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Is troponin-I a predictor of a delayed diagnosis of atrial fibrillation in acute ischemic stroke and transient ischemic attack? | Prolonged cardiac monitoring detects higher rates of atrial fibrillation (AF) in ischemic stroke and transient ischemic attack (TIA) but is costly and has practical implications. The use of admission troponin-I (TnI) level to identify patients at high risk of delayed AF detection was investigated. Consecutive ischemic stroke and TIA cases presenting to our institute over a 13-month period were identified from the Irish Stroke and TIA Register. Electronic databases and case notes were examined. "Delayed" AF was diagnosed after a sinus rhythm admission electrocardiogram and no documented history. Group comparisons were made by AF status. The association between TnI and AF was investigated using a multivariate regression model. A total of 185 cases (130 ischemic stroke) were analyzed. Mean age (standard deviation) was 73.3 (13.9) years, 47% female. Sixty-two cases (33.5%) had AF. The first documented presentation of AF was found in 21 cases, on admission electrocardiogram (n = 11) or inpatient telemetry (delayed, n = 10). TnI was higher in those with delayed AF than in those without AF (W = 194; P = .036). A higher proportion of those with an elevated TnI (30%) than those with a normal TnI (6.1%) had delayed diagnosis of AF (χ(2) = 6.41, P = .011). Having an abnormal TnI was a significant independent predictor of delayed AF detection (odds ratio, 5.8; P = .037). | The yeast Saccharomyces cerevisiae is unable to ferment pentose sugars like d-xylose. Through the introduction of the respective metabolic pathway, S. cerevisiae is able to ferment xylose but first utilizes d-glucose before the d-xylose can be transported and metabolized. Low affinity d-xylose uptake occurs through the endogenous hexose (Hxt) transporters. For a more robust sugar fermentation, co-consumption of d-glucose and d-xylose is desired as d-xylose fermentation is in particular prone to inhibition by compounds present in pretreated lignocellulosic feedstocks. Evolutionary engineering of a d-xylose-fermenting S. cerevisiae strain lacking the major transporter HXT1-7 and GAL2 genes yielded a derivative that shows improved growth on xylose because of the expression of a normally cryptic HXT11 gene. Hxt11 also supported improved growth on d-xylose by the wild-type strain. Further selection for glucose-insensitive growth on d-xylose employing a quadruple hexokinase deletion yielded mutations at N366 of Hxt11 that reversed the transporter specificity for d-glucose into d-xylose while maintaining high d-xylose transport rates. The Hxt11 mutant enabled the efficient co-fermentation of xylose and glucose at industrially relevant sugar concentrations when expressed in a strain lacking the HXT1-7 and GAL2 genes. |
Does deficiency in Nrf2 transcription factor decrease adipose tissue mass and hepatic lipid accumulation in leptin-deficient mice? | To evaluate whether Nrf2 deficiency impacts insulin resistance and lipid accumulation in liver and white adipose tissue. Lep(ob/ob) mice (OB) with targeted Nrf2 deletion (OB-Nrf2KO) were generated. Pathogenesis of obesity and type 2 diabetes was measured in C57BL/6J, Nrf2KO, OB, and OB-Nrf2KO mice. Hepatic lipid content, lipid clearance, and very low-density lipoprotein (VLDL) secretion were determined between OB and OB-Nrf2KO mice. OB-Nrf2KO mice exhibited decreased white adipose tissue mass and decreased adipogenic and lipogenic gene expression compared with OB mice. Nrf2 deficiency prolonged hyperglycemia in response to glucose challenge, which was paralleled by reduced insulin-stimulated Akt phosphorylation. In OB mice, Nrf2 deficiency decreased hepatic lipid accumulation, decreased peroxisome proliferator-activated receptor γ expression and nicotinamide adenine dinucleotide phosphate (NADPH) content, and enhanced VLDL secretion. However, this observation was opposite in lean mice. Additionally, OB-Nrf2KO mice exhibited increased plasma triglyceride content, decreased HDL-cholesterol content, and enhanced apolipoprotein B expression, suggesting Nrf2 deficiency caused dyslipidemia in these mice. | Recent evidence suggests that patients with a normal cranial CT scan after head injury can be safely discharged home from the emergency department. However, supporting data from previous studies has relied on incomplete patient follow-up. We utilized a statewide comprehensive hospital abstract reporting system (CHARS) to assess whether children with normal CT scans after head injury subsequently developed intracranial sequelae in the month following their initial injury. Retrospective case-series study, with comprehensive statewide follow-up for 1 month. The emergency department of a Level 1 Trauma Center in Seattle, Washington. All children (n = 400) with head injury, Glasgow Coma Score of 13 to 15, and initial normal CT scan seen over a 4.5-year time period. All were matched against CHARS to evaluate admissions within 30 days after emergency department disposition. For readmissions, International Classification of Diseases (9th revision) discharge and procedure information was collected. All children were also matched against the state death files. Four children were readmitted for neurologic reasons within 1 month following injury. One child on coumadin for heart disease developed a symptomatic subdural hematoma 5 days after head injury, requiring neurosurgical drainage. One child developed a symptomatic hemorrhagic contusion 3 days after injury, requiring observation only. Two children were readmitted 1 day after injury for concussive symptoms; both were discharged home after observation only. There were no deaths among the study population. |
Does ethanolic Ginkgo biloba leaf extract prevent renal fibrosis through Akt/mTOR signaling in diabetic nephropathy? | Recently, extract of Ginkgo biloba leaves (GbE) have become widely known phytomedicines and have shown various pharmacological activities, including improvement of blood circulation, protection of oxidative cell damage, prevention of Alzheimer's disease, treatment of cardiovascular disease and diabetes complications. This study was designed to investigate the effects of an ethanolic GbE on renal fibrosis in diabetic nephropathy (DN) and to clarify the possible mechanism by which GbE prevents renal fibrosis. We investigated the protective effects of GbE on renal fibrosis in STZ-induced diabetic rats. Rats were randomized into six groups termed normal control, diabetes mellitus, low dose of GbE (50 mg/kg/d), intermediate dose of GbE (100 mg/kg/d), high dose of GbE (200 mg/kg/d) and rapamycin (1 mg/kg/d). After 12 weeks, the rats were sacrificed and then fasting blood glucose (FBG), creatinine (Cr), blood urea nitrogen (BUN), urine protein, relative kidney weight, glycogen and collagen accumulation, and collagen IV and laminin expression were measured by different methods. The amounts of E-cadherin, α-SMA and snail, as well as the phosphorylation of Akt, mTOR and p70S6K in the renal cortex of rats, were examined by western blotting. Compared with diabetic rats, the levels of Cr, BUN, urine protein, relative kidney weight, accumulation of glycogen and collagen, and expression of collagen IV and laminin in the renal cortex were all decreased in GbE treated rats. In addition, GbE reduced the expression of E-cadherin, α-SMA, snail and the phosphorylation of Akt, mTOR and p70S6K in diabetic renal cortex. | Several studies have shown that contralateral prophylactic mastectomy (CPM) provides a disease-free and overall survival (OS) benefit in young women with estrogen receptor (ER)-negative breast cancer. We utilized the National Cancer Data Base to evaluate CPM's survival benefit for young women with early -stage breast cancer in the years that ER status was available. We selected 14,627 women ≤45 years of age with American Joint Committee on Cancer stage I-II breast cancer who underwent unilateral mastectomy or CPM from 2004 to 2006. Five-year OS was compared between those who had unilateral mastectomy and CPM using the Kaplan-Meier method and Cox regression analysis. A total of 10,289 (70.3 %) women underwent unilateral mastectomy and 4,338 (29.7 %) women underwent CPM. Median follow up was 6.1 years. After adjusting for patient age, race, insurance status, co-morbidities, year of diagnosis, ER status, tumor size, nodal status, grade, histology, facility type, facility location, use of adjuvant radiation and chemohormonal therapy, there was no difference in OS in women <45 years of age who underwent CPM compared towith those who underwent unilateral mastectomy (hazard ratio [HR] = 0.93; p = 0.39). In addition, Tthere was no improvement in OS in women <45 years of age with T1N0 tumors who underwent CPM versus unilateral mastectomy (HR = 0.85; p = 0.37) after adjusting for the aforementioned factors. Among women ≤45 years of age with ER-negative tumors who underwent CPM, there was no improvement in OS compared with women who underwent unilateral mastectomy (HR = 1.12; p = 0.32) after adjusting for the same aforementioned factors. |
Do large portion sizes increase bite size and eating rate in overweight women? | Larger food portions lead to increased intake but the mechanism behind this effect is unclear. We investigated the effect of portion size on bite size, eating rate, deceleration rate, and meal duration. Thirty-seven overweight women attended 5 visits after a 3 h fast and consumed a 229, 303, 400, 529 or 700 g portion of a lunch meal in random order. Meal eating parameters were measured with the Sussex Ingestion Pattern Monitor. Data were analyzed with mixed effects models. Average bite size increased by 0.22 g for every 100 g increase in portion size (p=0.001); portion size had a non-linear effect on eating rate, increasing with portion sizes up to about 540 g (p=0.01). Deceleration rate (reduction in speed of eating) decreased by 20% (p<0.001) and meal duration increased by 22.5% for every 100 g increase in portion size (p<0.001), relative to the smallest portion. | Stem/progenitor cells are in the focus of research as a future therapeutic option to stimulate regeneration in diseased renal parenchyma. However, current data indicate that successful seeding of implanted stem/progenitor cells is prevented by harmful interstitial fluid and altered extracellular matrix. To find out possible parameters for cell adaptation, the present investigation was performed. Renal stem/progenitor cells were mounted in an artificial interstitium for perfusion culture. Exposure to chemically defined but CO2-independent culture media was tested during 13 days. Cell biological features were then analyzed by histochemistry, while structural details were investigated by transmission electron microscopy after conventional and improved fixation of specimens. Culture of renal stem/progenitor cells as well in Leibovitz's L-15 Medium as CO2 Independent Medium shows in fluorescence microscopy spatial development of numerous tubules. Specimens of both media fixed by conventional glutaraldehyde exhibit in electron microscopy a homogeneous cell population in developed tubules. In contrast, fixation by glutaraldehyde including tannic acid illuminates that dispersed dark marked cells of unknown function are present. The screening further demonstrates that the dark cell type does not comply with cells found in embryonic, maturing or matured renal parenchyma. |
Does identification and correlate of weight loss in adolescents in a national sample? | Little is known about behaviors associated with successful weight loss during adolescence. The first objective of the current study was to identify meaningful weight loss, weight maintenance, and weight gain in male and female adolescents. The second objective of this study was to apply these methods to U.S. adolescents from the National Health and Nutrition Survey 1999 to 2002 data and to identify factors associated with these weight change outcomes. The current analyses include 1726 (female, 836; male, 890) 16- to 18-year-old adolescents who completed the questionnaire components and interview for either the 1999-2000 or the 2001-2002 National Health and Nutrition Survey study. Dietary intake, physical activity, and dieting attitudes were compared across the weight loss (L), maintain (M), and gain (G) groups in the entire sample and in a subset of adolescents who are overweight and at-risk-for-overweight (> or = 85th percentile). The tested method for identifying weight L, M, and G groups has both theoretical and statistical validity and, when applied to the sample, showed the expected direction of changes in weight. Results suggest that more overall physical activity, more vigorous exercise, and less sedentary activity are associated with being in the L group in both the full sample and the overweight and at-risk-for-overweight sample. In addition, fewer teens in the L groups endorsed efforts at trying to lose weight, compared with the M and G groups. | The prostamide bimatoprost and prostanoid FP receptor agonists are highly efficacious drugs for glaucoma treatment. The presence of both prostamide and prostanoid FP receptors in bimatoprost-sensitive preparations has made prostamide receptor classification difficult. This study investigated a novel bimatoprost-sensitive preparation. Human peripheral blood T lymphoblasts (Molt-3) and human osteoblasts (hFOB) were cultured for intracellular calcium signaling studies and quantitative real-time PCR analysis of RNA. Bimatoprost stimulated concentration-related increases in [Ca(2 +)](i) in a human T-cell line that does not express human FP receptor/variants, according to PCR analysis. The calcium signal induced by bimatoprost was not antagonized by prostanoid FP receptor antagonist/partial agonist AL-8810 or selective TP receptor antagonist SQ 29548. Conversely, bimatoprost did not elevate [Ca(2 +)](i) in human osteoblasts, which were confirmed to contain RNA of human FP receptor/variants. |
Are plasma coenzyme Q10 reference intervals , but not redox status , affected by gender and race in self-reported healthy adults? | Abnormal concentrations of coenzyme Q(10) have been reported in many patient groups, including certain cardiovascular, neurological, hematological, neoplastic, renal, and metabolic diseases. However, controls in these studies are often limited in number, poorly screened, and inadequately evaluated statistically. The purpose of this study is to determine the reference intervals of plasma concentrations of ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) for self-reported healthy adults. Adults (n=148), who were participants in the Princeton Prevalence Follow-up Study, were identified as healthy by questionnaire. Lipid profiles, ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) concentrations were measured in plasma. The method used to determine the reference intervals is a procedure incorporating outlier detection followed by robust point estimates of the appropriate quantiles. Significant differences between males and females were present for ubiquinol-10 and total coenzyme Q(10). Blacks had significantly higher Q(10) measures than whites in all cases except for the ubiquinol-10/total Q(10) fraction. | Esophageal cancer staging uses tumor depth as the sole criterion for assessment of the primary tumor (pT). To the authors' knowledge the impact of esophageal tumor length on long-term outcome and the esophageal cancer staging system has not been fully evaluated in the current era. All esophageal cancer patients (n = 209) undergoing surgery from 1995 to 2005 who did not receive preoperative chemotherapy or radiotherapy were reviewed. Maximum esophageal tumor length along a craniocaudal axis was determined pathologically after surgical resection. Univariate and multivariate analyses were used to assess the impact of esophageal tumor length (< or = 3 cm vs >3 cm) on long-term survival. Esophageal tumor length was closely associated with long-term survival (hazards ratio [HR] of 6.14 [95% confidence interval (95% CI), 4.1-9.25]; 5-year survival: < or = 3 cm = 68%, >3 cm = 10% [P < .001]). Multivariate Cox regression analyses demonstrated tumor length (HR of 2.13 [95% CI, 1.26-3.63]) was found to be a significant independent predictor of long-term survival even when controlled for sex, age, tumor location, histology, margin positivity, surgical procedure, and current pTNM criteria. The incorporation of tumor length in pTNM staging significantly improves the ability to predict the long-term survival of patients (5-year survival for patients with tumors < or = 3 cm and stages I, IIA, IIB, and III disease = 86%, 62%, 49%, and 22%, respectively; survival for patients with tumors measuring >3 cm and stages I, IIA, IIB, and III disease = 27%, 22%, 0%, and 8%, respectively [P < .1]). |
Is previous hepatitis a virus infection related to slower psychomotor speed in elderly adults? | Patients with chronic viral hepatitis are at a higher risk for cognitive dysfunction. Little is known about the association between hepatitis A virus (HAV) infection and cognitive function. From the National Health and Nutrition Examination Survey, 1999-2002, we selected study participants (> or =60 years, n = 1,529) without hepatitis B, C, or D virus infection; without previous hepatitis A vaccination; and without abnormal liver function. HAV-seropositive participants represented people with previous HAV infection. Psychomotor speed and executive functioning domain of cognitive function were measured by the Digit Symbol Substitution Test (DSST). HAV-seropositive participants had lower DSST scores than HAV-seronegative participants (weighted mean, 44.4 vs 53.9, p < .001). We designated HAV-seronegative participants as the reference group. Univariate analysis demonstrated that the weighted beta coefficient of DSST score was -9.55 (95% confidence interval [CI] -9.57 to -9.54, p < .001) for the HAV-seropositive participants. In a multivariable model, the weighted adjusted beta coefficient of DSST score was -2.48 (95% CI -2.49 to -2.46, p < .001) for the HAV-seropositive participants. | The combination of intracoronary transplantation and ultrasound-mediated microbubble destruction may promote effective and accurate delivery of bone marrow stem cells (BMSCs) into the infarct zone. To test this hypothesis in this study we examined the effectiveness of ultrasound-mediated microbubble destruction in combination with intracoronary transplantation of BMSCs for the treatment of myocardial infarction in canine model of acute myocardial infarction. The dogs were randomly assigned to four groups: PBS, ultrasound-mediated microbubble destruction, BMSCs, BMSCs together with ultrasound-mediated microbubble destruction. At 28 days post-surgery, cardiac function and the percentage of perfusion defect area to total left ventricular perfusion area (DA%) were determined by myocardial contrast echocardiography. Nitro blue tetrazolium staining was performed to determine myocardial infarct size, hematoxylin and eosin staining for assessing microvascular injury, Masson's staining for analyzing myocardial tissue collagen, immunohistochemical analysis of α-actin to measure cardiac contractile function and of BrdU-labeled myocardial cells to measure the number of the BMSCs homing to the infarcted region. The transplantation of BMSCs significantly improved heart function and DA% (P < 0.05). The group that received ultrasound-mediated microbubble destruction with BMSCs transplantation showed the most improvement in heart function and DA% (P < 0.05). This group also showed a denser deposition of BMSCs in the coronary artery and more BrdU positive cells in the infarcted region, had the maximum number of α-actin positive cells, showed the smallest myocardial infarct area compared to other groups (P< 0.05). |
Does resveratrol reduce morphine tolerance by inhibiting microglial activation via AMPK signalling? | Evidence has accumulated indicating that microglia within the spinal cord play a critical role in morphine tolerance. The present study investigated the effects and possible mechanisms of 5' adenosine monophosphate-activated protein kinase (AMPK) activator resveratrol and AICAR to inhibit microglial activation and to limit the decrease in antinociceptive effects of morphine. The microglial cell line BV-2 was used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signalling was assayed by Western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using the hot plate and tail-flick tests. (1) Morphine induces robust BV-2 cell activation, as evidenced by increased p38 mitogen-activated protein kinase phosphorylation, nuclear factor-κB translocation and mRNA expression of pro-inflammatory cytokines [including interleukin-1β (IL-1β), IL-6 and tumour necrosis factor-α], inducible nitric oxide synthase and Toll-like receptor-4, and these changes are inhibited by resveratrol. (2) Resveratrol activates AMPK to suppress morphine-induced BV-2 cell activation. AICAR, another AMPK activator, can mimic the effects of resveratrol, whereas compound C, an AMPK inhibitor, reverses the inhibitory effects of resveratrol treatment. (3) Systemic or spinal administration of resveratrol with morphine significantly blocks microglial activation in the spinal cord and then attenuates the development of acute and chronic morphine tolerance in both male and female mice. | A significant number of patients with pulmonary hypertension are resistant to medical therapy. We wanted to evaluate whether the modified technique of stent fenestration of the interatrial septum would be feasible and safe, and offer clinical benefit. The medical records of all patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension who underwent a stent fenestration of the interatrial septum between 2001 and 2008 were reviewed. In all fifteen patients (12 female, mean age 48.2 +/- 20.5 years) a successful fenestration procedure could be performed. Median follow-up time between diagnosis and fenestration was 2.3 years (range from 0.5 to 18.6 years). Mean event free survival since diagnosis and after septostomy was 9.8 +/- 2.9 and 3.2 +/- 0.8 years, respectively. When one extreme outlier was excluded, the 6 min walk distance improved significantly from 309 +/- 69 m immediately before fenestration to 374 +/- 84 m, 3-4 months after fenestration (n = 8, paired t-test, P = 0.03). No stent occlusion occurred. |
Is intermediate-term graft loss after renal transplantation associated with both donor-specific antibody and acute rejection? | Renal transplant recipients with de novo DSA (dDSA) experience higher rates of rejection and worse graft survival than dDSA-free recipients. This study presents a single-center review of dDSA monitoring in a large, multi-ethnic cohort of renal transplant recipients. The authors performed a nested case-control study of adult kidney and kidney-pancreas recipients from July 2007 through July 2011. Cases were defined as dDSA-positive whereas controls were all DSA-negative transplant recipients. DSA were determined at 1, 3, 6, 9, and 12 months posttransplant, and every 6 months thereafter. Of 503 recipients in the analysis, 24% developed a dDSA, of whom 73% had dDSA against DQ antigen. Median time to dDSA was 6.1 months (range 0.2-44.6 months). After multivariate analysis, African American race, kidney-pancreas recipient, and increasing numbers of human leukocyte antigen mismatches were independent risk factors for dDSA. Recipients with dDSA were more likely to suffer an acute rejection (AR) (35% vs. 10%, P<0.001), an antibody-mediated AR (16% vs. 0.3%, P<0.001), an AR ascribed to noncompliance (8% vs. 2%, P=0.001), and a recurrent AR (6% vs. 1%, P=0.002) than dDSA-negative recipients. At a median follow-up of 31 months, the death-censored actuarial graft survival of dDSA recipients was worse than the DSA-free cohort (P=0.002). Yet, for AR-free recipients, there was no difference in graft survival between cohorts (P=0.66). | To study the gastroprotective effect and in vivo antioxidant potential of a standardized iridoid fraction from B. prionitis leaves (BPE) against different gastric ulcer models in rats. The standardized iridoid fraction from BPE at 50, 100, and 200 mg/kg body weight was administered orally, twice daily for 5 days for prevention from aspirin, ethanol, cold-restraint stress (CRS), and pylorus ligation (PL)-induced ulcers. Estimation of the antioxidant enzyme activity was carried out in a CRS-induced ulcer model, and various gastric secretion parameters including volume of gastric juice, acid output, and pH value were estimated in the PL-induced ulcer model. BPE showed a dose-dependent ulcer protective effect in PL (18.67%-66.26% protection), aspirin (24.65%-63.25% protection), CRS (20.77%-59.42% protection), and EtOH (16.93%-77.04% protection)-induced ulcers. BPE treatment in PL-rats showed a decrease in acid-pepsin secretion, and enhanced mucin and mucosal glycoproteins. However, BPE reduced the ulcer index with significant decrease in LPO (P < 0.01-0.001), SOD (P < 0.01-0.001), and an increase in CAT (P < 0.01-0.001), activity in the CRS-induced model. |
Do elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro? | Hyperphosphatemia, elevated calcium x phosphorus product (Ca x P), and calcium burden, major causes of vascular calcification, are correlated with increased cardiovascular morbidity and mortality in dialysis patients. To address the underlying mechanisms responsible for these findings, we have utilized an in vitro human smooth muscle cell (HSMC) model of vascular calcification. Previous studies using this system demonstrated enhanced calcification of HSMC cultures treated with phosphorus levels in the hyperphosphatemic range, and implicated a sodium-dependent phosphate cotransport-dependent mechanism in this effect. In the present study, we examine the effect of increasing calcium concentrations on HSMC calcification in vitro. Increasing calcium to levels observed in hypercalcemic individuals increased mineralization of HSMC cultures under normal phosphorus conditions. Importantly, at these total calcium concentrations, ionized calcium levels increased from 1.2 mmol/L to 1.7 mmol/L, consistent with levels observed physiologically in normocalcemic and hypercalcemic individuals, respectively. Furthermore, increasing both calcium and phosphorus levels led to accelerated and increased mineralization in the cultures. Calcium-induced mineralization was dependent on the function of a sodium-dependent phosphate cotransporter, since it was inhibited by phosphonoformic acid (PFA). While elevated calcium did not affect short-term phosphorus transport kinetics, long-term elevated calcium treatment of HSMCs induced expression of the sodium-dependent phosphate cotransporter, Pit-1. | The presence of perianal disease in Crohn's disease patients is one of the factors of postoperative recurrence. The aim of this study is to evaluate long-term prognosis of perianal Crohn's disease patients in Asian. Patients with Crohn's disease who had undergone surgical bowel resection were divided into two groups according to the presence of perianal lesion. We monitored the occurrences of abdominal and/or perianal reoperation and readmission due to disease flare-up. The 132 patients included in the study were divided into 2 groups, those with perianal disease (45 patients, 34.1%) and those without perianal disease (87 patients, 65.9%). Patients with perianal disease was younger in age (33.8 years versus 39.8 years, p = 0.015) and had been diagnosed as CD at a younger age (21.9 years versus 28.6 years, p = 0.005) than patients without perianal disease. Patients with perianal disease showed more extra-intestinal manifestation than patients without perianal disease (8 versus 3, p = 0.008). Reoperation was required in 46 (44.8%) patients during the follow-up period. The presence of perianal disease independently increased the risk of reoperation [hazard ratio (HR), 3.112; confidence interval (CI), 1.707-5.675]. Furthermore, patients with perianal disease had increasing risks of abdominal reoperation (HR 1.978; 95% CI, 1.034-3.784). |
Does high expression of stathmin protein predict a fulminant course in medulloblastoma? | 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. | Recent studies have suggested that cannabis use is a risk factor for developing schizophrenia. We tested the hypothesis that cannabis use increases the likelihood of psychosis-like experiences in non-clinical participants who scored highly on a measure of schizotypy. The psychological effects of cannabis were assessed in 137 healthy individuals (76% female, mean age 22 years) using a newly developed questionnaire concerned with subjective experiences of the drug: the Cannabis Experiences Questionnaire. The questionnaire has three subscales: Pleasurable Experiences, Psychosis-Like Experiences and After-Effects. Respondents also completed the brief Schizotypal Personality Questionnaire. Cannabis use was reported by 72% of the sample. Use per se was not significantly related to schizotypy. However, high scoring schizotypes were more likely to report both psychosis-like experiences and unpleasant after-effects associated with cannabis use. The pleasurable effects of cannabis use were not related to schizotypy score. |
Are the importance of the belief that `` light '' cigarettes smoother in misperceptions of the harmfulness of `` light '' cigarettes in the Republic of Korea : a nationally representative cohort study? | A number of countries have banned misleading cigarette descriptors such as "light" and "low-tar" as called for by the WHO Framework Convention on Tobacco Control. These laws, however, do not address the underlying cigarette design elements that contribute to misperceptions about harm. This is the first study to examine beliefs about "light" cigarettes among Korean smokers, and the first to identify factors related to cigarette design that are associated with the belief that "light" cigarettes are less harmful. We analysed data from Wave 3 of the ITC Korea Survey, a telephone survey of a nationally representative sample of 1,753 adult smokers, conducted October - December 2010. A multinomial logistic regression was used to examine which factors were associated with the belief that "light" cigarettes are less harmful than regular cigarettes. One quarter (25.0 %) of smokers believed that "light" cigarettes are less harmful than regular cigarettes, 25.8 % believed that smokers of "light" brands take in less tar, and 15.5 % held both of these beliefs. By far the strongest predictor of the erroneous belief that "light" cigarettes are less harmful was the belief that "light" cigarettes are smoother on the throat and chest (p < 0.001, OR = 44.8, 95 % CI 23.6-84.9). | Coagulation and complement systems are simultaneously activated at sites of tissue injury, leading to thrombin generation and opsonisation with C3b. Thrombomodulin (TM) is a cell-bound regulator of thrombin activation, but can also enhance the regulatory activity of complement factor H (FH), thus accelerating the degradation of C3b into inactive iC3b. This study sought to determine the biophysical interaction affinities of two recombinant TM analogs with thrombin, FH and C3b in order to analyze their ability to regulate serum complement activity. Surface plasmon resonance (SPR) analysis was used to determine binding affinities of TM analogs with FH and C3b, and compared to thrombin as positive control. The capacity of the two recombinant TM analogs to regulate complement in serum was tested in standard complement hemolytic activity assays. SPR analysis showed that both TM analogs bind FH and C3b-Factor H with nanomolar and C3b with micromolar affinity; binding affinity for its natural ligand thrombin was several fold higher than for FH. At a physiological relevant concentration, TM inhibits complement hemolytic activity in serum via FH dependent and independent mechanisms. |
Is cow 's milk allergy in infants with atopic eczema associated with aberrant production of interleukin-4 during oral cow 's milk challenge? | A failure in the establishment and maintenance of oral tolerance in infancy may result in food allergy. To further assess the role of the intestinal immune system in cow's milk allergy (CMA), we investigated the systemic production of the pro-allergenic Th2 cytokine interleukin (IL)-4 and anti-allergenic cytokines IL-10, transforming growth factor (TGF)-beta1 and TGF-beta2 in infants suffering from atopic eczema with and without CMA during antigen elimination diet and oral antigen exposure. 18 infants (mean age, 9.6 months; 95% confidence interval 8.1-11.1 months) with atopic eczema and CMA and 17 infants (mean age, 9.7 months; 95% confidence interval 8.6-10.9 months) with atopic eczema tolerant to milk as assessed by a double blind, placebo-controlled cow's milk challenge were investigated. Peripheral blood mononuclear cells were obtained during antigen elimination diet and during oral cow's milk challenge and stimulated with Concanavalin-A or cow's milk or were left unstimulated. The cytokine concentrations were measured by enzyme-linked immunosorbent assay. During antigen elimination, the Concanavalin A-stimulated production of TGF-beta2 was significantly lower in infants with CMA as compared with infants without CMA: 129 pg/mL (interquartile ratio, 124-144 pg/mL) vs. 149 pg/mL (interquartile ratio, 133-169 pg/mL); P = 0.016. During oral antigen exposure, the immune responses in infants with CMA were characterized by significantly higher spontaneous production of IL-4 as compared with those without CMA: 12.0 pg/mL (interquartile ratio, 5.2-28.3 pg/mL) vs. 4.2 pg/mL (interquartile ratio, 1.5-7.6 pg/mL); P = 0.018. | To determine whether there is a significant correlation between optic nerve head circulation determined by pulse wave analysis of laser speckle flowgraphy (LSFG), and the cardio-ankle vascular index (CAVI), left ventricular (LV) function, and age. Forty-nine men who visited the Vascular Function Section of Toho University Sakura Medical Center, Chiba, Japan were studied. The mean age of the subjects was 60.7±10.6 years (range 29 to 80 years). The CAVI, left ventricular ejection fraction (LVEF) as a function of the systolic LV function, early diastolic mitral annulus velocity (e'), and the ratio of transmitral early peak velocity (E) to e' (E/e' ratio) as the diastolic LV function, and the optic nerve head circulation determined by pulse wave analysis of the LSFG. This parameter was named the blowout time (BOT). The BOT was significantly correlated with age, heart rate, body mass index (BMI), triglyceride, LVEF, e' velocity, E/e' ratio, and CAVI. The results of multiple regression analysis showed that age was significantly associated with CAVI (r= 0.36, p=0.002), BOT (r=-0.30, p=0.01) and e' velocity (r=-0.21, p=0.04). |
Does α-Methylacyl-CoA racemase ( AMACR ) serve as a prognostic biomarker for the early recurrence/metastasis of HCC? | Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it is still lacking effective prognostic biomarkers so far. Previous results of the iTRAQ-based quantitative proteomics study (iTRAQ-2DLC-MS/MS) have shown that α-methylacyl-CoA racemase (AMACR) might be a promising prognostic biomarker for the early recurrence/metastasis of hepatocellular carcinoma (HCC). Here a large-scale cohort clinical study was performed to evaluate its prognostic potential. HCC samples from patients (n=158) were used for the construction of tissue microarray. The expression level of AMACR was determined by immunohistochemical staining. A large-scale cohort clinical study between the expression of AMACR and some major clinical parameter has been performed to assess the prognostic potential of AMACR for the early recurrence/metastasis of HCC. Some important clinical parameters such as α-fetoprotein, tumour numbers, dissemination to regional lymph nodes, tumour capsule and portal vein tumour thrombosis are significantly associated with the low expression of AMACR. The expression of AMACR was an independent factor for the survival of patients with HCC. The median survival time was 17 months in the low-expression group compared with 45 months in the high-expression group. | To assess the effect of intrathecal baclofen on spastic dysarthia in cerebral palsy. Single case study. Functional outcome measures, including the Assessment of Intelligibility of Dysarthric Speech, were performed before and after a trial of intrathecal baclofen in an adult patient with spastic dysarthria due to cerebral palsy. The patient proceeded to intrathecal baclofen pump implantation and was reassessed after six months of continuous intrathecal baclofen therapy. Improvement in function including speech intelligibility was seen following the intrathecal baclofen trial. The improvement was sustained at six months post pump implantation. |
Is a polymorphism of EGFR extracellular domain associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment? | 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. | 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. |
Do circulating markers of endothelial dysfunction interact with proteinuria in predicting mortality in renal transplant recipients? | Proteinuria is associated with endothelial dysfunction (ED) and increased mortality. We investigated whether urinary protein excretion (UPE) is correlated with markers of ED and whether these markers affect the association of proteinuria with mortality in renal transplant recipients (RTR). Six hundred four RTR with a functioning graft for more than 1 year were included. RTR were divided according to UPE: less than 0.3, 0.3 to 1.0, and more than 1.0 g/24 hr. Soluble intercellular adhesion molecule type 1 (sICAM-1) and soluble vascular cellular adhesion molecule type 1 (sVCAM-1) were measured using ELISA. UPE (0.2 [0.0-0.5] g/24 hr), sICAM-1 (603 (514-721) ng/mL), and sVCAM-1 (952 [769-1196] ng/mL) were measured at 6.0 (2.6-11.4) years posttransplant. During follow-up for 5.3 (4.7-5.7) years, 94 (16%) RTR died. UPE was correlated with sVCAM-1 (standardized beta=0.13, P=0.001) but not with sICAM-1 (standardized beta=0.04, P=0.3). RTR with UPE more than 1.0 g/24 hr and high sICAM-1 (hazard ratio=4.7, 95% confidence interval 2.3-9.7, P<0.0001) or sVCAM-1 (hazard ratio=4.2, 95% confidence interval 2.0-8.6, P=0.0001) concentrations were at increased risk for death, whereas RTR with UPE more than 1.0 g/24 hr and low concentrations of sICAM-1 and sVCAM-1 were not. | Epoxyeicosatrienoic acids (EETs), a type of lipid mediators produced by cytochrome P450 epoxygenases, exert anti-inflammatory, angiogenic, anti-oxidative and anti-apoptotic effects. However, the role of EETs in cigarette smoke-induced lung injury and the underlying mechanisms are not fully known. The aim of this study was to explore the effects of CYP2J2-EETs on cigarette smoke extracts (CSE)-induced apoptosis in human bronchial epithelial cell line (Beas-2B) and the possible mechanisms involved. Cytochrome P450 epoxygenase 2J2 (CYP2J2) and its metabolites EETs were assessed by western blotting or LC-MS-MS. Cell viability and apoptosis were determined by MTT assay and AnnexinV-PI staining. Reactive oxygen species (ROS) were assessed by measuring H2DCFDA. Caspase-3, HO-1, MAPK and endoplasmic reticulum (ER) stress-related markers GRP78, p-elF2a, and CHOP were evaluated by western blotting. CSE suppressed expression of both CYP2J2 and EET by Beas-2B cells. CSE also induced apoptosis, the generation of ROS and the ER stress in Beas-2B cells. These changes were abolished by pretreatment with exogenous 14,15-EET while pretreatment with 14,15-EEZE, a selective EET antagonist, abolished the protective effects of 14,15-EET. In addition, EETs increased the expression of antioxidant enzyme HO-1. Furthermore, 14,15-EET reduced CSE-induced activation of p38 and JNK. |
Do [ Analysis of resistance phenotype and homology of Klebsiella pneumoniae in burn patients ]? | To study the resistance phenotype and homology of Klebsiella pneumoniae (KPN) in burn patients with infection. Fifty-four strains of KPN were isolated from wound excretion, blood, sputum, venous catheter, feces, and oral cavity of patients hospitalized in Institute of Burn Research of Southwest Hospital (briefly called our institute) from January 2007 to June 2011. Drug resistance of the 54 strains of KPN to 18 antibiotics commonly used in clinic, including ampicillin, ticarcillin, etc, was tested by K-B paper disk diffusion method after being identified. Extended-spectrum β-lactamase (ESBL)-producing KPN was screened based on the drug resistance result. The positive rates of drug-resistant genes SHV, TEM, and CTX-M of the ESBL-producing KPN were detected by polymerase chain reaction. The homology of the ESBL-producing KPN was analyzed by pulse field gel electrophoresis and clustering methodology. The homology of ESBL-producing KPN isolated in each year was analyzed too. (1) The sensitive rate of the 54 strains of KPN to imipenem, meropenem, and ertapenem was respectively 96.30%, 92.59%, and 81.48%, that of these strains to cefotetan and cefoxitin was respectively 70.37% and 64.81%, and that of these strains to ceftazidime was 57.41%. The sensitive rates of the 54 strains of KPN to the other antibiotics were all lower than 40.00%. (2) Twenty-six ESBL-producing KPN strains were screened and the positive rate of SHV, TEM, and CTX-M was 96.15% (25/26), 76.92% (20/26), and 57.69% (15/26), respectively. Detection rate of ESBL-producing KPN strains carrying three genes at the same time was 42.31% (11/26), that of these strains carrying both SHV and TEM was 34.62% (9/26), and those of these strains carrying only a single gene were all less than 10.00%. (3) The twenty-six ESBL-producing KPN were classified into 9 gene types, with 30.77% (8/26) in type A, 19.23% (5/26) in type B, 15.38% (4/26) in type C, 11.54% (3/26) in type D, 7.69% (2/26) in type E, and the rest four strains respectively in type F, G, H, I [3.85% (1/26)]. (4) The major gene type of ESBL-producing KPN in the year of 2007 and 2010 was type A, respectively accounting for 2/3 and 1/2, while that in the year of 2009 was type B, accounting for 1/2. The three strains in 2008 was respectively in type C, E, and F. The four strains in 2011 was respectively in type A, D, H, I. | Is the activity of sirtuin 3 (SIRT3) altered in granulosa and cumulus cells from young women with reduced ovarian reserve or women of advanced maternal age? |
Are high levels of EGFR expression in tumor stroma associated with aggressive clinical features in epithelial ovarian cancer? | The aim of this study was to investigate the clinical significance and biological function of epidermal growth factor receptor (EGFR) expressed in tumor stroma of epithelial ovarian cancer. Immunohistological staining of EGFR was evaluated in 242 patients with epithelial ovarian cancer. The correlations of EGFR expression in tumor stroma with clinicopathological features and with the expression level of Ki-67 were analyzed by SPSS software. Kaplan-Meier analysis and the Cox proportional hazard model were used to analyze the effect of EGFR expression in tumor stroma on the prognosis of patients with epithelial ovarian cancer. Meanwhile, the activities of proliferation and migration of tumor cells were detected when EGFR overexpressed in stroma cells. EGFR expression in tumor stroma correlated significantly with clinical stage (χ (2)=7.002, P=0.008) and distant metastases (χ (2)=16.59, P<0.001). Furthermore, there was a significantly positive correlation between the level of EGFR expressed in tumor stroma and the level of Ki-67 expressed in tumor cells (χ (2)=6.120, P=0.013). Patients with high EGFR expression level in tumor stroma showed poor survival (P=0.002). Multivariate analysis showed that high expression of EGFR in tumor stroma was an independent predictor for epithelial ovarian cancer patients (hazard ratio =1.703; 95% confidence interval 1.125-2.578, P=0.012). Furthermore, stroma cells overexpressing EGFR could promote the proliferation and migration of adjacent tumor cells. | A prospective, two-group comparative intervention study. To determine the acute and training effects of arm cranking exercise on blood lipid profiles in wheel chair bound individuals with spinal cord injury (SCI) and normal able-bodied subjects. Faculty of Science, School of Sport and Exercise Science, Liverpool John Moores University, England. Total cholesterol, triglyceride and high-density lipoprotein cholesterol (HDL-C) at rest and in response to arm cranking exercise before and after 12 weeks of training were compared between individuals with SCI (N = 5) and able-bodied subjects (N = 7). Following the determination of peak oxygen consumption (VO2peak), all subjects performed a submaximal arm cranking exercise at an intensity corresponding to 60-65% VO2peak for 30 min. Venous blood samples were obtained before and after submaximal exercise and measured for total cholesterol, triglycerides and HDL-C concentrations. These lipid parameters were remeasured in all subjects at rest and in response to the same submaximal arm cranking exercise after 12 weeks of individually supervised arm cranking training programme. Before training, the resting mean value of triglyceride in individuals with SCI was significantly (P < 0.05) higher than that found in able-bodied persons. Acute arm cranking exercise did not change total cholesterol or triglyceride concentrations in either the SCI or the able-bodied groups. However, HDL-C increased significantly following exercise in the able-bodied subjects. Following training, the resting mean value of total cholesterol in the group with SCI was significantly (P < 0.05) higher compared with able-bodied individuals. Furthermore, the resting and post submaximal arm cranking exercise mean values of total cholesterol in the able-bodied group, but not in the group with SCI, were significantly lower than those observed before training. While the resting mean value of HDL-C before training in the group with SCI was lower than that found in the able-bodied, this difference did not reach the designated level of significance (P > 0.05). Submaximal arm cranking exercise was followed by a significant increase in HDL-C only in the able-bodied individuals. Compared to pretraining, the resting and post arm cranking exercise levels of HDL-C in the group with SCI increased significantly (P < 0.05) after training. |
Do falling FSH levels predict poor IVF pregnancy rates in patients whom the gonadotropins are withheld? | To determine whether monitoring follicle stimulating hormone (FSH) levels in over-responding patients whom the gonadotropins were withheld would predict pregnancy outcome. A group of 33 female infertility patients aged between 20-40 years who had to be coasted during controlled ovarian hyperstimulation were recruited for this study. The FSH concentrations on human chorionic gonadotropin (HCG) day and on the four preceding days were measured to determine the threshold FSH concentration for follicular growth and conception. Mean and standard deviation were used for presenting parametric data. Student's t test and the Mann Whitney U test were used for statistical analysis. Two-tailed P < 0.05 was taken as significant. Receiver-operating characteristic (ROC) curves were performed to identify the cutoff level for FSH and E2 at HCG day and four preceding days. Of 33 cycles, 16 were stimulated with recombinant FSH and 17 with recombinant FSH and human menopausal gonadotropin (HMG). The basal and mean coasting FSH levels of FSH and FSH + HMG cycles did not reveal any differences. FSH concentrations decreased the day after coasting began in 26 cycles and fell by 30.2 +/- 2.7% (range 2-53). In 7 cycles, we observed 34.5 +/- 7.4% (range 6-56) declines in FSH levels beginning 2 days after coasting. Of the 31 women who received HCG, 21 conceived during in vitro fertilization and embryo transfer (IVF-ET). Gestational sac and fetal heart activity were visualized in 14 patients. ROC analysis releaved a cutoff value of 4.9 in FSH level at HCG day discriminative of conception or nonconception. | Bariatric surgery remains the most effective treatment for obesity and metabolic syndrome. Surgical benefit arises from early-phase resolution of hyperglycemia and late-phase weight loss. The adipokine chemerin is of interest given its roles in immunity, adipogenesis, and metabolism. The study objective was to examine the effects of biliopancreatic diversion with duodenal switch (BPD-DS) on plasma chemerin in the early and late post-operative stages. 83 adults with obesity undergoing BPD-DS, 45 obese non-surgical controls, and 9 lean surgical controls were enrolled. Plasma parameters and anthropometric measures were obtained at baseline and at, early (24 h, 5 D) and late (6 months and 12 months) post-operative stages. Plasma chemerin dropped from 176±49 ng/mL at baseline to 132±52 ng/mL 24 h after BPD-DS, rebounded to 200±66 ng/mL after 5 D, and declined to 124±51 and 110±34 ng/mL after 6 and 12 months. Plasma chemerin correlated negatively with measures of inflammation and hepatic injury and positively with measures of obesity, metabolic syndrome, and inflammation in the early and late post-operative periods, respectively. |
Does hBx inhibit the growth of CCL13-HBX-stable cells via the GSK-3beta/beta-catenin cascade? | The hepatitis B virus X protein (HBx) plays critical roles in cell survival via modulation of signaling pathways. In our previous studies, we reported that HBx inhibited the growth of CCL13-HBx-stable cells (Chang-HBx cells) in vitro and tumor formation in vivo in CCL13-HBx-cell-injected nude mice; however, this inhibition mechanism is unclear. To investigate the role of HBx in Wnt-3/beta-catenin signaling pathways, we focused on the key molecules GSK-3beta and beta-catenin, and analyzed by Western blotting and immunofluorescence staining. Results indicated that following HBx induction, GSK-3beta activity was up-regulated, the expression and accumulation of beta-catenin in the nucleus were decreased, and cell proliferation was suppressed. Inhibition of GSK-3beta activity by pharmacological inhibitors rescued the expression and accumulation of beta-catenin in the nucleus and facilitated cell proliferation and growth following HBx induction. The localization of beta-catenin, which is involved in cell proliferation, and mediated by GSK-3beta activation was also demonstrated. | Recent evidence suggests that climacteric symptoms may be intensified by specific temperament and personality traits in postmenopausal women. In this study we investigate Cloninger's model of personality in relation to menopausal symptoms. One-hundred and seventy peri- and postmenopausal women consecutively recruited from a menopause clinic of an academic hospital completed the Cloninger's Temperament and Character Inventory (TCI-140) which measures four dimensions of temperament: Harm avoidance, Novelty seeking, Reward dependence and Persistence, as well as three dimensions of character: Self-directedness, Cooperativeness, and Self-transcendence. Menopausal somatic, vasomotor and psychological symptoms were also assessed using the Greene Climacteric Scale. In comparison to the norms of the Greek general population, postmenopausal women presented lower scores in Novelty seeking and Reward dependence and higher scores in Persistence, Self-directedness, Cooperativeness and Self-transcendence. Higher harm avoidance (the inclination to avoid potential punishment, be shy and fearful of uncertainty) significantly correlated with anxiety and depressive symptoms while lower Self-directedness (the ability to have the willpower to adapt to or overcome any changes) correlated with depressive symptoms only. By multivariate regression analysis, higher Harm avoidance and lower Self-directedness were independently associated with the presence of depressive symptoms. No significant associations were observed between TCI-140 traits and somatic or vasomotor symptoms. |
Is 5-aminosalicylate therapy associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine? | Small uncontrolled trials have suggested that 5-aminosalicylate (5-ASA) medications increase 6-thioguanine nucleotide (6-TGn) levels in adults with Crohn's disease (CD) on azathioprine (AZA) or 6-mercaptopurine (6-MP), presumably through the inhibition of thiopurine methyltransferase (TPMT). We tested the theory that coadministration of 5-ASA agents with AZA/6-MP results in higher 6-TGn levels in a large cohort of children and adults with CD or ulcerative colitis (UC). A retrospective cohort study identified all children and adults treated for IBD with AZA/6-MP at 2 tertiary medical centers. Patients were included if their TPMT genotype was known and 6-TGn and 6-methymercaptopurine (6-MMP) levels had been obtained after 3 months of clinical remission at a stable dose of AZA/6-MP. 6-TGn and 6-MMP levels were compared between patients taking and those not taking 5-ASA medications through the use of linear regression models to identify and adjust for potentially confounding variables. Of the 126 patients included, 88 were taking 5-ASA medications. Patients on 5-ASA agents had higher mean 6-TGn levels after adjustment for confounding variables (Delta6-TGn, 47.6 +/- 21.8 pmol/8 x 10 red blood cells; P = 0.03). CD and TPMT heterozygosity was independently associated with higher 6-TGn levels (P = 0.01 and P = 0.03, respectively). 5-ASA exposure was not associated with a change in 6-MMP levels. | Focal adhesion kinase (FAK) is involved in processes integral to angiogenesis, such as cell growth, survival, and migration. FAK is activated by angiogenic growth factors, such as insulin-like growth factor (IGF)-I, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). The study was conducted to determine whether overexpression of FAK or FAK-related nonkinase (FRNK), an inhibitor of FAK, could influence human retinal endothelial cell (HREC) migration and in vivo angiogenesis. Migration in response to a combination of growth factors was examined in transfected HRECs overexpressing FAK or FRNK. The effect of FAK or FRNK overexpression on preretinal neovascularization was examined in a mouse model of oxygen-induced retinopathy. Overexpression of FAK in HRECs resulted in a 102% +/- 13% increase (P = 1.4 x 10(-4)) in cell migration, whereas overexpression of FRNK resulted in a 20% +/- 8% decrease (P = 0.01). Overexpression of FAK in mouse eyes led to formation of numerous large vascular tufts resembling glomeruli and a 57% +/- 7% increase in preretinal neovascularization (P = 3 x 10(-9)), whereas FRNK resulted in a 55% +/- 15% reduction (P = 5 x 10(-5)). |
Do long-term heavy marijuana users make costly decisions on a gambling task? | Chronic marijuana use has been associated with impairments of learning, memory, and executive functions. Little is known, however, about the effects of marijuana use on other cognitive domains, such as decision-making, which are thought to play an important role in addiction and drug abuse. The purpose of the present study was to determine if long-term heavy marijuana users employ different decision-making strategies than individuals with minimal marijuana exposure. Volunteers were assigned to a cannabis (n = 10) or control group (n = 10) based upon history of prior marijuana use. Demographic and neuropsychological variables were evaluated, and a decision-making task--the gambling task (GT) was administered. Although few demographic and neuropsychological differences were noted between groups, marijuana users made more decisions that led to larger immediate gains despite more costly losses than controls. | The purpose of the present study was to investigate the effect of the C1 esterase inhibitor (C1-INH) molecule against human complement attack on a swine endothelial cell (SEC) membrane. Human C1-INH functions as an inhibitor for complement reaction in the first step of the classical pathway in the fluid phase. A surface-bound form of human C1-INH (C1-INH-PI) consisting of a full-length coding sequence of C1-INH and a glycosylphosphatidylinositol (GPI) anchor of the decay-accelerating factor (CD55) was constructed, and stable Chinese hamster ovarian tumor (CHO) cell lines and SEC lines expressing C1-INH-PI were then prepared by transfection of the constructed cDNA. The basic function of the transfected molecules on the xenosurface was investigated using CHO transfectants for the sake of convenience. The efficacy of C1-INH-mediated protection of SEC from human complement was then assessed as an in vitro hyperacute rejection model of a swine-to-human discordant xenograft. Flowcytometric profiles of the stable CHO and SEC transfectants with C1-INH-PI showed a medium level of expression of these molecules. The C1-INH levels were significantly reduced as a result of phosphatidylinositol-specific phospholipase C (PI-PLC) treatment, suggesting that the molecules were present as the PI-anchor form. Approximately 51.3 x 10(4) and 13.3 x 10(4) molecules of C1-INH-PI blocked human complement-mediated cell lysis by approximately 75% on the CHO cell and by 60-65% on the SEC cell, respectively. In addition, the complement-inhibiting activity of human C1-INH molecules is not homologously restricted. |
Do peripheral blood mononuclear cells from severe asthmatic children release lower amounts of IL-12 and IL-4 after LPS stimulation? | Asthma is an inflammatory disorder of the airways associated with bronchial hyperresponsiveness, airway obstruction, and increased mucus production, with a predominance of type 2 immune response (Th2). According to the hygiene hypothesis, exposure to environmental bacterial lipopolysaccharide (LPS) may induce a type 1 immune response (Th1), modulating the development of asthma. In this study we investigated cytokine production by peripheral blood mononuclear cells (PBMC) from children and adolescents with severe asthma, in response to LPS stimulation in vitro. 26 children were selected: 13 severe asthmatics and 13 healthy controls, aged between 5 and 18 years. They were evaluated through routine medical history, physical examination and lung function test to diagnose severe asthma. Allergy status was confirmed by skin prick test and specific IgE assay. We collected blood samples to analyse in vitro LPS-induced cytokines release by PBMC. PBMC from severe asthmatic children produced lower levels of IL-12p70 in basal conditions and after 12 and 24h stimulation with LPS compared to healthy controls. PBMC from severe asthmatic children produced lower levels of IL-4 after 24h LPS stimulation compared to healthy controls. PBMC from severe asthmatic children produced more levels IL-17 and IL-10 after stimulus with LPS compared to healthy controls. The release of IFN-γ, IL-5 and TNF-α by PBMC from severe asthmatic children was similar to healthy controls. | Increased vascular endothelial growth factor (VEGF) expression is associated with colorectal cancer liver metastases. It is reasonable to expect that measurement of VEGF in liver metastases would provide the best prediction of therapy benefit for VEGF-targeted drugs, such as bevacizumab (Avastin). In this study, we evaluated how VEGF mRNA level in primary colorectal cancer was related to that in corresponding liver metastases. Thirty-one pairs of primary colorectal cancer and corresponding liver metastases were analyzed. Formalin-fixed, paraffin-embedded tumor specimens were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse transcription. Quantitation of VEGF and internal reference gene (beta-actin) was done using real-time PCR (Taqman PCR). There was no difference between median VEGF mRNA levels of primary colorectal cancer and liver metastases (median value 3.79 versus 3.97: P = 0.989). On an individual basis, there was a significant correlation in VEGF mRNA expression between primary colorectal cancer and corresponding liver metastases (r(s) = 0.6627, P < 0.0001). In addition, the VEGF mRNA levels of the patients who had two or more liver metastatic tumors were significantly higher than those of the patient who had solitary liver metastatic tumor in both primary cancer (5.02 versus 3.34: P = 0.0483) and liver metastases (4.38 versus 3.25: P = 0.0358). |
Are full-term , peri-urban South African infants under 6 months of age at risk for early-onset anaemia? | There is a paucity of data on the micronutrient status of low-income, lactating South African women and their infants under 6 months of age. The aim of this study was to elucidate the level of anaemia and vitamin A deficiency (VAD) in peri-urban breast-feeding women and their young infants. Cross-sectional study including anthropometric, biochemical and infant feeding data. Peri-urban settlement in Cape Town, South Africa. Breast-feeding women (n=113) and their infants (aged 1-6 months) attending a peri-urban clinic. Mean (standard deviation (SD)) haemoglobin (Hb) of the lactating mothers was 12.4 (1.3) g dl(-1), with 32% found to be anaemic (Hb<12 g dl(-1)). Maternal serum retinol was 49.8 (SD 13.3) microg dl(-1), with 4.5% VAD. Using breast milk, mean (SD) retinol concentration was found to be 70.6 (24.6) microg dl(-1) and 15.7 (8.3) microg/g milk fat, with 13% below the cut-off level of <8 microg/g fat. There was no correlation found between breast milk retinol and infant serum retinol. Z-scores (SD) of height-for-age, weight-for-age and weight-for-height were -0.69 (0.81), 0.89 (1.01) and 1.78 (0.83), respectively. Mean (SD) infant Hb was 10.9 (1.1) g dl(-1), with the prevalence of anaemia being 50%, 33% and 12% using Hb cut-offs below 11 g dl(-1), 10.5 g dl(-1) and 9.5 g dl(-1), respectively. Mean (SD) infant serum retinol was 26.9 (7.2) microg dl(-1), with 10% being VAD. None of the infants was exclusively breast-fed, 22% were predominantly breast-fed and 78% received complementary (mixed) breast-feeding. Thirty-two per cent of infants received weaning foods at an exceptionally young age (< or =1 month old). | We investigated the clinical significance of GALNT4 expression in patients with clear cell renal cell carcinoma. Enrolled in this study were 104 patients treated with curative nephrectomy at Zhongshan Hospital, Shanghai during 2004. Of the cohort 23 patients died of disease, 33 experienced recurrence and 3 died of another cause. GALNT4 density was assessed by immunohistochemistry in patient specimens. Univariate and multivariate Cox models, and ROC analysis were used to analyze the impact of prognostic factors on overall and relapse-free survival. Kaplan-Meier analysis with the log rank test was done to compare clinical outcomes between subgroups. Intratumor GALNT4 expression was significantly lower than peritumor expression. Low GALNT4 expression was associated with poor overall and relapse-free survival (p = 0.001 and 0.004, respectively). Intratumor GALNT4 expression, which negatively correlated with tumor size (p = 0.032), necrosis (p = 0.013) and TNM stage (p = 0.017), was an independent prognostic indicator for overall and relapse-free survival (HR 3.088, p = 0.020 and 2.173, p = 0.047, respectively). Extending the TNM staging system according to GALNT4 expression showed a better prognostic value for overall and relapse-free survival (AUC 0.786, p = 0.029 and 0.761, p = 0.040, respectively). |
Are twenty-four-month postradiation prostate biopsies strongly predictive of 7-year disease-free survival : results from a Canadian randomized trial? | The objective of this study was to evaluate the predictive value of prostate biopsies that were obtained 24 months after the completion of radiotherapy (RT) with respect to disease-free survival (DFS) in a randomized trial that compared 3 months versus 8 months of neoadjuvant hormone therapy before conventional dose external RT. From February 1995 to June 2001, 378 men were randomized to receive either 3 months or 8 months of combined flutamide and goserelin before they received 66 Gray of RT at 4 participating centers. By risk group, 26% of patients were categorized as low risk, 43% were categorized as intermediate risk, and 31% were categorized as high risk. The 2 treatment arms were balanced in terms of age, Gleason score, clinical tumor classification, risk group, and presenting prostate-specific antigen level. The median follow-up for the patients who remained alive was 6.6 years (range, 1.6-10.1 years). Of 361 evaluable patients, 290 patients remained alive. Post-RT prostate biopsies were performed between 24 and 30 months after the completion of RT in 3 of the 4 centers. Biopsies that had residual tumor with severe treatment effect were considered indeterminate, and biopsies that had minimal or no treatment effect were considered positive. The 5-year rate of actuarial freedom from any failure for the 3-month arm versus the 8-month arm was 72% versus 75% (P = .18). The DFS for patients who had negative and indeterminate biopsies was similar. Two-year post-treatment biopsy status was a strong predictor of 5-year DFS rate (82% and 83% for negative and indeterminate biopsies, respectively, vs 27% for positive biopsies; P < .0001). Multivariate analysis indicated that biopsy status (P < .0001) and Gleason score (P < .0001) were the strongest determinates of biochemical DFS. | Hemodynamic disturbed flow (DF) is associated with susceptibility to atherosclerosis. Endothelial Kruppel-Like Factor 4 (KLF4) is an important anti-inflammatory atheroprotective transcription factor that is suppressed in regions of DF. The plasticity of epigenomic KLF4 transcriptional regulation by flow-mediated DNA methylation was investigated in vitro and in arterial tissue. To recapitulate dominant flow characteristics of atheroprotected and atherosusceptible arteries, human aortic endothelial cells were subjected to pulsatile undisturbed flow or oscillatory DF containing a flow-reversing phase. Differential CpG site methylation was measured by methylation-specific polymerase chain reaction, bisulfite pyrosequencing, and restriction enzyme-polymerase chain reaction. The methylation profiles of endothelium from disturbed and undisturbed flow sites of adult swine aortas were also investigated. In vitro, DF increased DNA methylation of CpG islands within the KLF4 promoter that significantly contributed to suppression of KLF4 transcription; the effects were mitigated by DNA methyltransferase (DNMT) inhibitors and knockdown of DNMT3A. Contributory mechanisms included DF-induced increase of DNMT3A protein (1.7-fold), DNMT3A enrichment (11-fold) on the KLF4 promoter, and competitive blocking of a myocyte enhancer factor-2 binding site in the KLF4 promoter near the transcription start site. DF also induced DNMT-sensitive propathological expression of downstream KLF4 transcription targets nitric oxide synthase 3, thrombomodulin, and monocyte chemoattractant protein-1. In support of the in vitro findings, swine aortic endothelium isolated from DF regions expressed significantly lower KLF4 and nitric oxide synthase 3, and bisulfite sequencing of KLF4 promoter identified a hypermethylated myocyte enhancer factor-2 binding site. |
Does mixed hematopoietic molecular chimerism result in permanent transgene expression from retrovirally transduced hepatocytes in mice? | Cytotoxic immune elimination of transduced hepatocytes may limit gene therapy for inherited liver diseases. Using beta-galactosidase as a marker gene, we studied whether creation of mixed beta-galactosidase molecular hematopoietic chimerism could induce tolerance to beta-galactosidase-transduced hepatocytes. Molecular hematopoietic chimerism was established in irradiated recipient mice by transplantation of either a mixture of wild-type and beta-galactosidase-transgenic bone marrow or autologous bone marrow stem cells that were transduced with beta-galactosidase lentiviral vectors. After transplantation, mice were hepatectomized and injected with beta-galactosidase recombinant retroviruses to transduce regenerating hepatocytes. We monitored the presence of beta-galactosidase-expressing hepatocytes as well as the appearance of anti-beta-galactosidase antibodies during the time. In control animals, anti-beta-galactosidase antibodies and cytotoxic T-lymphocyte (CTL) response developed as early as 3 weeks after gene transfer. Transduced hepatocytes disappeared concomitantly. In bone marrow transplanted mice, tolerance could be observed in a significant proportion of animals. Tolerance resulted in permanent liver transgene expression and was absent unless a chimerism above 1% was achieved, demonstrating a threshold effect. | The symptoms of sleep apnea, such as sleep fragmentation and oxygen desaturation, might be risk factors for subsequent mood disorder (MD), but associations between sleep apnea and MD remain unclear. This nationwide population-based study thus aimed to identify the risk of MD in patients with vs. without sleep apnea. This cohort study used data from the National Health Insurance database. In total, 5415 patients diagnosed with sleep apnea between 2000 and 2010 were evaluated, and 27,075 matched non-sleep apnea enrollees were included as a comparison cohort. All subjects were followed until 2011. The Cox proportional hazard ratio (HR) was used to investigate the relationship between MD and sleep apnea while controlling covariates and comorbidities of sleep apnea. Of 5415, 154 patients with sleep apnea (2.84 %) were diagnosed with MD during the follow-up period in comparison with 306 of 27,075 individuals (1.13 %) without antecedent sleep apnea. After adjusting for the selected factors and comorbidities, we found that patients with sleep apnea were from 1.82- to 2.07-fold greater risk of MD than the comparisons. Of the three subcategories of MD (major depressive disorder, bipolar disorder, and unspecified MD), sleep apnea had the highest predisposing risk with respect to major depressive disorder (adjusted HR from 1.82 to 2.07) and bipolar disorder (adjusted HR from 2.15 to 3.24). |
Is a smaller amygdala associated with anxiety in Parkinson 's disease : a combined FreeSurfer-VBM study? | Up to 50% of all patients with Parkinson's disease (PD) suffer from anxiety symptoms, a much higher percentage than in the general population. This suggests that PD associated pathological alterations partly underlie these symptoms, although empirical evidence is limited. Here we investigated the association between anxiety symptoms measured with the Beck Anxiety Inventory (BAI) and hippocampal and amygdalar volume in 110 early-stage patients with PD. Measures of anxiety in PD are often obscured by overlap with the somatic symptoms. We therefore also used a subscale of the BAI, established by our recent factor analysis, that reflects 'psychological' anxiety symptoms and is independent of the severity of PD-related motor and autonomic symptoms. We used FreeSurfer and voxel-based morphometry for the volumetric analyses. Both software packages showed a negative correlation between the 'psychological' subscale of the BAI, but not total BAI and volume of the left amygdala, independent of the severity of motor symptoms, autonomic dysfunction and dopaminergic or anxiolytic medication status. | Ischemia/reperfusion injury (IRI) is a major problem in intestinal transplantation. Toll-like receptor 4 (TLR4) has been implicated as a possible link between the innate and adaptive immune systems, however little data exists regarding TLR4 in intestinal IRI. The goal of this study is to evaluate the involvement of TLR4 in intestinal IRI and to assess the effect on T cell related chemokine programs. C57BL6 mice underwent 100 minutes of warm intestinal ischemia by SMA clamping. Control WT mice underwent laparotomy without vascular occlusion. Separate survival and analysis groups were performed, and intestinal tissue was harvested at 1 hour, 2 hours, 4 hours, and 24 hours post-reperfusion. Analysis included histology, CD3 immunostaining, myeloperoxidase activity, Western blot, and PCR. Survival was significantly worse in the IRI group vs control (50% vs. 100%). IRI caused severe histopathological injury including mucosal erosions and villous congestion and hemorrhage. Myeloperoxidase activity increased in a time-dependent manner after IRI (2.71 0.25 at 1 hour, 2.92 0.25 at 2 hours, 4 0.16 at 4 hours, 5.1 0.25 at 24 hours vs 0.47 0.11 controls, P < .05). Protein expression of TLR4 followed by NF-kappaB was increased after IRI. Additionally, mRNA production of IP-10, MIP-2, MCP-1, and RANTES was increased at all time-points, as was mRNA for ICAM-1 and E-selectin. |
Does blockade of the interaction between PD-1 and PD-L1 accelerate graft arterial disease in cardiac allografts? | Programmed death-1 (PD-1), a member of the CD28 family, has been identified. PD-1 is involved in the negative regulation of some immune responses. We evaluated the role of PD-ligand 1 (PD-L1) in graft arterial disease (GAD) of cardiac allografts and in smooth muscle cells (SMCs). C57BL/6 murine hearts were transplanted into B6.C-H2<bm12>KhEg mice for examination of GAD. PD-L1 was expressed in SMCs of the thickened intima in the graft coronary arteries, and administration of anti-PD-L1 monoclonal antibody (mAb) enhanced the progression of GAD (luminal occlusion: 55+/-5.0% versus 9.8+/-4.3%, P<0.05). The expressions of interferon gamma (IFN-gamma) and tumor necrosis factor alpha of cardiac allografts were upregulated in response to anti-PD-L1 mAb treatment. In vitro, PD-L1 expression was induced in SMCs in response to IFN-gamma stimulation. Sensitized splenocytes increased SMC proliferation, and anti-PD-L1 mAb in combination with IFN-gamma stimulation increased this proliferation. | Segmental handling of sodium along the proximal and distal nephron might be heritable and different between black and white participants. We randomly recruited 95 nuclear families of black South African ancestry and 103 nuclear families of white Belgian ancestry. We measured the (FENa) and estimated the fractional renal sodium reabsorption in the proximal (RNaprox) and distal (RNadist) tubules from the clearances of endogenous lithium and creatinine. In multivariable analyses, we studied the relation of RNaprox and RNadist with FENa and estimated the heritability (h) of RNaprox and RNadist. Independent of urinary sodium excretion, South Africans (n = 240) had higher RNaprox (unadjusted median, 93.9% vs. 81.0%; P < 0.001) than Belgians (n = 737), but lower RNadist (91.2% vs. 95.1%; P < 0.001). The slope of RNaprox on FENa was steeper in Belgians than in South Africans (-5.40 +/- 0.58 vs. -0.78 +/- 0.58 units; P < 0.001), whereas the opposite was true for the slope of RNadist on FENa (-3.84 +/- 0.19 vs. -13.71 +/- 1.30 units; P < 0.001). h of RNaprox and RNadist was high and significant (P < 0.001) in both countries. h was higher in South Africans than in Belgians for RNaprox (0.82 vs. 0.56; P < 0.001), but was similar for RNadist (0.68 vs. 0.50; P = 0.17). Of the filtered sodium load, black participants reabsorb more than white participants in the proximal nephron and less postproximally. |
Is immature reticulocyte fraction an early predictor of bone marrow recovery post chemotherapy in patients with acute leukemia? | To establish the benefits of immature reticulocyte fraction (IRF) measurement using an automated hematology cells analyzer over absolute neutrophil count (ANC) in predicting bone marrow recovery post induction chemotherapy. A prospective observational study was carried out in the Departments of Pathology, Medicine, and Pediatrics, Universiti Kebangsaan Malaysia, Medical Center (UKMMC), Kuala Lumpur, Malaysia during a period of 19 months from April 2009 to December 2010 to assess the bone marrow recovery in patients with acute leukemia. A total of 22 patients in remission induction phases were enrolled in this study. The blood specimens were collected from day zero after chemotherapy, and every 3 days until patients recovered hematologically. All blood samples were measured for ANC and IRF using an automated hematology analyzer (Beckman-Coulter LH750). The percentage of patients showing IRF recovery earlier than ANC recovery was 63.6% (14 out of 22 patients). There was a significant difference in the mean number of days for IRF recovery as compared with ANC recovery (14.05 and 17.18 days), p=0.005. | 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). |
Is support from a prenatal instructor during childbirth associated with reduced rates of caesarean section in a Mexican study? | to assess the association between non-clinical factors and the incidence of caesarean section (CS); to estimate the effect of a prenatal instructor's presence during childbirth on birth outcome (vaginal or CS). cross-sectional study from a register of women who attended prenatal classes. Multivariate logistic regression was used to measure the effects of each variable on whether the birth was vaginal or CS. Mexico City, Mexico. 992 births to 847 women from the register of the Birth Education Centre (CEPAPAR) between 1987 and 2000. the incidence of CS was 33%. The most commonly reported (by the women) reason for performing a CS was dystocia (53%). Most women were middle or upper-middle class professionals, and 85% of the women gave birth in private institutions. Odds of having a CS were higher among women who gave birth in a large hospital, women who were over 25 years of age, primigravidae, and women who were not supported by a prenatal instructor during childbirth. | Classic studies of limb ischemia-reperfusion injury have been performed using young healthy mice. However, patients with peripheral vascular disease are older and often exhibit metabolic derangements that may delay healing after revascularization. Mice with genetic deletion of apolipoprotein E (ApoE(-/-)) have been used as a model in various experimental scenarios of hypercholesterolemia. These experiments evaluated the inflammatory response and changes in skeletal muscle morphology during the acute and chronic phases of limb ischemia-reperfusion injury in aged ApoE(-/-) mice. Age-matched ApoE(-/-) and wild-type (Wt) mice underwent 1.5 hours of unilateral hind limb ischemia, followed by 1, 7, or 14 days of reperfusion (DR). Histologic analysis of skeletal muscle fiber injury was assessed at 1DR. Morphologic evidence of muscular fiber maturation was assessed at 14DR. Levels of MyoD and myogenin, markers of skeletal muscle differentiation, were assessed at 7 and 14DR using Western blots. Markers of inflammation, including myeloperoxidase, macrophage inflammatory protein-2 (MIP-2), monocyte chemotactic protein-1 (MCP-1), and osteopontin, were assayed using enzyme-linked immunosorbent assay and chemokine (C-C motif) receptor 2 (CCR2) using Western blots at 1, 7, and 14DR. After 1DR, tissue adenosine 5'-triphosphate (ATP) levels were measured to assess metabolic activity. Unpaired t test and Mann-Whitney test were used for comparisons. Histologic evaluation of skeletal muscle after 1DR showed no difference in the degree of injury between Wt and ApoE(-/-) mice. However, at 14DR, ApoE(-/-) mice had higher percentage of immature muscle fibers than Wt mice. Myogenin level was lower in the ApoE(-/-) mice at 7DR. Injured skeletal muscle of ApoE(-/-) mice had lower levels of myeloperoxidase than Wt mice at 7 DR and higher levels of MCP-1 at 14DR. There was no difference in the levels of tissue ATP, MIP-2, osteopontin, or CCR2 at all experimental intervals. |
Is hAL-RAR ( Doppler guided haemorrhoid artery ligation with recto-anal repair ) a safe and effective procedure for haemorrhoids . Results of a prospective study after two-years follow-up? | To analyse prospectively results of HAL-RAR technique by evaluating pain, perioperative complications and clinical outcome after two years followup. A prospective study design including 30 consecutive patients with haemorrhoids grade III-IV treated from June 2012. After discharge, patients received a specific questionnaire to record postoperative pain, delayed complications, evolution/disappearance of the symptoms that led to the surgical intervention (bleeding, prolapse, itching, pain and soiling). A visual analog scale (VAS) was used to measure pain. Outpatient follow-up was carried out at 7 days, and 1, 6 and 12 months and annually thereafter. Pre, intra and postoperative data (including physical examination) had been recorded prospectively. The median operating time (range) was 40 (26-60) minutes. Average hospital stay (range) was 11 (3-25) hours. No postoperative complications were observed in 29 cases (96.6%). Median follow-up was 26 (12-36) months. All the patients attended the follow-up. Mean postoperative pain was VAS = 1.7 on the seventh day and it was practically non-existent (VAS = 0.7) 1 month after the procedure. 87.5% of patients confirmed complete relief of symptoms after 30 days and 93% of patients feel free of symptoms 6 months after the procedure. No patient has experienced late complications as dyschezia, urgency, soiling or faecal incontinence. After 24 months follow-up, recurrence of bleeding and prolapse was observed in only 1 patient; 93% of patients have considered results of HAL-RAR as very good or excellent. | Mycobacterium tuberculosis (M. tuberculosis) modulates host immune response, mainly T cell responses for its own survival leading to disease or latent infection. The molecules and mechanisms utilized to accomplish immune subversion by M. tuberculosis are not fully understood. Understanding the molecular mechanism of T cell response to M. tuberculosis is important for development of efficacious vaccine against TB. Here, we investigated effect of M. tuberculosis antigens Ag85A and ESAT-6 on T cell signalling events in CD3/CD28 induced Peripheral blood mononuclear cells (PBMCs) of PPD+ve healthy individuals and pulmonary TB patients. We studied CD3 induced intracellular calcium mobilization in PBMCs of healthy individuals and TB patients by spectrofluorimetry, CD3 and CD28 induced activation of mitogen activated protein kinases (MAPKs) in PBMCs of healthy individuals and TB patients by western blotting and binding of transcription factors NFAT and NFκB by Electrophorectic mobility shift assay (EMSA). We observed CD3 triggered modulations in free intracellular calcium concentrations in PPD+ve healthy individuals and pulmonary TB patients after the treatment of M. tuberculosis antigens. As regards the downstream signalling events, phosphorylation of MAPKs, Extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 was curtailed by M. tuberculosis antigens in TB patients whereas, in PPD+ve healthy individuals only ERK1/2 phosphorylation was inhibited. Besides, the terminal signalling events like binding of transcription factors NFAT and NFκB was also altered by M. tuberculosis antigens. Altogether, our results suggest that M. tuberculosis antigens, specifically ESAT-6, interfere with TCR/CD28-induced upstream as well as downstream signalling events which might be responsible for defective IL-2 production which further contributed in T-cell unresponsiveness, implicated in the progression of disease. |
Does cognitive impairment in patients with multiple sclerosis predict worse caregiver 's health-related quality of life? | Little information exists about how cognitive impairment in multiple sclerosis (MS) patients impacts on their caregivers' health-related quality of life (HRQoL). The objective of this paper is to examine the extent to which cognitive impairment in MS patients contributes to caregivers' HRQoL. A total of 63 MS patients, 63 caregivers and 59 matched controls were recruited. Patients and controls underwent a neuropsychological assessment, including tests of working memory, speed of information processing, executive function, and verbal fluency. HRQoL of the caregivers was assessed by CAREQOL-MS. In logistic regression models, we adjusted for the effects of confounding variables. In these models, the dependent variable was the CAREQOL-MS (higher median of CAREQOL-MS (worse HRQoL) vs. lower median of CAREQOL-MS (better HRQoL) (reference)), and the independent variable was the impairment on each neuropsychological test vs. its integrity (reference). Cognitive impairment in MS patients was significantly associated with worse caregiver HRQoL (adjusted odds ratio (OR) = 3.10, 95% confidence interval (CI) = 1.07-11.55, p = 0.04). In secondary analyses in which each neuropsychological test was entered in the analyses separately, only Symbol Digit Modalities Test (a measurement of information processing speed) impairment (OR = 4.22, 95%, CI = 1.16-14.53, p = 0.03) was significantly associated with worse caregiver HRQoL. | Pigs are frequently used as animal models in experimental medicine. To identify processes of vascular development or regression, vascular elements must be recognised and quantified in a three-dimensional (3D) arrangement. Vascular corrosion casts enable the creation of 3D replicas of vascular trees. The aim of our study was to identify suitable casting media and optimise the protocol for porcine liver vascular corrosion casting. Mercox II® (Ladd Research, Williston, Vermont, USA) and Biodur E20® Plus (Biodur Products, Heidelberg, Germany) were tested in 4 porcine livers. The resins (volume approximately 700 mL) were injected via the portal vein. Corrosion casts were examined by macro-computed tomography, micro-computed tomography and scanning electron microscopy. For hepatectomies, the operating protocol was optimised to avoid gas or blood clot embolisation. We present a protocol for porcine liver vascular bed casting based on corrosion specimens prepared using Biodur E20® epoxy resin. |
Do low Serum Levels of MicroRNA-19 Are Associated with a Stricturing Crohn 's Disease Phenotype? | Development of fibrosis and subsequent stricture formation in Crohn's disease (CD) increases morbidity and rates of surgery and reduces patients' quality of life. There are currently no biomarkers of intestinal fibrosis that might allow earlier identification and better management of patients at increased risk of stricture formation. MicroRNA profiling of serum from CD patients was used to identify microRNAs associated with stricture formation. Differential expression of miR-19a-3p and miR-19b-3p was validated by quantitative PCR in independent CD cohort of stricturing and nonstricturing patients (n = 46 and n = 62, respectively). Levels of miR-19a-3p and miR-19b-3p were also quantified in baseline serum samples, and expression compared between CD patients who subsequently developed stricture and those who did not (n = 11 and n = 44, respectively). Serum levels of miR-19a-3p and miR-19b-3p in the array were lower in CD patients with a stricturing phenotype than in control CD patients (P = 0.007 and 0.008, respectively). The reduction in miR-19a-3p and 19b-3p was verified in a second cohort (P = 0.002). The association of miR-19-3p with stricturing CD was independent of potential confounding clinical variables, including disease duration, disease activity, site, gender, and age. Serum analyses in patients with 4 years of follow-up support the hypothesis that reduced miR-19a-3p and miR-19b-3p predate stricture development with a trend toward significance (P = 0.077 and P = 0.060, respectively). | Oxygen free radicals may be implicated in the pathogenesis of ischemia reperfusion damage. The beneficial effects of antioxidant nutrients, as well as complex plant extracts, on cerebral ischemia-reperfusion injuries are well known. This study was conducted to determine the effects of the hydro-alcoholic root extract of Withania coagulans on CA1 hippocampus oxidative damages following global cerebral ischemia/reperfusion in rat. Male Wistar rats were randomly divided in five groups: control, sham operated, Ischemia/ Reperfiusion (IR), and Withania Coagulans Extract (WCE) 500 and 1000mg/kg + I/R groups. Ischemia was induced by ligation of bilateral common carotid arteries for 30 min after 30 days of WCE administration. Three days after, the animals were sacrificed, their brains were fixed for histological analysis (NISSL and TUNEL staining) and some samples were prepared for measurement of malondialdehyde (MDA) level and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity in hippocampus. WCE showed neuroprotective activity by significant decrease in MDA level and increase in the SOD, CAT and GPx activity in pretreated groups as compared to I/R groups (p<0.001). The number of intact neurons was increased while the number of TUNEL positive neurons in CA1 hippocampal region in pretreated groups were decreased as compared to I/R group (p<0.001). |
Does perfusion of his-tagged eukaryotic myocilin increase outflow resistance in human anterior segments in the presence of aqueous humor? | A previous study by the authors has shown that recombinant myocilin purified from a prokaryotic expression system increases outflow resistance in cultured human anterior segments. The present study was performed to determine whether full-length myocilin purified from a human trabecular meshwork cell expression system alters outflow resistance after infusion into human anterior segments. A feline immunodeficiency virus vector encoding both full-length myocilin (amino acids 1-503 fused to C-terminal V5 and six-histidine epitopes) and puromycin resistance was used to transduce a transformed trabecular meshwork cell line (TM5). Stably expressing cells were selected with puromycin. Recombinant myocilin was purified from the media using nickel ion affinity chromatography. Control purifications were performed on media from parental TM5 cells. Anterior segments of human eyes were placed in organ culture and perfused with either Dulbecco's modified Eagle's medium (DMEM) or DMEM supplemented with 50% porcine aqueous humor. One eye received an anterior chamber exchange with recombinant myocilin (2 microg/mL), whereas the fellow eye received an equal volume of control. Immunohistochemistry was performed with anti-myocilin and anti-V5 antibodies. Native polyacrylamide gel electrophoresis was used to analyze myocilin complex formation in porcine aqueous humor. Recombinant myocilin in porcine aqueous humor increased outflow resistance in cultured human anterior segments (91% +/- 68% [mean +/- SD] versus 18% +/- 31% in fellow control eye; n = 9, P = 0.004). Maximum outflow resistance was obtained 5 to 17 hours after infusion and remained above baseline for >3 days. Recombinant myocilin also increased outflow resistance in eyes incubated in DMEM, but only if myocilin was preincubated with porcine aqueous humor (78% +/- 77% when preincubated in DMEM containing porcine aqueous humor versus 13% +/- 15% when preincubated with DMEM alone, n = 6, P = 0.03). Recombinant myocilin appears to form a complex in porcine aqueous humor with a heat-labile protein(s). Immunohistochemistry revealed the presence of myocilin in the juxtacanalicular region of the trabecular meshwork. | Women with breast cancer are thought to be vulnerable to depression for reasons associated with impact of diagnosis, treatment, and metabolic/endocrine changes. While the literature shows that most of these women do not become clinically depressed, 15% to 30% report elevated depressive symptoms that may be clinically important. The purpose was to identify and determine the relative importance of predictors of depressive symptoms in women treated for early-stage breast cancer. A total of 2,595 women (< or = 4 years following completion of initial treatment for early-stage breast cancer) provided data on cancer-related variables, personal characteristics, health behaviors, physical functioning/symptoms, and psychosocial variables. Participants were divided into high or low depressive groups using the Center for Epidemiologic Studies Depression Scale screening form. Results of the binary logistic regression analysis were significant (overall R2 = 32.4%). Before entry of psychosocial variables, younger age, being unmarried, poorer physical functioning, and more vasomotor and gastrointestinal symptoms were significant risk factors for elevated depressive symptoms (R2 = 16.1%), but objective cancer-related variables were not. After inclusion of psychosocial variables in the model (DeltaR2 = 16.3%), none of the preceding variables remained significant. Greater risk for depressive symptoms was associated with stressful life events, less optimism, ambivalence over expressing negative emotions, sleep disturbance, and poorer social functioning. |
Does dexmedetomidine attenuate blood-spinal cord barrier disruption induced by spinal cord ischemia reperfusion injury in rats? | Dexmedetomidine has beneficial effects on ischemia reperfusion (I/R) injury to the spinal cord, but the underlying mechanisms are not fully understood. This study investigated the effects and possible mechanisms of dexmedetomidine on blood-spinal cord barrier (BSCB) disruption induced by spinal cord I/R injury. Rats were intrathecally pretreated with dexmedetomidine or PBS control 30 minutes before undergoing 14-minute occlusion of aortic arch. Hind-limb motor function was assessed using Tarlov criteria, and motor neurons in the ventral gray matter were counted by histological examination. The permeability of the BSCB was examined using Evans blue (EB) as a vascular tracer. The spinal cord edema was evaluated using the wet-dry method. The expression and localization of matrix metalloproteinase-9 (MMP-9), Angiopoietin-1 (Ang1) and Tie2 were assessed by western blot, real-time polymerase chain reaction, and immunofluorescence. Intrathecal preconditioning with dexmedetomidine minimized the neuromotor dysfunction and histopathological deficits, and attenuated EB extravasation after spinal cord I/R injury. In addition, dexmedetomidine preconditioning suppressed I/R-induced increase in MMP-9. Finally, Dexmedetomidine preconditioning enhanced the Ang1-Tie2 system activity after spinal cord I/R injury. | To measure the serum highly sensitive C-reactive protein (hs-CRP) and adiponectin levels, assess insulin sensitivity index (SI) and acute insulin response (AIR) in normal control (NC) subjects, patients with impaired glucose tolerance (IGT) and newly diagnosed type 2 diabetes mellitus (DM), and further explore the possible correlation between hs-CRP and SI, AIR and adiponectin in IGT and newly diagnosed type 2 DM groups. Age and sex matched 28 normal subjects, 31 patients with IGT, and 31 patients with newly diagnosed type 2 DM were included in the study. SI and AIR were assessed by the reduced sample number of Bergman's minimal model method with intravenous glucose tolerance test in subjects of each group. Compared with NC group, serum hs-CRP was significantly increased in IGT and type 2 DM groups (p < 0.001), although there was no significant difference between the latter groups. Hs-CRP was negatively correlated with high density lipoprotein cholesterol (HDL-C), SI and adiponectin levels (p < 0.05 to p < 0.001), and positively correlated with systolic blood pressure (SBP), fasting plasma glucose (FPG), BMI, waist-to-hip ratio (WHR), postprandial 2h plasma glucose (2hPG), fasting serum insulin (FINS) and postprandial serum insulin (PSI) in IGT and newly diagnosed type 2 DM groups (p < 0.05 to p < 0.001). In general multivariate regression, only adiponectin was the significantly independent determinant for serum hs-CRP (regression coefficient -1.380; 95% CI -2.062 to 0.698, p < 0.001); meanwhile, TG, SI, hs-CRP, FINS, 2hPG and WHR were significantly independent determinants for serum adiponectin concentration (p < 0.05 to p < 0.001). |
Do endometriotic ovarian cysts negatively affect the rate of spontaneous ovulation? | Do endometriotic ovarian cysts influence the rate of spontaneous ovulation? | This study aimed to investigate the effects of branched-chain amino acid (BCAA) supplementation on recovery of power-producing ability following a strength training (ST) session. Eleven resistance-trained males, performed baseline measures of a countermovement jump (CMJ) and a seated shot-put throw (SSPT). In a counterbalanced fashion, participants were provided with either 20-g of BCAA or a placebo. Each dose was divided into two equal quantities and consumed before and after a ST session consisting of various multi-joint barbell exercises. For both conditions, the CMJ and SSPT were repeated at 24-h post-ST, in addition participants attributed their perceived muscle soreness level via a 200-mm visual analogue scale. Following ST there were significant decrements in CMJ (Baseline; 55.2 ± 7.4-cm, BCAA; 52.8 ± 5.9-cm Placebo; 50.6 ± 7.3-cm) and SSPT (Baseline; 4.55 ± 0.56-m, BCAA; 4.37 ± 0.61-m, Placebo; 4.22 ± 0.64- m) for both conditions in comparison to baseline values (P < 0.05). However, BCAA was shown to attenuate the decrements in CMJ and SSPT performance compared to placebo (P < 0.05). Muscle soreness was significantly increased following ST for both conditions, however there were no differences in attributed values following BCAA and placebo ingestion. |
Do genomic selection accuracies within and between environments and small breeding groups in white spruce? | Genomic selection (GS) may improve selection response over conventional pedigree-based selection if markers capture more detailed information than pedigrees in recently domesticated tree species and/or make it more cost effective. Genomic prediction accuracies using 1748 trees and 6932 SNPs representative of as many distinct gene loci were determined for growth and wood traits in white spruce, within and between environments and breeding groups (BG), each with an effective size of Ne ≈ 20. Marker subsets were also tested. Model fits and/or cross-validation (CV) prediction accuracies for ridge regression (RR) and the least absolute shrinkage and selection operator models approached those of pedigree-based models. With strong relatedness between CV sets, prediction accuracies for RR within environment and BG were high for wood (r = 0.71-0.79) and moderately high for growth (r = 0.52-0.69) traits, in line with trends in heritabilities. For both classes of traits, these accuracies achieved between 83% and 92% of those obtained with phenotypes and pedigree information. Prediction into untested environments remained moderately high for wood (r ≥ 0.61) but dropped significantly for growth (r ≥ 0.24) traits, emphasizing the need to phenotype in all test environments and model genotype-by-environment interactions for growth traits. Removing relatedness between CV sets sharply decreased prediction accuracies for all traits and subpopulations, falling near zero between BGs with no known shared ancestry. For marker subsets, similar patterns were observed but with lower prediction accuracies. | We investigated the difference in incidence of acute akathisia related to the rate of infusion in patients receiving metoclopramide for acute nausea, vomiting, or migraine headache in the emergency department (ED). Randomized, prospective, double-blind clinical trial of patients aged 18 years and older who were to receive intravenous metoclopramide for the treatment of nausea, vomiting, or headache were eligible. Patients were excluded if they were taking medications that might mimic or mask akathisia, had a movement disorder, renal insufficiency, or were unable or unwilling to consent. Pregnant women and prisoners were also excluded. Subjects were randomized to receive 1 of 2 accepted metoclopramide administration regimens. The regimens included 10 mg of metoclopramide administered either as a 2-minute bolus (BG) or as a slow infusion for 15 minutes (IG). All patients received a normal saline placebo at the opposite rate to maintain blinding. The main outcome was development of akathisia noted at 60 minutes after drug administration as measured either with The Prince Henry Hospital akathisia rating scale or by sudden unexplained departure from the ED during treatment. One hundred twenty-seven patients were eligible for the study. Fifty-nine patients met exclusion criteria. Of the remaining 68 patients, 36 were randomized to the BG and 32 were randomized to the IG. In the BG, 11.1% of patients developed akathisia compared with 0% in the IG (P = .026). Four patients developed akathisia based on the scale and 2 departed suddenly from the ED. |
Do histological staining methods preparatory to laser capture microdissection significantly affect the integrity of the cellular RNA? | Gene expression profiling by microarray analysis of cells enriched by laser capture microdissection (LCM) faces several technical challenges. Frozen sections yield higher quality RNA than paraffin-imbedded sections, but even with frozen sections, the staining methods used for histological identification of cells of interest could still damage the mRNA in the cells. To study the contribution of staining methods to degradation of results from gene expression profiling of LCM samples, we subjected pellets of the mouse plasma cell tumor cell line TEPC 1165 to direct RNA extraction and to parallel frozen sectioning for LCM and subsequent RNA extraction. We used microarray hybridization analysis to compare gene expression profiles of RNA from cell pellets with gene expression profiles of RNA from frozen sections that had been stained with hematoxylin and eosin (H&E), Nissl Stain (NS), and for immunofluorescence (IF) as well as with the plasma cell-revealing methyl green pyronin (MGP) stain. All RNAs were amplified with two rounds of T7-based in vitro transcription and analyzed by two-color expression analysis on 10-K cDNA microarrays. The MGP-stained samples showed the least introduction of mRNA loss, followed by H&E and immunofluorescence. Nissl staining was significantly more detrimental to gene expression profiles, presumably owing to an aqueous step in which RNA may have been damaged by endogenous or exogenous RNAases. | To evaluate the effect of 3-month kale (Brassica oleracea acephala) juice supplementation on coronary artery disease risk factors among hypercholesterolemic men. Thirty-two men with hypercholesterolemia (> 200 mg/dL) were recruited after annual health examinations among the faculty and staff at university. The subjects consumed 150 mL of kale juice per day for a 12-week intervention period. Dietary and anthropometric assessments were performed and blood samples were collected to evaluate biochemical profiles before and after supplementation. Serum concentrations of HDL-cholesterol, and HDL- to LDL-cholesterol ratio were significantly increased by 27% (P<0.0001) and 52% (P<0.0001), respectively. The LDL-cholesterol concentration and the atherogenic index were significantly reduced by 10% (P=0.0007) and 24.2% (P<0.0001), respectively without affecting body mass index, waist and hip circumferences, or nutrient intakes after three months of supplementation. While there was no difference in the concentration of malondialdehyde, significant increase in glutathione peroxidase activity (P=0.0005) were accompanied by a significant increase in the serum selenium level (P=0.0132). It was also found that the responses of these risk factors to kale juice administration were dependent on smoking status. |
Does a meta-analysis of leptin reference range in the healthy paediatric prepubertal population? | The initial discovery of leptin (1994) has given rise to a substantial number of published studies. This study aimed at identifying the published data on the reference ranges of total, free and bound leptin concentration in the healthy prepubertal population. A search was conducted on original English language studies published from 1994 to 2005 in the following databases: PubMed (n = 58), EMBASE (n = 4), Biological Abstracts (n = 2) and Science Finder Scholar (n = 66). A cited reference search was completed in Science Citation Index on studies with a leptin range. A meta-analysis was completed on included studies containing a dataset and a sample size for a leptin concentration range and/or mean+/-standard deviation for a healthy prepubertal population. Preanalytical and analytical variations were examined. Preanalytical variables included aspects such as fasting state and gender, while analytical variation comprised the type of leptin assay methodology. Twelve studies met the inclusion criteria. One study examined free leptin; 11 studies examined total concentration. No studies reported leptin reference ranges established by Clinical and Laboratory Standards Institute (CLSI) criteria, although four studies reported specific study leptin ranges. The methodology of enzyme-linked immunosorbent assay demonstrated a wider leptin range than radio immunoassay (0.56-36.35 vs. 1.01-12.21 ng/mL). Males had a significantly lower mean leptin concentration than females (P = 0.0006); obese children had a higher concentration than non-obese (P = 0.0001). | Systemic sclerosis (SSc) is a connective-tissue disease characterized by vascular injury, immune-system disorders, and excessive fibrosis of the skin and multiple internal organs. Recent reports found that RhoA/Rho-kinase (ROCK) pathway is implicated in various fibrogenic diseases. Intradermal injection of hypochlorous acid (HOCl)-generating solution induced inflammation, autoimmune activation, and fibrosis, mimicking the cutaneous diffuse form of SSc in humans. Our study aimed firstly to describe pulmonary inflammation and fibrosis induced by HOCl in mice, and secondly to determine whether fasudil, a selective inhibitor of ROCK, could prevent lung and skin fibroses in HOCl-injected mice. Female C57BL/6 mice received daily intradermal injection of hypochlorous acid (HOCl) for 6 weeks to induce SSc, with and without daily treatment with fasudil (30 mg·kg(-1)·day(-1)) by oral gavage. HOCl intoxication induced significant lung inflammation (macrophages and neutrophils infiltration), and fibrosis. These modifications were prevented by fasudil treatment. Simultaneously, HOCl enhanced ROCK activity in lung and skin tissues. Inhibition of ROCK reduced skin fibrosis, expression of α-smooth-muscle actin and 3-nitrotyrosine, as well as the activity of ROCK in the fibrotic skin of HOCl-treated mice, through inhibition of phosphorylation of Smad2/3 and ERK1/2. Fasudil significantly decreased the serum levels of anti-DNA-topoisomerase-1 antibodies in mice with HOCl-induced SSc. |
Does missense mutation in the pore region of HERG cause familial long QT syndrome? | Long QT syndrome (LQT) is an inherited cardiac disorder that results in syncope, seizures, and sudden death. In a family with LQT, we identified a novel mutation in human ether-a-go-go-related gene (HERG), a voltage-gated potassium channel. We used DNA sequence analysis, restriction enzyme digestion analysis, and allele-specific oligonucleotide hybridization to identify the HERG mutation. A single nucleotide substitution of thymidine to guanine (T1961G) changed the coding sense of HERG from isoleucine to arginine (Ile593Arg) in the channel pore region. The mutation was present in all affected family members; the mutation was not present in unaffected family members or in 100 normal, unrelated individuals. | To determine if plasma levels of Interleukin-6 (IL-6) across the lifespan correlate with bone density or plasma osteocalcin. Cross-sectional study. Forty-five healthy community-dwelling volunteers aged 25-74 years. Exclusion criteria were smoking use of medications known to affect bone metabolism (corticosteroids, heparin, thyroxine, thiazides, and anticonvulsants), and presence of chronic inflammatory disease. Bone density was measured by dual-energy X-ray absorptiometry at the femoral neck and lumbar spine. Plasma levels of IL-6 and osteocalcin were determined by ELISA and RIA, respectively. Plasma levels of IL-6 increased with advancing age (P < .0001) and correlated with postmenopausal status (P < .0001). No correlation was observed between plasma IL-6 level and bone mineral density at either the lumbar spine or femoral neck, and none was observed with plasma osteocalcin. |
Does early insulin secretion failure lead to diabetes in Chinese subjects with impaired glucose regulation? | Both beta-cell dysfunction and decreased insulin sensitivity are involved in the pathogenesis of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), while their relative contribution in the progression to type 2 diabetes still remains controversial. The aim of the present study is to clarify this process in Chinese subjects by using cross-sectional method. 2,975 Chinese subjects were classified into: normal glucose tolerance (NGT), impaired glucose regulations (IGR), and diabetes mellitus (DM) based on oral glucose tolerance test (OGTT). The IGR group was sub-classified as isolated IFG, isolated IGT and combined glucose intolerance (CGI). The DM group was sub-classified as normal fasting plasma glucose and 2-hour hyperglycemia (N0D2), fasting hyperglycemia and normal 2-hour plasma glucose (D0N2), and both fasting and 2-hour hyperglycemia (D0D2). As far as insulinogenic index (IGI) was concerned, there was no difference between IFG and IGT in either gender, however, HOMA2-B% (homeostasis model assessment for beta-cell function) of IGT was higher than that of IFG and CGI in both male and female (P < 0.05). In the diabetic sub-groups, IGI of N0D2 was higher than that of D0N2, and both deteriorated compared with those of IGT and IFG, respectively. HOMA2-B% of N0D2 was still higher than that of D0N2 and D0D2. No significant difference was detected in OGIS and HOMA2-S% (homeostasis model assessment for insulin sensitivity) between IFG and IGT, and this was the case between N0D2 and D0N2. OGIS and HOMA-IR of IGR sub-groups were not different from those of their diabetic counterparts. | Although matrix metalloproteinase (MMP) activity increases, endothelial function decreases after myocardial infarction (MI). The antibiotic doxycycline inhibits MMP activity in vitro. The role of doxycycline-mediated MMP inhibition in endothelial function is unclear. Doxycycline ameliorates endothelial dysfunction, in part, by inhibiting MMP activity. We subjected Sprague-Dawley male rats to MI by ligating the left anterior descending arteries. We subjected another group of rats to sham surgery. We administered doxycycline in drinking water (0.67 mg/ml) to both groups 2 days before surgery: the sham group underwent sham surgery and received doxycycline therapy, and the MI group underwent MI and received doxycycline therapy (n = 6 in each group). After 4 weeks, we anesthetized rats and prepared left ventricular rings from infarcted-ischemic (I), non-infarcted near-infarcted (NI), and sham surgery hearts with and without doxycycline treatment. The MMP-2 activity increased significantly in I and NI hearts, and we observed a selective increase in MMP-9 activity only in I hearts, when compared with other groups (p < 0.05), measured by zymography. Cardiac inhibitor of metalloproteinase decreased only in I hearts (p < 0.05 vs other groups), measured by Western analysis, and doxycycline treatment reversed this decrease. Contractile response of rings to acetylcholine was attenuated in the I group, suggesting nitric oxide-mediated dysfunction, and was reversed by doxycycline. The response to nitroprusside was attenuated in I hearts and ameliorated by doxycycline, suggesting cardiomyocyte dysfunction. Bradykinin induced relaxation in rings from sham surgery hearts and from NI hearts, but induced paradoxic contraction in rings from I hearts. Treatment with doxycycline reversed the paradoxic contraction. |
Does upregulation of CRABP1 in human neuroblastoma cells overproducing the Alzheimer-typical Abeta42 reduce their differentiation potential? | Alzheimer's disease (AD) is characterized by neurodegeneration and changes in cellular processes, including neurogenesis. Proteolytic processing of the amyloid precursor protein (APP) plays a central role in AD. Owing to varying APP processing, several beta-amyloid peptides (Abeta) are generated. In contrast to the form with 40 amino acids (Abeta40), the variant with 42 amino acids (Abeta42) is thought to be the pathogenic form triggering the pathological cascade in AD. While total-Abeta effects have been studied extensively, little is known about specific genome-wide effects triggered by Abeta42 or Abeta40 derived from their direct precursor C99. A combined transcriptomics/proteomics analysis was performed to measure the effects of intracellularly generated Abeta peptides in human neuroblastoma cells. Data was validated by real-time polymerase chain reaction (real-time PCR) and a functional validation was carried out using RNA interference. Here we studied the transcriptomic and proteomic responses to increased or decreased Abeta42 and Abeta40 levels generated in human neuroblastoma cells. Genome-wide expression profiles (Affymetrix) and proteomic approaches were combined to analyze the cellular response to the changed Abeta42- and Abeta40-levels. The cells responded to this challenge with significant changes in their expression pattern. We identified several dysregulated genes and proteins, but only the cellular retinoic acid binding protein 1 (CRABP1) was up-regulated exclusively in cells expressing an increased Abeta42/Abeta40 ratio. This consequently reduced all-trans retinoic acid (RA)-induced differentiation, validated by CRABP1 knock down, which led to recovery of the cellular response to RA treatment and cellular sprouting under physiological RA concentrations. Importantly, this effect was specific to the AD typical increase in the Abeta42/Abeta40 ratio, whereas a decreased ratio did not result in up-regulation of CRABP1. | In liver cirrhosis, excessive splanchnic vasodilation is due to abnormal synthesis of endogenous vasodilators and to decreased sensitivity to vasoconstrictors. The role of mechanical stimuli such as wall shear stress (WSS) on splanchnic circulation remains unclear. The aim of this study was to assess the vasodilation induced by wall shear stress (WSS) and acute changes in blood flow in the mesenteric arteries in an experimental model of liver cirrhosis. The effect of acute changes in intraluminal flow (0, 10, and 20 μl/min) and WSS on the diameter of the mesenteric arteries (diameters <500 μm) of control and cirrhotic rats was assessed, at baseline and after the inhibition of nitric oxide synthase, cyclooxygenase and hemeoxygenase. Concentration-response curves to phenylephrine were also obtained. In controls, the increase in intraluminal flow led to a significant increase in arterial diameter (p < 0.05), while WSS remained stable; the effect was maintained in vessels pre-constricted with phenylephrine, blocked by the exposure to indomethacin and L-NAME and restored by the subsequent addition of chromium mesoporphyrin (p < 0.05). In cirrhotic arteries, arterial diameters did not change in response to acute increase in flow, neither at baseline nor after exposure to indomethacin and L-NAME, while WSS increased (p < 0.01). Responsiveness to flow was partially restored (p < 0.05) after exposure of the arteries to chromium mesoporphyrin in addition to indomethacin and L-NAME. |
Does angiopoietin-2 inhibition using siRNA or the peptide antagonist L1-10 result in antitumor activity in human neuroblastoma? | The angiopoietin/Tie-2 system has been identified as a key role player in tumor angiogenesis. We investigated whether angiopoietin-2 could be a promising target in human neuroblastoma. Angiopoietin-2 down-regulation by siRNA or shRNA was evaluated in vitro in Kelly cells. Angiopoietin-2 shRNA-transfected Kelly cells were tested in a chorioallantoic membrane (CAM) assay to evaluate tumor growth and microvessel density. The effects of L1-10, a peptide-Fc fusion molecule blocking angiopoietin-2/Tie-2 interaction, administered 3 times/week were assessed in a murine neuroblastoma xenograft model. Angiopoietin-2 down-regulation by siRNA or shRNA in Kelly cells inhibited cell proliferation and migration. In vivo growth and microvessel density of angiopoietin-2 shRNA-transfected Kelly cells in the CAM assay were reduced. Therapy of advanced tumors with L1-10 did not stop tumor progression. However, starting L1-10 treatment at the same time as neuroblastoma cell injection significantly inhibited tumor growth (vehicule: 903 ± 160 mm(3); L1-10: 270 ± 152 mm(3) after 26 days; P < 0.05). Microvessel density was reduced in both L1-10-treated tumors, whereas expression of angiopoietin-2 and VEGF-A did not change. | Previous data from our laboratory suggest that gonadally intact C57BL/6 male mice are more likely than their female counterparts to die from Plasmodium chabaudi infection, to recover more slowly from weight loss and hematocrit loss, and to have reduced interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) responses. Removal of the ovaries, and hence, the primary production of sex steroids in females, reverses these differences. We hypothesized that sex differences in response to P chabaudi may be mediated by differential synthesis of IFN-gamma and IL-10 that is influenced by estrogen, progesterone, or both. C57BL/6 female mice (n = 200; n = 10/time point/treatment/experiment) were ovariectomized and implanted with a 21-day controlled-release pellet containing either 0.1 mg of 17beta-estradiol (E(2)), 10 mg of progesterone (P(4)), 0.1 mg of E(2) plus 10 mg of P(4), or cholesterol (placebo). Females were inoculated with 10(6)P chabaudi-infected erythrocytes. Body mass, body temperature, hematocrit, parasitemia, cytokine production, and antibody responses were monitored 0, 3, 5, 7, 10, 14, and 21 days postinoculation. Administration of E(2), either alone or in combination with P(4), mitigated infection-induced weight loss, hematocrit loss, and hypothermia, compared with females receiving placebo pellets (P < 0.05 in each case). Hormone treatment did not affect levels of parasitemia. Females administered E(2) alone or in combination with P(4) produced 4 to 7 times higher IFN-gamma and IL-10 during peak parasitemia than did females implanted with pellets containing either P(4) alone or placebo (P < 0.05 in each case). Exposure to E(2), either alone or in combination with P(4), increased anti-P chabaudi immunoglobulin G (IgG1) responses and the ratio of IgG1 to IgG2c (P < 0.05 in each case). |
Does aortic pulse wave velocity predict mortality in chronic kidney disease stages 2-4? | Chronic kidney disease (CKD) is characterized by aortic stiffness and increased cardiovascular mortality. In end-stage renal disease, aortic stiffness predicts mortality, whereas this role remains uncertain in mild-to-moderate CKD. We aimed to investigate whether aortic pulse wave velocity (aPWV) predicts mortality and renal disease progression in CKD patients. We enrolled 135 CKD patients stages 2-4 [estimated glomerular filtration rate (eGFR): 41.1 (28.5-61.6) ml/min per 1.73 m] in the study and assessed aPWV. The combined renal end-point was defined as at least 50% decline in renal function and/or start of renal replacement therapy. During the observational period of 42 (30-50) months six patients were lost of follow-up, 13 patients died and 16 patients reached the combined renal end-point. Stratification according to the mean of aPWV (10 m/s), Kaplan-Meier analysis revealed increased mortality with aPWV ≥10 m/s (log-rank P < 0.05). Stepwise logistic regression analysis confirmed aPWV as an independent predictor for mortality in CKD stage 2-4. The hazard ratio of mortality in the cohort with an aPWV at least 10 m/s was 5.1 (1.1-22.9). By contrast, Kaplan-Meier analysis revealed no effect of aPWV on the combined renal end-point (log-rank P = 0.90). | The purpose of this study is to assess the exocrine and neuroendocrine properties of tumour cells in diffuse gastric cancer with signet ring cell differentiation. Mucin mRNA and protein expressions (MUC1, 2, 3, 4, 5AC, 6 and MUC13) were assessed by immunohistochemistry and in situ hybridization. The neuroendocrine properties were evaluated by protein and mRNA expression of the general neuroendocrine markers chromogranin A and synaptophysin. No MUC expression was observed in signet ring tumour cells including the amorphous substance in any of the nine cases. All cases showed immunoreactivity to synaptophysin, and seven out of nine cases immunoreactivity to chromogranin A in signet ring and non-signet ring tumour cells. Chromogranin A mRNA expression was observed in tumour cells in all samples with retained mRNA. |
Does iTRAQ-based quantitative proteome and phosphoprotein characterization reveal the central metabolism changes involved in wheat grain development? | Wheat (Triticum aestivum L.) is an economically important grain crop. Two-dimensional gel-based approaches are limited by the low identification rate of proteins and lack of accurate protein quantitation. The recently developed isobaric tag for relative and absolute quantitation (iTRAQ) method allows sensitive and accurate protein quantification. Here, we performed the first iTRAQ-based quantitative proteome and phosphorylated proteins analyses during wheat grain development. The proteome profiles and phosphoprotein characterization of the metabolic proteins during grain development of the elite Chinese bread wheat cultivar Yanyou 361 were studied using the iTRAQ-based quantitative proteome approach, TiO2 microcolumns, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Among 1,146 non-redundant proteins identified, 421 showed at least 2-fold differences in abundance, and they were identified as differentially expressed proteins (DEPs), including 256 upregulated and 165 downregulated proteins. Of the 421 DEPs, six protein expression patterns were identified, most of which were up, down, and up-down expression patterns. The 421 DEPs were classified into nine functional categories mainly involved in different metabolic processes and located in the membrane and cytoplasm. Hierarchical clustering analysis indicated that the DEPs involved in starch biosynthesis, storage proteins, and defense/stress-related proteins significantly accumulated at the late grain development stages, while those related to protein synthesis/assembly/degradation and photosynthesis showed an opposite expression model during grain development. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis of 12 representative genes encoding different metabolic proteins showed certain transcriptional and translational expression differences during grain development. Phosphorylated proteins analyses demonstrated that 23 DEPs such as AGPase, sucrose synthase, Hsp90, and serpins were phosphorylated in the developing grains and were mainly involved in starch biosynthesis and stress/defense. | Graft-versus-host-disease (GvHD) occurs in one-third or even half of bone marrow transplant (BMT) patients, involving three major target organs: gut, liver and skin. The histopathological and immunohistochemical features of normal-looking skin in oncohaematological patients on day 100 after BMT were studied to find a possible relationship between the histopathological findings and clinical variables (history or clinical evidence of GvHD, previous therapeutic regimens or infections). Fifty-one Caucasian oncohaematological patients, who had had an allogenic BMT, had a biopsy taken from normal-looking skin in nonsun-exposed areas (buttocks or the lumbar region), around the 100th day after BMT. The histology was studied, and the influence of clinical variables on the development of every different histopathological pattern was evaluated through statistical analysis. Histopathological analysis based on morphological criteria revealed the presence of three different patterns: a postinflammatory pattern (45%), changes similar to grade I and II of GvHD (31%) and no significant changes (24%). Statistical analysis revealed that only the presence of peaks of cytomegalovirus (CMV) antigen in the blood within 100 days from BMT was significantly associated with the pattern of GvHD-like changes. |
Does mALDI imaging on tissue microarrays identify molecular features associated with renal cell cancer phenotype? | To identify molecular features associated with clinico-pathological parameters in renal cell cancer. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging was employed for a kidney cancer tissue microarray containing tissue samples from 789 patients for which clinical follow-up data were available. A comparison of mass spectrometric signals with clinico-pathological features revealed significant differences between papillary and clear cell renal cell cancer. Within the subgroup of clear cell RCC, statistical associations with tumor stage (seven signals, p<0.01 each), Fuhrman grade (seven signals, p<0.0001 each), and presence of lymph node metastases (10 signals, p<0.01 each) were found. In addition, the presence of one signal was significantly linked to shortened patient survival (p=0.0198). | Presence of a tracheostomy tube often decreases the patient's ability to communicate and to tolerate oral intake. The initial tracheostomy tube change is often recommended between day 7 and 14 post insertion. Local guidelines permit tracheostomy tube change 5 days after insertion. We hypothesized that changing tracheostomy tubes before day 7 is associated with earlier use of a speaking valve as well as earlier oral intake, compared to changing tracheostomy tubes after 7 days. We prospectively enrolled 130 admitted subjects, after tracheostomy placement to a respiratory care unit between July 2008 and May 2010. Subject data were recorded from the electronic medical record. The primary end point was the time from tracheostomy tube placement to tolerating speaking valve. The secondary end point was the time from tracheostomy tube placement to tolerating oral intake. Complications of tracheostomy tube change were recorded. Thirty-eight subjects had the first tracheostomy tube change before 7 days (early group), and 92 subjects had the first tracheostomy tube change after 7 days (late group). The early group tolerated a speaking valve significantly sooner than the late group (7 d vs 12 d, P = .001). The early group also tolerated oral intake significantly sooner (10 d vs 20 d, P = .04). After change of the tracheostomy tube, the time to tolerating oral feeding was 5.5 days in both groups. There was no significant difference in time to decannulation between the groups. The early group had a shorter respiratory care unit stay (11 d vs 17 d, P = .001) and a shorter hospital stay (P = .05) than the late group. There was no difference in survival. There were no complications associated with tracheostomy tube change. |
Is [ Intensified insulin therapy plus antineuritic medication more effective than antineuritics alone in painful diabetic neuropathy ]? | The basis of the treatment of painful diabetic neuropathy is the use of drugs that block the transmission of pain (antineuritics) and a good metabolic control of underlying disease. To describe the outcomes of 17 type-2 diabetics with painful neuropathy, treated between 1988 and 2005 with symptomatic therapy plus intensified insulin. Review of medical records of 17 type-2 diabetic patients, aged 63+/-11 years and a duration of diabetes of 15+/-8 years. All patients received intensified insulin therapy with 0.35 units/kg of NPH insulin (2/3 before breakfast and 1/3 evening meal), plus capillary glucose measurements and regular insulin (with sliding-scale centered in approximately 0.1 units/kg) before the 3 main meals. All patients were also treated with gabapentin, nortriptyline or clomipramine. Pain was assessed using a visual analog score of 10 points. After 1 year, glycosilated hemoglobin decreased from 10.0+/-1.4% to 7.7+/-1.2% (p approximately =0.003). Pain decreased from 10 to 5.1+/-3.3 at one month, 2.3+/-3.2 at six months, and 3.1+/-3.6 at 1 year (p <0.01). There was a direct statistical correlation between the reduction of HbA1C and pain decline (r =0.736; p =0.037). Pain scores were lower than those reported elsewhere for Pregabalin (n =76; p =0.05), Lamotrigine (n =27; p <0.0005), Topiramate (n =208; p <0.005), and Gabapentin (n =84; p <0.025). The lack of difference to Sodium Valproate (n =21; p =0.07) had borderline significance. | Silicosis features foci of inflammation where macrophages and lymphocytes precede and accompany fibroblast proliferation, alveolar epithelial hyperplasia, and increased deposition of connective tissue matrix material. In the mouse following silica inhalation there is recruitment of natural killer-, B-, and CD4+ and CD8+ lymphocytes to the alveolar spaces, enlargement of bronchial-associated lymphoid tissues (BALT), and aggregation of lymphocytes surrounding small airways and blood vessels. A substantial fraction of the recruited lung lymphocytes produce interferon-gamma (IFN-gamma), and IFN-gamma gene-deleted mice develop less silicosis than wild-type mice. Interleukin-12 (IL-12) is an important pathway for driving the adaptive immune response towards a TH1-like phenotype. We hypothesized that IL-12 might stimulate lymphocyte activation and the up-regulation of IFN-gamma, and consequently be an essential mediator for silicosis. C57Bl/6 wild-type (WT) and IL-12 deficient (IL-12 KO) mice were exposed to sham-air or crystobalite silica (61 mg/m3) by inhalation for 5 hours/day for 12 days and then studied from 1 to 112 days after exposure. Mice exposed to sham-air had normal lung histology at all time points. WT mice exposed to titanium dioxide (72 mg/m3) showed pulmonary macrophage recruitment but no increase in lung collagen. Both WT and IL-12 KO mice exposed to silica showed similar progressive lung pathology, increased wet lung weight and increased total lung collagen (hydroxyproline). IL-12 p35 mRNA was not increased in either strain after silica exposure; IL-12 p40 mRNA was up-regulated after silica in WT mice and constitutively absent in the IL-12 KO mice. IL-18 mRNA was not increased after silica exposure. The expression of IL-15 (an important driver for innate immunity, Natural Killer cell activation, and IFN-gamma production) was abundant in air-exposed mice and was increased slightly in the lungs of mice with silicosis. |
Does severe cranial neuropathies caused by fall from heights in children? | Falls from heights are the most common traumatic event associated with emergency department visits in children. This study investigated the incidence and clinical course of cranial neuropathies caused by falls from heights in children. The computerized records of a tertiary pediatric medical center were searched for all patients admitted to the emergency department in 2004-2014 with a head injury caused by falling from a height. Those with cranial neuropathies involving optic and eye-motility disturbances were identified, and their clinical, imaging, and outcome data were evaluated. Of the estimated 61,968 patients who presented to the emergency department during the study period because of a fall, 18,758 (30.3 %) had head trauma. Only 12 (seven boys, five girls, average age 6.7 years) had a visual disturbance. Eight were diagnosed with traumatic optic neuropathy, one after a 6-month delay, including two with accompanying cranial nerve (CN) III injuries. Five patients had anisocoria or an abnormal pupillary response to light at presentation, one patient had CN VI paralysis and temporary vision loss, and one patient had an isolated CN III injury diagnosed on follow-up. Visual improvement varied among the patients. | Fulvestrant is a pure anti-estrogen hormoal agent formally lacking any estrogen-agonist activity. We analyze the effect(s) of fulvestrant treatment on estrogen target systems in hormoe-sensitive advanced breast cancer patients. Patients received a median of five fulvestrant injections (range 3-19). We observed a partial response in one patient, disease stability in 21 and disease progression in 29 patients with a clinical benefit of 43.2% and a median time to progression of 5 [range 3-20] mo. Total cholesterol levels significantly decreased during treatment (219.8 +/- 45.3 vs. 201.4 +/- 42.1 mg/dl; p = 0.0054) together with LDL-cholesterol (129.7 +/- 41.39 vs. 112.3 +/- 37.1 mg/dl; p = 0.018). HDL-cholesterol and triglycerides did not show significant changes. Reduction of total and LDL-cholesterol was independent from last hormoal treatment or treatment duration. All coagulation indices and mean endometrial mucosa thickness value did not vary. Fifty-one patients [median age 65 (range 48-82) y] were enrolled. All patients received previous hormoal treatments, with 90.2% receiving > or =2 courses. Last hormoal treatment was exemestane, letrozole, anastrozole and other in 30-10-7-4/51 patients respectively. Median withdrawal time was 18 d (range 3-1456). Complete fasting lipid blood profile and coagulation indices were assessed before fulvestrant administration, every 3 mo and at discontinuation time. Endometrial mucosa thickness was evaluated before fulvestrant administration and at end-study time. |
Does inactivation of Gram-negative and Gram-positive bacteria in red cell concentrate using INACTINE PEN110 chemistry? | The risk of transfusion-transmitted bacterial infections as a result of the presence of bacteria in blood is one of the major concerns in transfusion medicine. The purpose of this study was to investigate whether bacteria inoculated into red blood cell concentrates can be inactivated by the INACTINE PEN110 pathogen-reduction process. Four bacterial species were chosen for the study: anaerobic Gram-positive Clostridium perfringens and Propionibacterium acnes, known to be transfusion-transmitted; and two Gram-negative species, Acinetobacter johnsonii and Acinetobacter lwoffii, recently reported to be a common cause of transfusion-associated infections in Europe. Identical units of leucoreduced red cell concentrates were inoculated with A. johnsonii, A. lwoffii, C. perfringens, or P. acnes. The 4 degrees C control units were put on storage immediately after receiving the spike. The test units were subjected to PEN110 treatment and then stored. The bacterial titre in all units was monitored during a 6-week storage period. The PEN110 inactivation of all tested bacterial strains was time- and titre-dependent. For A. johnsonii and A. lwoffii, no viable bacteria were detected in the units spiked with up to 10(4) colony-forming units (CFU)/ml and treated with PEN110. For red cell units spiked with 10(4)-10(5) CFU/ml of C. perfringens and P. acnes, no viable bacteria were detected in the units treated with PEN110. In control units, there was a gradual decrease in A. johnsonii, A. lwoffii and C. perfringens titres during cold storage, while P. acnes titres remained stable. | Inflammatory cytokines and transforming growth factor-β (TGF-β) are mutually inhibitory. However, hyperactivation of nuclear factor-κB (NF-κB) and TGF-β signaling both emerge in glioblastoma. Here, we report microRNA-148a (miR-148a) overexpression in glioblastoma and that miR-148a directly suppressed Quaking (QKI), a negative regulator of TGF-β signaling. We determined NF-κB and TGF-β/Smad signaling activity using pNF-κB-luc, pSMAD-luc, and control plasmids. The association between an RNA-induced silencing complex and QKI, mitogen-inducible gene 6 (MIG6), S-phase kinase-associated protein 1 (SKP1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was tested with microribonucleoprotein immunoprecipitation and real-time PCR. Xenograft tumors were established in the brains of nude mice. QKI suppression induced an aggressive phenotype of glioblastoma cells both in vitro and in vivo. Interestingly, we found that NF-κB induced miR-148a expression, leading to enhanced-strength and prolonged-duration TGF-β/Smad signaling. Notably, these findings were consistent with the significant correlation between miR-148a levels with NF-κB hyperactivation and activated TGF-β/Smad signaling in a cohort of human glioblastoma specimens. |
Does oral citrulline supplementation protect female mice from the development of non-alcoholic fatty liver disease ( NAFLD )? | Impairments of intestinal barrier function are discussed as risk factors for the development and progression of non-alcoholic fatty liver disease (NAFLD). Studies suggest an association between arginine/citrulline homeostasis and the development of liver damages. Here, the effect of an oral L-citrulline (Cit) supplement on the development of a Western-style diet (WSD)-induced NAFLD was determined in mice. Female 6- to 8-week-old C57BL/6J mice were either pair-fed a liquid Western-style or control diet (C) ± 2.5 g/kg bodyweight Cit for 6 weeks (C + Cit or WSD + Cit). Indices of liver damage, glucose metabolism, intestinal barrier function and NO synthesis were measured. While bodyweight gain was similar between groups, markers of glucose metabolism like fasting blood glucose and HOMA index and markers of liver damage like hepatic triglyceride levels, number of neutrophils and plasminogen activator inhibitor-1 protein levels were significantly lower in WSD + Cit-fed mice when compared to WSD-fed mice only. Protein levels of the tight junction proteins occludin and zonula occludens-1 in duodenum were significantly lower in mice fed a WSD when compared to those fed a WSD + Cit (-~70 and -~60 %, respectively, P < 0.05), whereas portal endotoxin levels, concentration of 3-nitrotyrosine protein adducts in duodenum and toll-like receptor-4 mRNA expression in livers of WSD + Cit-fed mice were markedly lower than in WSD-fed mice (-~43 %, P = 0.056; -~80 and -~48 %, respectively, P < 0.05). | A moderate dose of radiation is the recommended treatment for solitary plasmacytoma (SP), but there is controversy over the role of surgery. Our study aimed at comparing different treatment modalities in the management of SP. Data from 38 consecutive patients with solitary plasmacytoma, including 16 with bone plasmacytoma and 22 with extramedullary plasmacytoma, were retrospectively reviewed. 15 patients received radiotherapy alone; 11 received surgery alone, and 12 received both. The median radiation dose was 50Gy. All operations were performed as radical resections. Local progression-free survival (LPFS), multiple myeloma-free survival (MMFS), progression-free survival (PFS) and overall survival (OS) were calculated and outcomes of different therapies were compared. The median follow-up time was 55 months. 5-year LPFS, MMFS, PFS and OS were 87.0%, 80.9%, 69.8% and 87.4%, respectively. Univariate analysis revealed, compared with surgery alone, radiotherapy alone was associated with significantly higher 5-year LPFS (100% vs 69.3%, p=0.016), MMFS (100% vs 51.4%, p=0.006), PFS (100% vs 33.7%, p=0.0004) and OS (100% vs 70%, p=0.041). |
Does improvement of contractility accompany angiogenesis rather than arteriogenesis in chronic myocardial ischemia? | Growth factor therapy provides a therapeutic alternative for "no option" patients with coronary disease. Fibroblast Growth Factor-2 (FGF-2) predominantly stimulates angiogenesis, the growth of new capillaries, whereas Monocyte Chemoattractant Protein-1 (MCP-1) is considered an arteriogenic agent. We hypothesised a synergetic effect of FGF-2 and MCP-1 in ischemic myocardium. A severe coronary stenosis was created in pigs. After one week, chronic ischemia was confirmed by angiography, echocardiography, reduced ejection fraction, and increase of marker enzymes. FGF-2, MCP-1, both, or vector only were then injected intramyocardially as plasmid DNA in the impaired area. Regional contractility and number of capillaries and arterial vessels were evaluated after three months. FGF-2, FGF-2+MCP-1, and vector, but not MCP-1 alone improved regional contractility at rest, whereas only FGF-2 alone ameliorated function under stress conditions. Angiogenesis in the ischemic area was stimulated by FGF-2 compared to MCP-1. In contrast, MCP-1 induced arteriogenesis relative to FGF-2. | Linalool is a commonly used fragrance terpene that forms potent sensitizers upon oxidation. In a recent multicentre study, we found that 7% of 2900 patients showed positive patch test reactions to oxidized linalool at 6.0%. No elicitation studies have been performed. To identify threshold concentrations for elicitation of allergic contact dermatitis caused by oxidized linalool in allergic individuals with repeated exposures. Repeated open application tests were performed in 6 participants previously diagnosed with contact allergy to oxidized linalool. Creams containing 3.0%, 1.0% and 0.30% oxidized linalool (corresponding to 0.56%, 0.19% and 0.056% linalool hydroperoxides, respectively) and 'fine fragrance' containing 1.0%, 0.30% and 0.10% oxidized linalool (corresponding to 0.19%, 0.056% and 0.019% linalool hydroperoxides, respectively) were used twice daily for up to 3 weeks. Patch testing with a dilution series of oxidized linalool was performed. Five of 6 participants reacted to the cream containing 3% oxidized linalool. With 1% oxidized linalool, a reaction was seen in 3 (cream) and 4 (fine fragrance) participants, respectively. With 0.3% oxidized linalool, 2 (cream) and 1 (fine fragrance) participants reacted. |
Does the p75 neurotrophin receptor appear in plasma in diabetic rats-characterisation of a potential early test for neuropathy? | This study tested the premise that immunoreactivity representing the p75 neurotrophin receptor (p75(NTR)) appears in plasma of diabetic rats in association with the early stages of neuronal dysfunction or damage. We also examined whether treatment beneficial to neuropathy might reduce the p75(NTR) immunoreactivity. Plasma proteins were fractionated by SDS-PAGE and immunoblots exposed to p75(NTR) antibody, using receptor protein from cultured PC12 cells as an external standard. Rats were made diabetic with streptozotocin for various periods and exsanguinated. Plasma glucose, HbA(1)c and plasma proteins were determined. We also studied plasma samples from diabetic mice lacking the gene coding for p75(NTR), as well as the effect of sciatic nerve crush on healthy male Wistar rats. Plasma p75(NTR) immunoreactivity began to exceed normal levels at 8 weeks after induction of diabetes, and was significantly raised at 10 (p<0.05) and 12 weeks (p<0.001). Treatment between 8 and 12 weeks with insulin, fidarestat (an aldose reductase inhibitor), nerve growth factor and neurotrophin 3 all normalised the plasma p75(NTR) immunoreactivity. Plasma from p75(NTR) (-/-) mice contained no such immunoreactivity, though it was present in plasma from wild-type mice. Following nerve crush, p75(NTR) immunoreactivity appeared in plasma of non-diabetic mice, indicating that this can be a result of nerve trauma. | The purpose of the current study was to determine whether smoking during chemotherapy or chemoradiation therapy for nonsmall cell lung cancer (NSCLC) affects treatment outcome. The authors reviewed the medical records of patients with NSCLC (AJCC Stage III or IV) who were treated with frontline chemotherapy or chemoradiation therapy at the University of Texas M. D. Anderson Cancer Center between January 1993 and December 2002. Treatment type, response, progression-free survival, and overall survival (OS) were correlated with patient demographic characteristics, clinical features, and smoking habits at the time of diagnosis and during therapy. Of 1370 patients who were eligible for analysis, 497 received chemoradiation therapy and 873 received chemotherapy. In the chemoradiation group, 6% of patients were never-smokers, 45% were former smokers, and 49% were current smokers. Multivariate analysis demonstrated no prognostic effect of smoking status on treatment response or OS rates in the chemoradiation therapy group. In the chemotherapy group, 16% of patients were never-smokers, 42% were former smokers, and 42% were current smokers; 20% of patients continued to smoke during therapy. Never-smokers had higher response rates (19% vs. 8% vs. 12%; P=.004) and lower rates of progressive disease (49% vs. 65% vs. 66%; P=.002) than former and current smokers, respectively. The OS rates were found to be higher among never-smokers (P<0001), women (P=.002), and those with a better Eastern Cooperative Oncology Group (ECOG) performance status (P<.0001). The multivariate Cox model indicated that with adjustment for age, gender, stage of disease, and ECOG performance status, the hazard ratio was 1.47 for former smokers (P=.003) and 1.55 for current smokers (P=.0004). Active smoking during therapy did not appear to impact outcome. |
Is cervical intraepithelial neoplasia associated with genital tract mucosal inflammation? | Clinical studies demonstrate increased prevalence of human papillomavirus (HPV)-associated disease in HIV-infected individuals and an increased risk of HIV acquisition in HPV-infected individuals. The mechanisms underlying this synergy are not defined. We hypothesize that women with cervical intraepithelial neoplasia (CIN) will exhibit changes in soluble mucosal immunity that may promote HPV persistence and facilitate HIV infection. The concentrations of immune mediators and endogenous anti-Escherichia coli activity in genital tract secretions collected by cervicovaginal lavage were compared in HIV-negative women with high-risk HPV-positive (HRHPV+) CIN-3 (n = 37), HRHPV+ CIN-1 (n = 12), or PAP-negative control subjects (n = 57). Compared with control subjects, women with CIN-3 or CIN-1 displayed significantly higher levels of proinflammatory cytokines including interleukin (IL)-1α, IL-1β, and IL-8 (P < 0.002) and significantly lower levels of anti-inflammatory mediators and antimicrobial peptides, including IL-1 receptor antagonist, secretory leukocyte protease inhibitor (P < 0.01), and human β defensins 2 and 3 (P < 0.02). There was no significant difference in endogenous anti-E. coli activity after controlling for age and sample storage time. | We tested the hypothesis that the negative functional effects of cyclic GMP would be attenuated by cyclic AMP and this interaction would be reduced in pacing-induced failure of hypertrophic hearts. 8-Bromo-cGMP (2 microg/kg/min) was infused into a coronary artery in eight control, eight ventricular hypertrophy (HYP), and eight hypertrophic failure (HYP-FAIL) dogs. Then isoproterenol (0.1 microg/kg/min) was infused, followed by 8 Br-cGMP. Regional myocardial work (force*shortening/min), and O(2) consumption (VO(2)) (coronary blood flow*O(2) extraction) were measured. Cyclic GMP levels were determined by radioimmunoassay. 8-Br-cGMP significantly decreased regional work from 3812 +/- 839 g*mm/min by 17% and VO(2) by 29% in control, but not in HYP (1073 +/- 182 by -10%, VO(2) by -16%) or HYP-FAIL (495 +/- 145 by -9%, VO(2) by 0%). Isoproterenol increased work by 43% and VO(2) by 48% in controls and in HYP (work by 54%, VO(2) by 39%), but not in HYP-FAIL (work by -28%, VO(2) by -5%). Subsequently, 8-Br-cGMP had no effect on work or VO(2) in control (-2%, -13%), HYP (-12%, -30%), or HYP-FAIL (+13%, +14%). Cyclic AMP levels were elevated by isoproterenol in control (381 +/- 115 versus 553 +/- 119 pmol/g) and HYP (313 +/- 55 versus 486 +/- 227), but not in HYP-FAIL (300 +/- 60 versus 284 +/- 126). After isoproterenol, 8-Br-cGMP further elevated cyclic AMP in control (687 +/- 122), but not in HYP or HYP-FAIL. |
Does serine threonine kinase Pim-3 regulate STAT3 pathway to inhibit proliferation of human liver cancers? | This study aimed to investigate the effects of serine threonine kinase Pim-3 on the growth of HepG2 cells and to explore the role of STAT3 signaling pathway. Synthetic Pim-3shRNA and negative control shRNA were independently transfected into HepG2 cells in the presence of Lipofectamine(TM) 2000. Cells were divided into 4 groups: Pim-3 shRNA group, negative control group, liposome control group, and blank control group. Flow cytometry was performed to detect the apoptosis of these cells; RT-PCR was employed to detect the mRNA expression of Pim-3; Western blot assay was done to measure the protein expression of Pim-3, STAT3, pSTAT3(Tyr705), Bcl-Xl, Bad and pBad(Ser112). When compared with blank control group, liposome group and negative control group, the apoptosis index increased and the protein expression of Pim-3, pSTAT3(Tyr705), Bcl-Xl and pBad(Ser112) and the Pim-3 mRNA expression reduced in the Pim-3 shRNA group, but the protein expression of STAT3 and Bad was comparable among groups. | To test the peripheral arterial vasodilation hypothesis of sodium retention in cirrhosis. This states that sodium retention is triggered by arterial underfilling and predicts that development of sodium retention will be associated with significant and related declines in indices of arterial filling that reverse when sodium retention resolves. Longitudinal evaluation of a cohort of patients with alcoholic liver disease. Eighteen men, 8 of whom were studied twice, 3 three times, 2 four times, and 5 five times (40 between-study comparisons). Between 23 studies, the patients were ascites-free (Group NN). Ascites spontaneously disappeared between seven studies (Group YN), appeared between six studies (Group NY), and remained present between four studies (Group YY). Between-study changes in blood volume, arterial blood pressure, cardiac output, systemic vascular resistance, left atrial volume, left ventricular diastolic diameter, aortic root diameter, aortic blood velocity, plasma norepinephrine and atrial natriuretic factor concentrations, plasma renin activity, and urinary sodium excretion were evaluated by paired t-tests. These changes were also compared among groups by analysis of variance. In addition, correlations among the changes were sought. Systolic, diastolic, and mean arterial pressures, left ventricular diastolic diameter, aortic root diameter, stroke volume, cardiac output, plasma norepinephrine concentration, and systemic vascular resistance were unchanged between studies. Left atrial volume increased between studies in Group NY. Pulse pressure fell more in Group NY than in Groups NN and YN, principally as a result of a decline in systolic blood pressure. Plasma norepinephrine concentration, plasma renin activity, and blood volume rose more in Group NY than in Groups NN, YN, and YY. Changes in both systolic and pulse pressures were directly correlated with the change in sodium excretion but unrelated to the change in plasma norepinephrine concentration. Changes in plasma norepinephrine concentration and plasma renin activity were unrelated to changes in blood pressure, systemic vascular resistance, and urinary sodium excretion. |
Are wA29 '' we all one '' compassionate cities `` a global community joined for care ''? | The NewHealth Foundation, a Spanish non-for-profit organisation, is leading the project Compassionate Cities. "We are all one". The project aims to involve citizens in creating communities of care to help people at the end of life phase. To design and develop a practical model to engage communities in the process of improving the quality of public palliative care. To empower key advocates of end-of-life care. To evaluate communities' interventions, their feasibility and impact in terms of shared benefit for stakeholders. Identification and recruitment of key advocates of care. Design of an innovative model of compassionate cities. Define community of care activities through a triple-dimension methodology: [To Want - To Know - To Do]. An innovative model has been developed: The Collaborating Centre (schools, colleges, cultural centres, professional's associations, patient's associations, NGOs, brotherhoods, churches, etc.) organises the agenda of training events and promotes networking. Citizens set up "care clusters", becoming available to provide care. The Beneficiaries Centres (hospices, nursing homes, residential centres, patient organisations, hospitals, health and social care centres, etc.) contact the clusters when care needs of patients are identified. The palliative care specialist supports Compassionate Communities training and refer patients to clusters. Local Government (also a collaborating centre) encourages awareness campaigns and provides institutional support. Companies collaborate in promoting and funding the project. Six cities in Spain and 3 in Colombia have already been selected and local initiatives are already being promoted (more results to be provided at the Congress). | In this study we sought to determine whether a Titin peptide fragment can serve as a clinical biomarker for changes in muscle mass. Mass spectrometry was used to identify Titin fragment in urine. An antibody against this Titin sequence was raised and used to develop a competitive ELISA assay for measurement in serum. Rat tissue extractions in the presence or absence of a series of proteases of interest were used to identify its enzymatic origin. A rat model of dexamethasone (DEX) induced muscle atrophy and a human 56-day bed rest study with and without vibration therapy were used to assess biological and clinical relevance. A technically robust ELISA measuring the Titin fragment was developed against a Titin peptide fragment identified in human urine. The fragment was shown to be produced primarily by MMP-2 cleavage of Titin. In the rat muscle DEX induced atrophy model, Titin-MMP2 fragment was decreased in the beginning of DEX treatment, and then significantly increased later on during DEX administration. In the human bed rest study, the Titin-MMP2 fragment was initially decreased 11.9 (±3.7) % after 1day of bed rest, and then gradually increased ending up at a 16.4 (±4.6) % increase at day 47. |
Does sex differences in the renal vascular response to angiotensin II involve the Mas receptor? | The renin-angiotensin system (RAS) depressor arm, particularly renal angiotensin type 2 receptor (AT(2) R) and Mas receptor (masR) expression, is enhanced in females, which may contribute to renal and cardiovascular protection. We examined the hypotheses that masR activation increases renal blood flow (RBF) at rest and attenuates the reduction in RBF in response to angiotensin II (AngII) infusion in female rats. Furthermore, we postulated that combined activation of the AT(2) R and masR would produce a greater response than masR activation alone. In anaesthetized male and female Wistar rats, mean arterial pressure (MAP) and RBF responses during graded AngII infusion (30-1000 ng kg(-1) min(-1) i.v.) were assessed following pre-treatment with vehicle, the masR antagonist A779, or A779 plus the AT(2) R antagonist PD123319. Basal MAP was not altered by any pre-treatment. Basal RBF decreased approx. 20% in female (P < 0.05), but not male rats in response to A779. However, basal RBF was not altered by A779 + PD123319. AngII infusion reduced RBF in a dose-related fashion (P(dose) < 0.0001) and masR blockade did not alter the RBF response to AngII infusion in male or female rats. However, A779 + PD123319 attenuated the reduction in RBF response to AngII in females (P(group) < 0.005), but not males. | The homeobox gene CDX2 is implicated in the appearance of intestinal metaplasia in Helicobacter pylori gastritis. The aim of this study was to investigate whether CDX2 expression in gastric mucosa occurs before the appearance of overt intestinal metaplasia in H. pylori gastritis, and whether or not this expression is reversible. CDX2 was studied by immunohistochemistry in a cohort of 38 patients with H. pylori gastritis before and after eradication (mean follow-up 6.3 years) of H. pylori. A cohort of 49 individuals with healthy stomachs was analysed as a control. In the control group no immunostaining of CDX2 in the epithelial cells of the gastric body was found, while in 57% of the cases a mild, aberrant nuclear immunostaining of CDX2 in the non-metaplastic epithelial cells in antrum, designated as "positive staining of single cells" (PSSC), was found. In H. pylori gastritis, the PSSC was seen in antrum and corpus in 100% and 26% of the cases, respectively. The prevalence of antral PSSC was significantly increased (on average by 4-fold) in H. pylori gastritis as compared with controls. After eradication of H. pylori, the prevalence of PSSC decreased significantly in antrum but not in corpus. |
Does head-Elevated Patient Positioning decrease Complications of Emergent Tracheal Intubation in the Ward and Intensive Care Unit? | Based on the data from elective surgical patients, positioning patients in a back-up head-elevated position for preoxygenation and tracheal intubation can improve patient safety. However, data specific to the emergent setting are lacking. We hypothesized that back-up head-elevated positioning would be associated with a decrease in complications related to tracheal intubation in the emergency room environment. This retrospective study was approved by the University of Washington Human Subjects Division (Seattle, WA). Eligible patients included all adults undergoing emergent tracheal intubation outside of the operating room by the anesthesiology-based airway service at 2 university-affiliated teaching hospitals. All intubations were through direct laryngoscopy for an indication other than full cardiopulmonary arrest. Patient characteristics and details of the intubation procedure were derived from the medical record. The primary study endpoint was the occurrence of a composite of any intubation-related complication: difficult intubation, hypoxemia, esophageal intubation, or pulmonary aspiration. Multivariable logistic regression was used to estimate the odds of the primary endpoint in the supine versus back-up head-elevated positions with adjustment for a priori-defined potential confounders (body mass index and a difficult intubation prediction score [Mallampati, obstructive sleep Apnea, Cervical mobility, mouth Opening, Coma, severe Hypoxemia, and intubation by a non-Anesthesiologist score]). Five hundred twenty-eight patients were analyzed. Overall, at least 1 intubation-related complication occurred in 76 of 336 (22.6%) patients managed in the supine position compared with 18 of 192 (9.3%) patients managed in the back-up head-elevated position. After adjusting for body mass index and the Mallampati, obstructive sleep Apnea, Cervical mobility, mouth Opening, Coma, severe Hypoxemia, and intubation by a non-Anesthesiologist score, the odds of encountering the primary endpoint during an emergency tracheal intubation in a back-up head-elevated position was 0.47 (95% confidence interval, 0.26-0.83; P = 0.01). | It is well known that vitamin D plays an important role in maintaining bone homeostasis and in regulating calcium absorption. The active form of vitamin D interacts with its receptor the VDR that is expressed in multiple tissues and it is involved in platelets (PLTs) function. In the present study we evaluate PLTs' VDR expression in osteoporotic as opposed to healthy subjects. We enrolled in the study 77 women with postmenopausal osteoporosis, 33 healthy women of childbearing age, 49 healthy men, and 11 healthy women matched with patients for age and postmenopausal period. Thirty-nine patients had had one femoral fracture occurred after the age of fifty and attributable to primary osteoporosis. Bone mineral density, markers of bone metabolism and VDR levels were measured in all the subjects. Our data show that VDR level is lower in patients as respect to controls and is positively correlated with bone density, but not with markers of bone metabolism. We also found a decrease in the phosphorus levels in patients without differences in vitamin D levels and in the dietary calcium intake. |
Does early aggressive nutrition enhance language development in very low-birthweight infants? | Inadequate nutrition in very-low-birthweight (VLBW) infants is known to be associated with growth failure and poor neurological outcomes. We aimed to investigate the association of early aggressive protein and energy intakes with weight gain and 18-month neurodevelopmental outcomes in VLBW infants. A total of 90 infants among 129 infants who survived to discharge were included and divided into two groups (early aggressive nutrition [n = 52] vs conventional nutrition [n = 38]). Clinical findings were compared between the two groups and daily protein and energy intakes were collected for the first 4 weeks of life. Multiple regression analyses tested the association between weekly protein or energy intakes and the result of each category of the Denver Developmental Screening Test II at 18 months' corrected age or weight gain. The early aggressive nutrition group had higher rates of normal language development and lower rates of growth failure (<10th percentile) at both 40 weeks' and 18 months' corrected age compared to the conventional nutrition group. After controlling for the confounding variables, higher first week protein and energy intakes each independently contributed to normal language development (odds ratio [95% confidence interval]; 9.4 [1.8-49.6] per 1 g/kg of protein increase and 1.7 [1.1-2.8] per 10 kcal/kg of energy increase). Higher first-week protein intake was associated with a higher weight at 40 weeks' corrected age (r = 0.41, P = 0.005). | We sought to determine whether outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) vary according to CTO target vessel: left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA). We evaluated the clinical and angiographic characteristics and procedural outcomes of 636 patients who underwent CTO PCI at 6 high-volume centres in the United States between January 2012 and March 2014. The CTO target vessel was the RCA in 387 cases (61%), LAD in 132 (21%), and LCX in 117 (18%). LCX lesions were more tortuous and RCA lesions had greater occlusion length and Japanese Chronic Total Occlusion (J-CTO) score, but were less likely to have a side branch at the proximal cap and had more developed collateral circulation. The rate of procedural success was lower in LCX CTOs (84.6%), followed by RCA (91.7%), and LAD (94.7%) CTOs (P = 0.016). Major complications tended to occur more frequently in LCX PCI (4.3% vs 1.0% for RCA vs 2.3% for LAD; P = 0.07). LCX and RCA CTO PCI required longer fluoroscopy times (45 [interquartile range (IQR), 30-74] minutes vs 45 [IQR, 21-69] minutes for RCA vs 34 [IQR, 20-60] minutes for LAD; P = 0.018) and LCX CTOs required more contrast administration (280 [IQR, 210-370] mL vs 250 [IQR, 184-350] mL for RCA and 280 [IQR, 200-400] mL for LAD). |
Does the role of amiodarone in recent-onset atrial fibrillation after ibutilide have failed to restore sinus rhythm? | Ibutilide is a class III antiarrhythmic drug that is used for the cardioversion of atrial arrhythmias, but it can cause torsades de pointes. Amiodarone is also used for the cardioversion of atrial fibrillation and prolongs the QT interval but rarely causes torsades de pointes. The study included 51 consecutive patients with recent onset atrial fibrillation in whom the administration of ibutilide failed to restore sinus rhythm. In those patients we decided to proceed to intravenous administration of amiodarone. The QT intervals were measured on 12-lead ECG. After 11 +/- 5 h of the administration of the amiodarone, 42 patients (82%) were on sinus rhythm. There was no episode of non-sustained torsades de pointes or hypotension that followed the administration of the two antiarrhythmic agents. | Vascular endothelial growth factor-C (VEGF-C), a lymphatic vessel growth factor, has been involved in the formation of lymph nodal metastases in different tumor types. Early evidences indicate that VEGF-C expression in human primary melanoma could be predictive of lymph nodal metastases, whereas the role of lymphangiogenesis is still controversial. By immunohistochemical analysis, we investigated VEGF-C or CC chemokine receptor 7 expression, together with the lymphatic and blood vessel network, in 36 patients with primary skin melanomas and metastases at the sentinel lymph node biopsy (SLN-positive), and 26 melanoma patients with negative SLN biopsy (SLN-negative). We found that VEGF-C expression in primary melanoma specimens was significantly associated with SLN-positive (p < 0.001), particularly in thin melanomas. An association between augmented peritumoral lymphatic vessel area and SLN-positive (p < 0.02) was also seen. Conversely, no association between either expression of the CC chemokine receptor 7 in the primary tumor, or intratumoral lymphatic vessel or peritumoral and intratumoral blood vessel area, and SLN-positive was found. |
Is metabolic syndrome an independent risk factor for stroke and acute renal failure after coronary artery bypass grafting? | Metabolic syndrome is common among patients having coronary artery bypass grafting. However, it remains unclear whether it has a significant impact on postoperative complications. We aimed to determine whether metabolic syndrome negatively influences the postoperative outcomes of coronary artery bypass grafting. We enrolled 1183 patients who had coronary artery bypass grafting at Juntendo University Hospital between 1984 and 1992. Patients were categorized by the presence or absence of metabolic syndrome using the modified National Cholesterol Education Program Adult Treatment Panel III definition with body mass index in the place of waist circumference. Multivariate analysis was performed to assess the relationships between preoperative presence of metabolic syndrome and postoperative outcomes. Metabolic syndrome was present in 551 (46.6%) patients and absent in 632 (53.4%). Postoperative stroke occurred in 4.7% of patients with metabolic syndrome and 2.1% of patients without metabolic syndrome (P < .0001). Postoperative acute renal failure occurred in 3.8% of patients with metabolic syndrome and 1.1% of patients without metabolic syndrome. On multivariate analysis, metabolic syndrome had odds ratios of 2.47 (95% confidence interval 1.22-4.99; P = .012) for postoperative stroke and 3.81 (95% confidence interval 1.42-10.3; P = .008) for postoperative acute renal failure. | The human endometrium is an important site for contact between the host and pathogens ascending the reproductive tract, and thus plays an important role in female reproductive tract immunity. Previous work in our laboratory has suggested that Toll-like receptors (TLRs) are involved in endometrial epithelial recognition of pathogens and that ligation of endometrial TLRs results in the production of cytokines and chemokines important for both immune and reproductive functions of the endometrium. We have also demonstrated cyclic regulation of TLR3 mRNA and protein expression in human endometrium, suggesting that steroid hormones might play a role in the expression and function of TLR3. In this study, the effects of 17beta-estradiol (E2) and progesterone (P) on TLR3 expression and function in endometrial cell lines were investigated. Endometrial epithelial cell lines were cultured and examined for the presence of TLR3 and hormone receptors by endpoint RT-PCR. For hormonal studies, cells were pre-treated with ethanol vehicle, 10(-8) M E2, and/or 10(-7) M P. For antagonist assays, cells were treated with the ER antagonist, ICI 182, 780, or the PR antagonist, RU486, for two hours prior to treatment with hormones. Following hormone or hormone/antagonist pre-treatment, cells were stimulated with vehicle, the synthetic TLR3 ligand, polyinosinic-polycytidylic acid (Poly I:C), a negative dsDNA control, or a positive control. Cytokine and chemokine production post-stimulation was measured by ELISA. The effects of E2 and P on TLR3 mRNA and protein expression were measured using Real Time RT-PCR and FACS analysis, respectively. Stimulation of TLR3-expressing cells with the synthetic TLR3 ligand, Poly I:C, resulted in the production of cytokines and chemokines important for endometrial function and regulation. Suppression of Poly I:C-induced cytokine and chemokine production by cells treated with 10(-8) M E2, but not cells treated with 10(-7) M P, was observed in endometrial epithelial cell lines expressing TLR3 and estrogen receptor alpha (ERalpha). The effects of E2 were not observed on cells which did not express ERalpha or in cells pre-treated with the ER antagonist, ICI 182, 780. Treatment with E2 did not affect TLR3 mRNA or protein expression. However, treatment with E2 did suppress cytokine and chemokine production resulting from TLR3 stimulation with Poly I:C, suggesting that E2 modulates TLR3 function. |
Does curcumin prevent diabetes-associated abnormalities in the kidneys by inhibiting p300 and nuclear factor-kappaB? | Diabetic nephropathy is a debilitating disease that leads to end-stage renal failure in the Western world. Hyperglycemia is the initiating factor in several chronic diabetic complications which mediates increased oxidative stress and eventually the increased production of vasoactive factors and extracellular matrix proteins. We hypothesized that curcumin, a potent antioxidant, might be beneficial in preventing the development of diabetic nephropathy because this compound has been shown to inhibit p300, a histone acetyltransferase that plays a role in regulating gene expression through its interaction with the transcription factor nuclear factor-kappaB. To test this hypothesis, male Sprague-Dawley rats were injected with streptozotocin to induce diabetes. These animals were subsequently treated with curcumin for a period of 1 mo. Real-time reverse transcriptase polymerase chain reaction analyses showed that diabetes-induced upregulation of vasoactive factors (endothelial nitric oxide synthase and endothelin-1), transforming growth factor-beta1 and extracellular matrix proteins (fibronectin and extradomain-B-containing fibronectin) in the kidneys. These changes were associated with increased oxidative stress, mesangial expansion, and p300 and nuclear factor-kappaB activity that were prevented with curcumin treatment. | Primary: to evaluate predictivity of liver stiffness (LS), spleen stiffness (SS), and their ratio assessed by real-time 2D shear wave elastography (RT-2D-SWE) for adverse outcomes (hepatic decompensation, hepatocellular carcinoma or death; "event") in compensated liver cirrhosis (LC) patients. Secondary: to evaluate ability of these measures to discriminate between cirrhotic patients with/without esophageal varices (EV). Predictivity of LS, SS, and LS/SS was assessed in a retrospectively analyzed cohort of compensated LC patients (follow-up cohort) and through comparison with incident patients with decompensated cirrhosis (DC) (cross-sectional cohort). Both cohorts were used to evaluate diagnostic properties regarding EV. In the follow-up cohort (n=44) 18 patients (40.9%) experienced an "event" over a median period of 28 months. LS≥21.5 kPa at baseline was independently associated with 3.4-fold (95% confidence interval [CI] 1.16-10.4, P=0.026) higher risk of event. Association between SS and outcomes was weaker (P=0.056), while there was no association between LS/SS ratio and outcomes. Patients with DC (n=43) had higher LS (35.3 vs 18.3 kPa, adjusted difference 65%, 95% CI 43%-90%; P<0.001) than compensated patients at baseline. Adjusted odds of EV increased by 13% (95% CI 7.0%-20.0%; Plt;0.001) with 1 kPa increase in LS. At cut-offs of 19.7 and 30.3 kPa, LS and SS had 90% and 86.6% negative predictive value, respectively, to exclude EV in compensated patients. |
Does metabolic syndrome negatively impact early patency of saphenous vein grafts? | Coronary artery bypass grafting has been performed for a long period utilizing saphenous vein grafts, the fate of which might be crucial to prognosis following the operation. Metabolic syndrome, on the other hand, has become an increasingly important part of cardiovascular practice. We examined whether there was any negative effect of metabolic syndrome on saphenous vein graft patency in a relatively short term (< or =5 years). Coronary angiograms of 314 consecutive patients (mean age 62.6+/-8.5 years), having at least one saphenous vein bypass graft within the last 5 years, were evaluated. One hundred and twenty-one patients (group 1) had either an occluded saphenous vein graft or a saphenous vein graft with a significant lesion, and 193 patients (group 2) had patent saphenous vein grafts. Metabolic syndrome was present in 46.2% of all patients (n=145), in 57% of patients in group 1 and in 39.4% of patients in group 2 (P=0.002). Having metabolic syndrome increased the risk of saphenous vein graft occlusion or having a significant lesion on saphenous vein grafts by 2.04-folds. In multivariable logistic regression, smoking (P=0.015, odds ratio=1.88), metabolic syndrome (P=0.019, odds ratio=1.81) and diabetes mellitus (P=0.048, odds ratio=1.36) were found to be associated with poor venous graft fate in the relatively short-term period after bypass. | Microglia are resident brain macrophages that can phagocytose dead, dying or viable neurons, which may be beneficial or detrimental in inflammatory, ischaemic and neurodegenerative brain pathologies. Cell death caused by phagocytosis of an otherwise viable cell is called 'primary phagocytosis' or 'phagoptosis'. Calreticulin (CRT) exposure on the surface of cancer cells can promote their phagocytosis via LRP (low-density lipoprotein receptor-related protein) on macrophages, but it is not known whether this occurs with neurons and microglia. We used primary cultures of cerebellar neurons, astrocytes and microglia to investigate the potential role of CRT/LRP phagocytic signalling in the phagocytosis of viable neurons by microglia stimulated with lipopolysaccharide (LPS) or nanomolar concentrations of amyloid-β peptide1-42 (Aβ). Exposure of CRT on the neuronal surface was investigated using surface biotinylation and western blotting. A phagocytosis assay was also developed using BV2 and PC12 cell lines to investigate CRT/LRP signalling in microglial phagocytosis of apoptotic cells. We found that BV2 microglia readily phagocytosed apoptotic PC12 cells, but this was inhibited by a CRT-blocking antibody or LRP-blocking protein (receptor-associated protein: RAP). Activation of primary rat microglia with LPS or Aβ resulted in loss of co-cultured cerebellar granule neurons, and this was blocked by RAP or antibodies against CRT or against LRP, preventing all neuronal loss and death. CRT was present on the surface of viable neurons, and this exposure did not change in inflammatory conditions. CRT antibodies prevented microglia-induced neuronal loss when added to neurons, while LRP antibodies prevented neuronal loss when added to the microglia. Pre-binding of CRT to neurons promoted neuronal loss if activated microglia were added, but pre-binding of CRT to microglia or both cell types prevented microglia-induced neuronal loss. |
Does short-term high salt intake reduce brachial artery and microvascular function in the absence of changes in blood pressure? | The aims of this study were to test the hypothesis that short-term high salt intake reduces macrovascular and microvascular endothelial function in the absence of changes in blood pressure and to determine whether acute exercise restores endothelial function after high salt in women. Twelve women were administered high salt (11 g of sodium chloride for 7 days) and then underwent a weightlifting session. Brachial artery flow-mediated dilation and nitroglycerin dilation were measured with ultrasound at baseline, after high salt, and after weightlifting. Subcutaneous fat tissue biopsies were obtained at baseline, after high salt, and after weightlifting. Resistance arteries from biopsies were cannulated for vascular reactivity measurements in response to flow [flow-induced dilation (FID)] and acetylcholine. Blood pressure was similar before and after high salt diet. Brachial flow-mediated dilation was reduced after high salt diet but was not affected by acute weightlifting. Brachial nitroglycerin dilations were similar before and after high salt. FID and acetylcholine-induced dilation of resistance arteries were similar to that of before and after high salt diet. FID and acetylcholine-induced dilation was not altered by weightlifting after high salt diet. However, N-nitro-L-arginine methyl ester significantly reduced FID at baseline and after exercise but had no effect dilator reactivity after high salt diet alone. | Cytotoxic immune elimination of transduced hepatocytes may limit gene therapy for inherited liver diseases. Using beta-galactosidase as a marker gene, we studied whether creation of mixed beta-galactosidase molecular hematopoietic chimerism could induce tolerance to beta-galactosidase-transduced hepatocytes. Molecular hematopoietic chimerism was established in irradiated recipient mice by transplantation of either a mixture of wild-type and beta-galactosidase-transgenic bone marrow or autologous bone marrow stem cells that were transduced with beta-galactosidase lentiviral vectors. After transplantation, mice were hepatectomized and injected with beta-galactosidase recombinant retroviruses to transduce regenerating hepatocytes. We monitored the presence of beta-galactosidase-expressing hepatocytes as well as the appearance of anti-beta-galactosidase antibodies during the time. In control animals, anti-beta-galactosidase antibodies and cytotoxic T-lymphocyte (CTL) response developed as early as 3 weeks after gene transfer. Transduced hepatocytes disappeared concomitantly. In bone marrow transplanted mice, tolerance could be observed in a significant proportion of animals. Tolerance resulted in permanent liver transgene expression and was absent unless a chimerism above 1% was achieved, demonstrating a threshold effect. |
Does adaptation to pregnancy lead to attenuated rat uterine artery smooth muscle sensitivity to oxytocin? | We tested the hypothesis that oxytocin (OT) contracts blood vessels via vasopressin V1A (VP) receptors, and that this depends on pregnancy. Concentration-contraction relationships (CCR) to OT and VP (10(-12)-10(-6) mol/L) were obtained in different blood vessels. CCR were obtained in uterine arteries (UA) from nonpregnant, mid-pregnant, and late pregnant rats (n = 6-10 per group) in the absence and presence of selective antagonists (10(-7) mol/L). Sensitivity to OT, but not to VP, is attenuated in pregnant rat UA. Antagonists shifted CCR of OT and VP to the right, and, to a lesser extent, of the counterpart, in all UA. VP antagonist depresses oxytocin CCR much more than OT antagonist in pregnant rat UA. | To determine if hospital treatment in residential care facilities, led by a geriatric team, might be a viable alternative to inpatient admission for selected patients. Case series with a new intervention were compared with historical controls receiving the conventional treatment. Treatment in residential care facilities (TRC) by the Residential Care Intervention Program in The Elderly (RECIPE) service was compared against the conventional treatment group, aged care unit (ACU) inpatients. A total of 95 patients in TRC and 167 patients in ACU were included. The mean Charlson Comorbidity Index score was 7 in both groups and demographics were similar, except more patients in the TRC group had dementia. Palliative care support was provided to 35.8% in the TRC group, compared with 7.8% in ACU, P < 0.001. Six-month mortality rates were similar at 30% for both groups. Rehospitalization rates at 6 months were similar at 41% for both groups. Length of care was significantly shorter for TRC (mean 2 days) compared with ACU (mean 11 days), P < 0.001. |
Does systems analysis of quantitative shRNA-library screens identify regulators of cell adhesion? | High throughput screens with RNA interference technology enable loss-of-function analyses of gene activities in mammalian cells. While the construction of genome-scale shRNA libraries has been successful, results of large-scale screening of those libraries can be difficult to analyze because of the relatively high noise levels and the fact that not all shRNAs in a library are equally effective in silencing gene expression. We have screened a library consisting of 43,828 shRNAs directed against 8,500 human genes for functions that are necessary in cell detachment induced by a constitutively activated c-Abl tyrosine kinase. To deal with the issues of noise and uncertainty of knockdown efficiencies, we employed an analytical strategy that combines quantitative data analysis with biological knowledge, i.e. Gene Ontology and pathway information, to increase the power of the RNAi screening technique. Using this strategy we found 16 candidate genes to be involved in Abl-induced disruption of cell adhesion, and verified that the knockdown of IL6ST is associated with enhanced cell attachment. | The initial discovery of leptin (1994) has given rise to a substantial number of published studies. This study aimed at identifying the published data on the reference ranges of total, free and bound leptin concentration in the healthy prepubertal population. A search was conducted on original English language studies published from 1994 to 2005 in the following databases: PubMed (n = 58), EMBASE (n = 4), Biological Abstracts (n = 2) and Science Finder Scholar (n = 66). A cited reference search was completed in Science Citation Index on studies with a leptin range. A meta-analysis was completed on included studies containing a dataset and a sample size for a leptin concentration range and/or mean+/-standard deviation for a healthy prepubertal population. Preanalytical and analytical variations were examined. Preanalytical variables included aspects such as fasting state and gender, while analytical variation comprised the type of leptin assay methodology. Twelve studies met the inclusion criteria. One study examined free leptin; 11 studies examined total concentration. No studies reported leptin reference ranges established by Clinical and Laboratory Standards Institute (CLSI) criteria, although four studies reported specific study leptin ranges. The methodology of enzyme-linked immunosorbent assay demonstrated a wider leptin range than radio immunoassay (0.56-36.35 vs. 1.01-12.21 ng/mL). Males had a significantly lower mean leptin concentration than females (P = 0.0006); obese children had a higher concentration than non-obese (P = 0.0001). |
Are platelet levels of dopamine increased in migraine and cluster headache? | To measure plasma and platelet levels of dopamine in patients with migraine with aura, migraine without aura, and cluster headache. Clinical, genetic, and pharmacological evidences suggest that an abnormality of dopaminergic system plays a role in migraine pathogenesis. Direct evidence of an abnormal metabolism of dopamine in migraine, however, is lacking. Plasma and platelet levels of dopamine were measured in patients with migraine with aura or migraine without aura during headache-free periods and in patients with cluster headache during the remission and active periods, as compared with healthy control subjects, using a multichannel electrochemical high-performance liquid chromatography system. Plasma levels of dopamine were not detectable with our methodology. Platelet levels of dopamine were higher in both types of migraine (migraine without aura = .20 +/- .17 ng/10(8) platelets; migraine with aura = .16 +/- .19 ng/10(8) platelets) than in control subjects (.10 +/- .11 ng/10(8) platelets), although in migraine with aura patients the difference was not significant. Patients with cluster headache showed the highest levels of platelet dopamine (.34 +/- .36 ng/10(8) platelets). | The role of signal transducer and activator of transcription 3 (Stat3) in liver fibrosis is still controversial. Since hepatic stellate cells (HSCs) and transforming growth factor-β1 (TGF-β1) are central to the fibrogenesis, our goal was to clarify the mechanism of Stat3 crosslinking of TGF-β1 signaling. Stat3, TGF-β1 mRNA and protein expressions were examined in liver tissues of chronic hepatitis B (CHB) patients and diethylinitrosamine (DEN)-induced rat fibrosis model. The effect of Stat3 activation or suppression on TGF-β1 signaling in HSCs was tested in vitro and in vivo. Stat3 expression as well as TGF-β1 was increased in CHB patients and DEN-induced fibrosis rat model. This was strongly correlated with increase in fibrosis staging. TGF-β1, a mediator of fibrosis, was enhanced by Stat3, but suppressed by siRNA-mediated RNA knockdown of Stat3 (siStat3) or Janus kinase 2 inhibitor (AG490) both in vivo and in vitro. Stat3 crosslinking TGF-β1 signaling plays an important role in HSC activation and increasing fibrosis related products. TGF-β1 could not achieve profibrogenic cytokine and anti-apoptosis characteristics without Stat3 activation in HSCs. |
Are more favorable dietary patterns associated with lower glycemic load in older adults? | Glycemic load represents the total glycemic effect of the diet and may reduce the risk for chronic disease by affecting the risk for obesity and by altering metabolic endpoints. The food choices associated with lower-glycemic-load diets have received little investigation. Therefore, the purpose of this research was to examine the food patterns associated with lower-glycemic-load diets to establish targeted intervention messages. A random sample (n=179; 81 male and 98 female subjects) of older adults > or =65 years of age in the Geisinger Rural Aging study, a nutritional risk screening study. Standardized methodology was used to calculate the glycemic load from data obtained in five 24-hour recalls. Statistical analysis t tests compared dietary patterns between male and female subjects from two eating pattern clusters identified in previous cluster analysis based on food group intake. The mean (+/-standard deviation) glycemic load for the entire sample was 115.6 (+/-39.9). Two clusters were identified, and male and female subjects in one cluster had a lower glycemic load (113.7+/-44.2 and 94.0+/-27.5, respectively) than male and female subjects in the second cluster (139.9+/-38.8 and 110.7+/-35.9, respectively) ( P <.01). Participants in the lower-glycemic-load cluster consumed more carbohydrate from cereal, fruits, vegetables, and milk, whereas those in the higher-glycemic-load cluster consumed more breads and desserts. | Although stasis is important in the pathogenesis of deep vein thrombosis (DVT), how it contributes to thrombogenesis is largely unknown. To gain mechanistic insight, we used a rat model of inferior vena cava (IVC) ligation. Rats were subjected to IVC ligation for 15 to 60 minutes. Ligation resulted in rapid IVC dilatation and by 60 minutes, thrombi were detected in all rats. Small thrombi were detected in the IVC of most rats after 15 minutes of ligation. Thrombi were rich in fibrin, contained aggregated platelets as well as trapped leukocytes and red cells, and most originated at sites of localized endothelial denudation. Immunohistochemical analysis revealed tissue factor (TF)-expressing leukocytes within the thrombi and adherent to the vessel wall. Despite a largely intact vessel wall, endothelial cells also stained for TF. The expression of TF colocalized with that of protein disulfide isomerase (PDI), an enzyme implicated in TF decryption. |
Does blocking the CD28-B7 T-cell costimulatory pathway abrogate the development of obliterative bronchiolitis in a murine heterotopic airway model? | CTLA4IgG that binds to B7 effectively inhibits the signaling of CD28/B7 pathway and induces antigen-specific T-cell unresponsiveness in vitro and in vivo. We examined whether the development of obliterative bronchiolitis in a murine heterotopic airway transplantation model is T cell dependent and whether CTLA4IgG abrogates the development of obliterative bronchiolitis. Tracheae with main bronchi from C3H/He (H2k), BALB/C (H2d), or C57BL/6 (H2b) mice were transplanted heterotopically into subcutaneous pockets on the backs of BALB/C or BALB/C nu/nu mice on day 0. Recipient mice were untreated or intraperitoneally treated with either CTLA4IgG or human IgG with different time and dose schedules. The development of obliterative bronchiolitis, which leads to luminal obliteration by fibrous tissue in a murine heterotopic airway transplantation model, was T cell dependent and the development of obliterative bronchiolitis was significantly abrogated by the CTLA4IgG treatment. However, the normal ciliated columnar respiratory epithelial cells in allografts were lost and replaced by flattened attenuated epithelial cells even after the CTLA4IgG treatment. We further demonstrated that CTLA4IgG treatment did not result in the induction of donor-specific unresponsiveness. | The Dialysis Outcomes and Practice Patterns Study (DOPPS) reported high incidence of depression in haemodialysis patients. Hypercalcaemia and high parathyroid hormone (PTH) levels are aetiological factors of psychological disorders. We examined the association between mineral metabolism abnormalities and mental health in Japanese-DOPPS patients. We used baseline data of Japan-DOPPS, Phase 1 (2755 patients, 1999-2001) and Phase 2 (2286 patients, 2002-03). The outcome variable was mental health using the mental health domain of SF-36. We examined the association between serum corrected calcium, phosphorus, calcium x phosphorus product and intact PTH concentrations, and mental health using analysis of covariance and also the associations between corrected calcium levels and current use of vitamin D and calcium-containing phosphate binder. There was a significant association between mental health and corrected calcium levels. A significantly lower mental health score was noted in patients with corrected calcium > or = 11 mg/dl than in <8.4 (P = 0.04), > or =8.4 to <10.2 (P = 0.009) and > or =10.2 to <11 mg/dl (P = 0.003). The association was significant even after adjustment for age, sex and other confounders. However, there was no relationship between intact PTH and mental health. High-corrected calcium levels were significantly associated with the use of intravenous active vitamin D and calcium-containing phosphate binder. |
Do different components of opioid-substitution treatment predict outcomes of patients with and without a parent with substance-use problems? | The aim of this study was to determine how the treatment needs and outcomes of polysubstance-using patients entering opioid-substitution treatment (OST) may be affected if the patient had a parent with substance-use problems. This prospective observational study examined outcomes of 255 patients (97% male) entering OST at eight clinics in the Veterans Health Administration. Self-reported substance-use outcomes in the first year of treatment were compared between patients with (n = 121) and without (n = 134) a parent with substance-use problems. The association between receipt of practice guideline-recommended elements of care and treatment outcome was examined. Parent history-positive patients had greater drug use at 6 months, but by 12 months they had reduced their drug use to the same extent as parent history-negative patients. Ongoing methadone (Dolophine, Methadose) maintenance was associated with improved outcomes of drug use in parent history-negative patients; however, parent history-positive patients who ended methadone maintenance reduced drug use as much as those who continued treatment. The association between treatment received and outcome differed in these populations. In parent history-negative patients, reduced severity of substance use at 1 year was predicted solely by receiving methadone for a greater number of days. In parent history-positive patients, reduced severity of substance use was predicted by receiving methadone for fewer days, by greater satisfaction with and receipt of counseling services, and by lesser tendency for providers to encourage a reduction in methadone use. | Microparticles (MPs), small vesicles shed from stimulated cells, permit cross-talk between cells within a particular environment. Their composition is thought to reflect their cell of origin, and differs according to whether they are produced by stimulation or by apoptosis. Whether MP properties vary according to stimulus is not yet known. We studied the characteristics of MPs produced from monocytic THP-1 cells upon stimulation with lipopolysaccharide or a soluble P-selectin chimera, using proteomics, flow cytometry, western blotting, and electron microscopy. Utilizing a novel criterion of calcein-AM staining to define MPs, we found that MP populations were similar with respect to size, presence and organization of cytoskeleton, and expression of certain antigens. The MPs shared the same level of procoagulant activity. We found that MPs also have distinct characteristics, depending on stimuli. These include differences in phosphatidylserine expression and expression of proteins from specific subcellular locations such as the mitochondria, and of unique antigens such as leukocyte-associated immunoglobin-like-receptor (LAIR)-1, which was found only upon stimulation with the soluble P-selectin chimera. |
Does patient trust in physician influence colorectal cancer screening in low-income patients? | Colorectal cancer (CRC) screening is effective but underutilized. Although physician recommendation is an important predictor of screening, considerable variation in CRC screening completion remains. To characterize the influence of patient trust in care providers on CRC screening behavior. Data were collected as part of a cluster-randomized CRC screening intervention trial performed in the San Francisco Community Health Network from March 2007 to January 2012 (analysis, Spring 2012). All study participants received a recommendation to complete CRC screening from their primary care provider (PCP). Included participants were aged 50-79 years, not current with screening, and completed the Wake Forest Trust Scale (WFTS) measuring trust in PCPs and doctors in general. Primary outcome was CRC screening completion (colonoscopy or fecal occult blood testing) within 12 months following enrollment. Multivariable association adjusted for race/ethnicity, language, and other sociodemographics was estimated using generalized estimating equations with logit link and binomial distribution. WFTS response was 70.3% (701). Most participants (83%) were Latino, Asian, or black. Most had income <$30,000 (96%) and public health insurance (86%). Higher trust in PCP was associated with screening completion (OR=1.11, 95% CI=1.03, 1.17), but trust in doctors was not (OR=1.02, 95% CI=0.82, 1.28). Race, language, and other sociodemographic factors were not significant in multivariable analysis. | We determined the neuropathologic damage in a canine model of global incomplete ischemia commonly used in a variety of physiological experiments. We induced 20 minutes of incomplete ischemia in dogs (n = 9) by increasing intracranial pressure via intraventricular infusion of artificial cerebrospinal fluid to maintain a cerebral perfusion pressure of 10 mm Hg while keeping body temperature at 38 degrees C during and immediately after ischemia. After a 7-day recovery period, animals were perfusion-fixed for neuropathology. In hematoxylin and eosin preparations, ischemic neuronal injury was assessed, neurons were counted, and percentage of cell damage was determined. No focal neurological deficits or overt seizures were observed during the 7-day recovery period. In superior temporal gyrus, 49 +/- 11% and 70 +/- 10% damage (mean +/- SEM) was observed in layer III pyramidal cells in the crown and sulcus, respectively. All neocortical regions examined showed neuronal damage in layers III and/or V. In hippocampus, 59 +/- 11% damage of pyramidal neurons occurred in CA1, with dorsal (septal) hippocampus showing more injury than ventral (temporal) portions. The caudate nucleus (head) exhibited 27 +/- 7% neuronal injury. In cerebellar cortex (anterior lobule), 70 +/- 7% damage of Purkinje cells occurred, but different folia of cerebellum showed varying degrees of injury. Brain stem and thalamus were minimally affected despite reduced blood flow. Inflammatory changes (leukocytic infiltration and neuronal incrustations) were observed, but only when neuronal degeneration was severe. Pancellular necrosis and infarction did not occur. |
Does a20 suppress hepatocellular carcinoma proliferation and metastasis through inhibition of Twist1 expression? | Aberrant expression of A20 has been reported in several human malignancies including hepatocellular carcinoma (HCC). However, its clinical relevance and potential role in HCC remain unknown. Quantitative PCR, Western blots and immunohistochemistry analyses were used to quantify A20 expression in HCC samples and cell lines. The correlation of A20 expression with clinicopathologic features was analyzed in a cohort containing 143 patients with primary HCC. Kaplan-Meier curves were used to evaluate the association between A20 expression and patient survival. Functional studies were performed to determine the effects of A20 on proliferation and metastasis of HCC cells in vitro and in vivo. Expression of A20 was increased in HCC tissues and cell lines. Increased expression of A20 was negatively correlated with the tumor size, TNM stage, tumor thrombus formation, capsular invasion and serum AFP levels. Patients with higher A20 expression had a prolonged disease-free survival and overall survival than those with lower A20 expression. Forced expression of A20 significantly inhibited the proliferative and invasive properties of HCC cells both in vitro and in vivo, whereas knockdown of A20 expression showed the opposite effects. Further studies revealed that expression of A20 was inversely correlated with Twist1 levels and NF-κB activity in HCC tissues and cell lines. A20-induced suppression of proliferation and migration of HCC cells were mainly mediated through inhibition of Twist1 expression that was regulated at least partly by A20-induced attenuation of NF-κB activity. | To test the hypothesis that hot flashes specifically relate to verbal memory performance by examining the relationship between objective hot flashes and cognitive test performance in women with moderate to severe vasomotor symptoms. In an observational study, 29 midlife women (mean age, 53 y) with moderate to severe hot flashes provided measures of objective hot flashes with an ambulatory hot flash monitor, subjective hot flashes with a diary and questionnaire, and objective measures of verbal memory and other cognitive functions with standardized neuropsychological tests. The mean number of objective hot flashes was 19.5 per day (range, 6 to 35), including 15.3 (range, 6 to 35) during waking hours and 4.2 (range, 0 to 9) during sleep. The mean sensitivity (ie, subjective detection of objectively measured hot flashes) was 60%. Regression analyses revealed that total number of objective hot flashes, sleep duration, and verbal knowledge were significant predictors of delayed verbal memory. Verbal fluency correlated positively with objective daytime hot flashes. Hot flashes did not predict performance on any of the other secondary cognitive measures (ie, attention, working memory, visual memory), although poor sleep predicted worse performance on several outcome measures. |
Are pathogenic pathways activated in each major cell type of the glomerulus in the Cd2ap mutant mouse model of focal segmental glomerulosclerosis? | Mutations in several genes expressed in podocytes, including Cd2ap, have been associated with focal segmental glomerulosclerosis in humans. Mutant mouse models provide an opportunity to better understand the molecular pathology that drives these diseases. In this report we use a battery of transgenic-GFP mice to facilitate the purification of all three major cell types of the glomerulus from Cd2ap mutant mice. Both microarrays and RNA-seq were used to characterize the gene expression profiles of the podocytes, mesangial cells and endothelial cells, providing a global dual platform cross-validating dataset. The mesangial cells showed increased expression of profibrotic factors, including thrombospondin, Tgfb2 and Tgfb3, as well as the angiogenesis factor Vegf. They also showed upregulation of protective genes, including Aldh1a2, involved in retinoic acid synthesis and Decorin, a Tgfb antagonist. Of interest, the mesangial cells also showed significant expression of Wt1, which has generally been considered podocyte specific. The Cd2ap mutant podocytes showed upregulation of proteases as well as genes involved in muscle and vasculature development and showed a very strong gene expression signature indicating programmed cell death. Endothelial cells showed increased expression of the leukocyte adhesion associated factors Vcam1 and Sele, as well as Midkine (promoting angiogenesis), endothelin and many genes responsive to cytokines and interferons. | Although mitochondrion-derived markers such as ornithine carbamyltransferase (OCT) and glutamate dehydrogenase (GLDH) have been reported to be good markers for alcohol-induced hepatic injury, their use has been limited due to the notion that mitochondrial markers are less sensitive than cytosol-derived markers. We determined the clinical importance of mitochondrion-derived markers in the evaluation of alcohol-induced hepatotoxicity. Rats were administered alcohol chronically (5-30% ethanol in drinking water with or without high fat diet feeding for 15 weeks) and hepatic damages were evaluated by serum OCT and GLDH, together with other liver enzymes such as alanine aminotransferase and aspartate aminotransferase. Hepatic content of the enzymes was also evaluated in the chronic ethanol feeding model to confirm whether induction of the enzyme in the liver reflects the serum activity. The serum activities of OCT and GLDH increased significantly by chronic ethanol feeding while other markers did not. Although the hepatic content of OCT and GLDH also increased, the serum activities did not correlate with the hepatic activities and the extent of increase in the liver was much less than in serum. |
Are [ COX-2 and HO-1 involved in the delayed preconditioning elicited by bradykinin in rat hearts ]? | To investigate whether cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) are involved in the bradykinin-induced delayed protection. Cardiac contractility, lactate dehydrogenase (LDH) and infarct area were analyzed in isolated rat hearts undergoing ischemia-reperfusion injury induced by Langendorff method. Conscious rats received bradykinin (40 microg/kg), and the isolated hearts were subjected to 30 min of regional ischemia and 120 min of reperfusion 24 h later. Bradykinin pretreatment would improve post-ischemic performance, and reduced the release of LDH and infarct size. COX-2 inhibitor celecoxib (3 mg/kg) abolished bradykinin-induced protection, leading to poorer myocardial performance, release of more LDH and larger infarct sizes. Administration of HO-1 inhibitor ZnPP IX(20 microg/kg) before bradykinin partially abrogated the delayed protection. Pretreatment with the mitochondrial ATP sensitive potassium channel(mitoK(ATP) antagonist 5-HD before or 24 h after bradykinin administration also abolished the effect of protection. | To review the publication fate of abstracts presented at dental conferences and investigate the association between full publication proportion (FPP) and abstract characteristics, conference characteristics, and methodological quality of primary studies. PubMed, EMBASE, and Google Scholar were searched up to November 2014 for studies that reported at least one FPP of abstracts presented at dental conferences, with a follow-up length of no less than 48 months. Sixteen studies involving 10,365 abstracts presented at 52 conferences were included. The pooled FPP was 29.62% (95% confidence interval: 22.90%, 36.81%) for all presented abstracts and 51.97% (95% confidence interval: 43.19%, 60.70%) for randomized controlled trial abstracts. Abstract characteristics significantly associated with higher FPP included reporting of statistical analysis (P < 0.001), oral presentation (P < 0.001), basic science research (P = 0.047), and reporting of financial support (P = 0.009). Abstracts with positive (P = 0.29) or statistically significant results (P = 0.33) were not published more often than negative or nonsignificant results, respectively. In multivariable meta-regression analysis, conferences held in Asia (P < 0.001) and at a continental rather than national level (P < 0.001) were significantly associated with higher FPP. |
Do illness representations predict adherence in adolescents and young adults with type 1 diabetes? | Most adolescents and young adults (AYAs) with type 1 diabetes struggle with diabetes self-management and exhibit suboptimal glycemic control. This study examined two models of association between illness representations, a modifiable predictor of suboptimal outcomes, and adherence and glycemic control in AYAs with type 1 diabetes. Ninety-nine AYAs (ages 15-20 years) completed measures of illness representations and adherence at two visits. Blood glucose monitoring frequency and haemoglobin A1c were obtained via chart review. Relationships were examined using structural equation modelling. Illness representations accounted for a significant proportion of the variance in blood glucose monitoring frequency (ΔR2 = .23, p < .01) and adherence to emergency precautions at Time 1 (ΔR2 = .07, p = .03). Illness representations also accounted for significant variance in blood glucose monitoring frequency (ΔR2 = .08, p = .01), adherence to recommendations for insulin and food (ΔR2 = .08, p = .02) and exercise (ΔR2 = .10, p < .01), and adherence to emergency precautions (ΔR2)= .16, p < .01) at Time 2. | Celastrol is an active ingredient of traditional herbal medicine and has recently been identified as a potent natural proteasome inhibitor. In the present study, we evaluated the radiosensitizing potential of celastrol in the human prostate cancer PC-3 model. Clonogenic assays were performed to determine the radiosensitizing effect of celastrol. Apoptosis was examined by flow cytometry using Annexin V and propidium iodide staining and by a caspase-3 activation assay. DNA damage processing was examined by immunofluorescent staining and Western blot for phosphorylated H2AX (gammaH2AX). The PC-3 xenograft model in the athymic nude mouse was used for the determination of the in vivo efficacy of celastrol combined with radiotherapy. The tumor samples were also analyzed for apoptosis and angiogenesis. Celastrol sensitized PC-3 cells to ionizing radiation (IR) in a dose- and schedule-dependent manner, in which pretreatment with celastrol for 1 h followed by IR achieved maximal radiosensitization. Celastrol significantly prolonged the presence of IR-induced gammaH2AX and increased IR-induced apoptosis. Celastrol, combined with fractionated radiation, significantly inhibited PC-3 tumor growth in vivo without obvious systemic toxicity. The combination treatment increased gammaH2AX levels and apoptosis, induced cleavage of poly(adenosine diphosphate-ribose)polymerase and Mcl-1, and reduced angiogenesis in vivo compared with either treatment alone. |
Does rosuvastatin improve basal nitric oxide activity of the renal vasculature in patients with hypercholesterolemia? | Impaired endothelium-dependent vasodilation represents an early manifestation of atherosclerosis. Prospective studies have demonstrated that impaired endothelial function in the peripheral circulation of hypercholesterolemic patients predicts CV events and can be restored by statin treatment. Whether this also holds true in the renal circulation has not yet been adequately addressed. In a double-blind, randomized, placebo-controlled cross-over trial, 40 hypercholesterolemic patients were randomly assigned to receive rosuvastatin (10mg/day) and matching placebo. The primary objective of the study was to assess the effect of 6-week treatment with rosuvastatin on basal NOS activity of the renal vasculature, as assessed by measuring renal plasma flow (RPF) both before and after blockade of NOS with systemic infusion of N(G)-monomethyl-L-arginine (L-NMMA). In a subgroup of 20 patients we also studied the effects of a 3-day treatment regimen. Compared to placebo treatment, rosuvastatin decreased LDL-cholesterol levels both after 3 days and 6 weeks of treatment. The decrease in RPF in response to L-NMMA was significantly more pronounced after 6-week therapy with rosuvastatin compared to placebo (-13.7+/-1.0% versus -11.3+/-0.7%; p=0.046), indicating increased basal NOS activity with rosuvastatin treatment. A trend towards improved basal NOS activity was already evident after 3-day treatment. | Recently, the authors identified molecular signatures and pathways associated with nonsmall cell lung carcinoma histology and lung development. They hypothesized that genetic classifiers of histology would provide insight into lung tumorigenesis and would be associated with clinical outcome when evaluated in a broader set of specimens. Associations between patient survival and immunostaining for 11 representative histologic classifiers (epidermal growth factor receptor [EGFR], CDK4, syndecan-1, singed-like, TTF-1, keratin 5, HDAC2, docking protein 1, integrin alpha3, P63, and cyclin D1) were examined using a tissue microarray constructed from nonsmall cell lung carcinoma specimens. Sixty-three tumors were examined, including 43 adenocarcinomas, 11 large cell carcinomas, and 9 squamous cell carcinomas. Sixty-three percent of tumors were clinical Stage I lesions, and 37% were Stage II-III lesions. In a multivariate analysis that controlled for age, gender, and race, syndecan-1 expression was found to be associated with a significant reduction in the risk of death (hazard ratio, 0.31 [95% confidence interval, 0.18-0.87]; P < 0.05). Multivariate analysis also indicated that EGFR expression was associated with a significant reduced risk of death. |
Are human adipocytes highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression? | Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmented inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages. Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes. | To compare the streams of expenses and revenues associated with investment in a cohort of basic science investigators at the University of Rochester School of Medicine & Dentistry for seven years. The authors evaluated a medical school's financial investment in 25 basic science faculty who were hired between 1999 and 2004 to expand basic science research. The authors compared direct and indirect costs with the extramural grant support generated by these investigators through 2006. To facilitate a comparison of investments made and grants generated, the authors calculated present value (in 2006 dollars) of revenues and expenses using the school's approximate cost of capital. Of the 25 faculty members hired, 24 (96%) remained at the school through 2006. From 1999 to 2006, the school invested a total of $69.0 million ($33.1 million in start-up costs and $35.9 million in indirect costs) to support the faculty members. Through 2006, these faculty members generated $99.7 million in extramural grant revenue ($70.7 million in direct grant revenue and $29.1 million in indirect grant revenue). Whereas the faculty generated $1.45 in total grant revenue per dollar invested, start-up expenses and incomplete recovery of indirect costs required the school to add 40 cents to every grant dollar generated to achieve financial equilibrium. |
Is production of hemolysin BL by Bacillus cereus group isolates of dairy origin associated with whole-genome phylogenetic clade? | Bacillus cereus group isolates that produce diarrheal or emetic toxins are frequently isolated from raw milk and, in spore form, can survive pasteurization. Several species within the B. cereus group are closely related and cannot be reliably differentiated by established taxonomical criteria. While B. cereus is traditionally recognized as the principal causative agent of foodborne disease in this group, there is a need to better understand the distribution and expression of different toxin and virulence genes among B. cereus group food isolates to facilitate reliable characterization that allows for assessment of the likelihood of a given isolate to cause a foodborne disease. We performed whole genome sequencing of 22 B. cereus group dairy isolates, which represented considerable genetic diversity not covered by other isolates characterized to date. Maximum likelihood analysis of these genomes along with 47 reference genomes representing eight validly published species revealed nine phylogenetic clades. Three of these clades were represented by a single species (B. toyonensis -clade V, B. weihenstephanensis - clade VI, B. cytotoxicus - VII), one by two dairy-associated isolates (clade II; representing a putative new species), one by two species (B. mycoides, B. pseudomycoides - clade I) and four by three species (B. cereus, B. thuringiensis, B. anthracis - clades III-a, b, c and IV). Homologues of genes encoding a principal diarrheal enterotoxin (hemolysin BL) were distributed across all, except the B. cytotoxicus clade. Using a lateral flow immunoassay, hemolysin BL was detected in 13 out of 18 isolates that carried hblACD genes. Isolates from clade III-c (which included B. cereus and B. thuringiensis) consistently did not carry hblACD and did not produce hemolysin BL. Isolates from clade IV (B. cereus, B. thuringiensis) consistently carried hblACD and produced hemolysin BL. Compared to others, clade IV was significantly (p = 0.0001) more likely to produce this toxin. Isolates from clade VI (B. weihenstephanensis) carried hblACD homologues, but did not produce hemolysin BL, possibly due to amino acid substitutions in different toxin-encoding genes. | Patients with autosomal dominant polycystic kidney disease have significant morbidity due to large kidney size and the resultant compression of adjacent organs. Surgical extirpation is limited to the most severe cases due to the risk of complications. Typically surgical extirpation of autosomal dominant polycystic kidney disease kidneys and renal transplantation are performed in staged fashion. The additive risks of these 2 procedures have been a barrier to a simultaneous surgical approach. The risks include transplant compromise due to cyst rupture, bleeding, adjacent organ injury and anti-HLA antibody sensitization from transfusion in cases of pretransplant nephrectomy. We reviewed the results of and graft survival data on bilateral nephrectomy for autosomal dominant polycystic kidney disease with simultaneous live donor renal transplantation. From August 2003 to November 2007, 20 sets of kidneys were removed in patients with autosomal dominant polycystic kidney disease, followed by simultaneous live donor transplantation. We retrospectively reviewed the outcomes in terms of surgical time, complications, length of stay, transfusion rate and transplant kidney status. A total of 20 sets of kidneys were removed and these patients then underwent immediate live donor renal transplantation. Mean operative time was 190 minutes for the bilateral nephrectomy portion alone with an average estimated blood loss of 723 cc. Complications were rare and well tolerated. Mean hospital stay was 7.2 days for this procedure. Graft survival was 100% and all patients reported relief of symptoms. |
Does adrenomedullin contribute to vascular hyporeactivity in cirrhotic rats with ascites via a release of nitric oxide? | Plasma levels of adrenomedullin, a potent vasodilator peptide, are increased in cirrhotic patients, whereas its role in vascular hyporeactivity in cirrhosis has not been clarified. Adrenomedullin expression was evaluated by radioimmunoassay and reverse-transcription polymerase chain reaction. Vascular reactivity to phenylephrine, alpha-adrenoceptor agonist, was investigated in the aortic rings from control rats and CCl-induced cirrhotic rats with ascites in the presence of the neutralizing antibody against adrenomedullin, human adrenomedullin and/or N-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor. Plasma adrenomedullin levels were significantly higher in cirrhotic rats than in controls (16.3 +/- 2.9 versus 7.4 +/- 1.7 fmol/mL, P < 0.05) and correlated negatively with systemic arterial pressure (r = -0.62, P < 0.05). Gene expression of adrenomedullin in various organs (liver, kidney, lung) and vessels (portal vein, aorta) was enhanced in cirrhotic rats compared with controls. Neutralizing antibody against adrenomedullin ameliorated the blunted contractile response to phenylephrine in cirrhotic aorta (Rmax: 1.5 +/- 0.1 versus 1.0 +/- 0.1 g/mg tissue, P < 0.05), whereas contraction remained unchanged in control aorta (Rmax: 1.9 +/- 0.2 versus 1.9 +/- 0.2 g/mg tissue). Intravenous infusion of human adrenomedullin induced a reduction of mean arterial pressure together with an increase of serum nitrate levels, which was abolished by neutralizing antibody against adrenomedullin. Human adrenomedullin caused a blunted contractile response to phenylephrine in both control and cirrhotic aortas, which was not observed in the presence of N-nitro-L-arginine methyl ester. | The etiology of idiopathic scoliosis remains unknown, but growth is a risk factor for progression. Growth pattern differs in children with and without scoliosis. Cartilage oligomeric matrix protein (COMP) may be associated with scoliosis and growth. We, therefore, studied COMP in children with and without idiopathic scoliosis. We included 105 children, with mean age 14.4 years (range 10-16), under observation or treatment for idiopathic scoliosis, and 103 children from an age-matched population-based cohort. COMP was measured in serum at the time of inclusion. Growth velocity was estimated from repeated height measurements. T tests, analysis of covariance or linear regression were used for statistical comparisons. COMP was mean (SD) 11 (5) units/liter (U/L) in children with scoliosis and 13 (5) U/L in the control cohort (p = 0.005, adjusted for sex and sampling time of the day). When patients and controls were analyzed together, high COMP was correlated with high growth velocity (β = 0.19, p = 0.003). When patients and controls were analyzed separately, COMP was correlated with growth velocity in children with scoliosis (β = 0.27, p = 0.007), but not in children without scoliosis (β = 0.02, p = 0.83) (all analyses adjusted for age, sex and sampling time). Low COMP was significantly correlated with large curve size in children with scoliosis (β = -0.29, p = 0.003), but not after adjustment for age, sex and sampling time (β = -0.16; p = 0.14). |
Does aPOE genotype modulate the effect of serum calcium levels on cognitive function in old age? | The APOE genotype and serum calcium levels have both been associated with cognitive impairment. Animal studies have shown variation in apoE isoforms to play a critical role in intraneuronal calcium homeostasis, but the contribution of this interaction to cognitive function in man is unknown. Here, we studied whether the APOE genotype modulates the association between serum calcium levels and cognition. Within the Leiden 85-plus Study, a prospective population-based study of 599 subjects aged 85 years, we measured serum calcium levels and APOE genotype at baseline. During a 5-year follow-up period, cognitive function was annually assessed using the Mini-Mental State Examination (MMSE) and a standardized neuropsychological test battery. Both at baseline and during follow-up, high serum calcium levels were associated with worse cognitive function in epsilon3epsilon4 carriers and to a lesser extent in epsilon3epsilon3 carriers, but not in epsilon2epsilon3 carriers. The MMSE score during the entire follow-up period differed between those with high and low serum calcium levels, with 5.5 points in epsilon3epsilon4 carriers (p < 0.001), 1.6 points in epsilon3epsilon3 carriers (p = 0.010), and 0.1 point in epsilon2epsilon3 carriers (p = 0.935). Formal testing showed an interaction between APOE genotype and serum calcium levels in relation to global cognitive function (p = 0.003). | Contact of blood with artificial surfaces and air as well as ischemia/reperfusion injury to the heart and lungs mediate systemic and local inflammation during cardiopulmonary bypass (CPB). Activation of complement and coagulation cascades leads to and accompanies endothelial cell damage. Therefore, endothelial-targeted cytoprotection with the complement inhibitor and endothelial protectant dextran sulfate (DXS, MW 5000) may attenuate CBP-associated myocardial and pulmonary injury. Eighteen pigs (DXS, n=10; phosphate buffered saline [PBS], n=8) underwent standard cardiopulmonary bypass. After aortic cross-clamping, cardiac arrest was initiated with modified Buckberg blood cardioplegia (BCP), repeated after 30 and 60 min with BCP containing either DXS (300 mg/10 ml, equivalent to 5mg/kg) or 10 ml of PBS. Following 30 min reperfusion, pigs were weaned from CPB. During 2h of observation, cardiac function was monitored by echocardiography and invasive pressure measurements. Inflammatory and coagulation markers were assessed regularly. Animals were then sacrificed and heart and lungs analyzed. DXS significantly reduced CK-MB levels (43.4+/-14.8 ng/ml PBS, 35.9+/-11.1 ng/ml DXS, p=0.042) and significantly diminished cytokine release: TNFalpha (1507.6+/-269.2 pg/ml PBS, 222.1+/-125.6 pg/ml DXS, p=0.0071), IL1beta (1081.8+/-203.0 pg/ml PBS, 110.7+/-79.4 pg/ml DXS, p=0.0071), IL-6 (173.0+/-91.5 pg/ml PBS, 40.8+/-19.4 pg/ml DXS, p=0.002) and IL-8 (304.6+/-81.3 pg/ml PBS, 25.4+/-14.2 pg/ml DXS, p=0.0071). Tissue endothelin-1 levels were significantly reduced (6.29+/-1.90 pg/100mg PBS, 3.55+/-1.15 pg/100mg DXS p=0.030) as well as thrombin-anti-thrombin formation (20.7+/-1.0 microg/ml PBS, 12.8+/-4.1 microg/ml DXS, p=0.043). Also DXS reduced cardiac and pulmonary complement deposition, neutrophil infiltration, hemorrhage and pulmonary edema (measured as lung water content, 81+/-3% vs 78+/-3%, p=0.047), indicative of attenuated myocardial and pulmonary CPB-injury. Diastolic left ventricular function (measured as dp/dt(min)), pulmonary artery pressure (21+/-3 mmHg PBS, 19+/-3 mmHg DXS, p=0.002) and right ventricular pressure (21+/-1 mmHg PBS, 19+/-3 mmHg DXS p=0.021) were significantly improved with the use of DXS. |
Does human pituitary tumor-transforming gene 1 overexpression reinforce oncogene-induced senescence through CXCR2/p21 signaling in breast cancer cells? | hPTTG1 (human pituitary tumor-transforming gene 1) is an oncogene overexpressed in breast cancer and several other types of cancer. Increased hPTTG1 expression has been shown to be associated with poor patient outcomes in breast cancer. Although hPTTG1 overexpression plays important roles in promoting the proliferation, invasion, and metastasis of cancer cells, it also has been suggested to induce cellular senescence. Deciphering the mechanism by which hPTTG1 overexpression induces these contradictory actions in breast cancer cells is critical to our understanding of the role of hPTTG1 in breast cancer development. MCF-10A and MCF-7 cells were used to identify the mechanism of hPTTG1-induced senescence. The interplay between hPTTG1 overexpression and chemokine C-X-C motif receptor 2 (CXCR2)/p21-dependent senescence in tumor growth and metastasis of MCF-7 cells was investigated by orthotopic transplantation of severe combined immunodeficiency (SCID) mice. Additionally, human invasive ductal carcinoma (IDC) tissue arrays were used to confirm the hPTTG1/CXCR2/p21 axis established in vitro. In this study, we investigated the mechanism of hPTTG1-induced senescence as well as its role in breast cancer progression and metastasis. Herein, we showed that hPTTG1 overexpression reinforced senescence through the CXCR2/p21 signaling. Furthermore, hPTTG1 overexpression activated NF-κB signaling to transactivate the expression of interleukin (IL)-8 and growth-regulated oncogene alpha (GROα) to execute CXCR2 signaling in MCF-7 cells. When CXCR2 expression was knocked down in hPTTG1-overexpressing MCF-7 cells, hPTTG1-induced senescence was abrogated by alleviating CXCR2-induced p21 expression. In a mouse model, CXCR2-mediated senescence limited hPTTG1-induced tumor growth and metastasis. Moreover, CXCR2 knockdown in hPTTG1-overexpressing MCF-7 tumors dramatically accelerated tumor growth and metastasis. Our in vitro and in vivo results demonstrated that hPTTG1 overexpression reinforces senescence through CXCR2 signaling, and the evasion of CXCR2/p21-dependent senescence was critical to hPTTG1 exerting its oncogenic potential. Interestingly, although CXCR2-dependent senescence restrained hPTTG1-induced tumor progression, when MCF-7 cells and hPTTG1-overexpressing MCF-7 cells were co-transplanted into the mammary fat pads of SCID mice, hPTTG1-overexpressing senescent cells created a metastasis-promoting microenvironment that promoted lung metastasis of the MCF-7 cells. Immunohistochemical analysis of human breast tumor samples also confirmed the importance of the hPTTG1/CXCR2 axis in promoting breast cancer metastasis. | Terlipressin decreases portal pressure. However, its effects on variceal pressure have been poorly investigated. This study investigated the variceal, splanchnic and systemic hemodynamic effects of terlipressin. Twenty cirrhotic patients with esophageal varices grade II-III, and portal pressure > or =12 mmHg were studied. Hepatic venous pressure gradient, variceal pressure and systemic hemodynamic parameters were obtained. After baseline measurements, in a double-blind administration, 14 patients received a 2mg/iv injection of terlipressin and six patients received placebo. The same measurements were repeated 60 min later. No demographic or biochemical differences were observed in basal condition between groups. Terlipressin produced significant decreases in intravariceal pressure from 20.9+4.9 to 16.3+/-4.7 mmHg (p<0.01, -21+/- 16%), variceal pressure gradient from 18.9+/-4.8 to 13.5+/-6.0 mmHg (p<0.01, -28+/-27%), estimated variceal wall tension from 78+/-29 to 59+/-31 mmHg x mm (p<0.01, -27+/-22%), and hepatic venous pressure gradient from 19.4+/-4.5 to 16.8+/-5 mmHg (p<0.01, -14+/-12%) at 60 min. The change in variceal pressure after 60 min of terlipressin administration was greater than the change in wedge hepatic venous pressure (-4.7 mmHg vs -0.5 mmHg, respectively, p<0.0001). Terlipressin also caused significant decreases in heart rate and cardiac index and increases in mean arterial pressure and peripheral vascular resistance. |
Is integrin β-8 , but not β-5 or -6 , protein expression increased in livers of children with biliary atresia? | Our previous work demonstrated altered messenger RNA expression of integrin β-5 and -8, using an in silico analysis of publically available data from patients with biliary atresia (BA); however, we were unable to demonstrate statistically significant differences in protein expression because of sample size. In the present study, we repeated the analysis of liver fibrosis and protein expression of the integrins in a larger cohort of patients with BA and compared them with patients undergoing liver biopsy for other diagnoses, with the hypothesis that ≥ 1 of the integrins would be differentially expressed. Liver specimens were obtained at 2 collaborating institutions. Samples from infants with BA (n = 23) were compared with samples from those who underwent liver biopsy for neonatal hepatitis (n = 9). All of the specimens were analyzed by 2 pathologists (C.R. and R.A.), who were blinded to the diagnoses. Standard Ishak scoring was performed to evaluate fibrosis and inflammation, and immunohistochemical (IHC) positivity was graded from 0 to 4. Comparisons between the IHC positivity and Ishak scoring for the BA and control groups were performed using the Student t test with P < 0.01 considered significant because of the multiple comparisons. Interobserver variability was assessed by intraclass correlation (ICC). Pooled analysis from specimens from patients with BA showed significantly more fibrosis than controls based on Ishak scores (3.21 ± 1.82 vs 1.17 ± 1.00, P < 0.005). IHC evaluation showed increased integrin ανβ8 protein expression when compared with controls (2.67 ± 0.81 vs 1.72 ± 0.62, P < 0.005); however, there were no significant differences in integrin ανβ5 (1.93 ± 0.84 vs 1.50 ± 0.90, P = 0.23) or integrin ανβ6 (0.85 ± 1.20 vs 0.94 ± 0.85, P = 0.82) expression. These data were confirmed on individual analysis. Interobserver agreement was fair for integrin ανβ5 (ICC 0.52), good for integrin ανβ6 (ICC 0.72), and excellent for integrin ανβ8 (ICC 0.79) and fibrosis (ICC 0.89). | Adult acquired flatfoot deformity is characterized by midfoot abduction and collapse of the medial longitudinal arch. Lateral column lengthening osteotomies primarily correct the abduction deformity, but the effects of graft shape on deformity correction and forefoot loading are unclear. Therefore, the purpose of this study was to demonstrate the effect of graft shape and taper on deformity correction and forefoot loading mechanics in a cadaveric flatfoot model. Flatfoot deformity was simulated in 18 cadaveric specimens. A lateral column lengthening osteotomy was performed using a triangular, trapezoidal, and rectangular graft for each specimen. During each testing condition, talonavicular joint angles and forefoot plantar pressures were measured. Each graft shape corrected abduction and dorsiflexion deformity at the talonavicular joint. Coronal plane correction was affected by graft shape, and the less tapered trapezoidal and rectangular grafts overloaded the lateral forefoot compared to the intact condition. The more tapered triangular graft did not cause a lateral shift in forefoot pressures. Forefoot plantar pressures were strongly correlated with talonavicular abduction correction (R (2) = .473, P < .001). |
Does increased skeletal muscle capillarization after aerobic exercise training and weight loss improve insulin sensitivity in adults with IGT? | Transcapillary transport of insulin is one determinant of glucose uptake by skeletal muscle; thus, a reduction in capillary density (CD) may worsen insulin sensitivity. Skeletal muscle CD is lower in older adults with impaired glucose tolerance (IGT) compared with those with normal glucose tolerance and may be modifiable through aerobic exercise training and weight loss (AEX+WL). We tested the hypothesis that 6-month AEX+WL would increase CD to improve insulin sensitivity and glucose tolerance in older adults with IGT. Sixteen sedentary, overweight-obese (BMI 27-35 kg/m2), older (63 ± 2 years) men and women with IGT underwent hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, oral glucose tolerance tests, exercise and body composition testing, and vastus lateralis muscle biopsies to determine CD before and after 6-month AEX+WL. Insulin sensitivity (M) and 120-min postprandial glucose (G120) correlated with CD at baseline (r = 0.58 and r = -0.60, respectively, P < 0.05). AEX+WL increased maximal oxygen consumption (VO2max) 18% (P = 0.02) and reduced weight and fat mass 8% (P < 0.02). CD increased 15% (264 ± 11 vs. 304 ± 14 capillaries/mm(2), P = 0.01), M increased 21% (42.4 ± 4.0 vs. 51.4 ± 4.3 µmol/kg FFM/min, P < 0.05), and G120 decreased 16% (9.35 ± 0.5 vs. 7.85 ± 0.5 mmol/L, P = 0.008) after AEX+WL. Regression analyses showed that the AEX+WL-induced increase in CD independently predicted the increase in M (r = 0.74, P < 0.01) as well as the decrease in G120 (r = -0.55, P < 0.05). | Microbiota has been suggested in promoting chronic inflammation in human tissues which, in turn, promotes tumor development. This study tests a hypothesis that high-risk human papillomavirus (HR-HPV) infection may correlate with proinflammatory Stat3 signaling activities and IL-17 levels in breast cancer (BC) patients. This study examined HPV infection by GenChip technology, constitutively active Stat3 (p-Stat3) and IL-17 levels by immunohistochemistry (IHC) using specific antibodies in 379 BC patients, together with 245 paired adjacent breast adenosis (ABA) tissues and 100 unrelated breast adenosis (BA) tissues. We obtained four major findings: (1) HR-HPV16/18 infections existed in 10.5% (34/325) of BC issues, higher than control BA tissues (4%, 4/100, P = 0.047). (2) Using IHC methodology, BC tissues showed more overactive p-Stat3 (2+/3+, 38.5%, 146/379) than ABA tissues (27.3%, 67/245, P < 0.001); similarly, BC also had more tissues overexpressing IL-17 (2+/3+, 61.5%, 233/379) than ABA tissues (51.8%, 127/245, P < 0.001). (3) High levels (2+/3+) of both active p-Stat3 and IL-17 correlated with poor differentiation and lymph nodal metastasis in BC (both with P < 0.05), but not with patients' prognosis. (4) HR-HPV infections correlated with both active p-Stat3 (P = 0.018) and its downstream IL-17 levels (P = 0.021) in BC tissues. |
Do adolescents with skin disease have specific quality of life issues? | Adolescence is a period of life with its own unique characteristics. To provide an in-depth understanding of the impact of skin disease on different aspects of adolescents' health-related quality of life (HRQoL). Semi-structured qualitative interviews were conducted with a sample of dermatology patients between 12 and 19 years of age, attending the dermatology outpatient clinic of a secondary referral centre. Participants were invited to talk in detail about all the ways their lives had been affected by their skin disease. Interviews were transcribed verbatim. Thirty-two adolescents (males = 10, females = 22) with a mean age of 15.7 years (range = 12-18 years) participated in the interviews. Twenty-eight HRQoL themes adversely affected by skin diseases were identified from the interviews which were grouped under 6 main HRQoL domains - psychological impact (91% of patients), physical impact (81%), social impact (81%), impact on lifestyle (63%), need for support (41%) and education and employment (34%). The number of HRQoL themes affected in each individual varied between 1 and 23 (mean = 8.1). | Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a metabolic regulator induced during ischemia that prevents cardiac remodeling in animal models. The activity of PGC-1α can be estimated in patients with ST-segment elevation acute myocardial infarction. The aim of the present study was to evaluate the value of blood PGC-1α levels in predicting the extent of necrosis and ventricular remodeling after infarction. In this prospective study of 31 patients with a first myocardial infarction in an anterior location and successful reperfusion, PGC-1α expression in peripheral blood on admission and at 72 hours was correlated with myocardial injury, ventricular volume, and systolic function at 6 months. Edema and myocardial necrosis were estimated using cardiac magnetic resonance imaging during the first week. At 6 months, infarct size and ventricular remodeling, defined as an increase > 10% of the left ventricular end-diastolic volume, was evaluated by follow-up magnetic resonance imaging. Myocardial salvage was defined as the difference between the edema and necrosis areas. Greater myocardial salvage was seen in patients with detectable PGC-1α levels at admission (mean [standard deviation (SD)], 18.3% [5.3%] vs 4.5% [3.9%]; P = .04). Induction of PGC-1α at 72 hours correlated with greater ventricular remodeling (change in left ventricular end-diastolic volume at 6 months, 29.7% [11.2%] vs 1.2% [5.8%]; P = .04). |
Is total laparoscopic resection for advanced gastric cancer safe and feasible in the Western population? | There is debate surrounding the use of laparoscopic resection for advanced gastric cancer in the Western population. Here we aim to assess the feasibility and short-term outcomes of laparoscopic gastrectomy in consecutive patients in a Western population. From 2012 to 2014, retrospective review of 28 patients with clinically staged advanced gastric cancer (≥T3 or ≥N1) treated with laparoscopic resection. Sixty-one percentage of patients were male. Median age was 67 years (range 35-86). Median BMI was 26.5 (range 19.4-46.1). Resection types were proximal (n = 2), distal (n = 14), and total (n = 12). Twenty-six (93 %) patients underwent D2 lymphadenectomy. Four patients underwent conversion to open. Median blood loss was 125 mL (range 30-300). Median LOS was 7 days (range 4-16). Of postoperative complications, five were minor: arrhythmia (n = 1), surgical site infection (n = 3), in-hospital fall (n = 1); and four were major (intra-abdominal abscess, stricture, PE, and anastomotic bleed). T stages were Tx (n = 1), T2 (n = 3), T3 (n = 18), and T4 (n = 6). N stages were N0 (n = 4), N1 (n = 8), N2 (n = 1), and N3 (n = 15). Median tumor size was 5.8 cm (range 0-9.5). Median lymph node yield was 22 (range 6-53). All margins were negative. Median follow-up was 12.8 months (range 2-27). Six patients have died of progressive disease. | Zidovudine (AZT) is mainly used to prevent mother-to-child HIV-1 transmission (PMTCT). Despite serious concerns on AZT-associated toxicity, there is little information on pharmacokinetics of intracellular AZT metabolites in infants. We conducted a prospective study in 31 HIV-uninfected infants who received AZT for PMTCT. Blood samples were obtained from 14 infants on postdelivery days (PDD) 1, 7, 14, and 28 and from 17 infants at 0 and 4 hours after dosing on PDD-1. Plasma AZT concentrations (pAZT) and intracellular concentrations of AZT-monophosphate (icAZT-MP), diphosphate (icAZT-DP), and triphosphate (icAZT-TP) were determined. Plasma AZT and icAZT-MP concentrations were 2713 nmol/L and 79 fmol/10 cells in PDD-1, but decreased to 1437 nmol/L and 31 fmol/10 cells by PDD-28 (P = 0.02 and P = 0.07 for all PDDs, respectively), whereas those of icAZT-DP and icAZT-TP remained low throughout the sampling period (P = 0.29 and P = 0.61 for all PDDs, respectively) There were no differences in icAZT-TP between infants of the 2 mg/kg 4 times a day dose and 4 mg/kg twice daily dose (P = 0.25), whereas pAZT and icAZT-MP levels were higher in the latter (P < 0.01 and <0.01, respectively). The pAZT and icAZT-MP significantly increased from 0 to 4 hours after dosing (P < 0.001 and <0.001, respectively), whereas icAZT-DP, icAZT-TP levels were not changed (P = 0.41 and 0.33, respectively). |
Does desensitization to strong vestibular stimuli improve tolerance to simulated aircraft motion? | The extent to which tolerance acquired in one motion environment can be transferred to another has not been fully elucidated. This study compares three provocative motion stimuli and whether tolerance acquired from cross-coupled motion and torso rotation can be transferred to simulated aircraft motion. There were 18 healthy subjects (9 men and 9 women), 18-44 yr of age, who were divided into 3 groups. Each group was exposed to the following desensitization procedure in a pseudo-random repeated measures design. In condition D1, subjects were exposed to 4 consecutive days of cross-coupling and on the 5th d they were exposed to simulated aircraft motion. In D2, subjects were exposed to 4 consecutive days of torso rotation and on the 5th day they were exposed to the simulated aircraft motion as in D1. In D3, subjects were exposed to 5 consecutive days of simulated aircraft motion. Based on Graybiel's diagnostic criteria, severity of motion sickness on the 1st and 5th day in D1, D2, and D3 were compared. Cross-coupled motion was the most provocative stimulus followed by torso rotation and simulated aircraft motion. Within each motion stimulus, there was evidence of desensitization (p < 0.001) within 4 d. There were no significant differences in the severity of motion sickness observed on the 5th day regardless of the desensitization stimuli. | In several malignant tissues, the angiopoietins are principal regulators of vascular growth and regression, but in normal prostate and prostate tumors the role of the angiopoietins is unknown. Angiopoietin (ang) 1 and 2 were immunolocalized in TUR-diagnosed prostate tumors with long follow-up and the expression was related to vascular density and clinicopathological variables. Ang 1 was strongly expressed in the basal epithelial cell layer in non-malignant tissue, whereas tumors had lower levels localized to the epithelial cells. A weak ang 2 immunoreaction was observed in non-malignant tissue and in low to intermediate Gleason score (GS) tumors, with a similar expression pattern. However, most high GS tumors showed an intense ang 2 staining. Ang 2 was significantly correlated to GS, density of endoglin stained blood vessels, metastases, and to cancer specific survival. |
Do genetic loci contribute to the progression of vascular and cardiac hypertrophy in salt-sensitive spontaneous hypertension? | The salt-sensitive Dahl rat and the spontaneously hypertensive rat develop comparable spontaneous hypertension on a low-salt diet, whereas only the salt-sensitive Dahl rat strain develops a striking increase in blood pressure and cardiovascular hypertrophy on a high-salt diet. We set out to identify quantitative trait loci (QTLs) contributing to the progression of salt-induced organ damage in hypertension by studying an F2 population derived from both strains. We determined systolic blood pressure (SBP), vascular aortic hypertrophy (AH), cardiac left ventricular (LV) hypertrophy (LVH), and LV fibrosis in 230 male F2-animals on a high-salt diet. A strong correlation between AH and LVH was found (r=0.58, P<0.0001), and genome-wide QTL mapping detected suggestive or significant QTLs in overlapping chromosomal fragments for AH and LVH on chromosomes 1, 3, and 19, respectively. A significant influence of SBP on the extent of LVH and AH was evident at all QTLs, although significant linkage to SBP (together with LVH) was only found on chromosome 9. No QTLs for LV fibrosis were detected. | Because of the side effects of Teflon, the risk of infection from the use of collagen, autologous fat resorption, and the lack of alternative substances, injection laryngoplasty tends to be replaced by laryngeal framework surgery as the method of choice for the treatment of unilateral vocal cord recurrent paralysis (LP). The aim of this study was to evaluate the results, for morbidity and voice quality, of treating this paralysis by injection of a silicone suspension elastomer implant (SSEI). The study was retrospective, and 19 patients were included. Average follow-up was 25 months (range: 8.3-43). Each patient underwent clinical and videostroboscopic assessment, and had an electroglottographic recording. Subjective assessment was obtained by self-evaluation. Results were classified as good, fair, or poor, and were based on 2 objective and 3 subjective criteria. A search was made for biologic signs of autoimmune disorders. Good, fair, and poor results were respectively 79%, 16%, and 5%. Each set of subjective data showed voice improvement (P < 0.05). The fundamental frequency range, percentage of irregularity, and aspiration decreased significantly (P < 0.05). There was only one case of postoperative dyspnea, which resolved after steroid injection. No biologic signs of autoimmune disorders were found. |
Do small-scale randomized controlled trials need more powerful methods of mediational analysis than the Baron-Kenny method? | To devise more-effective physical activity interventions, the mediating mechanisms yielding behavioral change need to be identified. The Baron-Kenny method is most commonly used, but has low statistical power and may not identify mechanisms of behavioral change in small-to-medium size studies. More powerful statistical tests are available. Inactive adults (N=52) were randomized to either a print or a print-plus-telephone intervention. Walking and exercise-related social support were assessed at baseline, after the intervention, and 4 weeks later. The Baron-Kenny and three alternative methods of mediational analysis (Freedman-Schatzkin; MacKinnon et al.; bootstrap method) were used to examine the effects of social support on initial behavior change and maintenance. A significant mediational effect of social support on initial behavior change was indicated by the MacKinnon et al., bootstrap, and, marginally, Freedman-Schatzkin methods, but not by the Baron-Kenny method. No significant mediational effect of social support on maintenance of walking was found. | To investigate the effect of hypotonic stress on human colonic crypts cells in terms of ion channel activity and intracellular Ca2+ concentration. Single crypts were isolated from biopsies taken during colonoscopy. The patch clamp technique was used (in the cell-attached mode) to observe the activity of ion channels during hypotonic stress. Calcium measurements were made using the fluophores Fluo 3 or 4. The intermediate conductance (29 pS), Ca2+ -sensitive, K+ channel (also known as KCNN4) previously described (Sandle et al. 1994) was seen in 54 of 149 patches (36%) when the crypts were bathed in normal extracellular solution (290 mOsm kg(-1)). Forty-one patches could be used for further analysis. Activation of one or several 29 pS channels was seen in 15 of 41 patches (39%) after 30 s to 4 min of exposure to hypotonic solution (160 mOsm kg(-1)). The open probability increased from 0.0043 in control solution to 0.44 at 5 min of hypotonic stress. When the crypts were exposed to hypotonic solution, an increase in intracellular Ca2+ could be seen. The increase in intracellular Ca2+ emanates mainly from intracellular stores. |
Do astragalus membranaceus flavonoids ( AMF ) ameliorate chronic fatigue syndrome induced by food intake restriction plus forced swimming? | Alteration of immune function may be associated with chronic fatigue syndrome (CFS) and this study reveals the immunoregulatory effect of Astragalus membranaceus flavonoids (AMF). CF rats were induced by food intake restriction plus forced swimming for 6 weeks. An atrophied spleen associated with a significantly decreased spleen/body weight ratio and a reduced spleen cells proliferation was found in CF rats when compared with home cage controls. AMF given orally at 20, 50 and 100 mg/kg body weight once a day consecutively for 6 weeks could recover the reduced cell proliferation. A switch to Th1-dominated immune regulation was observed in CF rats as the cultured splenocytes produced more interleukin-2 (IL-2) but less IL-4 when compared with controls. Supplementation with AMF could significantly counteract the aberrant cytokine production and rats received AMF exhibited higher endurance capacity to swim when compared with those without AMF administration. Checking the spectrum signals confirmed that the three major isoflavones contained in AMF were ononin, formononetin, and demethylhomopterocarpin. | Although increased procollagen gene expression and synthesis have been implicated in the progression of abdominal aortic aneurysms (AAA), factors modulating this change have not been identified. Furthermore, it is not known whether the increase in AAA procollagen expression is specific to this disease or also occurs in tissue affected by atherosclerotic occlusive disease (AOD). If paracrine rather than autocrine factors are responsible for increased gene expression in AAA, this effect should be transferable to target smooth muscle cells through conditioned media. Our objectives were to determine 1 alpha (I) procollagen messenger RNA levels in AOD tissue compared with normal and AAA and to determine whether differences noted in tissue procollagen gene expression could be transferred through conditioned media from normal, AOD, and AAA tissues to target smooth muscle cells in primary culture. Normal, AOD, and AAA tissue was used for tissue RNA extraction or was minced and washed with serum-free media (4 degrees C) x 30 minutes and the media applied to human aortic smooth muscle cells (SMC) in primary culture for 36 hours. Total RNA from tissue and SMC exposed to conditioned media was analyzed by Northern and dot blot analysis for 1 alpha (I) procollagen. Relative tissue 1 alpha (I) procollagen levels were not increased in AOD (0.23 +/- 0.05) as compared with normal (0.17 +/- 0.03); both were decreased compared with AAA (0.53 +/- 0.07; p < 0.01). The 1 alpha (I) procollagen levels in SMC exposed to conditioned media from AAA (1.73 +/- 0.15) were increased (p < 0.05) compared with AOD (1.10 +/- 0.12) and normal (1.16 +/- 0.16). |
Is regular Chinese Green Tea Consumption Protective for Diabetic Retinopathy : A Clinic-Based Case-Control Study? | To determine the association between regular Chinese green tea consumption and the risk of diabetic retinopathy (DR) in diabetic patients in China. 100 DR patients and 100 age-sex-matched diabetic controls without retinopathy were recruited in a clinic-based, case-control study. DR was defined from retinal photographs and detailed information on Chinese green tea consumption of the participants was collected through a face-to-face interview. The crude odds ratio [OR] of Chinese green tea consumption for DR was 0.49 (95% confidence interval: 0.26-0.90). When stratified by sex, the protective effect of Chinese green tea consumption on DR was statistically significant in women (P = 0.01) but not in men (P = 0.63). After adjusting for age, sex, and other confounders, DR was significantly associated with Chinese green tea consumption (OR = 0.48; P = 0.04), higher systolic blood pressure (OR = 1.02; P = 0.05), longer duration of diabetes (OR = 1.07; P = 0.02), and the presence of family history of diabetes (OR = 2.35; P = 0.04). | To study the value of objective pressure-volume characteristics for predicting optimal airway pressures and the development of atelectasis and overstretching during a structured lung volume recruitment procedure with subsequent reduction in airway pressures. We used a mathematical model of a lung with adjustable characteristics of acute respiratory distress syndrome (ARDS) characteristics. Simulations were performed in five grades of ARDS in the presence of pure alveolar or combined alveolar-small airway closure as well complete or incomplete lung volume recruitability. For each simulation optimal end-expiratory pressure was determined. A static pressure-volume curve was constructed and objective characteristics of this curve calculated. The predictive value of these characteristics for end-expiratory atelectasis, overstretching, and optimal end-expiratory pressure was assessed. Simultaneous alveolar recruitment and overstretching during inflation were more pronounced than alveolar derecruitment and overstretching during deflation. End-expiratory pressure needed to prevent significant alveolar collapse in severe ARDS resulted in maximal safe tidal volumes that may be insufficient for adequate ventilation using conventional mechanical ventilatory modes. Plateau pressures well below the "upper corner point" (airway pressure where compliance decreases) resulted in significant alveolar overstretching. |
Do multiple syntrophic interactions drive biohythane production from waste sludge in microbial electrolysis cells? | Biohythane is a new and high-value transportation fuel present as a mixture of biomethane and biohydrogen. It has been produced from different organic matters using anaerobic digestion. Bioenergy can be recovered from waste activated sludge through methane production during anaerobic digestion, but energy yield is often insufficient to sludge disposal. Microbial electrolysis cell (MEC) is also a promising approach for bioenergy recovery and waste sludge disposal as higher energy efficiency and biogas production. The systematic understanding of microbial interactions and biohythane production in MEC is still limited. Here, we report biohythane production from waste sludge in biocathode microbial electrolysis cells and reveal syntrophic interactions in microbial communities based on high-throughput sequencing and quantitative PCR targeting 16S rRNA gene. The alkali-pretreated sludge fed MECs (AS-MEC) showed the highest biohythane production rate of 0.148 L·L(-1)-reactor·day(-1), which is 40 and 80 % higher than raw sludge fed MECs (RS-MEC) and anaerobic digestion (open circuit MEC, RS-OCMEC). Current density, metabolite profiles, and hydrogen-methane ratio results all confirm that alkali-pretreatment and microbial electrolysis greatly enhanced sludge hydrolysis and biohythane production. Illumina Miseq sequencing of 16S rRNA gene amplicons indicates that anode biofilm was dominated by exoelectrogenic Geobacter, fermentative bacteria and hydrogen-producing bacteria in the AS-MEC. The cathode biofilm was dominated by fermentative Clostridium. The dominant archaeal populations on the cathodes of AS-MEC and RS-MEC were affiliated with hydrogenotrophic Methanobacterium (98 %, relative abundance) and Methanocorpusculum (77 %), respectively. Multiple pathways of gas production were observed in the same MEC reactor, including fermentative and electrolytic H2 production, as well as hydrogenotrophic methanogenesis and electromethanogenesis. Real-time quantitative PCR analyses showed that higher amount of methanogens were enriched in AS-MEC than that in RS-MEC and RS-OCMEC, suggesting that alkali-pretreated sludge and MEC facilitated hydrogenotrophic methanogen enrichment. | Interferon alfa has been suggested as a possible treatment for choroidal neovascularization. However, retinal complications following interferon therapy have been reported. To evaluate the effects of interferon alfa on leukocyte dynamics in the rat retinal microcirculation. Interferon alfa of different doses was intravenously administered in rats. Leukocyte dynamics were observed with acridine orange digital fluorography, which uses a nuclear fluorescent dye of acridine orange and scanning laser ophthalmoscopy. This technique allows visualization of leukocyte movements in the retinal microcirculation in vivo. After interferon alfa was administered, leukocytes adhered to vascular walls and became trapped in the retinal microcirculation. Leukocyte trapping was dose-dependent. |
Does measurement of a MMP-2 degraded Titin fragment in serum reflect changes in muscle turnover induced by atrophy? | In this study we sought to determine whether a Titin peptide fragment can serve as a clinical biomarker for changes in muscle mass. Mass spectrometry was used to identify Titin fragment in urine. An antibody against this Titin sequence was raised and used to develop a competitive ELISA assay for measurement in serum. Rat tissue extractions in the presence or absence of a series of proteases of interest were used to identify its enzymatic origin. A rat model of dexamethasone (DEX) induced muscle atrophy and a human 56-day bed rest study with and without vibration therapy were used to assess biological and clinical relevance. A technically robust ELISA measuring the Titin fragment was developed against a Titin peptide fragment identified in human urine. The fragment was shown to be produced primarily by MMP-2 cleavage of Titin. In the rat muscle DEX induced atrophy model, Titin-MMP2 fragment was decreased in the beginning of DEX treatment, and then significantly increased later on during DEX administration. In the human bed rest study, the Titin-MMP2 fragment was initially decreased 11.9 (±3.7) % after 1day of bed rest, and then gradually increased ending up at a 16.4 (±4.6) % increase at day 47. | Laparoscopic colectomy (LC) is a widely accepted treatment for various diseases of the colon. Transumbilical single-incisional laparoscopic surgery (SILS) offers excellent cosmetic results compared with standard multi-port laparoscopic surgery. We describe a new hybrid laparoscopic procedure, SILSOID colectomy, which combines conventional LC with SILS. We performed SILSOID colectomy to treat four patients with colorectal disease. Three ports were inserted through the single transumbilical incision, and an additional port was inserted in the flank at a site that depended on the location of the lesion. Division and anastomosis of the colon were performed extracorporeally. SILSOID colectomy was carried out uneventfully in all four cases. The median operation time was 220 minutes (range, 179-320 min), and the median blood loss was negligible (range, negligible-285 mL), respectively. Although one patient experienced a postoperative wound infection, no other postoperative complications occurred. |
Is the Amyloid Precursor Protein rapidly transported from the Golgi apparatus to the lysosome and where it is processed into beta-amyloid? | Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid peptide (Aβ). Aβ is produced by sequential cleavage of the Amyloid Precursor Protein (APP) by β- and γ-secretases. Many studies have demonstrated that the internalization of APP from the cell surface can regulate Aβ production, although the exact organelle in which Aβ is produced remains contentious. A number of recent studies suggest that intracellular trafficking also plays a role in regulating Aβ production, but these pathways are relatively under-studied. The goal of this study was to elucidate the intracellular trafficking of APP, and to examine the site of intracellular APP processing. We have tagged APP on its C-terminal cytoplasmic tail with photoactivatable Green Fluorescent Protein (paGFP). By photoactivating APP-paGFP in the Golgi, using the Golgi marker Galactosyltranferase fused to Cyan Fluorescent Protein (GalT-CFP) as a target, we are able to follow a population of nascent APP molecules from the Golgi to downstream compartments identified with compartment markers tagged with red fluorescent protein (mRFP or mCherry); including rab5 (early endosomes) rab9 (late endosomes) and LAMP1 (lysosomes). Because γ-cleavage of APP releases the cytoplasmic tail of APP including the photoactivated GFP, resulting in loss of fluorescence, we are able to visualize the cleavage of APP in these compartments. Using APP-paGFP, we show that APP is rapidly trafficked from the Golgi apparatus to the lysosome; where it is rapidly cleared. Chloroquine and the highly selective γ-secretase inhibitor, L685, 458, cause the accumulation of APP in lysosomes implying that APP is being cleaved by secretases in the lysosome. The Swedish mutation dramatically increases the rate of lysosomal APP processing, which is also inhibited by chloroquine and L685, 458. By knocking down adaptor protein 3 (AP-3; a heterotetrameric protein complex required for trafficking many proteins to the lysosome) using siRNA, we are able to reduce this lysosomal transport. Blocking lysosomal transport of APP reduces Aβ production by more than a third. | Response to eucapnic voluntary hyperventilation (EVH) has not been compared with methacholine challenge testing (MCCT) in nonathletes being evaluated for dyspnea on exertion. To determine the airway response to EVH and MCCT in a population of nonathletes who exercise regularly but have symptoms with exertion. We reviewed records for all patients with exercise symptoms who underwent both EVH and MCCT. Presenting symptoms, comorbid diseases, and results of bronchoprovocation (BP) testing were recorded. This study was approved by the institutional review board at our hospital. A total of 131 patients (mean age 32.3 ± 11.6, body mass index (BMI) 27.1 ± 4.7 kg/m(2), 59.5% male) had an EVH, MCCT, and clinical evaluation performed. Overall, 37 (28.2%) patients had positive BP testing and met criteria for exercise-induced bronchoconstriction (EIB). There were 32 (24.4%) patients with a positive EVH, compared with only 11 patients with a positive MCCT (8.4%). There were 26 patients (19.8%) who had a positive EVH but a negative MCCT, and correlation between the two tests was poor to moderate (r = 0.11-0.57). A complaint of chest pain and younger age were independent predictors for a positive EVH, whereas a history of tobacco use and a decreased FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) predicted a positive MCCT. A previous diagnosis of asthma was an independent predictor for a response to either test. Discussion. In a population of nonathletes who exercise regularly and have symptoms with exertion, EIB is common. Correlation between EVH and MCCT in this population is poor, and although the tests are somewhat complementary, a large percentage of patients had a negative MCCT but a positive EVH. |
Do mesenchymal stem cells regulate airway contractile tissue remodeling in murine experimental asthma? | Mesenchymal stem cells may offer therapeutic potential for asthma due to their immunomodulatory properties and host tolerability, yet prior evidence suggests that bloodborne progenitor cells may participate in airway remodeling. Here, we tested whether mesenchymal stem cells administered as anti-inflammatory therapy may favor airway remodeling and therefore be detrimental. Adipose tissue-derived mesenchymal stem cells were retrovirally transduced to express green fluorescent protein and intravenously injected into mice with established experimental asthma induced by repeat intranasal house dust mite extract. Controls were house dust mite-instilled animals receiving intravenous vehicle or phosphate-buffered saline-instilled animals receiving mesenchymal stem cells. Data on lung function, airway inflammation, and remodeling were collected at 72 h after injection or after 2 weeks of additional intranasal challenge. The mesenchymal stem cells homed to the lungs and rapidly downregulated airway inflammation in association with raised T-helper-1 lung cytokines, but such effect declined under sustained allergen challenge despite a persistent presence of mesenchymal stem cells. Conversely, airway hyperresponsiveness and contractile tissue underwent a late reduction regardless of continuous pathogenic stimuli and inflammatory rebound. Tracking of green fluorescent protein did not show mesenchymal stem cell integration or differentiation in airway wall tissues. | Freezing of gait (FOG) is a major concern for Parkinson's disease (PD) patients because it is a leading cause of falls and is associated with poor quality of life. The pathophysiology is unknown but it is hypothesized that it relates to cognitive abnormalities; particularly executive and visuospatial dysfunction. However, prior results have been discrepant. Pharmacologic subtypes of FOG include those that are responsive and unresponsive to levodopa. To determine whether executive and visuospatial dysfunction are associated specifically with the levodopa unresponsive subtype of FOG. 135 PD subjects completed a single assessment included FOG questionnaire, UPDRS motor scale, comprehensive cognitive battery and measure of hallucinations. Analyses compared unresponsive (n = 16), responsive (n = 20) and no FOG (n = 99) subtypes. The unresponsive subtype had a significantly older age of onset of PD than the responsive group (p = .03) and had worse motor scores (p = .003) than the no FOG group. Longer disease duration was associated with the responsive group compared to the no FOG group (p = .002). The unresponsive FOG group had significantly poorer visuospatial ability (p = .001) and executive functioning (p = .02) than both the no and responsive FOG subgroups. These latter groups were not significantly different. The responsive FOG group was associated with the presence of hallucinations. |
Do acute inflammatory biomarker profiles predict depression risk following moderate to severe traumatic brain injury? | To examine whether acute inflammation profiles predict posttraumatic depression (PTD) risk 6 and 12 months after traumatic brain injury. University-affiliated level 1 trauma center and community. Adults with moderate to severe traumatic brain injury (acute serum levels: n = 50; acute cerebrospinal fluid (CSF) levels: n = 41). Prospective cohort study. Patient Health Questionnaire; inflammatory biomarkers (interleukin [IL]-1β, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, tumor necrosis factor α, soluble vascular adhesion molecule [sVCAM-1], soluble intracellular adhesion molecule [sICAM-1], soluble Fas [sFAS]). Higher levels of acute CSF cytokine surface markers (sVCAM-1, sICAM-1, and sFAS) in an inflammatory biomarker risk (IBR) score were associated with a 3.920-fold increase in the odds of developing PTD at 6 months (95% confidence interval: 1.163-8.672). Having sICAM-1, sVCAM-1, or sFAS above the 75th percentile had a positive predictive value of 85.7% for PTD risk at 6 months. An IBR score including inflammatory biomarkers IL-7 and IL-8 showed a trending association with 12-month PTD risk (odds ratio = 3.166, 95% confidence interval: 0.936-10.708). | The aim of this review is to discuss the possibilities and disadvantages of the techniques for visual inspection of the uterine cervix with acetic acid (VIA) and with Lugol's iodine (VILI) for early detection of cervical neoplasia. Efficient cervical screening method, approved in practice, is cytology--PAP smear. The lack of organized screening program in Bulgaria is the reason why a lot of cases of cervical cancer are missed or diagnosed late. This raises the question for searching alternative tests to assess the uterine cervix that do not use special techniques and have a reasonable cost. Published results show that VIA and VILI represent an appropriate alternative for cervical screening. The results of VIA and VILI are immediately available and do not require any laboratory processing. |
Does the mitochondrial fission regulator DRP3B regulate cell death in plants? | Recent reports have described dramatic alterations in mitochondrial morphology during metazoan apoptosis. A dynamin-related protein (DRP) associated with mitochondrial outer membrane fission is known to be involved in the regulation of apoptosis. This study analysed the relationship between mitochondrial fission and regulation of plant cell death. Transgenic plants were generated possessing Arabidopsis DRP3B (K56A), the dominant-negative form of Arabidopsis DRP, mitochondrial-targeted green fluorescent protein and mouse Bax. Arabidopsis plants over-expressing DRP3B (K56A) exhibited long tubular mitochondria. In these plants, mitochondria appeared as a string-of-beads during cell death. This indicates that DRP3B (K56A) prevented mitochondrial fission during plant cell death. However, in contrast to results for mammalian cells and yeast, Bax-induced cell death was not inhibited in DRP3B (K56A)-expressing plant cells. Similarly, hydrogen peroxide-, menadione-, darkness- and salicylic acid-induced cell death was not inhibited by DRP3B (K56A) expression. | Selection of patients with the highest probability for therapeutic ERCP remains an important task in a clinical workup of patients with suspected choledocholithiasis (CDL). To determine whether an artificial neural network (ANN) model can improve the accuracy of selecting patients with a high probability of undergoing therapeutic ERCP among those with strong clinical suspicion of CDL and to compare it with our previously reported prediction model. Prospective, observational study. Single, tertiary-care endoscopy center. Between January 2010 and September 2012, we prospectively recruited 291 consecutive patients who underwent ERCP after being referred to our center with firm suspicion for CDL. Predictive scores for CDL based on a multivariate logistic regression model and ANN model. The presence of common bile duct stones confirmed by ERCP. There were 80.4% of patients with positive findings on ERCP. The area under the receiver-operating characteristic curve for our previously established multivariate logistic regression model was 0.787 (95% CI, 0.720-0.854; P < .001), whereas area under the curve for the ANN model was 0.884 (95% CI, 0.831-0.938; P < .001). The ANN model correctly classified 92.3% of patients with positive findings on ERCP and 69.6% patients with negative findings on ERCP. |
Does hippocampal laminar distribution of tau relate to Alzheimer 's disease and age of onset? | Cerebral deposition of phospho-tau in Alzheimer's disease (AD) occurs with varying patterns within hippocampus. Lamina-specific tau changes in AD may reflect trans-synaptic propagation of phospho-tau along neuroanatomical pathways. To study patterns of tau deposition within inner (IML) and outer (OML) molecular layers of dentate gyrus and their clinical and neuropathological correlates. 98 consecutive autopsied brains from the Columbia University Brain Bank were stained for phospho-tau using AT-8. Staining density was rated as High versus Low within IML and OML. Four patterns were observed among the 98 brains: High IML&OML, n = 44; High OML Only (n = 35); High IML Only (n = 5); and Low IML&OML (n = 14). Demographic, clinical, and neuropathological characteristics of these four groups were compared. High IML&OML subjects, versus High OML Only, were more likely to fulfill CERAD criteria for Definite AD (93% versus 66%, p < 0.01) and to have higher median Braak stage (6 versus 5, p < 0.01) and earlier mean age of onset (65.9 versus 73.7 y, p = 0.02), with similar symptom duration. Using logistic regression, the association between High IML&OML and AD remained significant after adjustment for demographics but not symptom duration. In the 70 subjects with Definite AD, High IML&OML was associated with younger age of onset (mean difference 3.7 years, 95%CI -6.7 to -0.7, p < 0.01), after adjustment for demographics and symptom duration. | External pneumatic compression (EPC) is being employed for a widening range of clinical and non-clinical populations. However, EPC devices vary markedly in treatment pressures, duty cycles and application sites, and the acute effects of whole limb, lower pressure EPC on peripheral vascular function have not been determined. The purpose of this study was to determine the acute effects of a single bout of peristaltic pulse EPC on peripheral conduit and resistance artery function. Twenty (n = 20; males = 12 and females = 8) young and apparently healthy subjects (aged 26.1 ± 8.2 years) participated in this study. A sequential EPC device with five inflation zones arranged linearly and inflating distal to proximal along the lower limbs was employed with target inflation pressures of 70 mmHg for 1 h. Flow-mediated dilation (FMD) of the brachial and popliteal arteries was evaluated with ultrasound before and after EPC. Venous occlusion plethysmography was employed to evaluate limb blood flow at rest and during reactive hyperemia (RH) in the forearm (FBF) and calf (CBF) before and after EPC. Peak RH CBF was increased by 9 % after EPC (P < 0.05), whereas peak RH FBF (-10 %) did not change significantly (P > 0.25). Normalized popliteal artery FMD post-EPC (2.24 ± 1.41) was significantly higher than pre-EPC (1.36 ± 0.67, P = 0.015) and post-sham (1.58 ± 0.86, P = 0.032) values. Similarly, normalized brachial artery FMD post-EPC (1.47 ± 0.32) was significantly higher than pre-EPC (1.11 ± 0.41, P = 0.004) and post-sham (0.99 ± 0.27, P = 0.026) values. |
Is bladder neck invasion an independent predictor of prostate-specific antigen recurrence? | The 1997 TNM staging system for prostatic carcinoma and the 2002 revision thereof classified prostatic carcinoma with bladder neck involvement classified as pT4 disease. This classification is based on the belief that tumors that invade surrounding structures are more aggressive and warrant higher staging than tumors that do not invade surrounding structures. Recent reports in the literature suggested that microscopic involvement of the bladder neck does not carry independent prognostic significance. Therefore, resection specimens with bladder neck involvement should not be classified as pT4. The current study prospectively examined the prognostic significance of bladder neck involvement by prostatic carcinoma. The authors analyzed the totally embedded and whole-mounted radical prostatectomy specimens from 364 consecutive patients. The mean patient age was 66 years (range, 41-77 years). The bladder neck, which had been coned from the specimen, was cut in a perpendicular fashion. Involvement of the bladder neck was defined as the presence of neoplastic cells within the smooth muscle bundles of the coned bladder neck. The data were prospectively collected. Bladder neck involvement was analyzed in relation to age, preoperative prostate-specific antigen (PSA) level, prostate weight, Gleason score, final pathologic classification, tumor volume, surgical margin status, the presence of high-grade prostate intraepithelial neoplasm, multifocality, seminal vesicle invasion, extraprostatic extension, perineural invasion, and PSA recurrence. Bladder neck involvement was found in 22 (6%) of 364 patients. Univariate results indicated that bladder neck involvement versus no bladder neck involvement was significantly associated with preoperative PSA (P < 0.001), higher pathologic classification (P < 0.001), larger tumor volume (P < 0.001), extraprostatic extension (P < 0.001), positive surgical margins (P < 0.001), and PSA recurrence (P = 0.003). In a multivariate logistic regression model controlling for pathologic classification, Gleason score, and surgical margin status, bladder neck involvement was an independent predictor of PSA recurrence (P = 0.04). The adjusted odds ratio for bladder neck involvement was 3.3 (95% confidence interval, 1.04-10.03). | Meta-analyses predict that a 25% lowering of plasma homocysteine would reduce the risk of coronary heart disease by 11% to 16% and stroke by 19% to 24%. Individuals homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism have reduced MTHFR enzyme activity resulting from the inappropriate loss of the riboflavin cofactor, but it is unknown whether their typically high homocysteine levels are responsive to improved riboflavin status. From a register of 680 healthy adults 18 to 65 years of age of known MTHFR 677C-->T genotype, we identified 35 with the homozygous (TT) genotype and age-matched individuals with heterozygous (CT, n=26) or wild-type (CC, n=28) genotypes to participate in an intervention in which participants were randomized by genotype group to receive 1.6 mg/d riboflavin or placebo for a 12-week period. Supplementation increased riboflavin status to the same extent in all genotype groups (8% to 12% response in erythrocyte glutathione reductase activation coefficient; P<0.01 in each case). However, homocysteine responded only in the TT group, with levels decreasing by as much as 22% overall (from 16.1+/-1.5 to 12.5+/-0.8 micromol/L; P=0.003; n=32) and markedly so (by 40%) in those with lower riboflavin status at baseline (from 22.0+/-2.9 and 13.2+/-1.0 micromol/L; P=0.010; n=16). No homocysteine response was observed in the CC or CT groups despite being preselected for suboptimal riboflavin status. |
Is reassessment of blood culture-negative endocarditis : its profile similar to that of blood culture-positive endocarditis? | Left-sided infective endocarditis with blood culture-negative has been associated with delayed diagnosis, a greater number of in-hospital complications and need for surgery, and consequently worse prognosis. The aim of our study was to review the current situation of culture-negative infective endocarditis. We analyzed 749 consecutive cases of left-sided infective endocarditis, in 3 tertiary hospitals from June 1996 to 2011 and divided them into 2 groups: group I (n=106), blood culture-negative episodes, and group II (n=643) blood culture-positive episodes. We used Duke criteria for diagnosis until 2002, and its modified version by Li et al. thereafter. Age, sex, and comorbidity were similar in both groups. No differences were found in the proportion of patients who received antibiotic treatment before blood culture extraction between the 2 groups. The interval from symptom onset to diagnosis was similar in the 2 groups. The clinical course of both groups during hospitalization was similar. There were no differences in the development of heart failure, renal failure, or septic shock. The need for surgery (57.5% vs 55.5%; P=.697) and mortality (25.5% vs 30.6%; P=.282) were similar in the 2 groups. | Both the epidermal growth factor receptor (EGFR) and the p53 homologue p63 are overexpressed in a significant number of cases of head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor and p63 both possess oncogenic properties, including the potential to increase cell proliferation and antagonize apoptosis. ZD1839 ("Iressa") is an adenosine triphosphate-competitive inhibitor specific to the EGFR tyrosine kinase currently under evaluation as a chemotherapeutic agent in HNSCC. The objective was to investigate whether p63 expression is decreased after treatment of HNSCC cells with ZD1839. Downregulation of p63 by ZD1839 would identify a potential molecular relationship between EGFR signaling and p63 and could provide insight into the mechanism of action of ZD1839. In vitro examination of p63 expression after ZD1839 treatment. A human HNSCC cell line, SCC-012, was treated with varying doses of ZD1839. p63 protein and messenger RNA levels were analyzed by Western and Northern blot analyses. The effect of ZD1839 on SCC-012 cell cycle was analyzed by flow cytometric analysis. In SCC-012 cells there was a dose-dependent decrease in p63 protein and messenger RNA levels over the course of ZD1839 treatment. Levels of phosphorylated MAPK decreased and p27KIP-1 levels increased after ZD1839 treatment. ZD1839 treatment induced a twofold increase in G1-phase cells and a 3.5-fold decrease in S-phase cells consistent with growth arrest. |
Is cD100 up-regulation induced by interferon-α on B cells related to hepatitis C virus infection? | CD100, also known as Sema4D, is a member of the semaphorin family and has important regulatory functions that promote immune cell activation and responses. The role of CD100 expression on B cells in immune regulation during chronic hepatitis C virus (HCV) infection remains unclear. We longitudinally investigated the altered expression of CD100, its receptor CD72, and other activation markers CD69 and CD86 on B cells in 20 chronic HCV-infected patients before and after treatment with pegylated interferon-alpha (Peg-IFN-α) and ribavirin (RBV) by flow cytometry. The frequency of CD5+ B cells as well as the expression levels of CD100, CD69 and CD86 was significantly increased in chronic HCV patients and returned to normal in patients with sustained virological response after discontinuation of IFN-α/RBV therapy. Upon IFN-α treatment, CD100 expression on B cells and the two subsets was further up-regulated in patients who achieved early virological response, and this was confirmed by in vitro experiments. Moreover, the increased CD100 expression via IFN-α was inversely correlated with the decline of the HCV-RNA titer during early-phase treatment. | When aortic valve replacement is performed in patients with a small aortic annulus, prosthesis-patient mismatch is of concern. Such prosthesis-patient mismatch may affect postoperative clinical status and survival. We investigated the outcomes of isolated aortic valve replacement performed with a 17-mm mechanical prosthesis in patients with aortic stenosis. Twenty-three patients with aortic stenosis (mean age, 74.6 +/- 6.3 years) underwent isolated aortic valve replacement with a 17-mm St. Jude Medical Regent prosthesis. Mean body surface area was 1.41 +/- 0.13 m(2). Preoperative echocardiography yielded a mean aortic valve area of 0.36 +/- 0.10 cm(2)/m(2), a mean left ventricular-aortic pressure gradient of 68.4 +/- 25.3 mm Hg, and a mean left ventricular mass index of 200 +/- 69 g/m(2). There was no operative mortality, and there were no valve-related events. Echocardiography at 14.0 +/- 10.0 months after aortic valve replacement showed a significant increase in the mean effective orifice area index (0.95 +/- 0.24 cm(2)/m(2)), decrease in the mean left ventricular-aortic pressure gradient (17.4 +/- 8.2 mm Hg), and decrease in the mean left ventricular mass index (124 +/- 37 cm(2)/m(2)). Prosthesis-patient mismatch (effective orifice area index < 0.85 cm(2)/m(2)) was present in 8 patients at discharge. In these patients as well as in those without prosthesis-patient mismatch, the left ventricular mass index decreased remarkably during follow-up. |
Does intrathecal injection of human umbilical cord blood stem cells attenuate spinal cord ischaemic compromise in rats? | Spinal cord ischaemia with resulting paraplegia remains a devastating and unpredictable complication after thoraco-abdominal aortic surgery. With the advent of stem cell therapy and its potential to induce nervous tissue regeneration processes, the interest in the use of these cells as a treatment for neurological disorders has increased. Human stem cells, derived from the umbilical cord, are one of the strong candidates used in cell therapy for spinal cord injury because of weak immunogenicity and ready availability. We sought to evaluate the use of human umbilical cord blood stem cells (HUCBSCs) to attenuate the neurological effects of spinal cord ischaemia induced by high thoracic aorta occlusion. Forty Wistar rats were randomized to receive intrathecal injection of 10 µl phosphate buffered saline (PBS) solution containing 1 × 10(4) HUCBSCs, 30 min before (Tpre group: n = 10) and 30 min after (Tpos group: n = 10) descending thoracic aorta occlusion by intraluminal balloon during 12 min. Control groups received only PBS solution (Cpre group: n = 10; and Cpos group: n = 10). During a 28-day observational period, motor function was assessed by a functional grading scale (Basso, Beattie and Bresnahan). Segments of thoracolumbar spinal cord specimens were analysed for histological and immunohistochemical assessment for detection and quantification of human haematopoietic cells (CD45(+)) and apoptosis (transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling). Overall mortality was 12 animals (30%). Therefore, the observational sample was composed of 28 animals. All groups showed similar incidence of paraplegia and mortality. The mean motor function scores showed no difference during time between the animals of each group, excepting for the Tpos group, which improved from 8.14 (±8.6) to 14.28 (±9.8) (P < 0.01). A treatment-by-time interaction was detected among animals that received HUCBSCs 30 min after ischaemia, with BBB scores higher from Days 14 to 28 compared with the first observational day with statistical difference (P = 0.01). Number of viable neurons was higher in the Tpos group (P = 0.14) and the incidence of apoptosis was lower in the same animals (P = 0.048), but showed no difference with its respective control. We confirmed the presence of CD45(+) cells 4 weeks after intrathecal injection in both therapeutic groups but mainly in the Tpos group. | Whether moderate to severe obesity (body mass index (BMI)≥30 to <40kg/m(2)) contributes to breast cancer recurrence and mortality remains uncertain. 1199 women, recruited within 12 months of their diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) invasive breast cancer completed an enrolment questionnaire and an annual follow-up questionnaire every 12 months for another 5 years. The impact of obesity on time to either local or distant recurrence or new breast cancer, or death due to breast cancer was determined by Cox regression. Women in the most extreme categories of BMI (<18.5 and ≥40) were excluded from the analysis. Of the 1155 included women, mean age, 58.4±11.6 years, 53.8% had Stage 1 disease and 88.9% received oral adjuvant endocrine therapy (OAET) within 2 years of diagnosis. The likelihood of an event was significantly associated with moderate to severe obesity (HR=1.71, 95%CI, 1.12-2.62, p=0.014), disease beyond Stage 1 (HR=2.87, 95% CI 1.73-4.75, p<0.001), OAET (HR=0.26, 95%CI 0.14-0.46, p<0.001), mastectomy (HR=3.28, 95%CI 1.98-5.44, p<0.001) and radiotherapy (HR=2.12, 95%CI 1.24-3.63, p=0.006). For Stage 1 disease, only moderate to severe obesity (HR 3.23, 95%CI 1.48-7.03, p=0.003) and OAET use (HR 0.41, 95%CI 0.17-0.98, p=0.046) were significantly associated with an event. |
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