell marker). After 1 day, NG2 expression was observed along 27 +/- 11% of network draining venules (14-55 microm) and after 3 days, 59 +/- 10% of draining venules (13-59 microm) stained positive for the proteoglycan. By 5 days poststimulation, the percentage of network draining venules (18-59 microm) staining positive for NG2 returned to 18 +/- 7%, indicating a downregulation of the proteoglycan toward quiescent levels along larger-sized venules. | The use of zidovudine is associated with a loss of subcutaneous adipose tissue (SAT). We assessed if zidovudine treatment also affects visceral adipose tissue (VAT) and if uridine supplementation abrogates the adverse effects of zidovudine on VAT. Rats were fed zidovudine for 21 weeks with or without simultaneous uridine supplementation. Control animals did not receive zidovudine, or were treated with uridine alone. Changes in SAT and VAT were monitored by magnetic resonance imaging. Adipose tissue was examined for structural and molecular signs of mitochondrial toxicity. Zidovudine induced lipoatrophy in SAT and fat hypertrophy in VAT. Compared with controls zidovudine-exposed VAT adipocytes had increased diameters, microvesicular steatosis and enlarged mitochondria with disrupted crystal architecture on electron microscopy. VAT adipocyte mitochondrial DNA (mtDNA) copy numbers were diminished, as were mtDNA-encoded respiratory chain proteins. The 'common' mtDNA deletion was detected in high frequencies in zidovudine treated animals, but not in the controls. Although mtDNA depletion was more profound in SAT compared with VAT, the 'common' deletion tended to be more frequent in the VAT than in the SAT. Uridine coadministration abrogated all effects of zidovudine on VAT and SAT pathology. |
Does human epidermal growth factor receptor-2 positivity predict locoregional recurrence in patients with T1-T2 breast cancer? | To determine the impact of biological subtypes defined by hormonal receptors and human epidermal growth factor receptor-2 status on risk of recurrence in women with invasive breast cancer treated with breast-conserving therapy. Between 2001-2005, we observed 590 women with invasive breast cancer. They underwent conservative surgery, adjuvant radiotherapy and hormonotherapy or chemotherapy. None received adjuvant trastuzumab. The Kaplan-Meier method was applied to calculate for the 36-month and 60-month rates of locoregional recurrence-free survival and overall survival. The overall 36- and 60-month actuarial Kaplan-Meier survival rates were 98.5% and 97.7%, respectively; the locoregional recurrence-free survival rates were 95.2% and 91.2%, respectively. Locoregional recurrence rate was significantly greater in patients with human epidermal growth factor receptor-2 (15.2% vs. 5.3%, p<0.001). | The large animal model of arterial hypertension is very valuable to test the antihypertensive drugs and devices. We characterized a novel swine model of spontaneous hypertension and investigated its response to renal denervation (RDN). The blood pressure (BP), levels of plasma catecholamines and urine vanillylmandelic acid, and the protein expressions of angiotensin-converting enzyme (ACE) and angiotensin II type 1 (AT1), and type 2 (AT2) receptors in the rostral ventrolateral medulla (RVLM) were compared between domestic pigs and Guizhou mini-pigs. Twelve-month-old Guizhou mini-pigs were divided into sham (n = 7) and ablation (n = 7) groups. The mini-pigs in ablation group received bilateral percutaneous RDN with a saline-irrigated Sniper ablation catheter. Three months after the procedure, the BP was measured and the histology of renal nerves and arteries was analyzed. The mini-pigs spontaneously developed hypertension by the age of 6 months and the BP (162.2 ± 11.4/111.8 ± 9.2mm Hg) was significantly higher than age-matched domestic pigs (137.5 ± 1.9/80.2 ± 4.1mm Hg, P < 0.05). The levels of plasma catecholamines and urine vanillylmandelic acid were higher in mini-pigs than domestic pigs. The expressions of ACE and AT1 were increased, but the AT2 was decreased, in RVLM from mini-pigs compared with domestic pigs. Three months after the procedure, the BP was sharply reduced in ablation group (113.8 ± 14.4/79.4 ± 11.7 mm Hg) compared with sham group (192.4 ± 10.5/141.2 ± 5.9 mm Hg, P < 0.01). Renal nerves were substantially destroyed, while renal arteries and function were not significantly affected by ablation. |
Does ten weeks of rapid ventricular pacing create a long-term model of left ventricular dysfunction? | Rapid ventricular pacing produces a reliable model of heart failure. Cessation after 4 weeks of rapid ventricular pacing results in rapid normalization of left ventricular function, but the left ventricle remains persistently dilated. We present novel data that show that prolonged rapid ventricular pacing (10 weeks) creates a model of chronic left ventricular dysfunction. In 9 dogs undergoing 10 weeks of rapid ventricular pacing, left ventricular function and volumes were serially assessed by using 2-dimensional echocardiography and pressure-volume analysis for 12 weeks after cessation of pacing. Increased end-diastolic volume and decreased systolic and diastolic function were seen at the end of pacing. By 2 weeks of recovery from rapid ventricular pacing, end-diastolic volume and ejection fraction were partially recovered but did not improve further thereafter. Load-independent and load-sensitive indices of function obtained by pressure-volume analysis at 8 and 12 weeks of recovery confirmed a persistence of both systolic and diastolic dysfunction. In addition, left ventricular mass increased with pacing and remained elevated at 8 and 12 weeks of recovery. Four of these dogs studied at 6 months of recovery showed similar left ventricular abnormalities. | The recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-gamma production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn's disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts. Here we report that the presence of TL1A gene haplotype B increases risk in Jewish CD patients with antibody titers for the E. coli outer membrane porin C (OmpC+) (Haplotype B frequency in Jewish CD patients: 24.9% for OmpC negative and 41.9% for OmpC positive patients, respectively, P< or =0.001). CD14+ monocytes isolated from Jewish OmpC+ patients homozygous for TL1A gene haplotype B express higher levels of TL1A in response to FcgammaR stimulation, a known inducing pathway of TL1A, as measured by ELISA. Furthermore, the membrane expression of TL1A is increased on peripheral monocytes from Jewish but not non-Jewish CD patients with the risk haplotype. |
Do patients with cystic fibrosis have inducible IL-17+IL-22+ memory cells in lung draining lymph nodes? | IL-17 is an important cytokine signature of the TH differentiation pathway TH17. This T-cell subset is crucial in mediating autoimmune disease or antimicrobial immunity in animal models, but its presence and role in human disease remain to be completely characterized. We set out to determine the frequency of TH17 cells in patients with cystic fibrosis (CF), a disease in which there is recurrent infection with known pathogens. Explanted lungs from patients undergoing transplantation or organ donors (CF samples=18; non-CF, nonbronchiectatic samples=10) were collected. Hilar nodes and parenchymal lung tissue were processed and examined for TH17 signature by using immunofluorescence and quantitative real-time PCR. T cells were isolated and stimulated with antigens from Pseudomonas aeruginosa and Aspergillus species. Cytokine profiles and staining with flow cytometry were used to assess the reactivity of these cells to antigen stimulation. We found a strong IL-17 phenotype in patients with CF compared with that seen in control subjects without CF. Within this tissue, we found pathogenic antigen-responsive CD4+IL-17+ cells. There were double-positive IL-17+IL-22+ cells [TH17(22)], and the IL-22+ population had a higher proportion of memory characteristics. Antigen-specific TH17 responses were stronger in the draining lymph nodes compared with those seen in matched parenchymal lungs. | The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study showed that 40 mg Olmesartan medoxomil (OM) versus placebo delayed microalbuminuria onset in patients with type 2 diabetes and normoalbuminuria. One thousand seven hundred and fifty-eight ROADMAP patients (placebo arm: 877; OM arm: 881) participated in the observational follow up (OFU) with an average of 3.3 years. They received standard medical care and micro- and macrovascular events were documented. During observational follow-up 62.9% and 60.1% in the former OM and placebo group, respectively, received treatment with a RAS blocking agent. During the OFU period the systolic blood pressure (SBP) increased to mean values of 135 mm Hg in both groups. Patients who had developed microalbuminuria during ROADMAP had a higher incidence of cardio- and cerebrovascular events (OR 1.77, CI 1.03 to 3.03, P=0.039) during the OFU period compared with patients in whom this was not the case. Diabetic retinopathy was significantly reduced in the former OM group (8 [0.9%] versus 23 [2.6%], OR: 0.34, CI 0.15 to 0.78, P=0.011) and the rate of microalbuminuria was numerically reduced. Congestive heart failure requiring hospitalization (3 [0.3%] versus 12 [1.4%], OR: 0.23, CI 0.06 to 0.85, P=0.027) was reduced and there was a trend of reduced cardio-/cerebrovascular events (OM versus Pb: 73 [8.3%] versus 86 [9.8%] patients). Seven (0.8%) deaths (including 2 CV events) were reported in former placebo patients versus 3 (0.3%) (non-CV events) in former OM patients. |
Is penile Doppler ultrasound in men with stuttering priapism and sickle cell disease -- a labile baseline diastolic velocity a characteristic finding? | Stuttering priapism (SP) is seen in sickle cell disease (SCD) and characterized by short-lived painful erections. Imbalanced vascular tone is the postulated cause and this may be reflected in changes in baseline penile blood flow as measured using penile Doppler ultrasound (PDU). The aim of this study was to investigate the baseline penile blood flow characteristics in men with SCD and SP, by comparing with men without SP. PDU findings were retrospectively analyzed in 100 men during flaccid state. Nine men had SP (age range 20-40 years), 4 had Peyronie's disease (PD) (35-48 years), 67 men had erectile dysfunction (16-67 years), and 20 men had normal erectile function (18-42 years). The variables measured were peak systolic and end-diastolic velocities, and the Doppler velocity waveform. Values in men with SP were compared with those in the other groups. Median systolic and diastolic velocity was significantly higher in men with SP (systolic/diastolic velocity was 26/4 cm/second in men with SP vs. 13/0 cm/second, 14/0 cm/second, and 16/0 cm/second in men with PD, ED, and normal erectile function, respectively; P=0.0001). Men with SP had a characteristic low peripheral resistance (PR) waveform with fluctuating velocities; the diastolic velocity was consistently positive (2-7 cm/second) and fluctuated between +2 and +8 cm/second. In comparison, the other 91 men had high PR waveform and consistently negative diastolic velocity (range 0 to -2 cm/second). | The use of Salmonella to deliver heterologous antigens from DNA vaccines is a well-accepted extension of the success of oral Salmonella vaccines in animal models. Attenuated S. typhimurium and S. typhi strains are safe and efficacious, and their use to deliver DNA vaccines combines the advantages of both vaccine approaches, while complementing the limitations of each technology. An important aspect of the basic biology of the Salmonella/DNA vaccine platform is the relative contributions of prokaryotic and eukaryotic expression in production of the vaccine antigen. Gene expression in DNA vaccines is commonly under the control of the eukaryotic cytomegalovirus (CMV) promoter. The aim of this study was to identify and disable putative bacterial promoters within the CMV promoter and evaluate the immunogenicity of the resulting DNA vaccine delivered orally by S. typhimurium. The results reported here clearly demonstrate the presence of bacterial promoters within the CMV promoter. These promoters have homology to the bacterial consensus sequence and functional activity. To disable prokaryotic expression from the CMV promoter a series of genetic manipulations were performed to remove the two major bacterial promoters and add a bacteria transcription terminator downstream of the CMV promoter. S. typhimurium was used to immunise BALB/c mice orally with a DNA vaccine encoding the C-fragment of tetanus toxin (TT) under control of the original or the modified CMV promoter. Although both promoters functioned equally well in eukaryotic cells, as indicated by equivalent immune responses following intramuscular delivery, only the original CMV promoter was able to induce an anti-TT specific response following oral delivery by S. typhimurium. |
Does brain classification reveal the right cerebellum as the best biomarker of dyslexia? | Developmental dyslexia is a specific cognitive disorder in reading acquisition that has genetic and neurological origins. Despite histological evidence for brain differences in dyslexia, we recently demonstrated that in large cohort of subjects, no differences between control and dyslexic readers can be found at the macroscopic level (MRI voxel), because of large variances in brain local volumes. In the present study, we aimed at finding brain areas that most discriminate dyslexic from control normal readers despite the large variance across subjects. After segmenting brain grey matter, normalizing brain size and shape and modulating the voxels' content, normal readers' brains were used to build a 'typical' brain via bootstrapped confidence intervals. Each dyslexic reader's brain was then classified independently at each voxel as being within or outside the normal range. We used this simple strategy to build a brain map showing regional percentages of differences between groups. The significance of this map was then assessed using a randomization technique. The right cerebellar declive and the right lentiform nucleus were the two areas that significantly differed the most between groups with 100% of the dyslexic subjects (N = 38) falling outside of the control group (N = 39) 95% confidence interval boundaries. The clinical relevance of this result was assessed by inquiring cognitive brain-based differences among dyslexic brain subgroups in comparison to normal readers' performances. The strongest difference between dyslexic subgroups was observed between subjects with lower cerebellar declive (LCD) grey matter volumes than controls and subjects with higher cerebellar declive (HCD) grey matter volumes than controls. Dyslexic subjects with LCD volumes performed worse than subjects with HCD volumes in phonologically and lexicon related tasks. Furthermore, cerebellar and lentiform grey matter volumes interacted in dyslexic subjects, so that lower and higher lentiform grey matter volumes compared to controls differently modulated the phonological and lexical performances. Best performances (observed in controls) corresponded to an optimal value of grey matter and they dropped for higher or lower volumes. | Tumor necrosis factor (TNF)-α inhibition was shown to reduce ischemia/reperfusion injury (IRI) after intestinal transplantation (ITX). We studied the effects of different TNFα inhibitors on acute IRI and long-term inflammatory responses in experimental ITX. Orthotopic ITX was performed in an isogenic ischemia/reperfusion model in Lewis rats. The TNFα inhibition groups received infliximab post-reperfusion; etanercept pre-reperfusion and at postoperative days (POD) 1, 3, 5, and 7; or pentoxifylline pre-reperfusion and at POD 1 to 5. Tissue samples were taken from proximal and distal graft sections and mesenteric lymph nodes at 20 min, 12 hr, 7 day, and 6 months post-reperfusion for histopathology, immunohistology, terminal deoxyribosyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and real-time RT-PCR. Lung sections were stained for the myeloperoxidase assay. TNFα inhibitors decreased inflammatory changes after IRI in all treatment groups. Infliximab significantly improved 7-day survival and reduced the histological and immunohistochemical signs of IRI, the numbers of graft-infiltrating T cells and ED1 monocytes and macrophages, and pulmonary neutrophil infiltration, and also enhanced the accumulation of cytoprotective markers. Graft injury was more prominent in the distal graft than in the proximal graft in all groups, regardless of TNFα inhibition. |
Is diabetes an independent risk factor for severe nocturnal hypoxemia in obese patients . A case-control study? | Type 2 diabetes mellitus (T2DM) and obesity have become two of the main threats to public health in the Western world. In addition, obesity is the most important determinant of the sleep apnea-hypopnea syndrome (SAHS), a condition that adversely affects glucose metabolism. However, it is unknown whether patients with diabetes have more severe SAHS than non-diabetic subjects. The aim of this cross-sectional case-control study was to evaluate whether obese patients with T2DM are more prone to severe SAHS than obese non-diabetic subjects. Thirty obese T2DM and 60 non-diabetic women closely matched by age, body mass index, waist circumference, and smoking status were recruited from the outpatient Obesity Unit of a university hospital. The exclusion criteria included chronic respiratory disease, smoking habit, neuromuscular and cerebrovascular disease, alcohol abuse, use of sedatives, and pregnancy. Examinations included a non-attended respiratory polygraphy, pulmonary function testing, and an awake arterial gasometry. Oxygen saturation measures included the percentage of time spent at saturations below 90% (CT90). A high prevalence of SAHS was found in both groups (T2DM:80%, nondiabetic:78.3%). No differences in the number of sleep apnea-hypopnea events between diabetic and non-diabetic patients were observed. However, in diabetic patients, a significantly increase in the CT90 was detected (20.2+/-30.2% vs. 6.8+/-13,5%; p = 0.027). In addition, residual volume (RV) was significantly higher in T2DM (percentage of predicted: 79.7+/-18.1 vs. 100.1+/-22.8; p<0.001). Multiple linear regression analyses showed that T2DM but not RV was independently associated with CT90. | Intraoperative electron radiation therapy (IOERT) is a therapeutic technique which administers a single high dose of ionizing radiation immediately after surgical tumor removal. IOERT induces a strong stress response: both tumor and normal cells activating pro- and antiproliferative cell signaling pathways. Following treatment, several genes and factors are differently modulated, producing an imbalance in cell fate decision. However, the contribution of these genes and pathways in conferring different cell radiosensitivity and radioresistance needs to be further investigated, in particular after high-dose treatments. Despite the documented and great impact of IOERT in breast cancer care, and the trend for dose escalation, very limited data are available regarding gene-expression profiles and cell networks activated by IOERT or high-dose treatment. The aim of the study was to analyze the main pathways activated following high radiation doses in order to select for potential new biomarkers of radiosensitivity or radioresistance, as well as to identify therapeutic targets useful in cancer care. We performed gene-expression profiling of the MCF7 human breast carcinoma cell line after treatment with 9- and 23-Gy doses (conventionally used during IOERT boost and exclusive treatments, respectively) by cDNA microarrays. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), immunofluorescence and immunoblot experiments were performed to validate candidate IOERT biomarkers. We also conducted clonogenic tests and cellular senescence assays to monitor for radiation-induced effects. The analyses highlighted a transcriptome dependent on the dose delivered and a number of specific key genes that may be proposed as new markers of radiosensitivity. Cell and molecular traits observed in MCF7 cells revealed a typical senescent phenotype associated with cell proliferation arrest after treatments with 9- and 23-Gy doses. |
Do bone Marrow Stromal Cells Inhibit the Activation of Liver Cirrhotic Fat-Storing Cells via Adrenomedullin Secretion? | Cirrhosis, or liver fibrosis, which is mainly triggered by cirrhosis fat-storing cells (CFSCs) activation, has traditionally been considered an irreversible disease. However, recent observations indicate that even advanced fibrosis is still reversible by removing the causative agents. Anti-fibrotic effects of bone marrow-derived stromal cells (BMSCs) have been demonstrated by inhibiting CFSCs via cytokines secretion; however, the mechanisms are still unclear. The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated CFSCs. After the co-culture of CFSCs with BMSCs supernatants with or without the addition of recombinant rat adrenomedullin (AM)/AM-specific siRNA, western blot analysis was mainly used to detect the differences of relative protein expression on CFSCs. BMSC-secreted adrenomedullin (AM) effectively inhibited the proliferation and activation of CFSCs by suppressing the expression of Ang II and its binding receptor, AT1, which resulted in a reduction of p47-phox formation. | The goal of this study was to compare language lateralization between pediatric epilepsy patients and healthy children. Two groups of subjects were evaluated with functional magnetic resonance imaging (fMRI) by using a silent verb-generation task. The first group included 18 pediatric epilepsy patients, whereas the control group consisted of 18 age/gender/handedness-matched healthy subjects. A significant difference in hemispheric lateralization index (LI) was found between children with epilepsy (mean LI =-0.038) and the age/gender/handedness-matched healthy control subjects (mean LI=0.257; t=6.490, p<0.0001). A dramatic difference also was observed in the percentage of children with epilepsy (77.78%) who had atypical LI (right-hemispheric or bilateral, LI<0.1) when compared with the age/gender/handedness-matched group (11.11%; chi(2)=16.02, p<0.001). A linear regression analysis showed a trend toward increasing language lateralization with age in healthy controls (R(2)=0.152; p=0.108). This association was not observed in pediatric epilepsy subjects (R(2)=0.004, p=0.80). A significant association between language LI and epilepsy duration also was found (R(2)=0.234, p<0.05). |
Does hypotension increase mortality in brain-injured patients more than it does in non-brain-injured Patients? | Hypotension increases mortality after all types of injuries. Prior studies comparing mortality of hypotensive traumatic brain injury (TBI) patients to normotensive TBI patients have implied that hypotension is particularly detrimental after TBI. It is unknown whether hypotension affects TBI patients more severely than it affects other types of patients. We hypothesized that hypotension does not increase mortality in TBI patients more than it does in non-TBI patients. National Trauma Data Bank (1994-2002) patients aged 18 to 45 years with blunt mechanisms of injury treated at Level I and Level II centers were included. Deaths occurring before 24 hours were excluded. Logistic regression was used to measure the association between hypotension (< or =90 mm Hg) and death after adjusting for confounding variables of age, gender, comorbidities, complications, Glasgow Coma Scale score, and severity of associated injuries. Odds ratios (95% confidence interval) indicate the risk of death in hypotensive patients in each group compared with normotensive patients in the same group. The study population consisted of 79,478 patients (TBI, 30,742; no TBI, 48,736). Hypotension independently quadrupled the risk of death after adjusting for confounding variables (odds ratio [OR], 4.8; 95% confidence interval [CI], 4.1-5.6). However, increase in this risk associated with hypotension was the same in TBI (OR, 4.1; 95% CI, 3.5-4.9) and non-TBI patients (OR, 4.6; 95% CI, 3.4-6.0). Furthermore, the relationship between hypotension and TBI did not change with increasing head Abbreviated Injury Scale score severity. | Cetuximab, a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR), is currently used in metastatic colorectal cancer (mCRC), but predictive factors for therapeutic response are lacking. Mutational status of KRAS and EGFR, and EGFR copy number are potential determinants of cetuximab activity. We analyzed tumor tissues from 32 EGFR-positive mCRC patients receiving cetuximab/irinotecan combination and evaluable for treatment response. EGFR copy number was quantified by fluorescence in situ hybridization (FISH). KRAS exon 1 and EGFR exons coding for extracellular regions were sequenced. Nine patients experienced an objective response (partial response) and 23 were considered as nonresponders (12 with stable disease and 11 with progressive disease). There was no EGFR amplification found, but high polysomy was noted in 2 patients, both of which were cetuximab responders. No EGFR mutations were found but a variant of exon 13 (R521K) was observed in 12 patients, 11 of which achieved objective response or stable disease. Progression-free and overall survivals were significantly better in patients with this EGFR exon 13 variant. KRAS mutations were found in 14 cases. While there was a trend for an increased KRAS mutation frequency in nonresponder patients (12 mutations out of 23, 52%) as compared to responder patients (2 out of 9, 22%), authentic tumor response or long-term disease stabilization was found in KRAS mutated patients. |
Do lactotripeptides lower ambulatory blood pressure in untreated whites : results from 2 controlled multicenter crossover studies? | Dietary factors directly influence blood pressure (BP). The lactotripeptides (LTPs) IPP (isoleucine-proline-proline) and VPP (valine-proline-proline), formed by hydrolyzing dairy proteins, and potassium, a mineral mainly found in fruit, vegetables, and dairy products, are extensively studied for their BP-lowering effect. The efficacy of LTPs seems modest in whites compared with that in Asians. The objective was to study the effects of enzymatically produced LTPs alone or in combination with potassium on ambulatory BP in whites. Two multicenter, placebo-controlled, randomized, crossover studies were conducted; each consisted of two 4-wk intervention periods separated by a 4-wk washout period. In study 1, 69 subjects received 200 g/d of a dairy drink with 5.8 mg IPP and 4.4 mg VPP or placebo. In study 2, 93 subjects received 100 g/d of a dairy drink with 2.7 mg IPP, 1.9 mg VPP, and 350 mg added K or placebo. The subjects were randomly assigned according to their daytime ambulatory BP. Mean 24-h systolic and diastolic BP (baseline values-study 1: 137.1/81.6 mm Hg; study 2: 139.2/80.9 mm Hg) remained similar with no significant differences between treatments in either study (P > 0.10). Office BP decreased over the course of both studies (systolic BP > 5 mm Hg), but differences between interventions were not significant (P > 0.10). In both studies, nighttime BP dipped during all treatments (> or =15%) but was statistically more significant with placebo (P < 0.05). Sodium excretion increased significantly after consumption of LTPs and potassium compared with after placebo intervention (P = 0.01), but not after consumption of LTPs alone. | Previous studies found that transforming growth factor-beta (TGF-beta) induces mesothelial production of connective tissue growth factor (CTGF), which may be downstream mediators of TGF-beta. Since high dose TGF-beta induces apoptosis of peritoneal mesothelial cells (PMC), we study the effect of CTGF blockade in the system of TGF-beta-induced PMC apoptosis. We examined the effect of TGF-W in primary culture of rat peritoneal mesothelial cells (PMC). PMC apoptosis was studied by flow cytometry. The effect of CTGF was blocked by antibody and short-interfering RNA (siRNA). Expression of apoptotic gene was studied by real-time polymerase chain reaction. In cultured unstimulated rat PMC, there is a low but definite incidence of spontaneous apoptosis. Stimulation with TGF-beta 50 pg/ml induces an upregulation of apoptotic gene BAX expression and a downregulation of anti-apoptotic gene BCL-2L expression, and a 4-fold increase in PMC apoptosis. The effect of TGF-beta-induced PMC apoptosis was partly prevented by antibody against CTGF, and completely abolished by CTGF-specific siRNA, while CTGF-blockade by siRNA had no effect on PMC necrosis. CTGF silencing by siRNA prevented the down-regulation of BCL-2L expression induced by TGF-beta, had no effect on the BAX expression. |
Is 10.5-kb homozygote of tumor necrosis factor-beta gene associated with a better prognosis in gastric cancer patients? | In NcoI restriction fragment length polymorphism analysis of tumor necrosis factor-beta (TNF-beta) gene, the frequency of 10.5-kb homozygote is low in patients with lung cancer and is associated with a better prognosis. These results should be examined in other malignancies. Using polymerase chain reaction, the authors performed NcoI restriction fragment length polymorphism analysis in 152 patients with gastric cancer, in 69 patients with benign gastric lesion, and in 141 healthy volunteers. In 3-year survival, the 10.5-kb homozygote showed a better prognosis (87.1%) than other alleles (5.5-kb homozygote, 52.5%; heterozygote, 79.1%), and there was a statistically significant difference between the 10.5-kb homozygote and the 5.5-kb homozygote. In 3-year survival for Stages III and IV, the 10.5-kb homozygote also showed a better prognosis (64.9%) than other alleles (5.5-kb homozygote, 16.7%; heterozygote, 41.4%). There were statistically significant differences (10.5-kb homozygote vs. 5.5-kb homozygote, P < 0.01; heterozygote vs. 5.5-kb homozygote, P < 0.05). There was a statistical difference between all patients and Stages III and IV (P < 0.05). | Reduced fertilization rates in women with minor endometriosis may be the result of direct effects on the ovary or to primary dysfunction within the hypothalamic-pituitary-ovarian axis. This controlled study was designed to examine the steroidogenic potential of luteinized granulosa cells in women with minor endometriosis. Granulosa cells were harvested at oocyte recovery and incubated for 3 hr in increasing concentrations of luteinizing hormone (LH). The dissociation constant for added concentrations of LH was computed (as Km LH) and the results were compared between women with endometriosis and controls. Women with minor endometriosis had a higher dissociation constant than women with tubal damage [Km 0.98 (0.58-9.24) versus 0.33 (0.28-0.72) ng/mL, P = 0.019], indicating reduced sensitivity to LH. |
Do hER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients? | Early metastasis in node-negative breast cancer indicates that breast cancer cells obviously can bypass the lymph nodes and disseminate directly hematogenous to distant organs. For this purpose, we evaluated the prognostic value of blood-borne, HER2-positive circulating tumor cells (CTC) in the peripheral blood from 42 breast cancer patients with a median follow-up of 95 months. Cells were isolated by the patented combined buoyant density gradient and immunomagnetic separation procedure and analyzed by immunocytochemistry. We detected one to eight CTCs in the peripheral blood of 17 of 35 patients (48.6%) presenting no overt metastasis. As a positive control, 7 of 7 (100%) patients with metastatic disease presented positive. Healthy persons and patients (n = 32) operated for nonmalignant diseases presented negative for CTCs. The presence and frequency of HER2-positive CTCs correlated with a significantly decreased disease-free survival (P < 0.005) and overall survival (P < 0.05). Interestingly, in 12 patients with HER2-positive CTCs, the primary tumor was negative for HER2 as assessed by immunohistochemical score and fluorescence in situ hybridization. | Serotonergic dysfunction is implicated in depression, psychiatric disorders and suicidal behaviors. The first and rate-limiting step in the synthesis of serotonin is catalyzed by tryptophan hydroxylase (TPH) which is encoded by TPH1 and THP2 genes. Genetic association studies have revealed contradictory results about the effect of the TPH1 A218C (rs1800532) polymorphism on suicidal behavior in different populations. In this study, we investigated A218C polymorphism in 109 suicide attempters and 98 healthy controls. Socio-demographic characteristics of participants were obtained through questionnaire. DNA was extracted from peripheral blood and genotyping was performed by Real Time PCR. Fisher's exact test was used to evaluate the significance of the difference among the independent variables. Hardy-Weinberg equilibrium was tested using Pearson's goodness-of-fit chi-squared test. The frequency of A allele was significantly higher in suicide attempters than controls (46.33% vs. 35.71%, p=0.0357). However, there were no differences in genotype frequencies of this locus between participants having attempted suicide and controls (p>0.05). Among males, frequencies of CC genotype and C allele were found to be significantly higher in controls (p=0.0125, p=0.0298). With regard to the female subjects and female controls, no significant association was detected between suicidal behavior and genotype/allele frequencies (p>0.05). |
Does alcohol disrupt levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis? | Excessive consumption of ethanol is one of the most common causes of acute and chronic pancreatitis. Alterations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) also cause pancreatitis. However, little is known about the role of CFTR in the pathogenesis of alcohol-induced pancreatitis. We measured CFTR activity based on chloride concentrations in sweat from patients with cystic fibrosis, patients admitted to the emergency department because of excessive alcohol consumption, and healthy volunteers. We measured CFTR levels and localization in pancreatic tissues and in patients with acute or chronic pancreatitis induced by alcohol. We studied the effects of ethanol, fatty acids, and fatty acid ethyl esters on secretion of pancreatic fluid and HCO3(-), levels and function of CFTR, and exchange of Cl(-) for HCO3(-) in pancreatic cell lines as well as in tissues from guinea pigs and CFTR knockout mice after administration of alcohol. Chloride concentrations increased in sweat samples from patients who acutely abused alcohol but not in samples from healthy volunteers, indicating that alcohol affects CFTR function. Pancreatic tissues from patients with acute or chronic pancreatitis had lower levels of CFTR than tissues from healthy volunteers. Alcohol and fatty acids inhibited secretion of fluid and HCO3(-), as well as CFTR activity, in pancreatic ductal epithelial cells. These effects were mediated by sustained increases in concentrations of intracellular calcium and adenosine 3',5'-cyclic monophosphate, depletion of adenosine triphosphate, and depolarization of mitochondrial membranes. In pancreatic cell lines and pancreatic tissues of mice and guinea pigs, administration of ethanol reduced expression of CFTR messenger RNA, reduced the stability of CFTR at the cell surface, and disrupted folding of CFTR at the endoplasmic reticulum. CFTR knockout mice given ethanol or fatty acids developed more severe pancreatitis than mice not given ethanol or fatty acids. | Decreases in mate and/or pollinator availability would be expected to affect the selective pressure on plant mating systems. An increase in self-fertilization may evolve to compensate for the negative effects of pollination failure. However, the benefit of selfing in variable pollination environments depends on the relative fitnesses of selfed and outcrossed progeny. We investigated the potential for selfing to provide reproductive assurance over the lifetime of a long-lived perennial species and its variation between plant patches of various sizes. Patch size is likely to affect mate and pollinator availabilities, thereby affecting pollination success and the rate of selfing. We estimated fruit and seed set, reproductive assurance, self-compatibility, the multilocus patch selfing rate and lifetime inbreeding depression in natural patches of Rhododendron ferrugineum (Ericaceae), a mass-flowering species characterized by considerable patch size variation (as estimated by the total number of inflorescences). Open seed set declined linearly with increasing patch size, whereas pollinator-mediated seed set (emasculated flowers) was not significantly affected. Progeny array analysis indicated that the selfing rate declined with increasing patch size, consistent with greater reproductive assurance in small sparse patches than in large, dense patches. However, fruit set and adult fitness decreased with decreasing patch size, with an estimated mean lifetime inbreeding depression of 0.9 (obtained by comparing F values in adults and progenies). |
Is dexamethasone diffusion across contact lenses inhibited by Staphylococcus epidermidis biofilms in vitro? | This study was designed to measure the impact of bacterial biofilms on diffusion of an ocular therapeutic through silicone hydrogel bandage lenses in vitro. An assay was designed to study the passage of a commonly used steroid, dexamethasone, through silicone hydrogel soft contact lenses. Diffused dexamethasone was measured using a spectrophotometer over a period of 18 hours and quantified using a standard curve. This assay was performed with control and Staphylococcus epidermidis biofilm-coated contact lenses comprised of lotrafilcon A and methafilcon. Biofilms were formed in brain heart infusion broth supplemented with D-glucose. The presented data validate a simple in vitro model that can be used to measure the penetration of a topical therapeutic through silicone hydrogel soft contact lenses. Using this model, we measured a reduction in dexamethasone diffusion up to 88% through S. epidermidis biofilm-coated silicone hydrogel lenses compared with control lenses. | Central core disease is a congenital myopathy, characterized by presence of central core-like areas in muscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is caused by mutations in the human ryanodine receptor gene (RYR1), which encodes a calcium-release channel. Since the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three 'hot spots', with particular attention to the C-terminal region. Recent next-generation sequencing methods are now identifying multiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult. In a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a new case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1 gene identified two different missense mutations: c.14256 A > C polymorphism in exon 98 and c.14693 T > C in exon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed because patient's daughter, mother and sister carried only the exon 98's mutation, a synonymous variant that was subsequently found in the frequency of 013-0,05 of alleles. Further next generation sequencing study of the whole RYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and 8 polymorphisms in heterozygosis. |
Are dietary fatty acid intakes related to the risk of ulcerative colitis : a case-control study? | The role of dietary fatty acids in ulcerative colitis (UC) pathogenesis has been shown in animal models; however, human studies are rare. We hypothesized that there might be a relationship between dietary fatty acid composition and the risk of developing incident UC. Overall, 62 new cases of UC and 124 healthy age and sex-matched controls were studied. Information on usual diet was measured by a validated country-specific food frequency questionnaire (FFQ). Logistic regression analysis adjusting for potential confounding variables was carried out to compare dietary fatty acid intakes between cases and controls. We found positive associations between dietary intake of total fat (P value for trend <0.01), oleic acid (P value for trend <0.01), saturated fatty acid (SAFA) (P value for trend = 0.02), total polyunsaturated fatty acid (PUFA) (P value for trend = 0.04), and trans fat (P value for trend <0.01). | The objective of this study was to determine the renal protective effects of TCV 116, a novel, non-competitive, angiotensin II type 1 (AT1) receptor antagonist, in rats with 5/6 renal mass ablation. Adult male Wistar rats were subjected to 5/6 nephrectomy and treated continuously with either TCV 116 (group I, n = 8; group III, n = 9) or vehicle (group II, n = 8; group IV, n = 8). The development of elevated systolic blood pressure, 24-h urinary protein excretion, glomerular hemodynamics and glomerular morphology were compared among groups. Systolic blood pressure rapidly reached hypertensive levels in group II, increasing from 175 +/- 8 mmHg after 3 weeks to 221 +/- 15 mmHg after 12 weeks, whereas group I rats remained normotensive (101 +/- 8 to 112 +/- 6 mmHg). Similarly, urinary protein excretion increased from 45 +/- 11 to 104 +/- 18 mg/day in group II, but remained low (6.9 +/- 1 to 19 +/- 4 mg/day) in group I. After 12 weeks, there was an average of 42 +/- 6% glomerulosclerosis in group II, but only 1.6 +/- 0.5% in group I. After 4-6 weeks, a markedly elevated glomerular capillary pressure (62 +/- 1.2 mmHg) was observed in group IV, but the pressure was normal in group III (50 +/- 1.1 mmHg). |
Does emulsified Isoflurane protect Against Transient Focal Cerebral Ischemia Injury in Rats via the PI3K/Akt Signaling Pathway? | Phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathway activation may promote neuronal survival via neuroprotection during inflammation after cerebral ischemia. In this study, we investigated whether IV pretreatment with emulsified isoflurane (EI) could decrease ischemic brain injury related to the PI3K/Akt pathway. Male Sprague-Dawley rats received different doses of IV EI (1, 2, 4, or 8 mL/kg/h) or Intralipid (8 mL/kg/h) for 30 minutes (n = 6-12 per group), followed by middle cerebral artery occlusion (MCAO) for 100 minutes to induce transient focal ischemia. The neurologic score and infarct volume were measured 48 hours after MCAO. Immunostaining, Western blot analysis, and an enzyme-linked immunosorbent assay were used to assess EI effects on the cell inflammatory response, high-mobility group box-1 release, and phosphorylated Akt (expression. LY294002, a PI3K inhibitor, was also infused into the ventricular space before EI to determine the effect of EI. Four milliliters per kilogram per hour of EI reduced the infarct size (21.08 ± 11.24 vs 37.09 ± 10.46, P = 0.006), improved neurologic scores after MCAO (1.13 ± 0.48 vs 1.95 ± 0.65, P = 0.015), significantly reinforced neuronal survival (982.7 ± 364.4 vs 439.8 ± 278.4, P = 0.036), and inhibited CD68 macrophage/macroglial infiltration in the ischemic core (188.2 ± 49.1 vs 282 ± 49.4, P = 0.018) compared with the vehicle group. In the EI pretreatment group, the serum high-mobility group box-1 concentration (3.62 ± 0.72 vs 5.73 ± 0.65, P < 0.001) was decreased, and the cerebral phosphorylated Akt level (50.33 ± 4.73 vs 37.5 ± 3.11, P = 0.007) was increased at 48 hours, which was inhibited by LY294002 compared with the vehicle group (5.31 ± 0.72 vs 5.73 ± 0.65, P = 0.216; 43.00 ± 4.84 vs 37.5 ± 3.11, P = 0.091). | To compare the frequency of Pap test results in a prospective series of direct to vial ThinPrep tests to a cohort of conventionally prepared tests. To follow-up all test results for a minimum of 2 years and assess performance based on this outcome. All women presenting for either routine screening or colposcopic examination in 2001 were enrolled in the ThinPrep cohort. A similar, population of conventionally prepared tests was extracted from the year 2000 laboratory data. Information on all concurrent and follow-up cervical specimens over the ensuing 2 years was retrieved. The ThinPrep cohort comprised 2288 Pap tests and the conventional, 2211. The frequency of normal [within normal limits (WNL) and benign cellular changes (BCC)] results in the ThinPrep cohort was 6% lower and the frequency of abnormal [> or =atypical squamous cells of undetermined significance (ASCUS)] results was 6.8% higher. Respective ThinPrep and conventional cohort results were 1156 (51%) and 1291 (58%) WNL, 625 (27%) and 561 (25%) BCC, 101 (4%) and 65 (3%) ASCUS, 21 (1%) and 2 (0.1%) atypical glandular cells of undetermined significance, 301 (13%) and 224 (10%) low-grade squamous intraepithelial lesion (LSIL), and 74 (3%) and 40 (2%) high-grade SIL (HSIL) (P < 0.0001). Follow-up was available for nearly 80% of each cohort. LSIL or higher was confirmed in 57.5% (n = 266) of the abnormal ThinPrep and 60.9% (n = 190) of the abnormal conventional tests. The ThinPrep yield of confirmed tests however was almost 50% higher than the conventional test. |
Does germinal center B cell depletion diminish CD4+ follicular T helper cells in autoimmune mice? | Continuous support from follicular CD4(+) T helper (Tfh) cells drives germinal center (GC) responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization. Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model. | Although moderate (conscious) sedation is intended during elective gastrointestinal endoscopy, unintended levels of deep sedation occur. The aims of this study were to prospectively evaluate the incidence and risk factors of deep sedation during elective endoscopy with meperidine and midazolam intended to maintain a level of moderate sedation. Eighty American Society of Anesthesiology class 1-2, outpatients presenting for elective esophagogastroduodenoscopy (EGD), colonoscopy, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasonography (EUS) were offered enrollment. Intravenous meperidine and midazolam were administered according to a standardized protocol. Hemodynamic parameters and levels of sedation were assessed and recorded by a single observer at 3-min intervals. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale (ranging 1-5) is a subjective sedation assessment scale used to assess sedation levels. Occurrence of deep sedation, defined by MOAA/S 1-2, was recorded. Univariable and multivariable analyses were used to assess predictors of deep sedation. Deep sedation occurred in 54/80 (68%) patients for a total of 204/785 (26%) of total sedation assessments. The percentage of deep sedation episodes of all sedation-level observations by procedure was 26% for EGD, 11% for colonoscopy, 35% for ERCP, and 29% for EUS. Deep sedation occurred at least once in 60% of EGD, 45% of colonoscopy, 85% of ERCP, and 80% of EUS. Multivariable analysis showed that only ERCP and EUS were independent risk factors of deep sedation. |
Is systemic tacrolimus ( FK 506 ) effective for the treatment of psoriasis in a double-blind , placebo-controlled study . The European FK 506 Multicentre Psoriasis Study Group? | Fifty patients with severe recalcitrant plaque-type psoriasis were randomized to receive treatment with either oral tacrolimus (FK 506) (n=27) or placebo (n=23) for 9 weeks. The two treatment groups were comparable with respect to baseline demographic data. The initial dose was 0.05 mg/kg per day and, in cases of insufficient efficacy, could be increased to 0.10 and 0.15 mg/kg per day at the end of weeks 3 and 6, respectively. Treatment efficacy was based on the percentage reduction in the Psoriasis Area and Severity Index compared with baseline data. Patients were defined as responding to therapy if the percentage change in the Psoriasis Area and Severity Index from baseline after 3, 6, and 9 weeks was 20% or greater, 45% or greater, and 70% or greater, respectively. Safety was assessed on the basis of all adverse events reported. At the end of week 9, tacrolimus+-treated patients had a significantly greater reduction in the Psoriasis Area and Severity Index than did placebo-treated patients (tacrolimus, -83; placebo, -47; P<.02). Similar numbers of patients in both groups responded to therapy at the end of week 3, but at the end of weeks 6 and 9, more tacrolimus-treated patients responded to therapy (week 6 ,12 tacrolimus- and six placebo-treated patients; week 9, 12 tacrolimus- and three placebo-treated patients). Diarrhea, paresthesia, and insomnia were the most frequently reported causally related adverse events in the tacrolimus-treated group. All of the reported adverse events were mild or moderate in severity, and all resolved without a change in study medication. | The decrease in glomerular filtration rate (GFR), which is characteristic of obstructive uropathy, was suggested to be associated with attenuated nitric oxide (NO) generation. Since availability of L-arginine, the sole precursor for NO, governs NO synthesis, we aimed to determine the role of glomerular arginine transport in rats subjected to 24 h of bilateral ureteral ligation (BUO). Glomerular arginine transport was measured by uptake of radiolabeled arginine ([(3)H]-L-arginine), cationic amino acid transporters (CAT)-1 and -2 and arginases I and II mRNA expression were determined using reverse transcription-polymerase chain reaction. CAT-1, arginase I, and arginase II protein contents were evaluated by Western blotting. L-Arginine transport by freshly harvested glomeruli from BUO rats was significantly augmented than in controls. The aforementioned findings were associated with a significant increase in glomerular CAT-1 mRNA expression, while CAT-2 mRNA was unchanged. Western blotting demonstrated a significant increase in CAT-1 abundance in BUO. Expression of both glomerular arginase I and II mRNA and protein content were significantly elevated in BUO. |
Does usability testing found problems for novice users of pediatric portals? | Patient portals may improve pediatric chronic disease outcomes, but few have been rigorously evaluated for usability by parents. Using scenario-based testing with think-aloud protocols, we evaluated the usability of portals for parents of children with cystic fibrosis, diabetes or arthritis. DESIGN Sixteen parents used a prototype and test data to complete 14 tasks followed by a validated satisfaction questionnaire. Three iterations of the prototype were used. During the usability testing, we measured the time it took participants to complete or give up on each task. Sessions were videotaped and content-analyzed for common themes. Following testing, participants completed the Computer Usability Satisfaction Questionnaire which measured their opinions on the efficiency of the system, its ease of use, and the likeability of the system interface. A 7-point Likert scale was used, with seven indicating the highest possible satisfaction. Mean task completion times ranged from 73 (+/- 61) seconds to locate a document to 431 (+/- 286) seconds to graph laboratory results. Tasks such as graphing, location of data, requesting access, and data interpretation were challenging. Satisfaction was greatest for interface pleasantness (5.9 +/- 0.7) and likeability (5.8 +/- 0.6) and lowest for error messages (2.3 +/- 1.2) and clarity of information (4.2 +/- 1.4). Overall mean satisfaction scores improved between iteration one and three. | Recent studies show that erythropoietin (EPO) plays a protective role in brain ischemia. In this condition, administration of EPO protects neurons from ischemic damage. Recently, it has been shown that in patients with chronic heart failure (CHF), EPO treatment improved cardiac function. In the present study we assessed the role of EPO and EPO-receptor (EPO-R) in the heart. We studied the presence and functionality of the EPO-R in isolated rat hearts in the Langendorff set-up. Hearts were perfused for 20 min with 10 U/ml EPO or vehicle. Immunohistochemistry revealed the presence of the EPO-R on endothelial cells, fibroblasts and to a lesser extent cardiomyocytes. Furthermore, perfusion with EPO resulted in a 50% increase in the phosphorylated MAP kinases p42/p44. To evaluate the protective role of EPO in cardiac ischemia, we performed low-flow (0.6 ml/min) ischemia/reperfusion experiments in isolated rat hearts. Administration of EPO (10 U/ml) reduced the cellular damage by 56% (P<0.05) during reperfusion, diminished apoptosis by 15% (P<0.05) and resulted in a significantly improved recovery of left ventricular pressure (P=0.02) and coronary flow (P=0.01). |
Are non-targeted transcription factors motifs a systemic component of ChIP-seq datasets? | The global effort to annotate the non-coding portion of the human genome relies heavily on chromatin immunoprecipitation data generated with high-throughput DNA sequencing (ChIP-seq). ChIP-seq is generally successful in detailing the segments of the genome bound by the immunoprecipitated transcription factor (TF), however almost all datasets contain genomic regions devoid of the canonical motif for the TF. It remains to be determined if these regions are related to the immunoprecipitated TF or whether, despite the use of controls, there is a portion of peaks that can be attributed to other causes. Analyses across hundreds of ChIP-seq datasets generated for sequence-specific DNA binding TFs reveal a small set of TF binding profiles for which predicted TF binding site motifs are repeatedly observed to be significantly enriched. Grouping related binding profiles, the set includes: CTCF-like, ETS-like, JUN-like, and THAP11 profiles. These frequently enriched profiles are termed 'zingers' to highlight their unanticipated enrichment in datasets for which they were not the targeted TF, and their potential impact on the interpretation and analysis of TF ChIP-seq data. Peaks with zinger motifs and lacking the ChIPped TF's motif are observed to compose up to 45% of a ChIP-seq dataset. There is substantial overlap of zinger motif containing regions between diverse TF datasets, suggesting a mechanism that is not TF-specific for the recovery of these regions. | Decreased local availability of nitric oxide (NO) may mediate chronic vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Previous reports have shown that early treatment with NO prevents vasospasm in animals. We evaluated the efficacy of controlled-release polymers that contain the NO donor diethylenetriamine (DETA-NO) for the delayed treatment of vasospasm in a rabbit model of SAH. DETA-NO 20% (wt/wt) was incorporated into ethylene-vinyl acetate (EVAc) polymers. Animals (n = 52) were randomized to two experimental groups. In the first group (n = 32), animals received SAH and implantation of either 20% DETA-NO/EVAc polymer at a dose of 0.5 mg/kg of DETA-NO (n = 16) or empty EVAc polymer (n = 16). Polymers were implanted 24 (n = 16) or 48 hours (n = 16) after SAH. In the second group (n = 20), animals received SAH and implantation of either 20% DETA-NO/EVAc polymer at a dose of 1.3 mg/kg (n = 10) or empty EVAc (n = 10). Polymers were implanted 24 (n = 10) or 48 hours (n = 10) after SAH. An additional group (n = 16) underwent either sham operation (n = 6) or SAH only (n = 10). Animals were killed 3 days after hemorrhage, and the basilar arteries were processed for morphometric measurements. Results were analyzed using Student's t test. Treatment with 20% DETA-NO/EVAc polymers at a dose of 1.3 mg/kg significantly increased basilar artery lumen patency when administered at 24 (97 +/- 6% versus 73 +/- 10%; P = 0.0396) or 48 hours (94 +/- 6% versus 71 +/- 9%; P = 0.03) after SAH. Treatment with 20% DETA-NO/EVAc polymers at a dose of 0.5 mg/kg administered 48 hours after SAH significantly increased lumen patency (82 +/- 8% versus 68 +/- 12%; P = 0.03); a dose of 0.5 mg/kg, 24 hours after SAH, did not reach statistical significance (74 +/- 7% versus 65 +/- 9%; P = 0.16). The SAH-only group had a lumen patency of 67 +/- 12%. |
Does aLDH2 promoter polymorphism have no effect on the risk for alcoholism? | To test for the possible association between mitochondrial aldehyde dehydrogenase (ALDH2) promoter polymorphism and alcoholism. Genotyping to identify the polymorphisms in 515 alcoholic patients and 361 normal controls was performed. There were no significant differences between the genotype and allele frequencies of the -357A/G polymorphism in alcoholics and normal controls. Linkage disequilibrium was observed between the promoter and exon 12 polymorphisms. | Platelets are a natural source of growth factors, cytokines and chemokines, that regulate angiogenesis and inflammation. It has been suggested that differential release of pro- and anti-angiogenic growth factors from platelet α-granules by protease-activated receptors (PAR) 1 and 4 may be important for the regulation of angiogenesis. We aimed to compare the releasates of unstimulated platelets with PAR-1- and PAR-4-stimulated platelets. The release of β-thromboglobulin, platelet factor (PF)-4, thrombospondin, platelet-derived growth factor (PDGF)-A/B, regulated and normal T-cell expressed and secreted (RANTES/CCL5), endostatin, CXCL12, and vascular endothelial growth factor (VEGF) was measured with enzyme-linked immunosorbent assay (ELISA). Mass spectrometry (MS)-based quantitative proteomics identified 93 proteins from platelets stimulated with PAR-1 and PAR-4. A strong correlation between the factors released after either stimulus was observed (Spearman's r 0.94, P < 0.001). Analysis with ELISA showed that stimulation with PAR-1 or PAR-4 lead to non-differential release of β-thromboglobulin, PF-4, thrombospondin, PDGF-A/B, RANTES/CCL5, endostatin, CXCL12, and VEGF. Release of thrombospondin was slightly lower after PAR-1 stimulation (7.2 μg/mL), compared with PAR-4 induced release (9.8 μg/mL; P < 0.05). |
Do parents as moderators of longitudinal associations between sexual peer norms and Dutch adolescents ' sexual initiation and intention? | The present study investigated how parents and peers interact in promoting or delaying Dutch adolescents' sexual initiation and intention and focused specifically on parents as moderators of peer influence. Using a longitudinal design, two waves of online questionnaire data were collected among 900 Dutch adolescents (M = 13.8 years at T1), who were sexually inexperienced at baseline. At T1, participants reported on three types of perceived sexual peer norms: friends' sexual behaviors (descriptive norms), friends' sexual attitudes (injunctive norms), and experienced peer pressure to have sex. They also rated two parenting aspects at T1: the general quality of their relationship with parents and the frequency of sexuality-specific communication with their parents. Six months later, the participants reported on their experience with different sexual behaviors ranging from naked touching or caressing to intercourse and their intention to have sex in the next school year. Relationship quality with parents was significantly associated with both outcomes, with a higher relationship quality predicting smaller odds of sexual initiation and less intention to have sex. Two significant interaction effects showed that frequent sexual communication with parents significantly reduced the effects of sexually active friends and experienced peer pressure on adolescents' intention to have sex. | We assessed whether postgastrectomy polyneuropathy associated with thiamine deficiency is clinicopathologically identical to beriberi neuropathy, including a biochemical determination of thiamine status. Clinicopathologic features of 17 patients who had postgastrectomy polyneuropathy with thiamine deficiency were compared with those of 11 patients who had thiamine-deficiency neuropathy caused by dietary imbalance. The typical presentation for the two etiologies was as a symmetric sensorimotor polyneuropathy predominantly involving the lower limbs. A variety of clinical features, including neuropathic symptoms, progression, and coexistence of heart failure or Wernicke's encephalopathy, was seen similarly in both conditions. In both groups, the main electrophysiologic findings were those of axonal neuropathy, most prominently in the lower limbs. Sural nerve biopsy specimens also indicated axonal degeneration in both groups. Subperineurial edema was commonly observed. |
Does sTAT3/5-Dependent IL9 Overexpression contribute to Neoplastic Cell Survival in Mycosis Fungoides? | Sustained inflammation is a key feature of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). Resident IL9-producing T cells have been found in skin infections and certain inflammatory skin diseases, but their role in MF is currently unknown. We analyzed lesional skin from patients with MF for the expression of IL9 and its regulators. To determine which cells were producing IL9, high-throughput sequencing was used to identify malignant clones and Vb-specific antibodies were employed to visualize malignant cells in histologic preparations. To explore the mechanism of IL9 secretion, we knocked down STAT3/5 and IRF4 by siRNA transfection in CTCL cell lines receiving psoralen+UVA (PUVA) ± anti-IL9 antibody. To further examine the role of IL9 in tumor development, the EL-4 T-cell lymphoma model was used in C57BL/6 mice. Malignant and reactive T cells produce IL9 in lesional skin. Expression of the Th9 transcription factor IRF4 in malignant cells was heterogeneous, whereas reactive T cells expressed it uniformly. PUVA or UVB phototherapy diminished the frequencies of IL9- and IL9r-positive cells, as well as STAT3/5a and IRF4 expression in lesional skin. IL9 production was regulated by STAT3/5 and silencing of STAT5 or blockade of IL9 with neutralizing antibodies potentiated cell death after PUVA treatment in vitro IL9-depleted mice exhibited a reduction of tumor growth, higher frequencies of regulatory T cells, and activated CD4 and CD8 T lymphocytes. | To evaluate the concordance between thallium-201 uptake and echocardiographic wall thickening, which are both indicators of potentially reversible myocardial dysfunction, in patients with chronic ischaemic left ventricular failure and to assess their relative contribution to predicting improvement in regional function after revascularisation in a subgroup. 45 patients with chronic ischaemic left ventricular dysfunction (mean (SD) ejection fraction 25 (8)%) underwent echocardiography before and after dobutamine infusion (10 micrograms/kg/min). Of these, 22 patients underwent rest echocardiography at a mean (SD) of 9 (1) weeks after revascularisation. 201Tl imaging was performed during dobutamine echocardiography and at rest, 1, and 4 h after treatment with sublingual glyceryl trinitrate on two separate days. Potentially reversible dysfunction was thought to be present when a myocardial segment contained a Tl score of > or = 3 (ascending score 1-4), or showed improved wall thickening of a dysynergic segment during dobutamine stimulation. Of the 201Tl protocols, the redistribution scan 1 h after treatment with glyceryl trinitrate best demonstrated myocardial viability. Concordance between 201Tl and dobutamine induced wall thickening was 82% (kappa = 0.59) for detecting potentially reversible myocardial dysfunction before revascularisation (n = 45). Regional function improved in 18 of 22 patients after revascularisation. There were 168 dysynergic segments before intervention. The sensitivity of echocardiography and 201Tl imaging for detecting "recoverable" or viable segments after revascularisation was 87% and 92% respectively and specificity was 82% and 78% respectively (P = NS). |
Does methylenetetrahydrofolate reductase genotype affect risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia? | Methylenetetrahydrofolate reductase (MTHFR) directs intracellular folate toward homocysteine metabolism and away from nucleotide synthesis. Two common MTHFR polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. We evaluated the association of these polymorphisms with risk of relapse and bcr-abl mRNA transcript detection among 336 Caucasian patients who underwent allogeneic hematopoietic cell transplantation for chronic myelogenous leukemia. Data on the transplant course and folate-related exposures were abstracted from medical records. MTHFR C677T and A1298C genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Qualitative bcr-abl mRNA testing was conducted using a two-step reverse transcription-polymerase chain reaction assay. Cox regression analysis was used to assess the association between MTHFR genotypes and time to relapse and bcr-abl mRNA detection. A statistically significant decreased risk of relapse was observed in patients with the variant A1298C genotype [1298AC, hazard ratio (HR)=0.48 and 95% confidence interval (CI)=0.26-0.88; 1298CC, HR=0.28 and 95% CI=0.09-0.84; P-trend <0.01). For the joint C677T/A1298C genotype, variant genotypes were associated with a decreased risk of relapse when compared with the wild-type 677CC/1298AA genotype. This risk was lowest for the 677CC/1298CC genotype (HR, 0.23; 95% CI, 0.08-0.72). MTHFR genotypes were not associated with bcr-abl transcript detection. | To evaluate the efficacy of the commercially available product Mitigator Sting and Bite Treatment in reducing the pain after imported fire ant stings. Twenty-four volunteer subjects were exposed to imported fire ant stings on both fore-arms. The subjects received Mitigator paste on 1 arm and calamine lotion on the opposite arm, in a blinded manner, from 90 seconds to 10 minutes after exposure. Subjects recorded pain on a 100-mm visual analog scale 60 seconds, 20 minutes, and 3 days after exposure. A 2-tailed paired t test was used to compare the difference in reduction of pain over time between the Mitigator-treated arms and the calamine-treated arms. At 60 seconds, the mean visual analog scale pain score was 23.9 mm for the Mitigator group and 24.5 mm for the calamine group. At 20 minutes, the mean score was 7.6 mm (delta = 16.3) for the Mitigator group and 12.7 mm (delta = 11.8) for the calamine group. At 3 days, the mean score was 2.4 mm (delta = 21.5) for the Mitigator group and 2.9 mm (delta = 21.6) for the calamine group. There was no significant difference between groups for change in visual analog scale pain score at 60 seconds, 20 minutes (P = .256), or 3 days (P = .64). |
Is childhood sexual abuse associated with physical illness burden and functioning in psychiatric patients 50 years of age and older? | To examine the association of childhood sexual abuse (CSA) with cumulative illness burden, physical function, and bodily pain (BP) in a sample of male and female psychiatric patients >or=50 years of age. Previous research on the health consequences of sexual abuse has focused on nonpsychiatric samples of younger-age adults, especially women. The health implications of abuse for mixed-gender samples of older psychiatric patients have not been explored. Participants were 163 patients with primary mood disorders. Sexual abuse histories were collected via patient self-report, as was BP. The measure of medical illness burden was based on chart review. Clinical interviewers rated physical function, using the activities of daily living (ADLs) and instrumental activities of daily living (IADLs) scales. Linear and logistic regressions examined the association between CSA and health outcomes. As hypothesized, severe childhood sexual abuse was associated with higher cumulative medical illness burden, worse physical function, and greater BP. Comparisons of regression coefficients revealed that severe CSA's influence on illness burden is roughly comparable to the effects of adding 8 years of age. For ADL impairment and BP, the effects are comparable to adding 20 years of age. | During short-term hypoxia, Hypoxia Inducible Factors (particular their subunits HIF-1α and HIF-2α) regulate the expression of many genes including the potent angiogenesis stimulator VEGF. However, in some pathological conditions chronic hypoxia occurs and is accompanied by reduced angiogenesis. We investigated the effect of prolonged hypoxia on the proliferation and sprouting ability of human microvascular endothelial cells and the involvement of the HIFs and Dll4/Notch signaling. Human microvascular endothelial cells (hMVECs), cultured at 20% oxygen for 14 days and seeded on top of 3D fibrin matrices, formed sprouts when stimulated with VEGF-A/TNFα. In contrast, hMVECs precultured at 1% oxygen for 14 days were viable and proliferative, but did not form sprouts into fibrin upon VEGF-A/TNFα stimulation at 1% oxygen. Silencing of HIF-2α with si-RNA partially restored the inhibition of endothelial sprouting, whereas HIF-1α or HIF-3α by si-RNA had no effect. No involvement of Dll4/Notch pathway in the inhibitory effect on endothelial sprouting by prolonged hypoxia was found. In addition, hypoxia decreased the production of urokinase-type plasminogen activator (uPA), needed for migration and invasion, without a significant effect on its inhibitor PAI-1. This was independent of HIF-2α, as si-HIF-2α did not counteract uPA reduction. |
Is myocardial scar detected by contrast-enhanced cardiac magnetic resonance imaging associated with ventricular tachycardia in hypertrophic cardiomyopathy patients? | Hypertrophic cardiomyopathy (HCM) is associated with myocardial scarring and ventricular tachycardia (VT). Contrast-enhanced cardiac magnetic resonance imaging (CE-CMR) can quantify myocardial scar, and scar imaging has been documented in patients with HCM. We investigated the assessment of myocardial scar in HCM patients using CE-CMR, and its correlation with proven VT. Twenty-five patients (mean age 54 +/- 8) with HCM who underwent CE-CMR were identified, and clinical data obtained from chart review. Parameters of LV function were calculated from cine imaging, and myocardial scar was assessed using delayed enhancement imaging following gadolinium administration. Myocardial scar was detected in 16 (64%) patients with a mean mass 9 +/- 15 g. Scar was patchy, mid-myocardial and located in the basal anteroseptum, and RV insertion sites. Scar was seen in septal, apical and concentric variants of HCM. Scar mass correlated with both LV Mass (r2 = 0.74) and maximal LV wall thickness (r2 = 0.42). VT occurred in 32% of patients, and was associated with both increased scar mass and wall thickness compared to non-VT patients (21 +/- 22 g vs. 4 +/- 6 g, and 2.4 +/- 0.5 cm vs. 1.8 +/- 0.5 cm, p < 0.05). LV size and function were similar in patients with and without VT. A scar mass of >7 g predicted the presence of VT with a sensitivity of 75% and specificity 82%. | Innate immune recognition of pathogens by sinonasal epithelial cells may play an important role in the pathogenesis of chronic rhinosinusitis (CRS). Previous studies have indicated that toll-like receptor (TLR) mRNA is present in sinonasal mucosa, and levels of TLR9 expression are decreased in recalcitrant CRS with nasal polyps (CRSwNP). However, the cellular source and function of TLR9 in the sinonasal epithelium is not known. In this study, primary epithelial cell cultures were analyzed from control subjects and CRSwNP patients to determine the presence and function of TLR9 protein. Primary epithelial cell cultures were established from 5 controls and 10 CRSwNP patients undergoing sinus surgery. Flow cytometry was used to confirm purity of epithelial cells and to assess expression of TLR9 protein. Epithelial cells were stimulated with TLR9 agonist, and mRNA was analyzed by real-time PCR for expression of human beta-defensin (HBD) 2 and interleukin (IL)-8. Flow cytometry showed TLR9 protein in 100% of epithelial cells from controls and CRSwNP patients. The level of expression was 50% lower in CRS patients than in controls. Stimulation of epithelial cells with TLR9 agonist produced a 1.5- to 9-fold increase in HBD-2 and IL-8 mRNA expression. |
Does fK778 ameliorate post-transplant expression of fibrogenic growth factors and development of chronic rejection changes in rat kidney allografts? | Acute rejection is the major risk factor for the development of subsequent chronic allograft nephropathy (CAN), which is the primary reason for late allograft loss in kidney transplantation. Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are the main mitogens mediating mesenchymal cell proliferation. Their early post-transplant induction may start cascades leading to the development of CAN. An immunosuppressive drug, FK778, inhibits de novo pyrimidine biosynthesis and several receptor tyrosine kinases (RTKs). Here we investigated its effects on acute and chronic rejection as well as post-transplant PDGF and TGF-beta expression in combination therapy with calcineurin inhibitors (CNIs). Kidney transplantations were performed from DA to WF rats. Syngenic DA-DA grafts were used as controls. Allografts were immunosuppressed with a combination of FK778 (10 mg/kg/day p.o.) and CsA (1.5 mg/kg/day s.c.) or tacrolimus (Tac) (1.5 mg/kg/day p.o.). Grafts were harvested 5 and 90 days after transplantation for histology and immunohistochemistry (PDGF-A, PDGF-B, PDGFR-alpha, PDGFR-beta, TGF-beta, TGF-betaR). The dose response of FK778 on acute rejection was studied with monotherapy of 5, 10 and 20 mg/kg/day. Chronic changes were scored according to the Chronic Allograft Damage Index (CADI). FK778 ameliorated the early post-transplant inflammatory response dose dependently. Additive effects were seen with FK778 and CNIs. Significantly lower CADI scores were seen in combination therapy of FK778 and CNIs compared with CNI monotherapies. FK778 also significantly reduced both early and late PDGF and TGF-beta expression when combined with CNIs. | Gastric Helicobacter pylori (H. pylori) infection and colorectal polyps are more prevalent in African Americans than in the general population. We aimed to investigate whether gastric H. pylori infection is associated with colorectal polyps in African Americans. Medical records of African Americans, 40 years and older (n = 1256) who underwent bidirectional gastrointestinal endoscopy on the same day were reviewed. H. pylori status was assessed by immunohistochemistry on gastric specimens. Colorectal polyps were confirmed by histological examination of colorectal biopsies. A subset of serum samples from healthy and polyp-bearing patients (n = 163) were analyzed by ELISA for anti-H. pylori and anti-CagA antibodies. The crude and adjusted effect of H. pylori on the risk of colorectal adenoma and polyp were computed by logistic regression models. The prevalence of colorectal polyps and adenomas were 456 (36%) and 300 (24%) respectively. Colorectal polyps were more prevalent in gastric H. pylori infected than non-infected subjects [43% vs. 34%; Odds Ratio (OR) (95% CI): 1.5 (1.2-1.9), P = 0.001]. Patients with H. pylori-associated chronic active gastritis were at high risk to have adenomas [Unadjusted OR (95% CI): 1.3 (1.0-1.8); P = 0.04]. There was no difference in histopathology, size, or location of polyps with respect to H. pylori status. Gastric H. pylori infection, age, male gender and high risk clinical presentations were independent risk factors for colorectal polyps. Serological testing also revealed a higher prevalence of H. pylori and its toxin Cag-A in polyp patients vs. non polyp patients' sera, although in a non-statistically significant manner. |
Are higher mitochondrial potential and elevated mitochondrial respiration associated with excessive activation of blood platelets in diabetic rats? | The high glucose concentration observed in diabetic patients is a recognized factor of mitochondrial damage in various cell types. Its impact on mitochondrial bioenergetics in blood platelets remains largely vague. The aim of the study was to determine how the metabolism of carbohydrates, which has been impaired by streptozotocin-induced diabetes may affect the functioning of platelet mitochondria. Diabetes was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin. Platelet mitochondrial respiratory capacity was monitored as oxygen consumption (high-resolution respirometry). Mitochondrial membrane potential was assessed using a fluorescent probe, JC-1. Activation of circulating platelets was monitored by flow cytometry measuring of the expressions of CD61 and CD62P on a blood platelet surface. To determine mitochondrial protein density in platelets, Western Blot technique was used. The results indicate significantly elevated mitochondria mass, increased mitochondrial membrane potential (ΔΨm) and enhanced respiration in STZ-diabetic animals, although the respiration control ratios appear to remain unchanged. Higher ΔΨm and elevated mitochondrial respiration were closely related to the excessive activation of circulating platelets in diabetic animals. | The purpose of this study is to examine the effect of insurance coverage on stage of presentation, treatment, and survival of head and neck cancer (HNC). A retrospective study was conducted using the Surveillance, Epidemiology, and End Results (SEER) program to identify patients diagnosed with HNC. The primary variable of interest was insurance analyzed as a dichotomous variable: Patients were considered uninsured if they were classified as "uninsured" by SEER, whereas patients were considered insured if they were defined by SEER as "any Medicaid," "insured," or "insured/no specifics." The outcomes of interest were cancer stage at presentation (M0 vs M1), receipt of definitive treatment, and HNC-specific mortality (HNCSM). Multivariable logistic regression modeled the association between insurance status and stage at presentation, as well as between insurance status and receipt of definitive treatment, whereas HNCSM was modeled using Fine and Gray competing risks. Sensitivity logistic regression analysis was used to determine whether observed interactions remained significant by insurance type (privately insured, Medicaid, and uninsured). Patients without medical insurance were more likely to present with metastatic cancer (adjusted odds ratio, 1.60; P < .001), were more likely to not receive definitive treatment (adjusted odds ratio, 1.64; P < .001), and had a higher risk of HNCSM (adjusted hazard ratio, 1.20; P = .002). Sensitivity analyses showed that when results were stratified by insurance type, significant interactions remained for uninsured patients and patients with Medicaid. |
Does prevalence and correlate of ADHD symptoms in the national health interview survey? | Study the prevalence and correlates of ADHD symptoms in the National Health Interview Survey (NHIS). NHIS includes 10,367 children ages 4 to 17. Parents report lifetime diagnosis of ADHD and complete the Strengths and Difficulties Questionnaire (SDQ). Prevalences of clinically significant ADHD and comorbid symptoms by race and ethnicity, gender, and age are presented. Prevalence of clinically significant SDQ ADHD symptoms is 4.19% (males) and 1.77% (females). Male prevalence by race is 3.06% for Hispanics, 4.33% for Whites, and 5.65% for Blacks. Significant differences in prevalence occur across gender (p < .01) and among males across race (p < .01), age (p < .01), and income (p < .02). In the full sample, 6.80% of males and 2.50% of females have a parent-reported lifetime ADHD diagnosis but are negative for SDQ ADHD. Likewise, 1.59% of males and 0.81% of females are positive for SDQ ADHD but negative for parent report of ADHD diagnosis. SDQ ADHD positive children have substantially higher proportions of elevated scores on other SDQ subscales. | This study was designed to test whether early castration-induced short-term cellular changes in primary prostate tumours could predict clinical outcome in advanced disease. Biopsies from 83 patients obtained before and within two weeks after surgical castration were investigated. Tumour epithelial cell apoptosis, proliferation, and prostate specific antigen (PSA) levels were quantified using immunohistochemistry, laser capture micro-dissection, and real time RT-PCR. Cellular effects were related to changes in serum PSA levels and clinical outcome. Decreased proliferation and PSA mRNA levels, and increased apoptosis were observed in most tumours. These early cellular responses were not correlated to each other and did not predict serum PSA response or cancer-specific survival. A nadir PSA level below 1 ng/ml predicted a longer cancer-specific survival after castration therapy. |
Do incidence and indications for revision cochlear implant surgery in adults and children? | To identify the incidence of and common causes for cochlear implant revision. Retrospective case series. Operative records were reviewed for all cases of revision cochlear implantation from 1992 to 2006. The causes for reimplantation were classified as hard device failure, soft device failure, exposure/infection, receiver/stimulator migration, and electrode migration. Manufacturers' failure analysis of explanted devices was likewise determined. Eight hundred and six cochlear implants were performed during the study period including 44 (5.5%) revision procedures. The revision rate was 7.3% for children and 3.8% for adults and reached statistical significant difference. The most common reasons for revision were device failure (78%; 55% hard failure, 23% soft failure) followed by electrode migration (9%) and receiver/stimulator migration (7%). Manufacturers' analysis of failed devices revealed loss of hermetic seal and cracked cases to be the most common causes of failure. Bench analysis of 5/10 explanted devices that were soft failures demonstrated identifiable device defects. | We previously reported a negative association of circulating plasmalogens (phospholipids with proposed atheroprotective properties) with coronary artery disease. Plasmalogen modulation was previously demonstrated in animals but its effect on atherosclerosis was unknown. We assessed the effect of plasmalogen enrichment on atherosclerosis of murine models with differing levels of oxidative stress. Six-week old ApoE- and ApoE/glutathione peroxidase-1 (GPx1)-deficient mice were fed a high-fat diet with/without 2% batyl alcohol (precursor to plasmalogen synthesis) for 12 weeks. Mass spectrometry analysis of lipids showed that batyl alcohol supplementation to ApoE- and ApoE/GPx1-deficient mice increased the total plasmalogen levels in both plasma and heart. Oxidation of plasmalogen in the treated mice was evident from increased level of plasmalogen oxidative by-product, sn-2 lysophospholipids. Atherosclerotic plaque in the aorta was reduced by 70% (P = 5.69E-07) and 69% (P = 2.00E-04) in treated ApoE- and ApoE/GPx1-deficient mice, respectively. A 40% reduction in plaque (P = 7.74E-03) was also seen in the aortic sinus of only the treated ApoE/GPx1-deficient mice. Only the treated ApoE/GPx1-deficient mice showed a decrease in VCAM-1 staining (-28%, P = 2.43E-02) in the aortic sinus and nitrotyrosine staining (-78%, P = 5.11E-06) in the aorta. |
Does adjuvant therapy with the monoclonal antibody Edrecolomab plus fluorouracil-based therapy improve overall survival of patients with stage III colon cancer? | Edrecolomab (ED) is a murine monoclonal antibody targeting the EpCam antigen. This phase III randomized multicenter trial investigated the benefit of adding ED to fluorouracil (FU) based therapy in patients with stage III colorectal cancer. Patients with stage III colon cancer were randomly assigned to one of two treatments after curative surgery. Patients in arm 1 received five infusions of ED together with FU-based chemotherapy; patients in arm 2 received FU-based chemotherapy alone. The primary end point was overall survival (OS). One thousand eight hundred thirty-nine patients were randomly assigned; results were analyzed on an intent-to-treat basis. Patient characteristics were well-balanced across treatment arms. Five-year follow-up has been completed. Patients randomly assigned to ED plus FU-based therapy showed a 5-year survival rate of 69.6% while for patients receiving FU-based therapy, the rate was 68.2%. The hazard ratio for death with ED plus FU-based therapy compared to FU-based therapy was 0.896 (95% CI, 0.752 to 1.068), which was not statistically significant (P = .220). The adverse effect profiles of the two treatment arms were similar, with the main adverse effects being diarrhea, abdominal pain, and nausea. Anaphylaxis occurred in fewer than 1% of patients receiving ED. | Macrophage metalloelastase (matrix metalloproteinase [MMP]-12) is upregulated in atherosclerotic lesions and aneurysm; thus, increased MMP-12 activity may play an important role in the pathogenesis of atherosclerosis. However, the pathological roles of MMP-12 in the initiation and progression of atherosclerosis have not been defined. We compared the susceptibility of MMP-12 transgenic (Tg) rabbits to cholesterol-rich diet-induced atherosclerosis with that of non-Tg littermate rabbits. The rabbits were maintained at either relatively lower levels of hypercholesterolemia for shorter periods or higher levels of hypercholesterolemia for longer periods through a diet containing different amounts of cholesterol. We found no significant difference in the aortic atherosclerotic lesion size or quality between Tg and non-Tg rabbits at lower hypercholesterolemia. At higher hypercholesterolemia for longer periods, however, Tg rabbits developed more extensive atherosclerosis in the aortas and coronary arteries than did non-Tg rabbits. Histological examinations revealed that atherosclerotic lesions of Tg rabbits contained prominent macrophage infiltration associated with marked disruption of the elastic lamina in the tunica media with occasional formation of aneurysm-like lesions. Furthermore, increased expression of MMP-12 derived from macrophages was associated with elevated expression of MMP-3, suggesting that MMP-12 may play a pivotal role in the cascade activation of other MMPs, thereby exacerbating extracellular matrix degradation during the progression of atherosclerosis. |
Is expression of epigenetic modifiers significantly altered by exposure to secondhand smoke? | Secondhand smoke (SHS) is a major risk factor for lung cancer in nonsmokers. DNA damage-derived mutagenicity is a well-established mechanism of SHS-carcinogenicity; however very little is known about the impact of SHS exposure on the epigenome. We have investigated whether exposure to SHS can modulate the expression of key epigenetic regulators responsible for the establishment and/or maintenance of DNA methylation and histone modification patterns in vivo. We have sub-chronically exposed mice to a mutagenic but non-tumorigenic dose of SHS, and subsequently determined the expression levels of major epigenetic modifiers in the lungs of SHS-exposed mice, immediately after termination of exposure and following 7-month recovery in clean air. | To quantify the costs of treatment in critical limb ischaemia (CLI) and to compare costs and effectiveness of two treatment strategies: spinal cord stimulation (SCS) and best medical treatment. One hundred and twenty patients with CLI not suitable for vascular reconstruction were randomised to either SCS in addition to best medical treatment or best medical treatment alone. Primary outcomes were mortality, amputation and cost. Cost analysis was based on resources used by patients for 2 years after randomisation. Both medical and non-medical costs were included. Patient and limb survival were similar in the two treatment groups. Costs of in-hospital-stay and institutional rehabilitation constituted the predominant part (+/-70%) of the total costs of medical care in CLI. Cost of SCS-implantation and complications (7950 euro per patient) exceeded by far cost due to amputation procedures (410 euro per patient). The total costs of treatment were 36,600 euro per patient over 2 years for the SCS-group vs. 28,700 euro for best medical treatment alone (28% higher for SCS-group, p=0.009). |
Do monocytes and neutrophils expressing myeloperoxidase occur in fibrous caps and thrombi in unstable coronary plaques? | Myeloperoxidase (MPO) -containing macrophages and neutrophils have been described at sites of plaque rupture. The presence of these cells in precursor lesions to acute rupture (thin cap atheroma, or vulnerable plaque) and within thrombi adjacent to ruptures has not been described, nor an association with iron-containing macrophages within unstable plaques. We studied 61 acute ruptures, 15 organizing ruptures, 31 thin cap fibroatheromas, and 28 fibroatheromas from 72 sudden coronary death victims by immunohistochemical and histochemical techniques. Inflammatory cells were typed with anti-CD68 (macrophages), anti-BP-30 (neutrophil bactericidal glycoprotein), and anti-MPO. Iron was localized by Mallory's Prussian blue stain. In selected plaques alpha smooth muscle actin (DAKO, Carpinteria, CA, clone M0851) was performed. MPO positive cells were present in 79% of ruptured caps, 28% of thin cap fibroatheroma, and no fibroatheromas; neutrophils were present in 72% of ruptures, 8% of thin cap fibroatheromas, and no fibroatheromas. Iron containing foam cells were present in the caps of 93% of acute ruptures, of 85% of organizing ruptures, 20% of thin cap atheromas, and 10% of fibroatheromas. MPO positive cells were more frequent in occlusive than non-occlusive thrombi adjacent to ruptures (p = .006) and were more numerous in diabetics compared to non-diabetics (p = .002) | To determine if adolescents with unilateral hearing loss (UHL) demonstrate worse language skills than their siblings with normal hearing (NH). Case-control study of 12-17-year-old adolescents with UHL (20 cases) compared with sibling controls with NH (13 controls). Scores on the oral portion of the Oral and Written Language Scales (OWLS) and the Clinical Evaluation of Language Fundamentals (CELF) were the primary outcome measure. Wechsler's Abbreviated Scales of Intelligence (WASI) scores were also used as an outcome measure. Adolescents with UHL demonstrated worse overall and expressive language scores than controls, (98 vs. 114, P=0.001; 100 vs. 114, P=0.006) and had significantly lower full scale (98 vs. 112, P=0.017), verbal (101 vs. 113, P=0.032), and performance IQ (95 vs. 107, P=0.037). |
Is sARS-CoV envelope protein palmitoylation or nucleocapid association required for promoting virus-like particle production? | Coronavirus membrane (M) proteins are capable of interacting with nucleocapsid (N) and envelope (E) proteins. Severe acute respiratory syndrome coronavirus (SARS-CoV) M co-expression with either N or E is sufficient for producing virus-like particles (VLPs), although at a lower level compared to M, N and E co-expression. Whether E can release from cells or E/N interaction exists so as to contribute to enhanced VLP production is unknown. It also remains to be determined whether E palmitoylation or disulfide bond formation plays a role in SARS-CoV virus assembly. SARS-CoV N is released from cells through an association with E protein-containing vesicles. Further analysis suggests that domains involved in E/N interaction are largely located in both carboxyl-terminal regions. Changing all three E cysteine residues to alanines did not exert negative effects on E release, E association with N, or E enhancement of VLP production, suggesting that E palmitoylation modification or disulfide bond formation is not required for SARS-CoV virus assembly. We found that removal of the last E carboxyl-terminal residue markedly affected E release, N association, and VLP incorporation, but did not significantly compromise the contribution of E to efficient VLP production. | To assess whether nocturnal blood pressure dipping status in type 1 diabetes is correlated with specific sleep characteristics and differences in nocturnal glycemic profiles. Twenty type 1 diabetic adult patients underwent sleep studies with simultaneous 24-h ambulatory blood pressure monitoring and continuous nocturnal glucose monitoring. Altogether, 55% of patients exhibited blunted blood pressure dipping. They did not differ from the dipper group in age, BMI, or systolic (SBP) and diastolic (DBP) blood pressure. Total sleep period (TSP) was higher in the dipper group (497 +/- 30 vs. 407 +/- 44 min for dippers and nondippers, respectively, P < 0.001). TSP was correlated with SBP and DBP day-night differences (r = 0.44 and 0.49, respectively). Periods of nocturnal hypoglycemia (i.e., % of TSP with glycemia <70 mg/dl) were longer in the dipper group (8.1 +/- 10.7 vs. 0.1 +/- 0.4% for dippers and nondippers, respectively, P = 0.02). |
Does long noncoding RNA DANCR increase stemness features of hepatocellular carcinoma by derepression of CTNNB1? | Tumor cells with stemness (stem-cell) features contribute to initiation and progression of hepatocellular carcinoma (HCC), but involvement of long noncoding RNAs (lncRNAs) remains largely unclear. Genome-wide analyses were applied to identify tumor-associated lncRNA-DANCR. DANCR expression level and prognostic values of DANCR were assayed in two HCC cohorts (China and Korea, n = 135 and 223). Artificial modulation of DANCR (down- and overexpression) was done to explore the role of DANCR in tumorigenesis and colonization, and tumor-bearing mice were used to determine therapeutic effects. We found that lncRNA-DANCR is overexpressed in stem-like HCC cells, and this can serve as a prognostic biomarker for HCC patients. Experiments showed that DANCR markedly increased stemness features of HCC cells to promote tumorigenesis and intra-/extrahepatic tumor colonization. Conversely, DANCR knockdown attenuated the stem-cell properties and in vivo interference with DANCR action led to decreased tumor cell vitality, tumor shrinkage, and improved mouse survival. Additionally, we found that the role of DANCR relied largely on an association with, and regulation of, CTNNB1. Association of DANCR with CTNNB1 blocked the repressing effect of microRNA (miR)-214, miR-320a, and miR-199a on CTNNB1. This observation was confirmed in vivo, suggesting a novel mechanism of tumorigenesis involving lncRNAs, messenger RNAs, and microRNAs. | To assess the effects of different exercise intensities and antioxidant supplementation on plasma protein modification. Trained men (n = 41) from a homogenous population were randomly assigned to perform cycle ergometer exercise either at 70% or 80% of individual .VO2max. Each intensity group was randomly assigned to receive either juice powder concentrate (JPC 70%, n = 11; JPC 80%, n = 10) or placebo (Plac 70%, n = 10; Plac 80%, n = 10) capsules for 28 wk. Four controlled exercise bouts and blood collections were conducted at baseline and study weeks 4, 16, and 28. Blood samples were drawn before (BE), immediately after (IE), and 30 min (30M) and 30 h (30H) postexercise. These samples were analyzed to estimate concentrations of carbonyl groups on plasma proteins (CP) and the redox state of human serum albumin (HSA). In the Plac group, CP concentrations increased at 80% of .VO2max IE and 30M, returning to preexercise concentrations by 30H (P < 0.05). At both 16 and 28 wk, the Plac groups had significantly higher BE and 30H CP concentrations than the JPC groups (P < 0.05). The reduced fraction of HSA, human mercaptalbumin (HMA), decreased at all four exercise tests at both exercise intensities IE and 30M, returning to preexercise values by 30H (P < 0.05). Supplementation had no influence on HSA. |
Does roux-en-Y gastric bypass improve the nonalcoholic steatohepatitis ( NASH ) of morbid obesity? | Hepatic steatosis and nonalcoholic steatohepatitis (NASH) have been increasingly implicated in the genesis of hepatic fibrosis and cirrhosis. However, no consensus exists about whether weight reduction may reverse this process. To assess the effect of Roux-en-Y gastric bypass (RYGBP) on the histological evolution of NASH diagnosed in 64 patients by routine liver biopsy ("first" biopsy) performed during surgery, we performed a "second" biopsy after 23.5 +/- 8.4 months in 16 patients (14 female, 2 male). From the first to the second biopsy, BMI decreased from 53.4 +/- 8.8 kg/m2 to 31.1 +/- 4.7 kg/m2, arterial hypertension decreased from 75% to 43.8%, and type 2 diabetes decreased from 43.8% to zero. On the first biopsy, nonalcoholic fatty liver disease (NAFLD) type 3 was observed in 12 patients (75%) and type 4 in 4 (25%). The second biopsy revealed complete regression of NAFLD in 15 patients (93.7%) and only 1 (6.3%) had NAFLD type 1 (mild steatosis without inflammation). Complete regression of necroinflammatory activity was observed in all patients. Among the 4 patients presenting fibrosis in the first biopsy, complete remission was observed in 1 and improvement in 1. Two continued to show the same degree of fibrosis without evidence of disease activity. No worsening of steatosis, necroinflammatory activity or fibrosis was observed in any of the patients, and none progressed to cirrhosis. | We have investigated the influence of Ca2+ ions on the basic biophysical properties of T-type calcium channels. The Cav3.1 calcium channel was transiently expressed in HEK 293 cells. Current was measured using the whole cell patch clamp technique. Ca2+ or Na+ ions were used as charge carriers. The intracellular Ca2+ was either decreased by the addition of 10 mm ethyleneglycoltetraacetic acid (EGTA) or increased by the addition of 200 microm Ca2+ into the non-buffered intracellular solution. Various combinations of extra- and intracellular solutions yielded high, intermediate or low intracellular Ca2+ levels. The amplitude of the calcium current was independent of intracellular Ca2+ concentrations. High levels of intracellular Ca2+ accelerated significantly both the inactivation and the activation time constants of the current. The replacement of extracellular Ca2+ by Na+ as charge carrier did not affect the absolute value of the activation and inactivation time constants, but significantly enhanced the slope factor of the voltage dependence of the inactivation time constant. Slope factors of voltage dependencies of channel activation and inactivation were significantly enhanced. The recovery from inactivation was faster when Ca2+ was a charge carrier. The number of available channels saturated for membrane voltages more negative than -100 mV for the Ca2+ current, but did not reach steady state even at -150 mV for the Na+ current. |
Does elevated elafin/trappin-2 in the female genital tract is associate with protection against HIV acquisition? | 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. | To evaluate the relationship between the intensity of murmurs and severity of mitral and aortic regurgitation. Consecutive patients with chronic isolated aortic (n = 40) or mitral (n = 170) regurgitation undergoing echocardiographic quantitation of regurgitation between 1990 and 1991 were studied. Regurgitant volume and fraction were measured using two simultaneous methods (quantitative Doppler echocardiography and quantitative two-dimensional echocardiography); the intensity of the regurgitant murmur (grade 0 to 6) was noted by physicians unaware of the study. Correlations between murmur intensity and regurgitant volume and fraction were good in aortic regurgitation (r = .60 and r = .67, respectively; P < 0.001) and mitral regurgitation (r = .64 and r = .67, respectively; P < 0.001) but weaker (r = .47 and r = .45, respectively) in the subset of mitral regurgitation of ischemic or functional cause. Murmur intensity grades > or = 3 for aortic regurgitation and > or = 4 for mitral regurgitation predicted severe regurgitation (regurgitant fraction > or = 40%) in 71% and 91% of patients, respectively. Murmur grades < or = 1 for aortic regurgitation and < or = 2 for mitral regurgitation predicted "not severe" regurgitation in 100% and 88% of patients, respectively. Murmur grades 2 for aortic regurgitation and 3 for mitral regurgitation were not correlated to degree of regurgitation. The severity of regurgitation was the most powerful determinant of intensity of murmur. |
Is a sheathless retrograde approach via the popliteal artery useful and safe for treating chronic total occlusions in the superficial femoral artery? | To compare the safety and success of a retrograde approach using a microcatheter vs. a sheath in the treatment of superficial femoral artery (SFA) chronic total occlusions (CTOs). From April 2007 to December 2012, 188 consecutive patients underwent EVT for 229 de novo SFA CTOs using the retrograde approach in 68 patients (35 men; mean age 72 years). This cohort was divided into cases performed with a 4-F or 6-F sheath (n=28, 36 limbs) and those with a 2.1-F microcatheter (n=35, 49 limbs). The primary outcomes were mean time to hemostasis and number of intra- and postoperative puncture site complications, as well as the success of popliteal artery puncture, lesion crossing, and reperfusion. There were no significant differences between two groups in baseline characteristics. PA puncture was successful in all limbs, and the success in crossing the lesion with the wire was not significantly different (91.9% in the sheath group vs. 89.8% in the microcatheter group). Mean time to hemostasis was 8.9±8.8 minutes in the microcatheter group vs. 47.7±13 minutes in the sheath group (p<0.0001). There was a significant difference in intraoperative and postoperative complications (22.2% in the sheath group vs. 2.0% in the microcatheter group, p=0.002). | Virus-induced wheezing episodes in infancy often precede the development of asthma. Whether infections with specific viral pathogens confer differential future asthma risk is incompletely understood. To define the relationship between specific viral illnesses and early childhood asthma development. A total of 259 children were followed prospectively from birth to 6 years of age. The etiology and timing of specific viral wheezing respiratory illnesses during early childhood were assessed using nasal lavage, culture, and multiplex reverse transcriptase-polymerase chain reaction. The relationships of these virus-specific wheezing illnesses and other risk factors to the development of asthma were analyzed. Viral etiologies were identified in 90% of wheezing illnesses. From birth to age 3 years, wheezing with respiratory syncytial virus (RSV) (odds ratio [OR], 2.6), rhinovirus (RV) (OR, 9.8), or both RV and RSV (OR , 10) was associated with increased asthma risk at age 6 years. In Year 1, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased asthma risk at age 6 years. By age 3 years, wheezing with RV (OR, 25.6) was more strongly associated with asthma at age 6 years than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in Year 3 had asthma at 6 years of age. |
Do two decades of British newspaper coverage regarding attempt cardiopulmonary resuscitation decisions : Lessons for clinicians? | To review UK newspaper reports relating to Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) decisions in order to identify common themes and encourage dialogue. An online media database (LexisNexis(®)) was searched for UK Newspaper articles between 1993 and 2013 that referenced DNACPR decisions. Legal cases, concerning resuscitation decisions, were identified using two case law databases (Lexis Law(®) and Westlaw(®)), and referenced back to newspaper publications. All articles were fully reviewed. Three hundred and thirty one articles were identified, resulting from 77 identifiable incidents. The periods 2000-01 and 2011-13 encompassed the majority of articles. There were 16 high-profile legal cases, nine of which resulted in newspaper articles. Approximately 35 percent of newspaper reports referred to DNACPR decisions apparently made without adequate patient and/or family consultation. "Ageism" was referred to in 9 percent of articles (mostly printed 2000-02); and "discrimination against the disabled" in 8 percent (mostly from 2010-12). Only five newspaper articles (2 percent) discussed patients receiving CPR against their wishes. Eighteen newspaper reports (5 percent) associated DNACPR decisions with active euthanasia. | To explore lens crystallin characteristics and morphology of rabbit regenerated lenses in comparison with wild type natural lenses by means of proteomic analysis and histological assay. The lens regeneration model of the New Zealand rabbit was established, and lens regeneration was observed by slit lamp examination and photography. A histological assay was evaluated under light microscopy and transmission electron microscopy (TEM). Protein samples of regenerated lenses were collected from experimental rabbit eyes 2, 4, and 16 weeks after surgery. Two-dimensional gel electrophoresis (2-DE) was performed. Image analyses was done using the ImageMaster 2D Elite 3.01 software package. The protein spots were trypsinized and identified by matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry. Lens regeneration began in the periphery of the capsule bag about one to two weeks after the surgery and proceeded to regenerate toward the center. The regenerated lens appeared spherical in shape with a fairly translucent cortical structure and a nuclear opacity. Histological findings showed that the remnant lens epithelial cells differentiate at the lens capsule equator and new lens fibers form in a concentric pattern in a manner similar to that observed in natural lenses. However, TEM showed morphological changes in the epithelial cells of the regenerated lenses as compared with natural lenses. 2-D electrophoresis revealed that the patterns of protein spots from regenerated lenses (two weeks, four weeks, and 16 weeks) were analogous to those of 16-week-old natural lenses but were substantially different from those of two-week-old natural lenses, particularly when the two-week-old regenerated lenses were compared with the two-week-old natural lenses. |
Is abnormal uterine artery Doppler in pregnancies suspected of a SGA fetus related to increased risk of recurrence during next pregnancy? | To investigate if placental Doppler velocimetry can predict the recurrence of a small-for-gestational age (SGA) fetus in subsequent pregnancies. Retrospective study. City cohort over 15 years attending a university hospital. A total of 196 pregnancies suspected of a SGA fetus (<3rd percentile) evaluated by uterine and umbilical artery Doppler velocimetry. Blood velocity waveform was analyzed for pulsatility index (PI) as well as the uterine artery waveform for notching in early diastole. The occurrence of a SGA newborn during the succeeding pregnancy by Doppler results from the previous pregnancy. In the group of 196 pregnancies suspected for SGA, 27 (13.8%) delivered a SGA newborn in the following pregnancy. Thirty-seven (18.9%) of the 196 had an abnormally high PI in the uterine arteries in their first pregnancy, 12 (32.4%) of these delivered a SGA child in the next pregnancy (relative risk 3.44, p<0.001). The corresponding figure for those with normal uterine artery PI was 15 (9.4%). Abnormal umbilical artery Doppler was a worse predictor of recurrence of SGA (p=0.051). Uterine artery notching was not related to a SGA newborn during next pregnancy. | Bacillus Calmette Guerin (BCG)-immunotherapy has a well-documented and successful clinical history in the treatment of bladder cancer. However, regularly observed side effects, a certain degree of nonresponders and restriction to superficial cancers remain a major obstacle. Therefore, alternative treatment strategies are intensively being explored. We report a novel approach of using a well defined immunostimulatory component of Mycobacterium tuberculosis for the treatment of bladder cancer. The phosphate transport protein PstS1 which represents the phosphate binding component of a mycobacterial phosphate uptake system is known to be a potent immunostimulatory antigen of M. tuberculosis. This preclinical study was designed to test the potential of recombinant PstS1 to serve as a non-viable and defined immunotherapeutic agent for intravesical bladder cancer therapy. Mononuclear cells (PBMCs) were isolated from human peripheral blood and stimulated with PstS1 for seven days. The activation of PBMCs was determined by chromium release assay, IFN-gamma ELISA and measurement of lymphocyte proliferation. The potential of PstS1 to activate monocyte-derived human dendritic cells (DC) was determined by flow cytometric analysis of the marker molecules CD83 and CD86 as well as the release of the cytokines TNF-alpha and IL-12. Survival of presensitized and intravesically treated, tumor-bearing mice was analyzed by Kaplan-Meier curve and log rank test. Local and systemic immune response in PstS1-immunotherapy was investigated by anti-PstS1-specific ELISA, splenocyte proliferation assay and immunohistochemistry. Our in vitro experiments showed that PstS1 is able to stimulate cytotoxicity, IFN-gamma release and proliferation of PBMCs. Further investigations showed the potential of PstS1 to activate monocyte-derived human dendritic cells (DC). In vivo studies in an orthotopic murine bladder cancer model demonstrated the therapeutic potential of intravesically applied PstS1. Immunohistochemical analysis and splenocyte restimulation assay revealed that local and systemic immune responses were triggered by intravesical PstS1-immunotherapy. |
Does electrical forepaw stimulation during reversible forebrain ischemia decrease infarct volume? | Functional stimulation is accompanied by increases in regional cerebral blood flow which exceed metabolic demands under normal circumstances, but it is unknown whether functional stimulation is beneficial or detrimental in the setting of acute ischemia. The aim of this study was to determine the effect of forepaw stimulation during temporary focal ischemia on neurological and tissue outcome in a rat model of reversible focal forebrain ischemia. Sprague-Dawley rats were prepared for temporary occlusion of the right middle cerebral artery (MCA) using the filament model. Cerebral blood flow in the MCA territory was continuously monitored with a laser-Doppler flowmeter. Subdermal electrodes were inserted into the dorsal forepaw to stimulate either the forepaw ipsilateral or contralateral to the occlusion starting 1 minute into ischemia and continuing throughout the ischemic period. A neurological evaluation was undertaken after 24 hours of reperfusion, and animals were then euthanized and brain slices stained with 2,3,5-triphenyltetrazolium chloride. Cortical and striatal damage was measured separately. The cortical and striatal infarct volumes were both significantly reduced in the contralateral stimulated group compared with the ipsilateral stimulated group (48% total reduction). There were no statistically significant differences in the neurobehavioral scores between the 2 groups, or in the laser-Doppler flow measurements from the MCA core. | The HLA-DRB1 locus within the major histocompatibility complex (MHC) at 6p21.3 has been identified as a susceptibility gene for rheumatoid arthritis (RA); however, there is increasing evidence of additional susceptibility genes in the MHC region. The aim of this study was to estimate their number and location. A case-control study was performed involving 977 control subjects and 855 RA patients. The HLA-DRB1 locus was genotyped together with 2,360 single-nucleotide polymorphisms in the MHC region. Logistic regression was used to detect DRB1-independent effects. After adjusting for the effect of HLA-DRB1, 18 markers in 14 genes were strongly associated with RA (P<10(-4)). Multivariate logistic regression analysis of these markers and DRB1 led to a model containing DRB1 plus the following 3 markers: rs4678, a nonsynonymous change in the VARS2L locus, approximately 1.7 Mb telomeric of DRB1; rs2442728, upstream of HLA-B, approximately 1.2 Mb telomeric of DRB1; and rs17499655, located in the 5'-untranslated region of DQA2, only 0.1 Mb centromeric of DRB1. In-depth investigation of the DQA2 association, however, suggested that it arose through cryptic linkage disequilibrium with an allele of DRB1. Two non-shared epitope alleles were also strongly associated with RA (P<10(-4)): *0301 with anti- cyclic citrullinated peptide-negative RA and *0701 independently of autoantibody status. |
Does cigarette smoke impair clearance of apoptotic cells through oxidant-dependent activation of RhoA? | Cigarette smoke (CS) is the primary cause of chronic obstructive pulmonary disease (COPD), an effect that is, in part, due to intense oxidant stress. Clearance of apoptotic cells (efferocytosis) is a critical regulator of lung homeostasis, which is defective in smokers and in patients with COPD, suggesting a role in disease pathogenesis. We hypothesized that CS would impair efferocytosis through oxidant-dependent activation of RhoA, a known inhibitor of this process. We investigated the effect of CS on efferocytosis in vivo and ex vivo, using acute, subacute, and long-term mouse exposure models. Acute and subacute CS exposure suppressed efferocytosis by alveolar macrophages in a dose-dependent, reversible, and cell type-independent manner, whereas more intense CS exposure had an irreversible effect. In contrast, CS did not alter ingestion through the Fc gamma receptor. The inhibitory effect of CS on apoptotic cell clearance depended on oxidants, because the effect was blunted in oxidant-resistant ICR mice, and was prevented by either genetic or pharmacologic antioxidant strategies in vivo and ex vivo. CS inhibited efferocytosis through oxidant-dependent activation of the RhoA-Rho kinase pathway because (1) CS activated RhoA, (2) antioxidants prevented RhoA activation by CS, and (3) inhibitors of the RhoA-Rho kinase pathway reversed the suppressive effect of CS on apoptotic cell clearance in vivo and ex vivo. | Stathmin, an important cytosolic phosphoprotein, is involved in cell proliferation and motility. This study was performed to elucidate the role of stathmin in the progression of medulloblastoma. The expression of stathmin protein was examined by immunohistochemical staining of tumor sections obtained in 17 consecutive patients with medulloblastoma who underwent resection between 1995 and 2005. Four patients were excluded because they were either lost to follow-up or underwent biopsy sampling only, leaving a total of 13 patients in the study. The stathmin expression was scored according to the immunoreactive fraction of tumor cells, and the level was correlated with various clinicopathological factors. The expression level of stathmin protein was < or = 10% in 9 patients, 11-50% in 1, and > 50% in 3. No staining was seen in the tissues adjacent to the tumors. For comparison, the authors grouped the expression level of stathmin into high (> 50%) and low (< or = 50%). It was found that patients with high expression of stathmin had more frequent tumor dissemination at the time of resection or soon after total excision of the tumor (p = 0.0035), and hence experienced a fulminant course with lower patient survival (p < 0.0001), with an average survival period of 6.7 months (range 2-10 months). The expression level of stathmin did not correlate with patient age, sex, CSF cytological findings, use of adjuvant therapies, Ki 67 index, or risk classification of the tumors according to previously described categories in the literature. |
Are reliability and validity of a modified MEDFICTS dietary fat screener in South African schoolchildren determined by use and outcome measures? | In South Africa, noncommunicable diseases and obesity are increasing and also affect children. No validated assessment tools for fat intake are available. To determine test-retest reliability and relative validity of a pictorial modified meats, eggs, dairy, fried foods, fats in baked goods, convenience foods, table fats, and snacks (MEDFICTS) dietary fat screener. We determined test-retest reliability and diagnostic accuracy with the modified MEDFICTS as the index test and a 3-day weighed food record and parental completion of the screener as primary and secondary reference methods, respectively. Grade-six learners (aged 12 years, 4 months) in an urban, middle-class school (n=93) and their parents (n=72). Portion size, frequency of intake, final score, and classification of fat intake of the modified MEDFICTS, and percent energy from fat, saturated fatty acids, and cholesterol of the food record. For categorical data agreement was based on kappa statistics, McNemar's test for symmetry, and diagnostic performance parameters. Continuous data were analyzed with correlations, mean differences, the Bland-Altman method, and receiver operating characteristics. The classification of fat intake by the modified MEDFICTS was test-retest reliable. Final scores of the group did not differ between administrations (P=0.86). The correlation of final scores between administrations was significant for girls only (r=0.58; P=0.01). Reliability of portion size and frequency of intake scores depended on the food category. For girls the screener final score was significantly (P<0.5) correlated to total, saturated fat, and cholesterol intakes (but not to percent energy from fat and saturated fatty acids intakes). The sensitivity of the modified MEDFICTS was very high (>90%), but chance corrected agreement between the classifications was poor. Parents did not agree with their children. | Docetaxel-based chemotherapy against castration-resistant prostate cancer (CRPC) has recently been shown to be effective and tolerable. The objective of this study was to retrospectively evaluate the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone. Thirty-seven CRPC patients were administered a treatment regimen consisting of 50 mg/m2 docetaxel once every 3-4 weeks and 1 mg dexamethasone daily at our institution, between November 2004 and April 2014. Twenty-four patients (65%) had a decrease in serum prostate-specific antigen (PSA) >50%. The median overall survival (OS) and PSA progression-free survival were 26.2 and 10.0 months, respectively. Ten of 12 patients (83%) taking analgesic agents reduced their intake because of decreased pain levels. Grade 3 febrile neutropenia occurred in 2 patients (5%). Nonhematological toxicities were less frequent but sometimes severe. Treatment-related death occurred in 2 octogenarian patients, 1 due to gastric bleeding and the other due to infective endocarditis. |
Does the circadian rhythm of tryptophan in breast milk affect the rhythms of 6-sulfatoxymelatonin and sleep in newborn? | The hormone melatonin regulates the sleep and this pineal hormone is synthesized in the organism from the amino acid tryptophan. It is known that breast-fed babies have better sleep patterns and a better entrained sleep/wake cycle than bottle-fed babies (adapted formula). To compare the circadian rhythm of 6-sulfatoxymelatonin (aMT6s)--the metabolite of melatonin excreted in the urine--in urine of bottle-fed and breast-fed children, and relate it to the circadian rhythm of tryptophan in breast milk, also evaluating the possible effects on the baby's night-time rest. 16 infants of 12 weeks of age were studied, divided into two groups depending on their exclusively natural or artificial feeding. The circadian rhythm of 6-sulfatoxymelatonin in urine was measured for the two groups of infants and for the breast-feeding mothers. In the breast milk, the circadian rhythm of the amino acid tryptophan was measured. The rest of the infants was tested by wrist actimeters for a week and the sleep parameters of the infants were measured and evaluated. The tryptophan in the breast milk presented a circadian rhythm with acrophase at around 03:00. This affected the 6-sulfatoxymelatonin circadian rhythm with acrophase at 06:00 in the breast-fed infants, and also promoted nocturnal sleep. Assumed sleep, actual sleep, and sleep efficiency were significantly increased in the breast fed infants with respect the formula fed infants. | Estimated glomerular filtration rate (eGFR) before coronary artery bypass graft (CABG) surgery is a key risk factor of in-hospital mortality. However, in patients with normal renal function before CABG, acute kidney injury develops after the procedure, making postoperative renal function assessment necessary for evaluation. Postoperative eGFR and its association with long-term survival have not been well studied. We studied 13,593 consecutive CABG patients in northern New England from 2001 to 2006. Patients with preoperative dialysis were excluded. Data were linked to the Social Security Association Death Master File to assess long-term survival. Kaplan-Meier and log-rank techniques were used. Patients were stratified by established categories of postoperative eGFR (90 or greater, 60 to 89, 30 to 59, 15 to 29, and less than 15 mL x min(-1) x 1.73 m(-2)). Median follow-up was 2.8 years (mean, 2.7; range, 0 to 5.5). Patients with moderate to severe acute kidney injury (less than 60) after CABG had significantly worse survival than patients with little or no acute kidney injury (90 or greater). |
Does [ Early prediction of psychosocial intervention need in pneumology patients after nurses ' evaluation ]? | This study was aimed to verify whether it is possible to detect at hospital admission, by means of INTERMED, pneumonology patients at risk of "complexity" and of specialized psychosocial intervention. With the Spanish version of INTERMED (for detection of risk for complexity of care) 144 patients were interviewed at admission by a standardized nurse. At discharge, patients were reassessed blindly with standardized Spanish versions of instruments including the Hospital Anxiety and Depression Scale (HADS). Somatic illness variables were independently documented, and severity was assessed by means of the Cumulative Illness Rating Scale. All variables were operationalized including complex (IM+; INTERMED>20) and non-complex patients (IM-), and probable need of psychosocial treatment/intervention. Statistical analysis included multivariate logistic regression. A complex course was documented in 9.6% of patients, and 28.8% had complex discharge. Significantly higher proportions of severe anxiety and/or depression were documented in IM+ cases (12.1%) when compared to IM- cases (0.9%), and the need of psychosocial treatment/intervention was also significantly more frequent among the former (24.2% versus 6.3% respectively). Furthermore, in the multivariate analysis and controlling for medical and sociodemographic confounders INTERMED was significantly associated with the variable need of psychosocial intervention. | To explore suppression of allograft vasculopathy by transfer of the calcitonin gene-related peptide (CGRP). The descending thoracic aortas from Lewis rats were grafted to the abdominal aortas of F344 rats, and the rats were randomized into 2 groups. A gene construct containing sequences from the adenoviral oncoprotein, the CGRP, and the enhanced green fluorescent protein was transferred into 1 group, and the sequences for the adenoviral oncoprotein and enhanced green fluorescent protein were transferred into a control group. Specimens were harvested at 4 and 8 weeks. Gene transfer was confirmed at fluorescence microscopy of frozen tissue sections, and expression was measured using reverse transcriptase-polymerase chain reaction. We determined the locations and levels of vascular cell adhesion molecule-1 (VCAM-1) and inducible nitric oxide synthase (iNOS) at immunohistochemistry and measured apoptosis. The CGRP gene was expressed only in the CGRP group at 4 weeks. The vascular luminal occlusion score in the CGRP group was lower than in the control group. The apoptotic index of the CGRP group was lower than in the control group only at 4 weeks. The VCAM-1 immunohistochemistry score in the CGRP group was lower than in the control group; however, the iNOS immunohistochemistry score in the CGRP group was lower than in the control group in the intima only at 4 weeks. |
Does improving Spleen Volume Estimation Via Computer-assisted Segmentation on Clinically Acquired CT scan? | Multi-atlas fusion is a promising approach for computer-assisted segmentation of anatomic structures. The purpose of this study was to evaluate the accuracy and time efficiency of multi-atlas segmentation for estimating spleen volumes on clinically acquired computed tomography (CT) scans. Under an institutional review board approval, we obtained 294 de-identified (Health Insurance Portability and Accountability Act-compliant) abdominal CT scans on 78 subjects from a recent clinical trial. We compared five pipelines for obtaining splenic volumes: Pipeline 1 - manual segmentation of all scans, Pipeline 2 - automated segmentation of all scans, Pipeline 3 - automated segmentation of all scans with manual segmentation for outliers on a rudimentary visual quality check, and Pipelines 4 and 5 - volumes derived from a unidimensional measurement of craniocaudal spleen length and three-dimensional splenic index measurements, respectively. Using Pipeline 1 results as ground truth, the accuracies of Pipelines 2-5 (Dice similarity coefficient, Pearson correlation, R-squared, and percent and absolute deviation of volume from ground truth) were compared for point estimates of splenic volume and for change in splenic volume over time. Time cost was also compared for Pipelines 1-5. Pipeline 3 was dominant in terms of both accuracy and time cost. With a Pearson correlation coefficient of 0.99, average absolute volume deviation of 23.7 cm(3), and time cost of 1 minute per scan, Pipeline 3 yielded the best results. The second-best approach was Pipeline 5, with a Pearson correlation coefficient of 0.98, absolute deviation of 46.92 cm(3), and time cost of 1 minute 30 seconds per scan. Manual segmentation (Pipeline 1) required 11 minutes per scan. | Plants, fungal endophytes (FEs) and the changing environment interact with each other forming an interlaced network. This study evaluates nonadditive and interactive effects of the FE Acremonium strictum and drought treatment on Atractylodes lancea plantlets. By applying FEs (meristem cultures of At. lancea, fungal inoculation of Ac. strictum and plantlet acclimatization) and drought treatment (regular watering, mild drought, severe drought), a research system of At. lancea ramets under different treatments was established. During 12 days of drought treatment, the plantlets' physiological responses and basic growth traits were measured and analysed. Although drought and FE presence affected plantlet traits to differing degrees, the interactive effects of the two were more pronounced. In particular under mild drought treatment, the FE conferred drought tolerance to plantlets by enhancing leaf soluble sugars, proteins, proline and antioxidant enzyme activity; decreasing the degree of plasmalemma oxidation; and increasing the host's abscisic acid level and root:shoot ratio. When exposed to regular watering or severe drought, these effects were not significant. |
Does the C57BL/6 genetic background confer cardioprotection in iron-overloaded mice? | Chronic transfusion therapy causes a progressive iron overload that damages many organs including the heart. Recent evidence suggests that L-type calcium channels play an important role in iron uptake by cardiomyocytes under conditions of iron overload. Given that beta-adrenergic stimulation significantly enhances L-type calcium current, we hypothesised that beta-adrenergic blocking drugs could reduce the deleterious effects of iron overload on the heart. Iron overload was generated by intraperitoneal injections of iron dextran (1g/kg) administered once a week for 8 weeks in male C57bl/6 mice, while propranolol was administered in drinking water at the dose of 40 mg/kg/day. Cardiac function and ventricular remodelling were evaluated by echocardiography and histological methods. As compared to placebo, iron injection caused cardiac iron deposition. Surprisingly, despite iron overload, myocardial function and ventricular geometry in the iron-treated mice resulted unchanged as compared to those in the placebo-treated mice. Administration of propranolol increased cardiac performance in iron-overloaded mice. Specifically, as compared to the values in the iron-overloaded group, in iron-overloaded animals treated with propranolol left ventricular fractional shortening increased (from 31.6% to 44.2%, P =0.01) whereas left ventricular end-diastolic diameter decreased (from 4.1 ± 0.1 mm to 3.5 ± 0.1 mm, P =0.03). Propranolol did not alter cardiac systolic function or left ventricular sizes in the placebo group. | We previously demonstrated than an enhanced reverse transcriptase-polymerase chain reaction assay for prostate specific antigen (PSA) can predict final pathological stage in radical prostatectomy patients. The potential role of the assay in predicting serum PSA recurrence after radical prostatectomy was explored. We evaluated 100 radical prostatectomy candidates by reverse transcriptase polymerase chain reaction preoperatively, and status was compared to serum PSA, Gleason score and final pathological results. Potential surgical failure was defined as tumor at the surgical margin or extending into the seminal vesicle. Patients were monitored postoperatively by serum PSA every 4 months. Kaplan-Meier analysis was used to evaluate the correlation between reverse transcriptase polymerase chain reaction and disease recurrence, defined as a PSA of 0.2 ng/ml. or greater. Enhanced reverse transcriptase polymerase chain reaction for PSA had a stronger correlation with potential surgical failure than preoperative serum PSA or Gleason score (relative risks 15.2, 5.9 and 3.2, respectively). The correlation between these modalities and PSA recurrence was evaluated during a mean followup of 13.6 months (range 5 to 26). Of 36 patients with positive reverse transcriptase polymerase chain reactions 9 had failure by PSA compared to 3 of 64 (4.7%) with negative polymerase chain reactions (p<0.0286). The relative risk for failure by reverse transcriptase polymerase chain reaction was 3.6. Gleason score and serum PSA had higher correlations with postoperative PSA elevations (relative risk 13.2 and 7.6, respectively). A Cox regression analysis model demonstrated that reverse transcriptase polymerase chain reaction for PSA can be used in conjunction with Gleason score and provides statistically significant risk information. |
Does activation of peroxisome proliferator-activated receptor β/δ attenuate acute ischemic stroke on middle cerebral ischemia occlusion in rats? | Peroxisome proliferator-activated receptor (PPAR)-β/δ is a transcription factor that belongs to the nuclear hormone receptor family. There is little information about the effects of the immediate administration of specific ligands of PPAR-β/δ (GW0742) in animal models of acute ischemic stroke. Using a rat model of middle cerebral ischemia occlusion (MCAO) in vivo, we have investigated the effect of pretreatment with GW0742 before MCAO. The neuroprotective effect of GW0742 against acute ischemic stroke was evaluated by the neurologic deficit score (NDS), dry-wet weight, and 2,3,5-triphenyltetrazolium chloride staining. The levels of interleukin (IL)-1β, nuclear factor (NF)-κB, and tumor necrosis factor (TNF)-α were detected by an enzyme-linked immunosorbent assay. The expressions of inducible nitric oxide synthase (iNOS), Bax, and Bcl-2 were detected by Western blot. The apoptotic cells were counted by in situ terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay. The pretreatment with GW0742 significantly increased the expression of Bcl-2, and significantly decreased in the volume of infarction, NDS, edema, expressions of IL-1β, NF-κB, TNFα, and Bax, contents of iNOS and the apoptotic cells in infarct cerebral hemisphere compared with rats in the vehicle group at 24 hours after MCAO. | Linear furrows are the most frequently found endoscopic abnormality in patients with esophageal eosinophilia (EE); however, the precise endoscopic features remain to be fully elucidated. Here, we aimed to clarify the endoscopic features of EE, essential for the diagnosis of eosinophilic esophagitis (EoE), by focusing on the specific locations of linear furrows in a Japanese population. We enrolled 70 cases with EE (≥15 eosinophils/high-power field) who were diagnosed at our hospital and related facilities. Information regarding endoscopic findings and clinical parameters was retrospectively reviewed. Next, the position of linear furrows in relation to esophageal longitudinal folds (ridge or valley) was evaluated in each case and compared with the position of mucosal breaks in patients with reflux esophagitis. Finally, the relationship between linear furrows and eosinophilic infiltration was evaluated. Of the 70 EE patients, 63 (90%) had linear furrows. Those occurred in a radial pattern and were widespread throughout the lower to upper esophagus, and exclusively found in esophageal longitudinal mucosal fold valleys, not on ridges, which was different from the position of mucosal breaks in patients with reflux esophagitis. Increased eosinophilic infiltration was significantly more frequent in linear furrows in the valleys (93%) as compared to mucosa on adjacent ridges (60%) (P < 0.05). |
Does coronary oxygen persufflation combined with HTK cardioplegia prolong the preservation time in heart transplantation? | One of the most restricting factors remaining in heart transplantation is the limited myocardial ischemia time. A new approach towards the prolongation of this time is the combination of primary cardioplegic arrest followed by continuous coronary oxygen persufflation (COP) with gaseous oxygen. This technique was applied in pig hearts, which we transplanted orthotopically after cardioplegic arrest by original (n = 5) and modified (addition of hyaluronidase: n = 11) Bretschneider HTK solution and 14 h of hypothermic preservation. Depending on the different preservation techniques, we created four groups: (1), original HTK (HTK), n = 5; (2), modified HTK (mHTK), n = 5; (3), modified HTK solution plus COP (mHTK + COP), n = 6; and (4), as a control five hearts were transplanted after cardioplegic arrest by the original HTK solution and a cold ischemia time of 3 h comparable to clinical routine procedure. After 14 h of preservation and orthotopic transplantation, cardiac functional recovery in mHTK + COP hearts was similar to control hearts, and improved compared to hearts of both other groups. Hemodynamics were significantly better in hearts preserved by mHTK + COP and in the control group compared to the HTK-hearts (P < 0.05), not significant compared to mHTK hearts (dp/dt(max) in % of preoperative +/- standard error of mean (SEM): mHTK + COP, 85 +/- 9; control, 85 +/- 10.5; mHTK, 59 +/- 14; HTK, 50 +/- 4). The cardiac output (CO) in % of preoperative was: mHTK + COP, 68 +/- 5.4; control, 64 +/- 4; mHTK, 44 +/- 2.7; HTK, 25 +/- 11. The ATP of left ventricular myocardium in mHTK + COP hearts at 14.7 +/- 1 micromol/g dry weight (DW) and in the control at 14.59 +/- 1.8 was higher compared to that in mHTK at 12.2 +/- 2.8 (P is non-significant (n.s.) versus mHTK + COP and control) and in HTK-hearts at 7.0 +/- 0.5 (P < 0.05 versus mHTK + COP and control). CK-MB in percent of CK showed no increase in either group. | Currently, there is no standardised screening for prostate cancer in Europe. Assessment of risk is opportunistically undertaken in consultation with the GP or urologist. Evaluation of the prostate gland consists of a prostate-specific antigen (PSA) serum level and a digital rectal examination (DRE) of the gland. DRE is an essential part of the assessment that can independently predict prostate cancer in the setting of a normal PSA level. To evaluate the clinical usefulness of the DRE in general practice and urology clinics, and to ascertain its positive predictive value and sensitivity. A retrospective analysis study of a cohort of Irish men who underwent TRUS guided biopsy of the prostate in a single Irish tertiary referral centre, despite a normal PSA level. Patients were identified from a Rapid Access Prostate Clinic patient database. Pathological biopsy results were correlated with clinical DRE findings. Patient demographics, PSA levels, and DRE findings from a prospectively established database and hospital data systems from May 2009 to October 2013 were analysed. Of 103 men referred over a 53-month period with a normal age-adjusted PSA level, 67% were referred on the basis of an abnormal DRE alone. Thirty-five per cent of males with a normal PSA had prostate cancer. DRE alone had a sensitivity and specificity of 81% and 40% respectively in diagnosing prostate cancer, with a positive predictive value of 42%. Seventy-six per cent of these men had high-grade disease. |
Does low energy shock wave therapy induce angiogenesis in acute hind-limb ischemia via VEGF receptor 2 phosphorylation? | Low energy shock waves have been shown to induce angiogenesis, improve left ventricular ejection fraction and decrease angina symptoms in patients suffering from chronic ischemic heart disease. Whether there is as well an effect in acute ischemia was not yet investigated. Hind-limb ischemia was induced in 10-12 weeks old male C57/Bl6 wild-type mice by excision of the left femoral artery. Animals were randomly divided in a treatment group (SWT, 300 shock waves at 0.1 mJ/mm2, 5 Hz) and untreated controls (CTR), n = 10 per group. The treatment group received shock wave therapy immediately after surgery. Higher gene expression and protein levels of angiogenic factors VEGF-A and PlGF, as well as their receptors Flt-1 and KDR have been found. This resulted in significantly more vessels per high-power field in SWT compared to controls. Improvement of blood perfusion in treatment animals was confirmed by laser Doppler perfusion imaging. Receptor tyrosine kinase profiler revealed significant phosphorylation of VEGF receptor 2 as an underlying mechanism of action. The effect of VEGF signaling was abolished upon incubation with a VEGFR2 inhibitor indicating that the effect is indeed VEGFR 2 dependent. | To determine the frequency of nutritional deficiencies and thyroid dysfunction in children with celiac disease (CD) and during follow-up after initiation of a gluten-free diet. Laboratory investigations of hemoglobin, ferritin, calcium, folate, vitamin B12, vitamin D, and thyroid function are regularly ordered in children with CD despite sufficient evidence for these. Between 2009 and 2014, test results of hemoglobin, ferritin, folate, vitamin B12, calcium, vitamin D (25[OH]D), free thyroxin, and thyroid stimulating hormone of children with CD regularly seen at the Leiden University Medical Center were investigated. Laboratory reference ranges were used to define abnormal results. Pearson χ(2) test for trend, unpaired t test, and 1-way ANOVA were used for statistical analysis. Of the 182 children evaluated, 119 were newly diagnosed. On average, 17% of results per year were missing because of incomplete blood investigations. Iron deficiency (28%) and iron deficiency anemia (9%) were found at the time of diagnosis of CD. Folate (14%), vitamin B12 (1%), and vitamin D deficiencies (27%) were also seen. No hypocalcemia or thyroid dysfunction was found. At follow-up, iron deficiency, iron deficiency anemia, and folate and vitamin D deficiency were observed in 8%, 2%, 3%, and 25% of patients, respectively. Vitamin B12 deficiency, hypocalcemia, and thyroid disease were not found. |
Is midline uterine defect size correlated with miscarriage of euploid embryos in recurrent cases? | To compare subsequent pregnancy outcomes after two or more miscarriages in patients with and without congenital uterine anomalies. Case-control study. Nagoya City University Hospital. A total of 42 patients with a bicornuate or septate uterus and 1528 with normal uteri. No surgery. The cumulative success rate for birth, abnormal chromosome karyotype rate in aborted concepti, and the predictive values of the height of the defect/length of the remaining uterine cavity ratio (D/C ratio). Of the total of 1676 patients, 54 (3.2%) had congenital uterine anomalies; 25 (59.5%) of the 42 patients with a bicornuate or septate uterus had a successful first pregnancy after examination, while this was the case for 1096 (71.7%) of the 1528 with normal uteri. There was no difference in the cumulative live-birth rate (78.0% and 85.5%) within the follow-up period. However, the rates for an abnormal chromosome karyotype in aborted concepti in cases with and without uterine anomalies were 15.4% (two of 13) and 57.5% (134 of 233), respectively, with the latter being significantly higher. The D/C ratio in the miscarriage group was also significantly greater than that for the live-birth group. | Temperature increase, oxidative stress, and inflammatory reactions after endurance exercise were expected to stimulate the synthesis of heat shock proteins (HSP) in peripheral blood leukocytes. Furthermore, it was of interest whether regular endurance training influences HSP expression. The expression of HSP27, HSP60, HSP70, constitutive HSC70, and HSP90 in the cytoplasma and surface of lymphocytes, monocytes, and granulocytes of 12 trained athletes was analyzed by flow cytometry before and after (0, 3, and 24 h) a half marathon. Twelve untrained persons at rest were included as control. After the race, there was a significantly greater percentage of leukocytes expressing cytoplasmic HSP27, HSP60, and HSP70 (P < 0.01), whereas HSC70 and HSP90 remained unchanged. The fluorescence intensity increased significantly in monocytes for HSP27 (0 and 3 h) and HSP70 (0, 3, and 24 h) and in granulocytes, only 24 h postexercise for HSP70. The percent values of trained athletes at rest were significantly lower compared with untrained persons (P < 0,01). |
Do basophils and mast cells play critical roles for leukocyte recruitment in IgE-mediated cutaneous reverse passive Arthus reaction? | The pathogenic role of IgE has been implicated in a variety of allergic and inflammatory diseases. We have previously established an IgE-mediated cutaneous reverse passive Arthus model in which eosinophil infiltration is a prominent feature. This uniquely provides a model of type III hypersensitivity in which Fc classes of Ig that forms immune complex differentially determine the disease manifestation. To investigate the mechanisms of how mast cells and basophils regulate this IgE-mediated Arthus reaction. IgE-mediated cutaneous reverse passive Arthus reaction was induced in wild-type C57BL/6 or WBB6F1-+/+ mice and mast-cell-deficient WBB6F1-W/W(v) mice by intradermal injection of IgE anti-trinitrophenyl antibodies followed immediately by intravenous administration of trinitrophenyl bovine serum albumin. Basophils were depleted in vivo using anti-CD200R3 monoclonal antibody prior to the IC challenge. Hemorrhage and infiltration of eosinophils, neutrophils, and basophils were significantly reduced but were not completely abrogated in WBB6F1-W/W(v) mice compared with those in wild-type WBB6F1-+/+ mice. Wild-type C57BL/6 mice treated by basophil-depleting mAb also showed significantly decreased hemorrhage and inflammatory cell infiltration, especially that of eosinophils, compared with control mice. Furthermore, basophil depletion in WBB6F1-W/W(v) mice led to nearly complete inhibition of eosinophil recruitment. By contrast, basophil depletion did not further decrease neutrophil infiltration in WBB6F1-W/W(v) mice. | Given the role of microRNA in colorectal cancer (CRC) progression, we explored the association between microRNA (miRNA) expression and CRC-related prognosis. Three types of tissue samples (primary CRC lesions without liver metastasis, primary lesions with liver metastasis, and liver metastatic tissues) were used for miRNA profiling to identify differentially expressed miRNA. Quantitative real-time PCR was used to examine miRNA expression in CRC cells and in tumor tissues. MiR-132 was significantly down-regulated in primary CRC tissues with liver metastasis and liver metastatic lesions compared to primary lesions without liver metastasis. Multivariate analysis for overall survival indicated that low miR-132 expression was an independent prognostic factor for CRC patients (overall survival P = 0.040, disease-free survival P = 0.015). Ectopic expression of miR-132 significantly inhibited cell proliferation and cell invasion. The luciferase reporter assay revealed that anoctamin 1 (ANO1) was a direct target of miR-132. Kaplan-Meier survival curves showed that high ANO1 expression was a significant prognostic factor for overall survival of patients with CRC (P = 0.0344). |
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