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Is metabolic syndrome in female migraine patients associated with medication overuse headache : a clinic-based study in China? | Migraine and metabolic syndrome have been reported to coexist to a marked degree, especially in women migraine patients, but the relationship between these two conditions is still unclear. This study was performed to evaluate the association of headache characteristics and its comorbidities with metabolic syndrome (MetS) and its components in female migraine patients. A total of 142 women with migraine who fulfilled the criteria of the International Classification of Headache Disorders 2nd edition were recruited in a neurological outpatient department in China. The characteristics of migraine and its comorbidities (analgesic use, psychiatric disorders and disability) were assessed with a detailed questionnaire. Anthropometrics, blood biochemistry and transcranial Doppler sonography were used for metabolic measurements and vascular function. Of 142 participants, 70.4% had one or more metabolic abnormalities and 12.0% had MetS. After adjustment for age, residence, body mass index, waist-to-height ratio, smoking and drinking history, chronic migraine in women patients was associated with MetS [odds ratio (OR) = 5.342, P = 0.032], but when the chronic migraine patients were comorbid with medication overuse headache (MOH), the risk for MetS increased significantly (OR = 12.68, P = 0.007). In addition, MOH was associated with abdominal obesity and hypertension amongst the components of MetS (OR = 4.205 and 3.234, P = 0.043 and 0.039, respectively). | An alteration in the expression of and response to transforming growth factor-beta 1 (TGF-beta 1) appears to be an important event during colorectal carcinogenesis. However, the precise role of TGF-beta 1 in colorectal carcinogenesis is not clear. We have previously described in detail the changes in cell proliferation and differentiation caused by chronic exposure to TGF-beta 1. In this study we sought to better characterize the changes in tumor cell-cell matrix interactions seen during TGF-beta 1-mediated intestinal transformation. Rat intestinal epithelial cells (RIE) and RIE cells transformed by chronic exposure to TGF-beta 1 (RIE-Tr) were treated with TGF-beta 1 and production of components of the plasmin/plasminogen system measured by ELISA and Western blotting. TGF-beta 1 effects on invasion and adhesion were determined in vitro. The role of urokinase on TGF-beta 1-mediated invasion and adhesion were determined using immunoneutralization. The role of COX-2 was determined using a specific COS-2 inhibitor. TGF-beta 1 had no effect on RIE-1 adhesion to collagen types I and IV, fibronectin, and laminin, or invasion through collagen types I and IV. However, 5 ng/mL TGF-beta 1 significantly increased the invasiveness and decreased the adhesiveness of RIE-Tr. This effect of TGF-beta 1 on RIE-Tr was associated with a significant increase in plasmin activity secondary to increased expression of uPA. TGF-beta 1 had no effect on either uPA receptor or PAI-1 in this system. Antibodies to uPA completely blocked the TGF-beta 1-mediated invasiveness of the RIE-Tr cells and returned their adhesiveness to basement membrane proteins to baseline. Addition of the selective Cox-2 inhibitor SC-58125 resulted in a dose-dependent decrease in TGF-beta 1-mediated invasion and uPA expression. |
Does aPOA5 variant Ser19Trp influence a decrease of the total cholesterol in a male 8 year cohort? | To evaluate whether the relationship between dietary composition and plasma lipid levels is genetically determined. We have evaluated the influence of common apolipoprotein A5 (APOA5) variants (T-1131 > C, Ser19 > Trp and Val153 > Met) on plasma lipid concentrations in 117 males for whom dietary composition markedly changed and total cholesterol decreased (from 6.21 +/- 1.31 mmol/L in 1988 to 5.43 +/- 1.06 mmol/L in 1996) over an 8 year follow-up study. APOA5 T-1131 > C and Val153 > Met variants did not influence the change in lipid measures over time. In Ser/Ser19 homozygotes, the plasma cholesterol was relatively stable over the years (6.1 +/- 1.2 mmol/L in 1988 and 5.6 +/- 1.0 mmol/L in 1996, -8%, P < 0.01). In contrast, in the Trp19 carriers, the decrease of the plasma cholesterol was more than 20% (6.5 +/- 1.6 mmol/L in 1988 and 5.1 +/- 1.0 mmol/L in 1996) (P < 0.001). The difference of the changes is significant (8% vs. 20%, P < 0.005). Changes in other analyzed lipid parameters have not been significantly associated with APOA5 variants. | To assess if titration of sevoflurane using the bispectral index (BIS) monitor improves the early and intermediate recovery in geriatric outpatients undergoing brief urologic procedures under general anesthesia without muscle relaxants. After a standardized induction with propofol and fentanyl, a laryngeal mask airway was inserted and sevoflurane was administered in combination with 60% nitrous oxide in oxygen for maintenance of anesthesia in spontaneously breathing outpatients. In the Control group (n = 25), sevoflurane and fentanyl were titrated according to standard clinical practice. In the BIS-directed group (n = 25), sevoflurane was titrated to maintain a BIS value between 50 and 60, and supplemental fentanyl, 25 mug iv boluses were administered to treat tachypnea. The intraoperative anesthetic and analgesic requirements, as well as the times to eye opening, removal of the laryngeal mask airway device, response to simple commands, orientation to person and place, and postanesthesia care unit discharge eligibility (fast-track score of 14) were assessed at specific time intervals. The minimum alveolar concentration-hour of sevoflurane (0.25 +/- 0.15 and 0.31 +/- 0.2) and end-tidal concentrations of sevoflurane at the end of surgery (0.3 +/- 0.3 and 0.4 +/- 0.20%) did not differ significantly between the Control and BIS-directed groups, respectively. Although the percentage of patients requiring supplemental boluses of fentanyl was reduced in the BIS-directed group (16 vs 48%, P <0.05), the intraoperative BIS values and recovery times were similar in the two groups. |
Does nAIF1 inhibit gastric cancer cells migration and invasion via the MAPK pathways? | Nuclear apoptosis-inducing factor 1 (NAIF1) could induce apoptosis in gastric cancer cells. Previously, we have reported that the expression of NAIF1 protein is down-regulated in gastric cancer tissues compared with the adjacent normal tissues. However, the role of NAIF1 in gastric cancer cells is not fully understood. The effects of NAIF1 on cell viability were evaluated by MTT and colony formation assays. The ability of cellular migration and invasion were analyzed by transwell assays. The expression levels of targeted proteins were determined by western blot. The relative RNA expression levels were analyzed using quantitative polymerase chain reaction assays. Xenograft experiment was employed to determine the anti-tumor ability of NAIF1 in vivo. The study demonstrates that transient transfection of NAIF1 in gastric cancer cells BGC823 and MKN45 could inhibit the cell proliferation, migration, and invasion of the two gastric cancer cell lines. The tumor size is smaller in NAIF1-overexpressed MKN45 cell xenograft mice than in unexpressed group. Further in-depth analysis reveals that NAIF1 reduces the expression of MMP2 as well as MMP9, and inhibits the activation of FAK, all of which are key molecules involved in regulating cell migration and invasion. In addition, NAIF1 inhibits the expression of c-Jun N-terminal kinase (JNK) by accelerating its degradation through ubiquitin-proteasome pathway. Meanwhile, NAIF1 reduces the mRNA and protein expression of ERK1/2. | Physical performances and cognition are positively related in cognitively healthy people. The aim of this study was to examine whether physical performances are related to specific cognitive functioning in older people with mild to severe cognitive impairment. This cross-sectional study included 134 people with a mild to severe cognitive impairment (mean age 82 years). Multiple linear regression was performed, after controlling for covariates and the level of global cognition, with the performances on mobility, strength, aerobic fitness, and balance as predictors and working memory and episodic memory as dependent variables. The full models explain 49-57% of the variance in working memory and 40-43% of episodic memory. Strength, aerobic fitness, and balance are significantly associated with working memory, explaining 3-7% of its variance, irrespective of the severity of the cognitive impairment. Physical performance is not related to episodic memory in older people with mild to severe cognitive impairment. |
Does blockade of p38 mitogen-activated protein kinase pathway ameliorate delayed gastric emptying in streptozotocin-induced diabetic rats? | Gastrointestinal dysfunction is one of the major complications of diabetes. The roles of inflammation in diabetes and its associated complications are increasingly recognized. p38 mitogen-activated protein kinase (MAPK) has been shown to be involved in the production of pro-inflammatory mediators. The aims of this study were to investigate the effects of SB203580, a specific p38 MAPK inhibitor, on delayed gastric emptying in diabetic rats and to elucidate its possible mechanism. SB203580 was administered in diabetic rats induced by intraperitoneal injection of streptozotocin. The gastric emptying rate of rats was measured by using phenol red solution, and blood glucose levels and body weights were observed. p38 MAPK activity and iNOS expression were assessed by Western blot analysis. The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were determined by enzyme-linked immunosorbent assay. Gastric emptying was delayed significantly in diabetic rats and improved significantly with SB203580; high glucose significantly activated p38 MAPK and increased the expression of iNOS, TNF-α and IL-1β. The administration of SB203580 led to a significant decrease in the activation of p38 MAPK and the expression of iNOS, TNF-α and IL-1β. | Exclusive right hemisphere language lateralization is rarely observed in the Wada angiography results of epilepsy surgery patients. Cortical stimulation mapping (CSM) is infrequently performed in such patients, as most undergo nondominant left hemisphere resections, which are presumed not to pose any risk to language. Early language reorganization is typically assumed in such individuals, taking left hemisphere epileptiform activity as confirmation of change resulting from a pathologic process. We present data from CSM and Wada studies demonstrating that right hemisphere language occurs in the absence of left hemisphere pathology, suggesting it can exist as a normal, but rare variant, in some individuals. Furthermore, these data confirm the Wada test findings of atypical dominance. Cortical stimulation mapping data were examined for all right hemisphere surgical patients with right hemisphere speech at our center between 1974 and 2006. Of 1,209 interpretable Wada procedures, 89 patients (7.4%) had exclusive right hemisphere speech, and 21 (1.7%) of these patients underwent surgery involving the right hemisphere. Language site location was determined by examining intraoperative photographs, and site distribution was statistically compared to published findings from left hemisphere language dominant patients. Language cortex was identified in the right hemisphere during CSM for all patients with available data. All sites could be classified in superior or middle temporal gyri, inferior parietal lobe, or inferior frontal gyrus, all of which were common zones where language was identified in the left hemisphere dominant comparison sample. |
Do an update on supported employment for people with severe mental illness? | Individual Placement and Support (IPS) is an effective intervention for helping people with severe mental illness obtain competitive employment, yet it has not been widely implemented. This review will examine and summarize the latest research on IPS. As the effectiveness of IPS has been well established in the literature, newer research is exploring nonvocational outcomes, such as quality of life and mental health services utilization and expanding the reach of IPS to include different countries and different population groups. There is also a growing literature exploring the cost-effectiveness of IPS compared with traditional vocational services, which has favored IPS. By far, the area of research that has expanded the most is aimed at enhancing IPS outcomes, at both the intervention level and the client level. Researchers are exploring the variance in IPS outcomes as a means of increasing competitive employment rates with IPS. | The molecular mechanisms of the vasoconstrictor responses evoked by hydrogen peroxide (H2O2) have not been clearly elucidated in skeletal muscle arterioles. Changes in diameter of isolated, cannulated and pressurized gracilis muscle arterioles (GAs) of Wistar-Kyoto rats were determined under various test conditions. H2O2 (10-100 µM) evoked concentration-dependent constrictions in the GAs, which were inhibited by endothelium removal, or by antagonists of phospholipase A (PLA; 100 µM 7,7-dimethyl-(5Z,8Z)-eicosadienoic acid), protein kinase C (PKC; 10 µM chelerythrine), phospholipase C (PLC; 10 µM U-73122), or Src family tyrosine kinase (Src kinase; 1 µM Src Inhibitor-1). Antagonists of thromboxane A2 (TXA2; 1 µM SQ-29548) or the non-specific cyclooxygenase (COX) inhibitor indomethacin (10 µM) converted constrictions to dilations. The COX-1 inhibitor (SC-560, 1 µM) demonstrated a greater reduction in constriction and conversion to dilation than that of COX-2 (celecoxib, 3 µM). H2O2 did not elicit significant changes in arteriolar Ca(2+) levels measured with Fura-2. |
Is regulation of glucose transporter expression in cardiac myocytes : p38 MAPK a strong inducer of GLUT4? | In vivo differentiation of cardiac myocytes is associated with downregulation of the glucose transporter isoform GLUT1 and upregulation of the isoform GLUT4. Adult rat cardiomyocytes in primary culture undergo spontaneous dedifferentiation, followed by spreading and partial redifferentiation, which can be influenced by growth factors. We used this model to study the signaling mechanisms modifying the expression of GLUT4 in cardiac myocytes. Adult rat cardiomyocytes in primary culture exhibited spontaneous upregulation of GLUT1 and downregulation of GLUT4, suggesting resumption of a fetal program of GLUT gene expression. Treatment with IGF-1 and, to a minor extent, FGF-2 resulted in restored expression of GLUT4 protein and mRNA. Activation of p38 MAPK mediated the increased expression of GLUT4 in response to IGF-1. Transient transfection experiments in neonatal cardiac myocytes confirmed that p38 MAPK could activate the glut4 promoter. Electrophoretic mobility shift assay in adult rat cardiomyocytes and transient transfection experiments in neonatal cardiac myocytes indicated that MEF2 was the main transcription factor transducing the effect of p38 MAPK activation on the glut4 promoter. | To evaluate a possible correlation between the International Prostate Symptom Score (IPSS) and the Sexual Health Inventory for Men (SHIM) in an unselected population of men presenting to a clinic, as lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are highly prevalent in ageing men, and recent largely community-based epidemiological studies reported a close association between ED and LUTS. This was a cross-sectional study in an unselected consecutive sample of 118 men aged >40 years attending a urology clinic; the reason for consulting was not ascertained. While in the waiting room the men were asked to participate in the study and on agreement were given the IPSS and the SHIM to complete. The mean (range) age of the participants was 61.7 (45-82) years. Overall, 19 (16%) and 47 (40%) of the men reported having moderate or severe LUTS, respectively. Erectile problems were also common, the prevalence of moderate ED was 11% and complete ED 29%. The Pearson correlation coefficient between the IPSS and the SHIM was - 0.32 (P < 0.001). |
Does hepatocyte growth factor enhance the inflammation-alleviating effect of umbilical cord-derived mesenchymal stromal cells in a bronchiolitis obliterans model? | Specific and effective therapy for prevention or reversal of bronchiolitis obliterans (BO) is lacking. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF) gene modified mesenchymal stromal cells (MSCs) on BO. A mouse model of experimental BO was established by subcutaneously transplanting the tracheas from C57BL/6 mice into Balb/C recipients, which were then administered saline, Ad-HGF-modified human umbilical cord-MSCs (MSCs-HGF) or Ad-Null-modified MSCs (MSCs-Null). The therapeutic effects of MSCs-Null and MSCs-HGF were evaluated by using fluorescence-activated cell sorting (FACS) for lymphocyte immunophenotype of spleen, enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (rt-PCR) for cytokine expression, and histopathological analysis for the transplanted trachea. The histopathologic recovery of allograft tracheas was improved significantly after MSCs-Null and MSCs-HGF treatment and the beneficial effects were particularly observed in MSCs-HGF-treated mice. Furthermore, the allo-transplantation-induced immunophenotype disorders of the spleen, including regulatory T (Treg), T helper (Th)1, Th2 and Th17, were attenuated in both cell-treated groups. MSCs-HGF treatment reduced expression and secretion of inflammation cytokines interferon-gamma (IFN-γ), and increased expression of anti-inflammatory cytokine interleukin (IL)-4 and IL-10. It also decreased the expression level of the profibrosis factor transforming growth factor (TGF)-β. | The aim of the study was to assess the effect of hyperglycaemia on regional concentrations of glucose and other substrates within the brain in non-diabetic individuals and in patients with type 1 diabetes. The brain metabolites of 17 men with type 1 diabetes and 12 age-matched non-diabetic men (22-43 years old) were studied after an overnight fast (plasma glucose 9.2 +/- 3.0 vs 4.8 +/- 0.5 mmol/l, respectively). N-Acetylaspartate (NAA), creatine, choline, myo-inositol (mI) and glucose in the frontal cortex, frontal white matter and thalamus were quantified with proton magnetic resonance spectroscopy. In the non-diabetic participants, the glucose level was 47% higher (p < 0.01) in the frontal cortex than in the frontal white matter. In contrast, this regional variation was not observed in the diabetic participants, in whom the glucose level in the frontal white matter was 64% higher (p < 0.001) and in the frontal cortex 25% higher (p = 0.033) than that of the non-diabetic participants. In the diabetic participants, the glucose level in each of the three regions studied correlated with fasting plasma glucose (r = 0.88-0.67, p < 0.01). In addition, in the diabetic participants, mI was 20% higher (p < 0.001) and NAA 6% lower (p = 0.037) in the frontal white matter, and mI was 8% higher (p = 0.042) in the frontal cortex, than in the non-diabetic participants. |
Does the spectrum of structural abnormalities on CT scan from patients with CF with severe advanced lung disease? | In cystic fibrosis (CF), lung disease is the predominant cause of morbidity and mortality. Little is known about the spectrum of structural abnormalities on CT scans from patients with CF with severe advanced lung disease (SALD). No specific CT scoring system for SALD is available. To design a quantitative CT scoring system for SALD, to determine the spectrum of structural abnormalities in patients with SALD and to correlate the SALD system with an existing scoring system for mild CF lung disease and pulmonary function tests (PFTs). 57 patients with CF contributed one CT made during screening for lung transplantation. For the SALD system, lung tissue was divided into four components: infection/inflammation (including bronchiectasis, airway wall thickening, mucus and consolidations), air trapping/hypoperfusion, bulla/cysts and normal/hyperperfused tissue. The volume proportion of the components was estimated on a 0-100% scale; mean volumes for the whole lung were computed. Scores were correlated with Brody-II scores and PFTs. The SALD system identified a wide spectrum of structural abnormalities ranging from predominantly infection/inflammation to predominantly air trapping/hypoperfusion. SALD infection/inflammation scores correlated with Brody-II scores (r(s) = 0.36-0.64) and SALD normal/hyperperfusion scores correlated with forced expiratory volume in 1 s (FEV(1); r(s) = 0.37). Reproducibility for both systems was good. | Rapa Nui (Easter Island), located in the easternmost corner of the Polynesian Triangle, is one of the most isolated locations on the planet inhabited by humans. Archaeological and genetic evidence suggests that the island was first colonized by Polynesians around AD 1200, during their eastward expansion. Although it remains contentious whether Polynesians reached South America, suggestive evidence has been brought forward supporting the possibility of Native American contact prior to the European "discovery" of the island in AD 1722. We generated genome-wide data for 27 Rapanui. We found a mostly Polynesian ancestry among Rapanui and detected genome-wide patterns consistent with Native American and European admixture. By considering the distribution of local ancestry tracts of eight unrelated Rapanui, we found statistical support for Native American admixture dating to AD 1280-1495 and European admixture dating to AD 1850-1895. |
Is angiopoietin-2 a potential mediator of endothelial barrier dysfunction following cardiopulmonary bypass? | Endothelial activation leading to vascular barrier dysfunction and organ failure is a well-recognized complication of cardiovascular surgery with cardiopulmonary bypass (CPB). The endothelial-specific angiopoietin-Tie2 ligand-receptor system has been identified as a non-redundant regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to the Tie2 receptor antagonizes Tie2 signaling and renders the endothelial barrier responsive to pro-inflammatory cytokines. We aimed to study the time course and potential triggering factors of Ang-2 release after CPB, as well as the association of Ang-2 changes with surrogates of increased vascular permeability, organ dysfunction, and outcome. Serum levels of Ang-2 from 25 adult patients (140 screened) were measured before and at 0, 12, and 24h following CPB procedure by in-house immuno-luminometric assay (ILMA), and compared with indices of organ dysfunction, duration of mechanical ventilation (MV), length of stay (LOS) in the intensive care unit (ICU), and hospital mortality. The effect of Ang-2 was studied in vitro by incubating high Ang-2 patient serum with endothelial cells (EC). Ang-2 levels steadily increased from 2.6 ± 2.4 ng/mL at 0 h up to 7.3 ± 4.6 ng/mL at 24h following CPB (P<0.001). The release of Ang-2 correlated with the duration of CPB, aortic cross-clamp time, and post-CPB lactate levels. Changes in Ang-2 during follow-up correlated with partial pressure of oxygen in arterial blood (PaO(2))/fraction of inspired oxygen (FiO(2)) ratio, alveolar-arterial oxygen tension difference (AaDO(2)), hemodynamics, fluid balance, and disease severity measures. Ang-2 levels at 12h predicted the duration of MV, ICU-LOS, and hospital mortality. High Ang-2 patient sera disrupted EC architecture in vitro, an effect reversed by treatment with the competitive Tie2 ligand angiopoietin-1 (Ang-1). | To observe the changes of sex hormones and sexual function in male patients with Graves' disease (GD) after Radioiodine-131 (I-131) therapy. Thirty-four male GD patients, aged 21 -40 (32.3 +/- 6.7) years, were treated with I-131 at the dose of 111 - 407 (237.8 +/- 51.8) MBq. The levels of serum sex hormones were measured, and the patients'scores on erectile function (IIEF-5) were obtained before and 3 and 6 months after the treatment. Another 20 healthy men aged 25 - 37 (31 +/- 3.1) years were enlisted as controls. The baseline levels of estrogen (E2), testosterone (T) and luteinizing hormone (LH) were (132.5 +/- 40.4) pmol/L, (21.6 +/- 4.6) nmol/L and (10.1 +/- 4.4) IU/L in the GD patients, significantly higher than (80.4 +/- 31.2) pmol/L, (14.5 +/- 4.2) nmol/L and (6.2 +/- 1.9) IU/L in the healthy controls (P < 0.05). The E2, T and LH levels showed a significant decrease in the GD patients after 3 months of treatment ([110.2 +/- 20.6] pmol/L, [17.7 +/- 5.5] nmol/L and (9.4 +/- 3.9) IU/L, P < 0.05), but exhibited no statistically significant differences from the healthy controls at 6 months ([82.6 +/- 30.1] pmol/L, [13.8 +/- 3.4 ] nmol/L and [6.6 +/- 1.5] IU/L, P > 0.05). The IIEF-5 score of the GD patients was 5 - 25 (15.5 +/- 3.5) before I-131 treatment, significantly lower than that of the controls (19 - 25, 24 +/- 0.5) (P < 0.05), and it was 8 - 25 (19.5 +/- 1.0) at 3 months and 10 - 25 (23.5 +/- 1.5) at 6 months, significantly higher in the latter than in the former (P < 0.05), and with no significant difference between the 6-month treated patients and the healthy controls (P > 0.05). |
Do dietary flavanols modulate the transcription of genes associated with cardiovascular pathology without changes in their DNA methylation state? | In a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation. Gene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 864 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNF-α-stimulated endothelial cells. Nuclear factor kappa B (NF-κB) reporter gene assays confirmed that MOF decrease the activity of NF-κB. Strong inter-individual variability in the leukocytes' DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found. | The purpose of this study was to determine the yield and clinical impact of sacrum and coccyx radiographs in the emergency department (ED). Consecutive sacrum and coccyx radiographs obtained in the EDs of four hospitals over a 6-year period were categorized as positive for acute fracture or dislocation, negative, or other. Five follow-up metrics were analyzed: follow-up advanced imaging in the same ED visit, follow-up advanced imaging within 30 days, new analgesic prescriptions, clinic follow-up, and surgical intervention within 60 days. Sacrum and coccyx radiographs from 687 patients (mean age, 48.1 years; 61.6% women and 38.4% men) obtained at level-1 (n = 335) and level-2 (n = 352) trauma centers showed a positivity rate of 8.4% ± 2.1% (n = 58/687). None of the 58 positive cases had surgical intervention. At the level-1 trauma centers, there was no significant association between sacrum and coccyx radiograph positivity and analgesic prescription or clinical follow-up (p = 0.12; odds ratio [OR], 2.3; 95% CI, 0.81-6.20). At the level-2 trauma centers, 97.1% (n = 34/35) of patients with positive sacrum and coccyx radiographs received analgesic prescriptions or clinical referrals, whereas negative cases were at 82.9% (OR, 7.0; 95% CI, 0.94-52.50). Of all cases, 5.7% (n = 39) and 4.3% (n = 29) had advanced imaging in the same ED visit and within 30 days, respectively. Sacrum and coccyx radiography results had no significant correlation with advanced imaging in the same ED visit (level-1, p = 0.351; level-2, p = 0.179). There was no significant difference in 30-day advanced imaging at the level-1 trauma centers (p = 0.8), but there was at the level-2 trauma centers (p = 0.0493). |
Does zuo Jin Wan reverse P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway? | Zuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro. We tested the dose-response relationship of ZJW on reversing drug-resistance by CCK-8 assay and flow cytometry analysis in vitro. The protein expression of P-gp, MRP-2, LRP, and ABCB1 mRNA expression level were evaluated by Western blot and quantitative RT-PCR. The activities of PI3K/Akt/NF-κB pathway were also examined with or without ZJW, including Akt, IκB, p65 and their phosphorylation expression. We found that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs and increased oxaliplatin (L-OHP)-induced cell apoptosis in a time- and dose-dependent manner. Moreover, both ZJW and a PI3K specific inhibitor (LY294002) suppressed phosphorylation of Akt (Ser473) and NF-κB, which is necessary in the activation of the PI3K/Akt/NF-κB pathway. The effect of ZJW in reversing drug-resistance and suppressing phosphorylation of Akt (Ser473) and NF-κB were weakened after treatment with a PI3K/Akt activator in HCT116/L-OHP cells. | Spinal anesthesia can be challenging in patients undergoing total joint arthroplasty because of poorly palpable surface landmarks and age-related changes in the lumbar spine. We hypothesized that pre-procedural ultrasound imaging would be effective in identifying the lumbar intervertebral spaces and would provide an accurate measure of the depth to the intrathecal space. Fifty patients undergoing elective total joint arthroplasty were recruited in this prospective descriptive study. Using a curved-array 2-5 MHz transducer, the lumbar spine was imaged in two views, i.e., longitudinal parasagittal (LP) and transverse midline (TM). The intervertebral levels were identified by counting upwards from the sacrum. The locations of the interlaminar spaces were identified by visualizing the ligamentum flavum-dura mater complex and the posterior aspect of the vertebral body. The needle insertion point for a midline approach was determined from the ultrasound examination and was marked on the skin of the patient's back. The mean patient age was 67 +/- 10 yr, and 46% of the patients had a body mass index >30 kg . m(-2). Surface landmarks were difficult or impossible to palpate in 38% of the patients. The scan quality on the LP and TM views was adequate or better in 100 and 98% of the patients, respectively. Dural puncture was achieved with one needle insertion attempt and within two needle insertion attempts in 84% and 98% of the patients, respectively. The ultrasound-measured depth to the intrathecal space correlated well with the actual needle insertion depth (concordance correlation coefficient = 0.82, accuracy 0.95, precision 0.86), with a tendency to overestimate the depth by just 2.1 +/- 5.4 mm. |
Does body mass index predict operative time in elective colorectal procedures? | Obesity currently affects more than a third of the United States population and is associated with increased surgical complications. Compared to all other subspecialties, colorectal surgery is the most affected by the increasing trend in obese surgical patients. Operative time has been found to have the greatest impact on hospital costs and physician workload. This study was conducted to determine whether obesity has a direct impact on operative time in elective colorectal procedures using a high-powered, nationally representative patient sample. A retrospective analysis was conducted on 45,362 patients who underwent open and laparoscopic ileocolic resections, partial colectomies, and low pelvic anastomoses using American College of Surgeons National Surgical Quality Improvement Program data from 2005-2009. Operative time was the main outcome variable, whereas body mass index (BMI) was the main independent variable. BMI was divided into three classes as follows: normal (<25), overweight and/or obese (25-35), and morbidly obese (>35). A univariate linear model was used to analyze the relationship while controlling for confounding factors such as demographics and preoperative conditions. Statistical significance was established at P ≤ 0.05. Morbidly obese patients were found to have longer operative times than did normal patients across each individual colorectal procedure (P < 0.001), ranging from a mean difference of 17.8 min for open ileocolic resections to 56.6 min for laparoscopic low pelvic anastomoses with colostomies. | Kawasaki disease (KD) is a multisystem vasculitis affecting children and is characterized by immune activation in the acute stage of disease. Systemic inflammation eventually subsides, although coronary arteritis persists, resulting in aneurysm formation. KD is the leading cause of acquired heart disease among children in North America. Accepted treatment guidelines include high-dose intravenous immunoglobulin (IVIG) and aspirin in the acute phase. Although this therapy is effective, the cellular and molecular mechanisms involved are not clear. The aim of this study was to examine the effect of IVIG and salicylate at each stage of disease development. Using a murine model of KD, we established and validated several in vitro techniques to reflect 3 key steps involved in disease pathogenesis, as follows: thymidine incorporation to evaluate T cell activation, enzyme-linked immunosorbent assay to measure tumor necrosis factor alpha (TNFalpha) production, and real-time polymerase chain reaction to examine TNFalpha-mediated expression of matrix metalloproteinase 9 (MMP-9). At therapeutic concentrations, IVIG, but not salicylate, effectively reduced the immune response leading to TNFalpha expression. Unexpectedly, pharmacologic doses of salicylate were not able to inhibit TNFalpha production and in fact enhanced its production. Neither drug directly regulated MMP-9 expression but did so only indirectly via modulating TNFalpha. TNFalpha activity was a prerequisite for local expression of MMP-9 at the coronary artery. |
Does fasudil alleviate traumatic optic neuropathy by inhibiting Rho signaling pathway? | The present study is to investigate the pathological changes in rabbits with traumatic optic neuropathy (TON), as well as the effect of fasudil on the lesions. A total of 144 New Zealand rabbits were successfully established as TON models. Twelve hours after surgery, the rabbits in control, dexamethasone, and fasudil groups were administrated with saline, dexamethasone, and fasudil via ear veins, respectively. Then, retinas of the rabbits were obtained at 72 h and on days 7, 14 and 21 after surgery. The pathological changes in retina and optic nerves were observed by hematoxylin and eosin staining and transmission electron microscopy. The expression levels of Rho-associated genes were measured using quantitative real-time polymerase chain reaction. In control group, the axons were swelling, and mitochondria showed vacuolation after optic nerve crush. Mitochondria were swelled slightly in dexamethasone group. By contrast, nerves in fasudil group were repaired. Retinal ganglion cells in control group were reduced significantly due to optic nerve crush. The loss of retinal ganglion cells was alleviated in fasudil group. Quantitative real-time polymerase chain reaction showed that the expression of Rho-associated genes were down-regulated. | Increasing age is associated with declining physical activity and a gain in fat mass. The objective was to observe the consequence of the age-associated reduction in physical activity for the maintenance of energy balance as reflected in the fat store of the body. Young adults were observed over an average time interval of more than 10 years. Physical activity was measured over two-week periods with doubly labeled water and doubly labeled water validated triaxial accelerometers, and body fat gain was measured with isotope dilution. There was a significant association between the change in physical activity and the change in body fat, where a high initial activity level was predictive for a higher fat gain. |
Does [ Tongxinluo improve vascular endothelial function in patients with type 2 diabetes ]? | To investigate the effects of Tongxinluo on vascular endothelial function in patients with type 2 diabetes. A total of 80 patients with type 2 diabetes were recruited and divided into two groups: Tongxinluo therapy group (n = 40) and conventional therapy group (n = 40). Plasma levels of NO, ET, 6-keto-PGF1alpha and TXB2 and diastolic functions of humeral arteries (measured by high-resolution ultrasound) were measured at baseline and 4 weeks later. The flow-mediated dilation was significantly increased from (8.19 +/- 0.71)% to (12.47 +/- 0.98)% (P < 0.05) in Tongxinluo therapy group after 4 weeks therapy compare to baseline level. Their plasma NO was significantly increased [(47.65 +/- 4.38) pg/ml to (52.91 +/- 4.83) pg/ml, P < 0.001] and plasma ET significantly reduced [(31.23 +/- 2.46) pg/ml to (24.34 +/- 2.46) pg/ml, P < 0.001] post 4 week Tongxinluo therapy. Parameters remained unchanged in the placebo group (P > 0.05) at baseline and 4 weeks later. Non-flow-mediated dilation was unaffected by Tongxinluo therapy. | The genetic polymorphism with an isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis. PNPLA3 polymorphism is shown to be associated with alcoholic liver disease (ALD). We performed a systematic review and meta-analysis to examine association of this genetic polymorphism with ALD spectrum and its severity. Medline, Embase, and Cochrane Library were searched for studies on association of PNPLA3 polymorphism and ALD spectrum: alcoholic fatty liver (AFL), alcoholic liver injury (ALI), alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Pooled data are reported as odds ratio (OR) with 95% confidence interval. Heterogeneity was assessed using the I(2) statistics and publication bias using Egger's test and Begg and Mazumdar's test. Individual participant data obtained from five studies were used for subgroup analyses. Among 10 studies included in this pooled analysis, compared with controls, OR for rs738409 CG and GG among ALI patients was 1.45 (1.24-1.69) and 2.22 (1.50-3.28), respectively, compared with CC. Respective OR among AC patients was 2.09 (1.79-2.44) and 3.37 (2.49-4.58) and among AC patients with HCC was 2.87 (1.61-5.10) and 12.41 (6.99-22.03). Data for AFL were inconsistent. Among ALD patients, OR of CG and GG genotypes was 2.62 (1.73-3.97) and 8.45 (2.52-28.37), respectively, for AC compared with fatty liver (FL) patients. Similar OR for AC compared with ALI was 1.98 (1.24-3.17) and 3.86 (1.18-12.60). The OR for CG and GG genotypes among AC patients for HCC occurrence was 1.43 (0.76-2.72) and 2.81 (1.57-5.01), respectively. Individual participant data analysis showed age to predispose to AC among ALI patients. |
Do neuroectodermal antigens persist in benign and malignant salivary gland tumor cultures? | To determine whether a heterogeneous collection of salivary gland tumors shared common antigenic characteristics and growth patterns in tissue culture. Cell cultures were derived from benign and malignant salivary gland neoplasms, cultured conservatively, and serially analyzed for epithelial, myoepithelial, and neuroectodermal antigens. Nineteen samples reflecting the spectrum of salivary tumor pathologic characteristics were established in tissue culture. Most were derived from benign pleomorphic adenomas, and several were from carcinomas, including carcinoma ex pleomorphic adenoma, and mucoepidermoid and adenoid cystic carcinoma. All cultures were epithelial as determined by morphologic and antigenic examination, using antibodies for cytokeratin. The phenotype of cells derived from benign tumors, especially the pleomorphic adenomas, resembled those in the original neoplasm. Those from carcinomas were similar, with less differentiated characteristics. Manipulation of growth conditions altered the phenotypes shown in culture. Some cultures contained cells expressing vascular smooth-muscle actin and glial fibrillary acidic protein or nestin. | Hemeproteins such as free myoglobin can undergo autoxidation and catalyse lipid peroxidation, increasing oxidative stress. Creatine phosphokinase (CPK) elevation is a marker for free myoglobin after myocyte damage. Since oxidative injury is a key mechanism of injury-related organ dysfunction, we hypothesised that serum CPK levels correlate with mortality and need for inotropic medication and duration of inotropic support, i.e. shock, among critically injured patients. We conducted a retrospective review of 17,847 patients admitted to a single Trauma Intensive Care Unit over 9 years. 2583 patients with serum CPK levels were included in the analysis. Patient data were collected continuously into an electronic ICU repository. Univariate analysis was accomplished using Spearman correlation and the Mann–Whitney U test. Propensity score adjustment models accounting for potential confounders were used to assess the independent effect of CPK level on mortality, need for inotropic support, and duration of inotropic support. Median CPK was significantly higher in patients who died (916 [IQR 332, 2472] vs. 711 [253, 1971], p = 0.004) and in those who required inotropic medications (950 [353, 2525] vs. 469 [188, 1220], p < 0.001). After adjusting for propensity score and potential confounders the odds of mortality increased by 1.10 (95% CI 1.02–1.19, p = 0.020) and the odds of inotropic medication use increased by 1.30 (95% CI 1.22–1.38, p < 0.001) per natural log unit increase in CPK. There was a significant association between CPK level and duration of inotropic support (Spearman's rho .237, p < 0.001) that remained significant in a propensity score-adjusted model. |
Does regular in situ simulation training of paediatric medical emergency team improve hospital response to deteriorating patients? | The introduction of a paediatric medical emergency team (pMET) was accompanied by integration of weekly in situ simulation team training into routine clinical practice. On a rotational basis, all key ward staff participated in team training, which focused on recognition of the deteriorating child, teamwork and early consultant review of patients with evolving critical illness. This study aimed to evaluate the impact of regular team training on the hospital response to deteriorating in-patients and subsequent patient outcome. Prospective cohort study of all deteriorating in-patients of a tertiary paediatric hospital requiring admission to paediatric intensive care (PICU) the year before, and after, the introduction of pMET and concurrent team training. Deteriorating patients were: recognised more promptly (before/after pMET: median time 4/1.5 h, p<0.001), more often reviewed by consultants (45%/76%, p=0.004), more often transferred to high dependency care (18%/37%, p=0.021) and more rapidly escalated to intensive care (median time 10.5/5 h, p=0.024). These improved responses by ward staff extended beyond direct involvement of pMET. There was a trend towards fewer PICU admissions, reduced level of sickness at the time of PICU admission, reduced length of PICU stay and reduced PICU mortality. Introduction of pMET coincided with significantly reduced hospital mortality (p<0.001). | Distant prostate cancers are commonly hormone refractory and exhibit increased growth no longer inhibited by androgen deprivation therapy. Understanding all molecular mechanisms contributing to uncontrolled growth is important to obtain effective treatment strategies for hormone refractory prostate cancers (HRPC). The aryl hydrocarbon receptor (AhR) affects a number of biological processes including cell growth and differentiation. Several studies have revealed that exogenous AhR ligands inhibit cellular proliferation but recent evidence suggests AhR may possess intrinsic functions that promote cellular proliferation in the absence of exogenous ligands. qRT-PCR and western blot analysis was used to determine AhR mRNA and protein expression in hormone sensitive LNCaP cells as well as hormone refractory DU145, PC3 and PC3M prostate cancer cell lines. LNCaP cells express AhR mRNA and protein at a much lower level than the hormone refractory cell models. Cellular fractionation and immunocytochemistry revealed nuclear localization of AhR in the established hormone refractory cell lines while LNCaP cells are devoid of nuclear AhR protein. qRT-PCR analysis used to assess basal CYP1B1 levels and a xenobiotic responsive element binding assay confirmed ligand independent transcriptional activity of AhR in DU145, PC3 and PC3M cells. Basal CYP1B1 levels were decreased by treatment with specific AhR inhibitor, CH223191. An in vitro growth assay revealed that CH223191 inhibited growth of DU145, PC3 and PC3M cells in an androgen depleted environment. Immunohistochemical staining of prostate cancer tissues revealed increased nuclear localization of AhR in grade 2 and grade 3 cancers compared to the well differentiated grade 1 cancers. |
Does the CRF1 receptor antagonist R121919 attenuate the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal? | Corticotropin-releasing factor (CRF) is the primary physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to globally coordinate the mammalian stress response. Hyperactivity of central nervous system CRF neurotransmission, acting primarily via the CRF(1) receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, there is evidence of enhanced CRF transcription, release, and neuronal activity after the administration of and withdrawal from several drugs of abuse, including cannabis, cocaine, ethanol, and morphine. Treatment with CRF antagonists has been demonstrated to reduce the severity of certain drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed after abrupt drug discontinuation. To extend these findings, we investigated whether pretreatment with the selective CRF(1) receptor antagonist R121919 decreases the behavioral and neuroendocrine activation observed after the precipitation of benzodiazepine (BZ) withdrawal in BZ-dependent rats. Pretreatment with R121919 attenuated the subsequent HPA axis activation, behavioral measures of anxiety, and expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA, which occurs after flumazenil-precipitation of withdrawal from the BZ, lorazepam. | Stringent control of proteolytic activity represents a major therapeutic approach for wound-bed preparation. We tested whether a protease-modulating polyacrylate- (PA-) containing hydrogel resulted in a more efficient wound-bed preparation of venous leg ulcers when compared to an amorphous hydrogel without known protease-modulating properties. Patients were randomized to the polyacrylate-based hydrogel (n = 34) or to an amorphous hydrogel (n = 41). Wound beds were evaluated by three blinded experts using photographs taken on days 0, 7 and 14. After 14 days of treatment there was an absolute decrease in fibrin and necrotic tissue of 37.6 ± 29.9 percentage points in the PA-based hydrogel group and by 16.8 ± 23.0 percentage points in the amorphous hydrogel group. The absolute increase in the proportion of ulcer area covered by granulation tissue was 36.0 ± 27.4 percentage points in the PA-based hydrogel group and 14.5 ± 22.0 percentage points in the control group. The differences between the groups were significant (decrease in fibrin and necrotic tissue P = 0.004 and increase in granulation tissue P = 0.0005, respectively). |
Do deep resting glabellar rhytides respond to BTX-A and Hylan B? | BTX-A is the standard treatment for glabellar furrows. However, some individuals have resting glabellar rhytides that are sufficiently deep that they respond poorly to BTX-A alone. To compare the efficacy of BTX-A combined with intradermal Hylan B with the efficacy of BTX-A alone in individuals with moderate to severe glabellar rhytides. This was a retrospective study of 16 subjects with moderate to severe glabellar rhytides. Their response to Hylan B plus BTX-A was compared clinically and photographically to their response to BTX-A alone. All subjects had moderate or severe glabellar rhytides at rest before treatment. After BTX-A alone, none (0%) had achieved no or mild rhytides. After BTX-A and Hylan B injection, only 1 of 16 (6%) had moderate glabellar rhytides, with the remainder (94%) being mild. | Natriuretic peptides and echocardiographic parameters both predict cardiovascular events in patients with CKD. However, it is unknown whether simultaneous assessment of amino-terminal probrain natriuretic peptide (NT-proBNP) and echocardiographic parameters provides complementary or redundant predictive information; in the latter case, one of these two might be dispensable. We aimed to analyze the implications of using NT-proBNP alone, echocardiographic parameters alone, or a combination of both for prediction of adverse cardiovascular outcome. Within the longitudinal Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation Study, we prospectively studied 496 patients with CKD stages G2-G4, in whom we measured NT-proBNP. Left ventricular mass index, left atrial volume index, diastolic left ventricular function, and systolic left ventricular function were assessed echocardiographically. During 4.5±2.0 years of follow-up, the occurrence of (1) decompensated heart failure or all-cause mortality and (2) atherosclerotic events or all-cause mortality was recorded. We assessed the association of NT-proBNP and echocardiographic parameters with outcome (using Cox models) and evaluated the increased discriminative value associated with the addition of echocardiographic parameters and NT-proBNP (using integrated discrimination improvement and net reclassification improvement). During follow-up, 104 patients suffered decompensated heart failure or all-cause mortality, and 127 patents had atherosclerotic events or all-cause mortality. In univariable analyses, NT-proBNP and echocardiographic parameters predicted cardiovascular events. NT-proBNP remained an independent predictor for both end points in multivariate analysis, whereas left ventricular mass index, left atrial volume index, and diastolic left ventricular function did not. The addition of NT-proBNP on top of clinical and various echocardiographic variables was associated with improvements in reclassification for decompensated heart failure or all-cause mortality (integrated discrimination improvement =6.5%-8.3%; net reclassification improvement =23.1%-27.0%; all P≤0.03). Adding echocardiographic variables on top of clinical variables and NT-proBNP was not associated with significant net reclassification improvement (all P>0.05). |
Does cD40L induce multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways? | CD40L was found to reduce doxorubicin-induced apoptosis in non Hodgkin's lymphoma cell lines through caspase-3 dependent mechanism. Whether this represents a general mechanism for other tumor types is unknown. The resistance induced by CD40L against apoptosis induced by a panel of cytotoxic chemotherapeutic drugs in non Hodgkin's lymphoma and breast carcinoma cell lines was investigated. Doxorubicin, cisplatyl, etoposide, vinblastin and paclitaxel increased apoptosis in a dose-dependent manner in breast carcinoma as well as in non Hodgkin's lymphoma cell lines. Co-culture with irradiated L cells expressing CD40L significantly reduced the percentage of apoptotic cells in breast carcinoma and non Hodgkin's lymphoma cell lines treated with these drugs. In breast carcinoma cell lines, these 5 drugs induced an inconsistent increase of caspase-3/7 activity, while in non Hodgkin's lymphoma cell lines all 5 drugs increased caspase-3/7 activity up to 28-fold above baseline. Co-culture with CD40L L cells reduced (-39% to -89%) the activation of caspase-3/7 induced by these agents in all 5 non Hodgkin's lymphoma cell lines, but in none of the 2 breast carcinoma cell lines. Co culture with CD40L L cells also blocked the apoptosis induced by exogenous ceramides in breast carcinoma and non Hodgkin's lymphoma cell lines through a caspase-3-like, 8-like and 9-like dependent pathways. | Children with type 1 diabetes have been identified as a risk group for non-alcoholic fatty liver disease (NAFLD). The aim was to compare total hepatic fat fraction and fat distribution across Couinaud segments in children with type 1 diabetes and controls and the relation of hepatic fat to plasma and anthropometric parameters. Hepatic fat fraction and fat distribution across Couinaud segments were measured with magnetic resonance imaging (MRI) in 22 children with type 1 diabetes and 32 controls. Blood tests and anthropometric data were collected. No children had NAFLD. Children with type 1 diabetes had a slightly lower hepatic fat fraction (median 1.3%) than controls (median 1.8%), and their fat had a different segmental distribution. The fat fraction of segment V was the most representative of the liver as a whole. An incidental finding was that diabetes patients treated with multiple daily injections of insulin (MDI) had a fat distribution more similar to controls than patients with continuous subcutaneous insulin infusion (CSII). |
Do peak oxygen uptake during the incremental shuttle walk test in a predominantly female population with Chagas heart disease? | Chagas heart disease (CHD) patients may have a reduced functional capacity (FC). Field tests, as the Incremental Shuttle Walk Test (ISWT), can estimate peak oxygen uptake (VO2 peak). However, the relationship between the ISWT and the Cardiopulmonary Exercise Testing (CPET), the gold standard in the assessment of FC, is not well established in CHD patients. This study aimed to evaluate the FC of CHD patients by ISWT with direct measurement of VO2 peak and to compare these findings with data obtained from CPET. A secondary goal was to derive a regression equation to calculate the VO2 peak by ISWT. Cross-sectional and correlative study. Research laboratory setting. Thirty-two CHD patients (58.8±9.0 years, 81.3% women) participated in this study. Eligible patients underwent clinical evaluation, echocardiography, CPET by ramp protocol and ISWT according to current guidelines. The distance walked in ISWT showed a positive correlation with VO2 peak from CPET and ISWT (r=0.456, P=0.009 and r=0.869, P<0.001, respectively). In the agreement analysis, the values of the differences between VO2 peak from CPET and ISWT showed absence of bias (mean bias ±95% CI and mean -1.29±5.09 mL.kg.min). Based in real values of VO2 obtained from ISWT, one equation including sex, functional class and distance walked was provided to predict the VO2 values in this test. | Ag-dependent activation of IgE-bearing mast cells is a critical first step in immediate hypersensitivity and other allergic responses. Recent studies have revealed Ag-independent effects of monoclonal mouse IgE molecules on mast cell survival and activation. However, no studies have been performed on the effects of polyclonal IgE molecules. Here, we tested whether polyclonal mouse and human IgE molecules affect survival and cytokine production in mast cells. Mast cells were cultured in the presence of polyclonal mouse and human IgE molecules, and cell survival and cytokine production were analyzed. Polyclonal mouse IgE molecules in sera from mice with atopic dermatitis-like allergic skin inflammation, enhanced survival and cytokine production in mast cell cultures. Similar to the effects of monoclonal IgE, the polyclonal IgE effects were mediated by the high-affinity IgE receptor, FcepsilonRI. Human polyclonal IgE molecules present in sera from atopic dermatitis patients were also capable of activating mast cells, and inducing IL-8 production in human cord blood-derived mast cells. |
Is fibre an essential ingredient of enteral diets to limit bacterial translocation in rats? | To assess the effect of six different enteral diets on the gut barrier. Laboratory study. University hospital, Germany. 70 Specific pathogen free female Crl:CDR BR rats. For 7 days, 6 groups of rats were fed orally with standard chow (n = 15); total parenteral nutrition solution (oral TPN, n = 15); elemental diet (ED, n = 10); nutrient-defined diet (NDD, n = 10); or the NDD supplemented with uracil (NDD+uracil, n = 10), or fibre (NDD+fibre, n = 10). Bacterial translocation to mesenteric lymph nodes, numbers of Gram negative enterobacteria and total aerobic bacteria in the caecum, and intestinal concentrations of secretory IgA. The incidence of bacterial translocation was significantly increased in the groups given oral TPN, ED, NDD, and NDD+uracil compared with the group given chow. Only NDD+fibre resulted in a similar degree of translocation to that in the chow group. All groups in which there was increased translocation had a highly significant overgrowth of aerobic bacteria in the caecum, mainly by Gram negative enteric organisms. The secretory IgA concentration was reduced in the group that had been given oral TPN, and that in the ED and NDD+uracil groups was similar to that in the chow group. NDD and NDD+fibre were associated with higher intestinal concentrations of secretory IgA than chow. | Enhanced activity of histone deacetylases (HDAC) is associated with more aggressive tumour behaviour and tumour progression in various solid tumours. The over-expression of these proteins and their known functions in malignant neoplasms has led to the development of HDAC inhibitors (HDI) as new anti-neoplastic drugs. However, little is known about HDAC expression in renal cell cancer. We investigated the expression of HDAC 1, 2 and 3 in 106 renal cell carcinomas and corresponding normal renal tissue by immunohistochemistry on tissue micro arrays and correlated expression data with clinico-pathological parameters including patient survival. Almost 60% of renal cell carcinomas expressed the HDAC isoforms 1 and 2. In contrast, HDAC 3 was only detected in 13% of all renal tumours, with particular low expression rates in the clear cell subtype. HDAC 3 was significantly higher expressed in pT1/2 tumours in comparison to pT3/4 tumours. Expression of class I HDAC isoforms correlated with each other and with the proliferative activity of the tumours. We found no prognostic value of the expression of any of the HDAC isoforms in this tumour entity. |
Does daily mini quiz as means for improving student performance in anatomy course? | To evaluate daily-written 10-question quizzes in a medical anatomy course as a way to integrate assessment into the course and to evaluate their effect on the course success. Students answering correctly 8/10 or more questions were awarded 0.5 points per quiz. There were 34 quizzes with a maximum point score 17. Measurable outcomes of academic progress in anatomy course (pass rates on 4 examination terms, total pass rate, and average marks) were calculated, and 2007/08 academic year was compared with the previous academic year in which daily written quizzes were not a part of the course. The relationship between cumulative points on daily quizzes and 3 components of the final examination (written, practical, and oral) for 2007/08 academic year was assessed by non-parametric correlation testing. Individual scores on quizzes ranged from 1.5 to 13.5 points. There was a positive correlation between scores on quizzes and grades on 3 components of the final examination: written (Spearman rho=0.784, P<0.001, n=79), practical (Spearman rho=0.342, P<0.002, n=79), and oral (Spearman rho=0.683, P<0.001, n=79) part. Compared with students in the previous academic year, students attending the course with daily quizzes significantly improved their academic achievement, expressed as the pass rate at the first examination term (39% vs 62%, respectively, chi(2) test, P=0.006, ) and the average course grade (2.71+/-1.08 vs 3.38+/-1.26, respectively; t test, P<0.001). | This study aims to describe trinitrotoluene (TNT)-induced endoplasmic reticulum stress (ERS) and apoptosis in HePG2 cells. HePG2 cells were cultured in vitro with 0, 6, 12, or 24 μg/ml TNT solution for 12, 24, and 48 h. Western blotting was performed to detect intracellular ERS-related proteins, including glucose-regulated protein (GRP) 78, GRP94, Caspase 4, p-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP). Real-time PCR was used to measure mRNA expression from the respective genes. The expressions of ERS-related proteins GRP78 and GRP94 as well as mRNA and protein expression of ERS signaling apoptotic CHOP in the TNT treatment group were significantly increased. In addition, the mRNA and protein expression levels of ERS-induced apoptotic protein Caspase-4 were significantly increased. Flow cytometry revealed that after TNT treatment, the apoptosis rate also significantly increased. |
Is hypocitraturia one of the major risk factors for nephrocalcinosis in very low birth weight ( VLBW ) infants? | Very low birth weight (VLBW) infants are at risk to develop nephrocalcinosis (NC). NC may result from spontaneous or therapy-induced imbalance between promoters and inhibitors of crystallization in the urine. However, data on "normal" urinary excretions of these parameters in VLBW infants are sparse. Therefore, we prospectively examined the urinary excretion of calcium, oxalate, uric acid, and citrate in VLBW infants during the first 8 weeks of life. Urine samples were collected once weekly in 124 VLBW infants. NC appeared in 16 infants, whose data were separately analyzed. The remaining 108 infants were divided into subgroups: A, <1000 g (N = 53); and B, 1000 to 1500 g (N = 55). Random urine samples were analyzed and the results were expressed as molar creatinine ratios. Calcium/citrate and oxalate/citrate expressed the risk for calcium oxalate crystallization. In group A, citrate excretion was lower at weeks 2 to 5 and 7; calcium/citrate was higher in weeks 2, 4, and 7; oxalate/citrate was higher in weeks 3, 4, 7, and 8; and calcium/creatinine ratio was higher in week 4 (P < 0.05). Citrate/creatinine ratios were low in nine infants with NC. Oxalate/creatinine and calcium/creatinine were elevated in five and calcium/citrate was increased in nine infants with NC. | there is ample literature showing pain and depression are related. However, different dimensions of pain have been used in former studies. the objective of the study was to compare the strength of the association of different pain dimensions with depression in older adults. assessments including evaluation of pain (severity, frequency, chronicity, quality, pain medication, painful body sites) and depression (measured by the Hospital Anxiety and Depression Scale) were performed in an observational study in community dwelling older adults (sample mean age 76, n = 1130) in Germany. The associations of different dimension of pain with depression were assessed using descriptive and multivariate methods. the number of painful body areas was most significantly associated with self-reported late life depression (OR 1.20, CI 1.11-1.31). Pain severity and frequency (OR 1.12, CI 1.01-1.23 and OR 1.18, CI 1.01-1.37) were also associated with depression; quality and duration were not. Except for severity (OR 1.12, CI 1.02-1.24) associations of pain dimensions were strongly reduced when controlling for relevant confounders and gender was an effect modifier. |
Does the 5-HT1A receptor agonist MKC-242 reverse isolation rearing-induced deficits of prepulse inhibition in mice? | Prepulse inhibition (PPI) of startle provides an operational measure of sensorimotor gating in which a weak stimulus presented prior to a startling stimulus reduces the startle response. PPI deficits observed in schizophrenia patients can be modeled in rats by individual housing from weaning until adulthood. The deficits in PPI produced by isolation rearing can be reversed by antipsychotics. We previously found that (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a highly potent 5-HT(1A) receptor agonist, reduced aggressive behavior selectively in isolation-reared mice. This study examines whether isolation rearing of mice produces PPI deficits and whether PPI deficits are attenuated by 5-HT(1A) receptor activation. Male ddY mice, 4 weeks old, were housed for more than 6 weeks singly or in groups of five or six. The PPI of the acoustic startle response was measured using SR-LAB systems. The PPI was less in isolation-reared mice than in group-reared mice. Oral administration of MKC-242 at 0.1-0.3 mg/kg reversed PPI deficits in isolation-reared mice, although it did not affect PPI in group-reared mice. MKC-242 did not affect MK-801-induced and apomorphine-induced PPI deficits in group-reared mice. The reversal by MKC-242 of isolation-induced PPI deficits was antagonized by the 5-HT(1A) receptor antagonist WAY100635 at low doses. | Even though anaemia has been shown to be a risk factor for adverse cardiovascular disease, there is scarce evidence of its relationship with angiographically proven coronary artery disease (CAD). The aim of this study was to evaluate the relationship between haemoglobin (Hb) levels and the extent of CAD. We measured Hb, mean corpuscular volume and red blood cell count in 2363 consecutive patients undergoing coronary angiography. Patients were divided into four groups according to quartile values of Hb (≤12.2 g/dl, group 1; 12.3-13.5 g/dl, group 2; 13.6-14.6 g/dl, group 3; >14.6 g/dl, group 4). Patients with lower Hb were older (P<0.001), there was a predominance of women (P<0.0001), and patients had diabetes (P<0.0001), hypertension (P=0.024), renal failure (P<0.0001), previous coronary artery bypass graft (P<0.0001), previous cerebrovascular accident (P=0.039) and platelet count (P<0.0001). In terms of angiographic features, low Hb levels were associated with a larger prevalence of calcified lesions (P<0.001), but a lower prevalence of thrombus-containing lesions (P<0.001). Hb was not associated with the prevalence of CAD [odds ratio (OR) (95% confidence interval (CI))=0.96 (0.89-1.04), P=0.35], whereas an association was observed with the severity of CAD [OR (95% CI)=0.92 (0.85-0.99), P=0.032] that was not confirmed after correction for baseline confounding factors [OR (95% CI)=0.98 (0.89-1.09), P=0.76]. Similar findings were observed for mean corpuscular volume and red blood cell count. |
Is vasopressin administered with epinephrine associated with a return of a pulse in out-of-hospital cardiac arrest? | Recent data suggest that using vasopressin in combination with epinephrine (adrenaline) may improve treatment of out-of-hospital cardiac arrest. This study examined local experience with the combination of epinephrine and vasopressin administration. Data were obtained from an urban, municipal emergency medical service that does not include vasopressin in its formulary. A physician is dispatched to the scene of all cardiac arrest patients treated by this system. Vasopressin could be administered in addition to epinephrine to subjects with out-of-hospital cardiac arrest by the on-scene physician. Demographic information, drug administration and return of pulses were abstracted from patient care records for a 1-year interval. Multivariate logistic regression was used to assess the relationship between vasopressin use and outcomes. During the study period, data were available for 298 subjects receiving epinephrine-only (n=231, 78%), a combination of 40 IU vasopressin and epinephrine (n=37, 12%) or no vasopressor drugs (n=30, 10%). Among patients receiving vasopressor drugs, pulse was restored for 74 subjects (28%), and 56 subjects (21%) had a pulse on arrival at the hospital. Return of pulses was associated with witnessed collapse, bystander CPR, and an initial ECG rhythm of ventricular fibrillation or tachycardia. Subjects receiving vasopressin and epinephrine were more likely to have a return of pulses during the resuscitation (LR: 2.73; 95% CI: 1.24, 6.03) and at hospital arrival (3.85; 1.71, 8.65) than subjects treated with epinephrine alone. | Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by severe joint erosion and systemic osteoporosis. Chronic T cell activation is a hallmark of RA, and agents that target the CD28 receptor on T cells, which is required for T cell activation, are being increasingly used as therapies for RA and other inflammatory diseases. Lymphocytes play complex roles in the regulation of the skeleton, and although activated T cells and B cells secrete cytokines that promote skeletal decline, under physiologic conditions lymphocytes also have key protective roles in the stabilization of skeletal mass. Consequently, disruption of T cell costimulation may have unforeseen consequences for physiologic bone turnover. This study was undertaken to investigate the impact of pharmacologic CD28 T cell costimulation blockade on physiologic bone turnover and structure. C57BL6 mice were treated with CTLA-4Ig, a pharmacologic CD28 antagonist or with irrelevant control antibody (Ig), and serum biochemical markers of bone turnover were quantified by enzyme-linked immunosorbent assay. Bone mineral density and indices of bone structure were further measured by dual x-ray absorptiometry and micro-computed tomography, respectively, and static and dynamic indices of bone formation were quantified using bone histomorphometry. Pharmacologic disruption of CD28 T cell costimulation in mice significantly increased bone mass and enhanced indices of bone structure, a consequence of enhanced bone formation, concurrent with enhanced secretion of the bone anabolic factor Wnt-10b by T cells. |
Does venezuelan equine encephalitis virus infection cause modulation of inflammatory and immune response genes in mouse brain? | Neurovirulent Venezuelan equine encephalitis virus (VEEV) causes lethal encephalitis in equines and is transmitted to humans by mosquitoes. VEEV is highly infectious when transmitted by aerosol and has been developed as a bio-warfare agent, making it an important pathogen to study from a military and civilian standpoint. Molecular mechanisms of VEE pathogenesis are poorly understood. To study these, the gene expression profile of VEEV infected mouse brains was investigated. Changes in gene expression were correlated with histological changes in the brain. In addition, a molecular framework of changes in gene expression associated with progression of the disease was studied. Our results demonstrate that genes related to important immune pathways such as antigen presentation, inflammation, apoptosis and response to virus (Cxcl10, CxCl11, Ccl5, Ifr7, Ifi27 Oas1b, Fcerg1,Mif, Clusterin and MHC class II) were upregulated as a result of virus infection. The number of over-expressed genes (>1.5-fold level) increased as the disease progressed (from 197, 296, 400, to 1086 at 24, 48, 72 and 96 hours post infection, respectively). | Re-stenosis after percutaneous coronary angioplasty (PTCA) is related to clinical and angiographic features. To describe the clinical and angiographic characteristic of our patients with coronary cardiopathy subjected to PTCA and the predictor factors for re-stenosis. We gathered the clinical and angiographic characteristics of all patients who underwent a successful PTCA of a native coronary artery. All patients had a clinical assessment one year after the procedure. Patients were classified in Group 1, if they did not have angina or coronary events after the angioplasty or Group 2, if they had angina or a coronary event after the procedure. Only Group 2 patients were subjected to a coronary angiogram. We collected 383 PTCA procedures. Follow up information was obtained in 92.2%. Three hundred forty two patients (89.3%) were assessed one year the procedure. Nine patients (2.3%) died of a cardiovascular cause. Ninety patients (26.3%) were classified in Group 2. In 65 patients, angiographic re-stenosis was demonstrated (19%). Re-stenosis occurred in 36 and 13% of patients with an without Diabetes Mellitus, respectively (p <0.01). The other clinical predictor variables were a history of myocardial infarction (p =0.007), obesity (p =0.041) and hypercholesterolemia (p =0.050). None of the angiographic characteristics predicted restenosis. Stents were protective factors against restenosis (15.6% in stented lesions vs 25.4% in nonstented; p =0.01). |
Is clarithromycin an effective immunomodulator in experimental pyelonephritis caused by pan-resistant Klebsiella pneumoniae? | To apply clarithromycin as an immunomodulatory treatment in experimental infection caused by pan-resistant Klebsiella pneumoniae. Acute pyelonephritis was induced in 80 rabbits after inoculation of the test isolate in the renal pelvis. Rabbits were divided into eight groups, with 10 animals in each group. In groups A-D, therapy was administered simultaneously with bacterial challenge as follows: A, controls; B, intravenous clarithromycin; C, amikacin; and D, both agents. In groups E-H, therapy was administered 24 h after bacterial challenge as follows: E, controls; F, intravenous clarithromycin; G, amikacin; and H, both agents. Blood was sampled for estimation of tumour necrosis factor-alpha (TNF-alpha) and malondialdehyde (MDA); monocytes were isolated for determination of intracellular activity of caspase-3 and ex vivo TNF-alpha secretion. Four days after bacterial challenge, animals were sacrificed for quantitative cultures and biopsies of organs. Serum TNF-alpha at 48 h was lower in groups B, C and D compared with group A. Activity of caspase-3 of monocytes was lower at 48 h in group D compared with group A. Bacterial loads of liver and spleen were decreased in group D compared with those of group A. The numbers of inflammatory cells of spleen of group B were lower compared with those of group A; those of kidney and mesenteric lymph nodes of group D were lower than those of group A. Serum MDA of group H was lower than that of group E and serum TNF-alpha of group F was lower compared with that of group E. TNF-alpha of monocyte supernatants and activity of caspase-3 of monocytes of group F were lower than those of group E. Bacterial tissue loads did not differ among groups E, F, G and H. The numbers of inflammatory cells of liver of groups F and H were lower compared with those of group E; those of kidney of groups F, G and H were lower compared with those of group E. | A profound reduction of spontaneous as well as stimulated GH secretion has been consistently observed in obesity. Dopamine promotes GH release through activation of dopamine D2 receptors (D2Rs). Dopamine D2R availability in the brain is reduced in obese humans in proportion to body adiposity. We hypothesized that impaired dopamine D2R signaling is mechanistically involved in the deficient GH secretion associated with obesity. To test this hypothesis, we studied the effect of short-term bromocriptine (B) (a D2R agonist) treatment on spontaneous 24-h GH secretion in obese women, while body weight and caloric intake remained constant. This was a prospective, fixed order, cross-over study. The study was performed in the Clinical Research Center at Leiden University Medical Center. There were 18 healthy obese women (body mass index 33.2 +/- 0.6 kg/m2) studied twice in the early follicular phase of their menstrual cycle. Eight days of treatment with B and placebo (Pl) was performed. Blood was collected during 24 h at 10-min intervals for determination of GH concentrations. GH secretion parameters were calculated using deconvolution analysis. Short-term treatment with B significantly enhanced diurnal GH secretion (Pl 121.4 +/- 16.4 vs. B 155.4 +/- 15.2 microg/liter(volume of distribution).24 h; P = 0.01), whereas IGF-I concentrations remained constant (Pl 22.4 +/- 2.4 vs. B 21.8 +/- 1.6 nmol/liter; P = 0.928). |
Is early Trauma-Induced Coagulopathy Associated with Increased Ventilator-Associated Pneumonia in Spinal Cord Injury Patients? | Early trauma-induced coagulopathy may increase susceptibility to nosocomial infections such as ventilator-associated pneumonia. However, the relationship between trauma- induced coagulopathy and the development of ventilator-associated pneumonia in spinal cord injury patients has not been evaluated. We conducted a 5-year retrospective study of 300 spinal cord injury patients admitted to Level 1 trauma center. Standard coagulation studies were evaluated upon arrival, prior to fluid resuscitative efforts, and at 24 h after admission. Based on these studies, three groups of patients were identified: no coagulopathy, latent coagulopathy, and admission coagulopathy. Ventilator- associated pneumonia was identified utilizing Centers for Disease Control and Prevention criteria. Since we used the data in the trauma registry and did not have the information on FiO2 and PEEP, we elected to use the VAP terminology and not the VAE sequence. Demographic, injury, and clinical characteristics were compared among no coagulopathy, latent coagulopathy, and admission coagulopathy groups using chi-square test and ANOVA for categorical and continuous variables, respectively. A logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between coagulopathy and both ventilator-associated pneumonia and mortality. The incidence of ventilator-associated pneumonia was 54.5% (OR 4.01, 95% CI 1.76-9.15) in spinal cord injury patients with admission coagulopathy, compared with the 17.5% in spinal cord injury patients with no coagulopathy. Mortality was significantly higher in spinal cord injury patients with admission coagulopathy than in spinal cord injury patients with no coagulopathy (OR 6.14, 95% CI 1.73-21.73).After adjusting for age, race, injury mechanism, Injury Severity Score, base deficit at admission, the number of pRBC units transfused in the first 24 h, and hospital stay, only the association of ventilator-associated pneumonia among those with admission coagulopathy remained significant (OR 3.51, 95% CI 1.48-8.32). Compared with those with no coagulopathy, patients with admission coagulopathy had a higher odds of death (4.10, 95% CI 1.53-11.02), though this association lost significance after adjustment (OR 3.56, 95% CI 0.90-14.12). There was no statistical difference in mortality for latent coagulopathy compared with no coagulopathy patients. | The presence of estrogen receptor (ER) and its therapeutic significance in ovarian borderline tumors (OBT) have not been established. We recently observed a response to tamoxifen therapy given empirically to a patient with unresectable, recurrent serous borderline tumor (SBT). In view of this observation the present study was undertaken to assess ER expression in 51 cases of OBT. ER expression was determined retrospectively, using an immunohistochemical method on formalin-fixed, paraffin-embedded specimens, from 35 cases of SBTs, 6 cases of mucinous mullerian (MMBT), and 10 cases of mucinous intestinal borderline tumors (MIBT). ER was considered positive if > 5% of tumor epithelial cell nuclei were immunostained. Both SBTs and mucinous borderline tumors (MBTs) were included to determine the influence of histologic type on ER expression. The patients ranged in age from 25 to 77 years (median 43 years for SBTs, 36 years for MMBTs, and 37 years for MIBTs). The stage distribution for the SBTs was stage I in 27 patients (77%), stage II in 4 patients (11.5%), and stage III in 4 patients (11.5%). All patients with MBTs were stage I. ER expression was observed in the majority of cases and correlated with histologic type: 94% (33/35) of SBTs and 100% (6/6) of MMBTs were ER positive compared to 0% (0/10) of MIBTs (P < 0.01). In the SBT category the presence of ER did not correlate significantly with stage or age. In addition, ER was positive in all four SBT implants (including one involved lymph node) and two recurrent SBTs analyzed. |
Are nailfold videocapillaroscopy and serum VEGF levels in scleroderma associated with internal organ involvement? | Nailfold videocapillaroscopy (NVC) identifies the microvascular hallmarks of systemic sclerosis (SSc) and vascular endothelial growth factor (VEGF) and may play a pivotal role in the associated vasculopathy. The aim of the present study was to compare NVC alterations with clinical subsets, internal organ involvement, and serum VEGF levels in a cohort of selected SSc cases. We studied 44 patients with SSc who were evaluated within 3 months from enrollment by NVC, skin score, severity index, pulmonary function tests, carbon monoxide diffusing capacity (DLCO), echocardiography, pulmonary high-resolution computed tomography (HRCT), gastroesophageal (GE) endoscopy or manometry or X-ray, and serum autoantibodies. Serum VEGF-A levels were determined by ELISA in 72 SSc patients and 31 healthy controls. Giant capillaries were inversely correlated with age (p = 0.034, r = -0.34) and to the extent of reticular pattern at HRCT (p = 0.04, r = -0.5). Avascular areas were directly correlated with capillaroscopy skin ulcer risk index (CSURI) (p = 0.006, r = +0.4) and severity index (p = 0.004, r = +0.5). The mean capillary density was directly correlated to the ulcer number (p = 0.02, r = +0.4) and to DLCO/alveolar volume (p = 0.02, r = +0.4) and inversely correlated with severity index (p = 0.01, r = -0.4) and skin score (p = 0.02, r = -0.4). Serum VEGF levels were higher in the SSc population vs controls (p = 0.03) and inversely correlated with DLCO (p = 0.01, r =-0.4) and directly with ground-glass and reticular pattern at HRCT (p = 0.04, r = +0.4 for both). | Neuropeptide Y (NPY) is a 36-amino acid neuromodulator that is expressed throughout the central nervous system. Recent genetic and pharmacological evidence suggests that the NPY Y1 receptor modulates ethanol intake. To further characterize the role of the Y1 receptor, we examined voluntary ethanol consumption by mice after administration of [(-)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl)ethylamino]-6-[2-(5-ethyl-4-methyl-1,3-tiazol-2-yl)ethyl]-4-morpholinopyridine] (compound A), a novel and selective Y1 receptor antagonist (Y1RA) that acts centrally on brain receptors when administered peripherally. C57BL/6J mice were habituated to drinking a 10% (v/v) ethanol solution by using a two-bottle-choice procedure and were then given an intraperitoneal (ip) injection (5 ml/kg) of the Y1RA (0, 25, 50, or 75 mg/kg). In a second study, mice were given intracerebroventricular infusion of the Y1RA (0, 30, or 100 microg). Finally, we determined whether the Y1RA alters open-field locomotor activity, ethanol-induced sedation (3.8 g/kg, ip), or blood ethanol levels. Relative to control treatment, ip injection (50 and 75 mg/kg) and intracerebroventricular infusion (100 microg) of the Y1RA significantly reduced ethanol consumption and food intake without altering water drinking. However, the Y1RA did not alter open-field locomotor activity, ethanol-induced sedation, or blood ethanol levels. |
Is prophylactic Plasma Transfusion Before Interventional Radiology Procedures Associated With Reduced Bleeding Complications? | To determine the association between prophylactic plasma transfusion and periprocedural red blood cell (RBC) transfusion rates in patients with elevated international normalized ratio (INR) values undergoing interventional radiology procedures. In this retrospective cohort study, adult patients undergoing interventional radiology procedures with a preprocedural INR available within 30 days of the procedure during a study period of January 1, 2009, to December 31, 2013, were eligible for inclusion. Baseline characteristics, coagulation parameters, transfusion requirements, and procedural details were extracted. Univariate and multivariable propensity-matched analyses were used to assess the relationships between prophylactic plasma transfusion and the outcomes of interest, with a primary outcome assessed a priori of RBC transfusion occurring during the procedure or within the first 24 hours postprocedurally. A total of 18,204 study participants met inclusion criteria for this study, and 1803 (9.9%) had an INR of 1.5 or greater before their procedure. Of these 1803 patients, 196 patients (10.9%) received prophylactic plasma transfusion with a median time of 1.9 hours (interquartile range [IQR], 1.1-3.2 hours) between plasma transfusion initiation and procedure initiation. In multivariable propensity-matched analysis, plasma administration was associated with increased periprocedural RBC transfusions (odds ratio, 2.20; 95% CI, 1.38-3.50; P<.001) and postprocedural intensive care unit admission rates (odds ratio, 2.11; 95% CI, 1.41-3.14; P<.001) as compared with those who were not transfused preprocedurally. Similar relationships were seen at higher INR thresholds for plasma transfusion. | Caenorhabditis elegans chemosensation has been successfully studied using behavioral assays that treat detection of volatile and water soluble chemicals as separate senses, analogous to smell and taste. However, considerable ambiguity has been associated with the attractive properties of the compound ammonium-acetate (NH(4)Ac). NH(4)Ac has been used in behavioral assays both as a chemosensory neutral compound and as an attractant. Here we show that over a range of concentrations NH(4)Ac can be detected both as a water soluble attractant and as an odorant, and that ammonia and acetic acid individually act as olfactory attractants. We use genetic analysis to show that NaCl and NH(4)Ac sensation are mediated by separate pathways and that ammonium sensation depends on the cyclic nucleotide gated ion channel TAX-2/TAX-4, but acetate sensation does not. Furthermore we show that sodium-acetate (NaAc) and ammonium-chloride (NH(4)Cl) are not detected as Na(+) and Cl(-) specific stimuli, respectively. |
Do vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects? | Angiogenesis and lymphangiogenesis are critical for several allergic, inflammatory, and neoplastic disorders. Mast cells infiltrate the sites of inflammation and tumors. We sought to characterize the expression and functions of vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) in human mast cells. VEGF expression was evaluated by means of RT-PCR and Western blotting in primary human lung mast cells and in the mast cell lines LAD-2 and HMC-1. Angiogenic activity of mast cell supernatants was determined by using the chick embryo chorioallantoic membrane assay. VEGFR expression was assessed by means of RT-PCR and flow cytometry. Modified Boyden chambers were used for chemotaxis assay. Human mast cells express VEGF-A, VEGF-B, VEGF-C, and VEGF-D at both the mRNA and protein level. Prostaglandin E(2) (PGE(2)) enhanced the expression of VEGFA, VEGFB, and VEGFC, whereas an adenosine analog (5'-[N-ethylcarboxamido] adenosine [NECA]) increased VEGFA, VEGFC, and VEGFD expression. In addition, PGE(2) and NECA enhanced VEGF-A release, and supernatants of PGE(2)- and NECA-activated human lung mast cells induced angiogenic responses in the chorioallantoic membrane assay that were inhibited by an anti-VEGF-A antibody. Mast cells expressed mRNA for VEGFR1 and VEGFR2. These receptors were present on the mast cell surface. VEGF-A(165), VEGF-B(167), VEGF-C, VEGF-D, and placental growth factor 1 induced mast cell chemotaxis. These chemotactic effects were mediated by the activation of both VEGFR-1 and VEGFR-2. | Mitochondrial dysfunction in adipose tissue has been implicated as a pathogenic step in the development of type 2 diabetes mellitus (T2DM). In adipose tissue, chronic nutrient overload results in mitochondria driven increased reactive oxygen species (ROS) leading to carbonylation of proteins that impair mitochondrial function and downregulation of key genes linked to mitochondrial biogenesis. In patients with T2DM, Roux-en-Y gastric bypass (RYGB) surgery leads to improvements in glycemic profile prior to significant weight loss. Consequently, we hypothesized that improved glycemia early after RYGB would be paralleled by decreased protein carbonylation and increased expression of genes related to mitochondrial biogenesis in adipose tissue. To evaluate this hypothesis, 16 obese individuals were studied before and 7-8 days following RYGB and adjustable gastric banding (AGB). Subcutaneous adipose tissue was obtained pre- and post-bariatric surgery as well as from eight healthy, non-obese individual controls. Prior to surgery, adipose tissue expression of PGC1α, NRF1, Cyt C, and eNOS (but not Tfam) showed significantly lower expression in the obese bariatric surgery group when compared to lean controls (p < 0.05). Following RYGB, but not after AGB, patients showed significant decrease in HOMA-IR, reduction in adipose protein carbonylation, and increased expression of genes linked to mitochondrial biogenesis. |
Does systemic endothelin receptor blockade decrease peripheral vascular resistance and blood pressure in humans? | Although local inhibition of the generation or actions of endothelin-1 has been shown to cause forearm vasodilatation, the systemic effects of endothelin receptor blockade in healthy humans are unknown. We therefore investigated the cardiovascular effects of a potent peptide endothelin ETA/B receptor antagonist, TAK-044, in healthy men. Two randomized, placebo-controlled, crossover studies were performed. In nine subjects, TAK-044 (10 to 1000 mg IV over a 15-minute period) caused sustained dose-dependent peripheral vasodilatation and hypotension. Four hours after infusion of the highest dose (1000 mg), there were decreases in mean arterial pressure of 18 mm Hg and total peripheral resistance of 665 AU and increases in heart rate of 8 bpm and cardiac index of 0.9 L x min(-1) x m(-2) compared with placebo. TAK-044 caused a rapid, dose-dependent increase in plasma immunoreactive endothelin (from 3.3 to 35.7 pg/mL within 30 minutes after 1000 mg). In a second study in eight subjects, intravenous administration of TAK-044 at doses of 30, 250, and 750 mg also caused peripheral vasodilatation, and all three doses abolished local forearm vasoconstriction to brachial artery infusion of endothelin-1. Brachial artery infusion of TAK-044 caused local forearm vasodilation. | Cysteine-rich 61 (Cyr61), a member of the CCN protein family, possesses diverse functionality in cellular processes such as adhesion, migration, proliferation, and survival. Cyr61 can also function as an oncogene or a tumour suppressor, depending on the origin of the cancer. Only a few studies have reported Cyr61 expression in colorectal cancer. In this study, we assessed the Cyr61 expression in 251 colorectal cancers with clinical follow up. We examined Cyr61 expression in 6 colorectal cancer cell lines (HT29, Colo205, Lovo, HCT116, SW480, SW620) and 20 sets of paired normal and colorectal cancer tissues by western blot. To validate the association of Cyr61 expression with clinicopathological parameters, we assessed Cyr61 expression using tissue microarray analysis of primary colorectal cancer by immunohistochemical analysis. We verified that all of the cancer cell lines expressed Cyr61; 2 cell lines (HT29 and Colo205) demonstrated Cyr61 expression to a slight extent, while 4 cell lines (Lovo, HCT116, SW480, SW620) demonstrated greater Cyr61 expression than HT29 and Colo205 cell lines. Among the 20 cases of paired normal and tumour tissues, greater Cyr61 expression was observed in 16 (80%) tumour tissues than in normal tissues. Furthermore, 157 out of 251 cases (62.5%) of colorectal cancer examined in this study displayed strong Cyr61 expression. Cyr61 expression was found to be associated with pN (p = 0.018). Moreover, Cyr61 expression was associated with statistically significant cancer-specific mortality (p = 0.029). The duration of survival was significantly lesser in patients with Cyr61 high expression than in patients with Cyr61 low expression (p = 0.001). These results suggest that Cyr61 expression plays several important roles in carcinogenesis and may also be a good prognostic marker for colorectal cancer. |
Does desflurane selectively suppress long-latency cortical neuronal response to flash in the rat? | The effect of inhalational anesthetics on sensory-evoked unit activity in the cerebral cortex has been controversial. Desflurane has desirable properties for in vivo neurophysiologic studies, but its effect on cortical neuronal activity and neuronal responsiveness is not known. The authors studied the effect of desflurane on resting and visual evoked unit activity in rat visual cortex in vivo. Desflurane was administered to adult albino rats at steady-state concentrations at 2%, 4%, 6%, and 8%. Flashes from a light emitting diode were delivered to the left eye at 5-s intervals. Extracellular unit activity within the right visual cortex was recorded using a 49-electrode array. Individual units were identified using principal components analysis. At 2% desflurane, 578 active units were found. Of these, 75% increased their firing rate in response to flash. Most responses contained early (0-100 ms) and late (150-1000 ms) components. With increasing desflurane concentration, the number of units active at baseline decreased (-13%), the number of early-responding units increased (+31%), and number of late-responding units decreased (-15%). Simultaneously, baseline firing rate decreased (-77%), the early response was unchanged, and the late response decreased (-60%). | Hemodialysis (HD) patients are exposed to a high risk of death. Nutritional status has been recognized as a key factor for patient survival. Nutritional markers have been shown to improve after HD onset. In this study we have analyzed the dynamics of target weight (TGW) change and the evolution of other nutritional parameters during the first year of HD treatment and their influence on patients' outcomes. We have analyzed a retrospective cohort of incident patients starting HD therapy between January 2000 and January 2009, and studied the values and changes in TGW, interdialytic weight gain (IDWG), predialysis systolic blood pressure, serum albumin, protein intake, C-reactive protein (CRP) from the start and first week (W1), W8, W12, W26 and W52 in patients who survived the first year of therapy. We have analyzed the relationship between TGW changes with other nutritional parameters and the patient survival. Among the cohort including 363 patients starting HD therapy, 251 (age 65.8 ± 14.8 years, 93 female/158 male, diabetes 36%) survived at least 1 year after dialysis onset and were followed for 44.9 months. During the first 8 weeks, the TGW decreased by 6.5 ± 5.6% (initial TGW change). The initial TGW change was correlated with IDWG at W12 and W26, and with changes in serum albumin and nPNA (normalized protein equivalent of nitrogen appearance) between HD W1 and W52 (respectively +7.8 and +11.4%). From W8 to W52, the TGW increased by +1.9 ± 7.4% (secondary TGW change). The Kaplan-Meier analysis displayed a significantly better survival in patients above the median (+2.3%) of the secondary TGW change (respectively -3.6 ± 5.2% and +7.6 ± 4.5%). The two groups above and below this median were not different according to age, diabetes or cardiovascular event history but the patients above the median had a significant higher IDWG and protein intake. In the Cox model analysis the patient overall mortality was related to age (p < 0.0001), to the secondary TGW change (p = 0.0001), and to the CRP level at W52 (p < 0.0001). |
Does altered fractalkine cleavage potentially promote local inflammation in NOD salivary gland? | In the nonobese diabetic (NOD) mouse model of Sjögren's syndrome, lymphocytic infiltration is preceded by an accumulation of dendritic cells in the submandibular glands (SMGs). NOD mice also exhibit an increased frequency of mature, fractalkine receptor (CX3C chemokine receptor [CX3CR]1) expressing monocytes, which are considered to be precursors for tissue dendritic cells. To unravel further the role played by fractalkine-CX3CR1 interactions in the salivary gland inflammation, we studied the expression of fractalkine in NOD SMGs. We studied protein expression using Western blot analysis of whole tissue lysates. Protease activity was measured in salivary gland tissue lysates using fluorimetric substrates. Digestive capacity of enzymes was determined by in vitro incubation of recombinant enzyme and fractalkine, followed by protein staining and Western blot. Fractalkine was detected in salivary glands of both NOD and control mice at all ages. Western blot analysis showed fractalkine cleavage with increasing age, which was more pronounced in NOD mice. This cleavage resulted in a decrease in the 31 kDa form of the protein, and the generation of an approximately 19 kDa band. Furthermore, in NOD animals older than 15 weeks, we noted the presence of a unique approximately 17 kDa fragment. This cleavage was organ specific, because it did not occur in brain or pancreas. Increased gelatinase and alpha-secretase activity were detected in NOD SMG and contributed to cleavage of the 31 kDa protein. Because aberrant cleavage products may induce autoimmunity, we studied the presence of autoantibodies against fractalkine. Indeed, NOD mice exhibited significantly more antibodies against fractalkine than did control animals. | The methods used to communicate relevant outcomes in oncology to patients will likely influence treatment decisions. The purpose of this study was to examine the influence of three different methods of describing the efficacy of therapy on treatment decisions regarding management of metastatic colorectal cancer. Participants reviewed a clinical scenario and randomly received one of three ways of describing efficacy of chemotherapy in metastatic colorectal cancer: (1) relative risk reduction, (2) tumor response rate, and (3) median overall survival. They received the same clinical scenario but were presented four treatment options: (1) observation and supportive care, (2) chemotherapy, (3) surgery, and (4) surgery and chemotherapy and the accompanying median overall survival estimate. Participants included 102 preclinical medical students. In the first scenario, 85% chose chemotherapy in the relative risk reduction group, as did 88% of the tumor response rate group, but significantly fewer participants did so in the median overall survival group (35%; P < .001). In the second scenario, there was a significant difference in treatment preferences, with 4% of participants choosing observation/supportive care. None chose chemotherapy only, 19% chose surgery only, and 77% chose surgery plus chemotherapy (P < .001). |
Is obstructive sleep apnea common in idiopathic pulmonary fibrosis? | From 1984 to 2006, studies of sleep in patients with interstitial lung disease revealed disturbed sleep, frequent nocturnal desaturations, nocturnal cough, and obstructive sleep apnea (OSA). Our goal was to analyze OSA in an outpatient population of stable patients with idiopathic pulmonary fibrosis (IPF). Patients with IPF who had been followed up in the Vanderbilt Pulmonary Clinic were asked to participate. All patients were given a diagnosis of IPF by the 2000 American Thoracic Society consensus statement criteria. Subjects completed an Epworth sleepiness scale (ESS) questionnaire and a sleep apnea scale of sleep disorders questionnaire (SA-SDQ) before undergoing nocturnal polysomnography (NPSG). OSA was defined as an apnea-hypopnea index (AHI) of > 5 events per hour. Fifty subjects enrolled and completed a NPSG. The mean age was 64.9 years, and the mean BMI was 32.3. OSA was diagnosed in 88% of subjects. Ten subjects (20%) had mild OSA (AHI, 5 to 15 events per hour), and 34 subjects (68%) had moderate-to-severe OSA (AHI, > 15 events per hour). Only 6 subjects (12%) had a normal AHI. One patient was asymptomatic as determined by ESS and SA-SDQ, but had an AHI of 24 events per hour. The sensitivity of the ESS was 75% with a specificity of 15%, whereas the SA-SDQ had a sensitivity of 88% with a specificity of 50%. BMI did not correlate strongly with AHI (r = 0.30; p = 0.05). | Formulation of DNA/cationic lipid complexes (lipoplexes) designed for nucleic acid delivery mostly results in positively charged particles which are thought to enter cells by endocytosis. We recently developed a lipoplex formulation called Neutraplex that allows preparation of both cationic and anionic stable complexes with similar lipid content and ultrastructure. To assess whether the global net charge could influence cell uptake and activity of the transported oligonucleotides (on), we prepared lipoplexes with positive and negative charges and compared: (i) their physicochemical properties by zeta potential analysis and dynamic light scattering, (ii) their cell uptake by fluorescence microscopy and flow cytometry, and (iii) the biological activity of the transported ON using a splicing correction assay. We show that positively or negatively charged lipoplexes enter cells cells using both temperature-dependent and -independent uptake mechanisms. Specifically, positively charged lipoplexes predominantly use a temperature-dependent transport when cells are incubated OptiMEM medium. Anionic lipoplexes favour an energy-independent transport and show higher ON activity than cationic lipoplexes in presence of serum. However, lipoplexes with high positive global net charge and OptiMEM medium give the highest uptake and ON activity levels. |
Do [ Diagnostic and treatment delays modify the treatment outcome of patients with multiform glioblastoma ]? | To assess waiting time effect in patient with multiform glioblastoma (GBM) treated with 3D conformal planned postoperative radiotherapy and to investigate the impact of chemotherapy as first adjuvant treatment. We retrospectively analyzed 94 consecutive patients with histologically proven GBM. Surgery was considered as macroscopically complete in 33 cases (35%). Median irradiation dose was 60 Gy (8-63, mean 56 Gy). Dose per fractions was 1.8 Gy (five patients), 2 Gy (76 patients) and 2.7 Gy (13 patients). Forty patients received adjuvant pre-radiotherapy chemotherapy as intra-operative carmustine (nine patients) and adjuvant five-day protocol temozolomide alone (31 patients) or with cisplatinum (two patients). All patients received only one chemotherapy cycle. There were 56 males and 38 females. Median age was 62.1 years old (7-82, mean: 59.2 year). Median follow-up was nine months (1-49). For overall patients, median waiting time between fist clinical sign and start of the non surgical treatment was 68 days ((3-274, mean: 81.9 days). For those who received chemotherapy as first treatment, this waiting time was 54 days (3-221, mean 68.3 days). For overall patients, median waiting time between surgery and beginning of radiotherapy was 46 days (8-401, mean 59.3 days). For patients who did not receive chemotherapy as first adjuvant treatment this waiting time was 46 days (-278, mean 55.4 days). Median local control was 14.5 months. Six, 12-, 18-, and 24-month local control rates were 75.6+/-4.6%, 57.6+/-6.2%, and 36.7+/-8% and 27.6+/-8.2%, respectively. According to multivariate analysis, we retrieved two independent prognostic factors of local control, macroscopically total removal of the tumor [RR=2.85, IC 95% (1.3-6.5), p=0.012] and irradiation dose above 60 Gy, [RR=3.14, IC 95% (1.5-6.6), p=0.002]. Median overall survival was 14.3 months. Six-, 12-, 18, and 24-month overall survival rates were 84+/-3.9%, 55.1+/-5.9%, 34.2+/-6.3% and 30.4+/-6.7%, respectively. There was no independent prognostic factor. | Increased triglyceride (TG) occurs in patients with acute coronary syndrome (ACS), and apolipoprotein AV (apoAV) has been shown to lower TG levels. In the present study, we investigated plasma apoAV level and its relationship with TG and C-reactive protein (CRP) in ACS patients. A total of 459 subjects were recruited and categorized into control group (n = 116), stable angina (SA) group (n = 115), unstable angina group (n = 116) and acute myocardial infarction group (n = 112). Plasma apoAV level was measured by a sandwich ELISA assay. Compared with controls ((100.27 +/- 22.44) ng/ml), plasma apoAV was decreased in SA patients ((76.54 +/- 16.91) ng/ml) but increased in patients with unstable angina ((330.89 +/- 66.48) ng/ml, P < 0.05) or acute myocardial infarction ((368.66 +/- 60.53) ng/ml, P < 0.05). Inverse correlations between apoAV and TG were observed in the control or stable angina groups (r = -0.573 or -0.603, respectively, P < 0.001), whereas positive correlations were observed in the patients with unstable angina or acute myocardial infarction (r = 0.696 or 0.690, respectively, P < 0.001). Furthermore, a positive relationship between apoAV and CRP was observed in the ACS patients but not in the non-ACS subjects. |
Is nuchal cord associated with adverse perinatal outcome? | The present study was aimed at evaluating the outcome of pregnancies with nuchal cord. A retrospective population-based study of all deliveries during the years 1988-2003 in a tertiary medical center was conducted. Immediate perinatal outcome of patients with and without nuchal cord was compared. Of 166,318 deliveries during the study period, 14.7% had a nuchal cord, documented at birth (n=24,392). Higher rates of labor induction and non-reassuring fetal heart rate patterns were noted among pregnancies with nuchal cord as compared with the control group (30.1% vs. 24.2%; OR=1.3, 95% CI 1.3-1.4, P<0.001 and 4.5% vs. 2.6%; OR=1.8, 95% CI 1.6-1.9, P<0.001; respectively). The cesarean delivery rate was significantly lower among pregnancies with nuchal cord (11.5% vs. 12.7%; OR=0.9, 95% CI 0.8-0.9, P=0.001). Although 1 min Apgar scores lower than 7 were more common in pregnancies with nuchal cord (4.8% vs. 4.4%; OR=1.1, 95% CI 1.01-1.2, P=0.008), these pregnancies actually had lower rates of 5 min Apgar scores less than 7 (0.5% vs. 0.7%; OR=0.8, 95% CI 0.6-0.9, P=0.004). Likewise, the perinatal mortality rate was significantly lower in pregnancies with nuchal cord as compared with the comparison group (11/1,000 vs. 16/1,000; OR=0.7, 95% CI 0.6-0.8, P=0.001). | MDMA (ecstasy; +3,4-methylenedioxymethamphetamine) damages brain serotonin (5-HT) neurons and, in non-human primates, a loss of various 5-HT axonal markers persists for several years. This raises the question of whether long lasting effects occur in human beings that persist even after they have stopped using MDMA. We therefore assessed the effects of an indirect 5-HT manipulation on functions thought to be affected by MDMA use in people who had stopped using MDMA (ex-users) compared with continuing users and non-users. Ninety-six participants were recruited: 32 ex-users who had stopped using MDMA for >1 year (mean, 2.4 years); 32 current users and 32 polydrug controls who had never used MDMA but were matched with ex-users and controls on cannabis use and pre-morbid IQ. Participants were given an amino acid mixture that contained either no tryptophan (T-) or augmented tryptophan (T+) and assessed before and 5 h after the drink on measures of cognitive function and mood. T+ and T- produced plasma tryptophan augmentation and depletion, respectively, in all three groups. Ex-users' plasma tryptophan levels in response to T+ were significantly higher than other groups. Ex-users' performance on a delayed prose recall task improved after T+ and lessened after T-. Changes in ex-users' free plasma tryptophan levels correlated highly (r=-0.9) with their baseline performance on immediate and delayed prose recall; change in total plasma tryptophan correlated (r=-0.81) with delayed recall. Further, total baseline plasma tryptophan correlated with number of years they had used MDMA before quitting. Baseline differences between groups were found on learning, working memory, aggression and impulsivity. T- did not produce differential effects in the three groups. |
Does coffee consumption and the risk of latent autoimmune diabetes in adults -- result from a Swedish case-control study? | Coffee consumption is associated with a reduced risk of Type 2 diabetes. Our aim was to investigate if coffee intake may also reduce the risk of latent autoimmune diabetes in adults, an autoimmune form of diabetes with features of Type 2 diabetes. We used data from a population-based case-control study with incident cases of adult onset (≥ 35 years) diabetes, including 245 cases of latent autoimmune diabetes in adults (glutamic acid decarboxylase antibody positive), 759 cases of Type 2 diabetes (glutamic acid decarboxylase antibody negative), together with 990 control subjects without diabetes, randomly selected from the population. Using questionnaire information on coffee consumption, we estimated the odds ratio of latent autoimmune diabetes in adults and Type 2 diabetes adjusted for age, sex, BMI, smoking, physical activity, alcohol, education and family history of diabetes. Coffee intake was inversely associated with Type 2 diabetes (odds ratio 0.92, 95% CI 0.87-0.98 per cup/day). With regard to latent autoimmune diabetes in adults, the general trend was weak (odds ratio 1.04, 95% CI 0.96-1.13), but stratification by degree of autoimmunity (median glutamic acid decarboxylase antibody levels) suggested that coffee intake may be associated with an increased risk of high glutamic acid decarboxylase antibody latent autoimmune diabetes in adults (odds ratio 1.11, 95% CI 1.00-1.23 per cup/day). Furthermore, for every additional cup of coffee consumed per day, there was a 15.2% (P = 0.0268) increase in glutamic acid decarboxylase antibody levels. | We compared conventional treatment with pumpless extracorporeal lung membrane (Interventional Lung Assist [iLA] Novalung; Novalung GmbH, Hechingen, Germany) support in a pig model of postpneumonectomy severe acute respiratory distress syndrome. Adult pigs underwent a left thoracotomy without (group I) or with a left extrapericardial pneumonectomy and radical lymphadenectomy (groups II to V). After stabilization, pigs belonging to group II were observed only, whereas in those belonging to groups III to V, a surfactant-depletion severe (Pao(2)/Fio(2) < 100) postpneumonectomy acute respiratory distress syndrome was induced. This was followed by observation (group III); treatment with conventional therapy including protective ventilation, steroids, and nitric oxide (group IV); or femoral arteriovenous iLA Novalung placement, near-static ventilation, steroids, and nitric oxide (group V). Each group included 5 animals. Primary outcome was extubation 12 hours postoperatively or postpneumonectomy acute respiratory distress syndrome. A severe postpneumonectomy acute respiratory distress syndrome was obtained after 9 +/- 2 alveolar lavages over 90 +/- 20 minutes. In group V pigs, the iLA Novalung device diverted 17% +/- 4% of the cardiac output, permitted an oxygen transfer and carbon dioxide removal of 298.4 +/- 173.7 mL/min and 287.7 +/- 87.3 mL/min, respectively, and static ventilation (tidal volume, 2.2 +/- 1 mL/kg; respiratory rate, 6 +/- 2.9 breaths/min). All but 1 pig belonging to group V could be extubated compared with none in groups III and IV (P < .01), and only their lungs normalized cytokine release (P < .001) and surfactant (P < .03) and displayed fewer parenchymal lesions (P < .05). |
Does protein phosphatase 5 mediate corticosteroid insensitivity in airway smooth muscle in patients with severe asthma? | The mechanisms driving glucocorticoid (GC) insensitivity in patients with severe asthma are still unknown. Recent evidence suggests the existence of GC-insensitive pathways in airway smooth muscle (ASM) caused by a defect in GC receptor (GRα) function. We examined whether other mechanisms could potentially explain the reduced sensitivity of ASM cells to GC in severe asthmatics. Airway smooth muscle cells from healthy and severe asthmatic subjects were treated with TNF-α and responses to corticosteroids in both cohorts were compared by ELISA, immunoblot, immunohistochemistry and real-time PCR. Immunohistochemistry and flow cytometry assays were used to assess the expression of the protein phosphatase PP5 in endobronchial biopsies and ASM cells. The production of CCL11 and CCL5 by TNF-α was insensitive to both fluticasone and dexamethasone in ASM cells from severe asthmatic compared to that in healthy subjects. Fluticasone-induced GRα nuclear translocation, phosphorylation at serine 211 and expression of GC-induced leucine zipper (GILZ) were significantly reduced in ASM cells from severe asthmatics compared to responses in healthy subjects. Levels of PP5 were increased in ASM cells from severe asthmatics and PP5 knockdown using siRNA restored fluticasone repressive action on chemokine production and its ability to induce GRα nuclear translocation and GRE-dependent GILZ expression. In vivo PP5 expression was also increased in the ASM bundles in endobronchial biopsies in severe asthmatics. | Endovascular intervention is increasingly accepted as an alternative to surgery for the treatment of tibial vessel disease. Tibial vessel disease can occur in isolation or in conjunction with disease that involves the proximal lower extremity vasculature (multilevel disease). This study evaluated the overall efficacy of endovascular intervention for tibial vessel disease and whether the requirement for single-level compared with multilevel intervention affected outcomes. This study evaluated a consecutive unselected group of patients who underwent an infrapopliteal intervention from November 2002 to February 2008. The primary end points evaluated were technical success, limb salvage, primary patency, and secondary patency. The secondary end points evaluated were 30-day access site (ie, hematoma, pseudoaneurysm, and wound infection), intervention site (ie, thrombosis), and systemic (ie, acute renal failure, myocardial infarction, and mortality) complications. Patency and limb salvage were evaluated using Kaplan-Meier life-table analyses and compared using Cox regression analysis. P < .05 was considered statistically significant. The study comprised 85 patients, 89 limbs, and 114 procedures. Age was 72.4 +/- 13.1 years, 67% were men, and follow-up was 245.8 +/- 290.8 days. The technical success rate for all procedures was 91%. Limb salvage rates for patients with critical limb ischemia at 6, 12 and 18 months were 85% +/- 0%, 81% +/- 0%, and 69% +/- 0%, respectively. For the complete patient cohort, primary patency rates at 6, 12 and 18 months were 68% +/- 6%, 50% +/- 8%, and 37% +/- 9%, respectively, and secondary patency rates were 81% +/- 5%, 71% +/- 7%, and 63% +/- 8%. Multilevel intervention was associated with significantly improved secondary patency compared with single-level intervention (P = .045). |
Is short sleep duration associated with a blood pressure nondipping pattern in type 1 diabetes : the DIAPASOM study? | To assess whether nocturnal blood pressure dipping status in type 1 diabetes is correlated with specific sleep characteristics and differences in nocturnal glycemic profiles. Twenty type 1 diabetic adult patients underwent sleep studies with simultaneous 24-h ambulatory blood pressure monitoring and continuous nocturnal glucose monitoring. Altogether, 55% of patients exhibited blunted blood pressure dipping. They did not differ from the dipper group in age, BMI, or systolic (SBP) and diastolic (DBP) blood pressure. Total sleep period (TSP) was higher in the dipper group (497 +/- 30 vs. 407 +/- 44 min for dippers and nondippers, respectively, P < 0.001). TSP was correlated with SBP and DBP day-night differences (r = 0.44 and 0.49, respectively). Periods of nocturnal hypoglycemia (i.e., % of TSP with glycemia <70 mg/dl) were longer in the dipper group (8.1 +/- 10.7 vs. 0.1 +/- 0.4% for dippers and nondippers, respectively, P = 0.02). | To reduce the side effects and improve the efficacy of chemoradiation therapy, taxanes were incorporated into polymeric nanoparticles (PNP), and their synergic effect on radiation therapy in non-small cell lung cancer was evaluated. The properties of PNP-taxanes were characterized by transmission electron microscopy and dynamic light scattering. The chemoradiotherapeutic efficacy of PNP-taxanes was determined by clonogenic assay, cellular morphology, and flow cytometry in A549 cells. In mice bearing A549-derived tumors, the tumor growth delay was examined after the treatment of PNP-taxanes and/or ionizing radiation (IR). The PNP-taxanes were found to be approximately 45 nm in average diameter and to have high solubility in water. They showed the properties of active internalization into cells and preserved the anticancer effect of free taxanes. The survival fraction of A549 cells by clonogenic assay was significantly reduced in the group receiving combined treatment of PNP-taxanes and IR. In addition, in vivo radiotherapeutic efficacy was markedly enhanced by the intravenous injection of PNP-taxanes into the xenograft mice. |
Is non-arteritic anterior ischaemic optic neuropathy nearly systematically associated with obstructive sleep apnoea? | To evaluate newly diagnosed non-arteritic anterior ischaemic optic neuropathy (NAION) patients for the existence of an associated sleep apnoea syndrome. Newly identified NAION patient underwent polysomnography. The prevalence of sleep apnoea in NAION patients was compared to the prevalence previously found in the general population. Hypertension, diabetes, hyperlipidaemia, and atheromatous lesions of carotid vessels as classic risk factors associated with NAION were also identified. 27 consecutive newly diagnosed NAION patients (18 men and nine women, mean age 65 (SD 8) years, body mass index 27.2 (3.8) kg/m2) were included in the study. 24 of these 27 NAION patients (89%) exhibited a sleep apnoea syndrome (respiratory disturbance index: 37.2/h (SD 18.3/h). Risk ratio for a NAION patient to have sleep apnoea was 4.9 compared to the general population (p < 0.001). Sleep apnoea was 1.5-2-fold more frequent than the rate of the other identified risk factors typically associated with NAION (hypertension, diabetes). | Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are considered to be crucial for cancer biology. The purpose of this study was to determine whether EMT directly led to the acquisition of tumour-initiating capacity in breast cancer cell lines. Epithelial-mesenchymal transition was induced in five breast cancer cell lines and one normal breast cell line by EMT-related cytokine stimulation. Mesenchymal-epithelial transition (MET) was induced by stably overexpressing miR-200c in three mesenchymal-like breast cancer cell lines. Molecular expression and cell function analysis were performed to evaluate the effect of EMT or MET on tumour-initiating capacity and other biological characteristics. The induction of EMT did not enhance tumour-initiating capacity but, instead, conferred a CD44(+)/CD24(-/low) phenotype as well as cell proliferation, migration, and resistance to doxorubicin and radiation on breast cancer cell lines. Furthermore, MET did not lead to inhibition or loss of the tumour-initiating capacity in mesenchymal-like breast cancer cell lines, but it markedly attenuated other malignant properties, including proliferation, invasion, and resistance to therapy. |
Does prolonged intra-aortic balloon pump support in biventricular heart failure induce right ventricular reverse remodeling? | Right ventricular dysfunction is associated with high morbidity and mortality in candidates for left ventricular assist device (LVAD) implantation or cardiac transplantation. We examined the effects of prolonged intra-aortic balloon pump (IABP) support on right ventricular, renal and hepatic functions in patients presenting with end-stage heart failure. Between March 2008 and June 2013, fifteen patients (mean age = 49.5 years; 14 men) with end-stage systolic heart failure (HF), contraindications for any life saving procedure (conventional cardiac surgery, heart transplantation, LVAD implantation) and right ventricular dysfunction were supported with the IABP. The patients remained on IABP support for a mean of 73 ± 50 days (median 72, range of 13-155). We measured the echocardiographic and hemodynamic changes in right ventricular function, and the changes in serum creatinine and bilirubin concentrations before and during IABP support. Mean right atrial pressure decreased from 12.7 ± 6.5 to 3.8 ± 3.3 (P < 0.001) and pulmonary artery pressure decreased from 35.7 ± 10.6 to 25 ± 8.4 mmHg (P = 0.001), while cardiac index increased from 1.5 ± 0.4 to 2.2 ± 0.7 l/m(2)/min (P = 0.003) and right ventricular stroke work index from 485 ± 228 to 688 ± 237 mmHg × ml/m(2) (P = 0.043). Right ventricular end-diastolic diameter decreased from 34.0 ± 6.5 mm to 27.8 ± 6.2 mm (P < 0.001) and tricuspid annular systolic tissue Doppler velocity increased from 9.6 ± 2.4 cm/s to 11.1 ± 2.3 cm/s (P = 0.029). Serum creatinine and bilirubin decreased from 2.1 ± 1.3 to 1.4 ± 0.6 mg/dl and 2.0 ± 1.0 to 0.9 ± 0.5 mg/dl, respectively (P = 0.002 and P < 0.001, respectively). | Atopic dermatitis (AD) is a chronically relapsing, pruritic, eczematous skin disorder accompanying allergic inflammation. AD is triggered by oxidative stress and immune imbalance. The effect of oral arjunolic acid (AA) on 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis in mice was investigated. Repeated epicutaneous application of DNCB to the ear and shaved dorsal skin of mice was performed to induce AD-like symptoms and skin lesions: 250mg/kg AA was given orally for three weeks to assess its anti-pruritic effects. Serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, immunoglobulin (Ig)E and caspase-3 were assessed by ELISA. We found that AA alleviated DNCB-induced AD-like symptoms as quantified by skin lesions, dermatitis score, ear thickness and scratching behavior. Levels of reactive oxygen species in the AA group were significantly inhibited compared with those in the DNCB group. In parallel, AA blocked a DNCB-induced reduction in serum levels of IL-4 and IL-10 associated with an attenuation of DNCB-induced increases in serum TNF-α, IL-6, IgE and caspase-3. |
Is cardiac development in zebrafish and human embryonic stem cells inhibited by exposure to tobacco cigarettes and e-cigarettes? | Maternal smoking is a risk factor for low birth weight and other adverse developmental outcomes. We sought to determine the impact of standard tobacco cigarettes and e-cigarettes on heart development in vitro and in vivo. Zebrafish (Danio rerio) were used to assess developmental effects in vivo and cardiac differentiation of human embryonic stem cells (hESCs) was used as a model for in vitro cardiac development. In zebrafish, exposure to both types of cigarettes results in broad, dose-dependent developmental defects coupled with severe heart malformation, pericardial edema and reduced heart function. Tobacco cigarettes are more toxic than e-cigarettes at comparable nicotine concentrations. During cardiac differentiation of hESCs, tobacco smoke exposure results in a delayed transition through mesoderm. Both types of cigarettes decrease expression of cardiac transcription factors in cardiac progenitor cells, suggesting a persistent delay in differentiation. In definitive human cardiomyocytes, both e-cigarette- and tobacco cigarette-treated samples showed reduced expression of sarcomeric genes such as MLC2v and MYL6. Furthermore, tobacco cigarette-treated samples had delayed onset of beating and showed low levels and aberrant localization of N-cadherin, reduced myofilament content with significantly reduced sarcomere length, and increased expression of the immature cardiac marker smooth muscle alpha-actin. | We evaluated assays for the measurement of acute phase protein levels in plasma for their usefulness to identify sensitively an inflammatory response to active cytomegalovirus CMV infection in HIV-infected patients. Plasma samples were collected from 28 CMV-seropositive patients with advanced HIV-infection (CD4-cell count <200/microl) before commencement of antiretroviral therapy. Sensitivity, specificity, and area under receiver operating characteristic curve for the selected acute phase protein assays (haptoglobin, fibronectin, high-sensitivity C-reactive protein (hs-CRP), human interleukin-6, serum amyloid A (SAA), and human lipopolysacharide binding protein) were compared with results of a CMV-specific PCR assay. CMV viremia was detectable in 8/28 patients. Levels of SAA correlated well with those of hs-CRP (r' = 0.439, P = 0.019 (Spearman rank correlation)). Levels of SAA >3 mg/L discriminated with 100% sensitivity and 40% specificity between HIV-infected patients with and without active CMV infection. Sensitivity of fibronectin was 100% and specificity 15% at a threshold-value corresponding with the lower limit of normal values as defined by the manufacturer of the assay (>29 mg/dL). Levels of the other acute phase proteins evaluated did not correlate with detection of CMV-DNA in plasma. |
Is recombinant bovine growth hormone-induced reduction of atrial natriuretic peptide associated with improved left ventricular contractility and reverse remodeling in cardiomyopathic UM-X7.1 hamsters with congestive heart failure? | To assess the effect of short-term treatment with GH on left ventricular contractility and remodeling, after the development of heart failure in cardiomyopathic hamsters (CMH). Two groups of 200-day-old UM-X7.1 CMH received daily subcutaneous injections of recombinant bovine (rb) GH (1mg/kg/day) or 0.9% NaCl for 40 days. Golden Syrian hamsters (GSH) were used as controls. At 240-day-old, the hamsters were randomly subjected to (i) assessment of left ventricular systolic function in a Langendorff perfused mode followed by the determination of the passive diastolic pressure-volume relationship and morphometric measurements; (ii) assessment of left ventricular mRNA expression of genes belonging to the fetal gene program including atrial (ANP) and brain (BNP) natriuretic peptides and cardiac myosin heavy chain isoforms and of the circulating levels of the natriuretic peptides. Hearts from CMH were hypertrophied and dilated (p<0.05) compared to hearts from GSH, along with a approximately 10-fold increase in the circulating ANP and BNP levels. Left ventricular BNP and ANP mRNAs were elevated by 2- and 3-fold, respectively, compared to GSH. rbGH reduced both ANP mRNA and ANP circulating levels by 34% (p<0.01) but did not significantly modulate BNP levels. This effect was associated with a preserved systolic function and reverse remodeling as assessed by a leftward shift of the passive diastolic pressure-volume relationship indicating reduced ventricular dilatation. | Chronic rhinosinusitis (CRS) is a heterogeneous disease with an uncertain pathogenesis. Group 2 innate lymphoid cells (ILC2s) represent a recently discovered cell population which has been implicated in driving Th2 inflammation in CRS; however, their relationship with clinical disease characteristics has yet to be investigated. The aim of this study was to identify ILC2s in sinus mucosa in patients with CRS and controls and compare ILC2s across characteristics of disease. A cross-sectional study of patients with CRS undergoing endoscopic sinus surgery was conducted. Sinus mucosal biopsies were obtained during surgery and control tissue from patients undergoing pituitary tumour resection through transphenoidal approach. ILC2s were identified as CD45(+) Lin(-) CD127(+) CD4(-) CD8(-) CRTH2(CD294)(+) CD161(+) cells in single cell suspensions through flow cytometry. ILC2 frequencies, measured as a percentage of CD45(+) cells, were compared across CRS phenotype, endotype, inflammatory CRS subtype and other disease characteristics including blood eosinophils, serum IgE, asthma status and nasal symptom score. 35 patients (40% female, age 48 ± 17 years) including 13 with eosinophilic CRS (eCRS), 13 with non-eCRS and 9 controls were recruited. ILC2 frequencies were associated with the presence of nasal polyps (P = 0.002) as well as high tissue eosinophilia (P = 0.004) and eosinophil-dominant CRS (P = 0.001) (Mann-Whitney U). They were also associated with increased blood eosinophilia (P = 0.005). There were no significant associations found between ILC2s and serum total IgE and allergic disease. In the CRS with nasal polyps (CRSwNP) population, ILC2s were increased in patients with co-existing asthma (P = 0.03). ILC2s were also correlated with worsening nasal symptom score in CRS (P = 0.04). |
Is persistent arm pain distinct from persistent breast pain following breast cancer surgery? | Persistent pain following breast cancer surgery is well documented. However, it is not well characterized in terms of the anatomic site affected (ie, breast, arm). In 2 separate growth mixture modeling analyses, we identified subgroups of women (N = 398) with distinct breast pain and arm pain trajectories. The fact that these latent classes differed by anatomic site, types of tissue affected, and neural innervation patterns suggests the need for separate evaluations of these distinct persistent pain conditions. The purposes of this companion study were to identify demographic and clinical characteristics that differed between the 2 arm pain classes and determine if differences existed over time in sensitivity in the upper inner arm and axillary lymph node dissection sites, pain qualities, pain interference, and hand and arm function, as well as to compare findings with persistent breast pain. Higher occurrence rates for depression and lymphedema were found in the moderate arm pain class. Regardless of pain group membership, sensory loss was observed in the upper inner arm and axillary lymph node dissection site. Arm pain was described similarly to neuropathic pain and interfered with daily functioning. Persistent arm pain was associated with sustained impairments in shoulder mobility. | Ficus religiosa L. is one of the most relevant members of the family of Moraceae. It is the most sacred tree of South Asia, and it is used in traditional Ayurvedic and Unani medicine to cure respiratory disorders like cough, wheezing and asthma. Some studies were performed to investigate the anti-asthmatic potential of F. religiosa bark, leaves and fruit extracts but none of them tested their antiviral activity against viruses responsible for the exacerbation of wheezing and asthma. The present study was undertaken to investigate the antiviral activity of F. religiosa L. extracts against respiratory viruses such as human respiratory syncytial virus (RSV) and human rhinovirus (HRV). The antiviral activity of F. religiosa L. was tested in vitro by plaque reduction and virus yield assays and the major mechanism of action was investigated by virus inactivation and time-of-addition assays. F. religiosa L. methanol bark extract was the most active against HRV with an EC50 of 5.52 µg/mL. This extract likely inhibited late steps of replicative cycle. Water bark extract was the most active against RSV with an EC50 between 2.23 and 4.37 µg/mL. Partial virus inactivation and interference with virus attachment were both found to contribute to the anti-RSV activity. Replication of both viruses was inhibited in viral yield reduction assays. |
Does preconditioning prevent postischemic dysfunction in aging heart? | This study was performed to investigate the effect of single or multiple brief periods of ischemia and the administration of exogenous norepinephrine before a more prolonged ischemic period and after reperfusion in adult and senescent isolated and perfused rat hearts. The mortality rate for coronary artery disease is greater in the elderly. Ischemic preconditioning has been proposed as an endogenous form of protection against ischemia-reperfusion injury. However, the role of preconditioning in aging heart is unknown. We compared the protective effect of preconditioning transient ischemic and norepinephrine stimuli against 20 min of global normothermic ischemia and 40 min of reperfusion in isolated perfused hearts of adult (6 months old) and senescent (24 months old) rats. Norepinephrine release in coronary effluent was determined by high performance liquid chromatography. Final recovery of percent developed pressure was improved after single preconditioning transient ischemic and norepinephrine stimuli in adult hearts (87.7 +/- 9% and 82.3 +/- 8.7%) versus unconditioned control hearts (50.6 +/- 4.8%, p < 0.01 [mean +/-SD]). The effect of preconditioning on developed pressure recovery was not present in senescent hearts after transient ischemic stimulus (39.8 +/- 4.9% vs. 41.6 +/- 5.8%, p = NS) but was present after norepinephrine stimulus (74.3 +/- 10.5, p < 0.01). Norepinephrine release significantly increased after preconditioning transient ischemic stimulus in adult but not in senescent hearts (p < 0.01 vs. adult). Transient ischemic- and norepinephrine-induced preconditioning was blocked by alpha-adrenergic receptor antagonists in both adult and senescent hearts. Multiple transient ischemic stimuli were able to reduce postischemic dysfunction in adult but not in senescent hearts. | Smoking, dietary factors, and alcohol consumption are known life style factors contributing to gastrointestinal carcinogenesis. Genetic variations in carcinogen handling may affect cancer risk. The multidrug resistance 1(MDR1/ABCB1) gene encodes the transport protein P-glycoprotein (a phase III xenobiotic transporter). P-glycoprotein is present in the intestinal mucosal lining and restricts absorption of certain carcinogens, among these polycyclic aromatic hydrocarbons. Moreover, P-glycoprotein transports various endogenous substrates such as cytokines and chemokines involved in inflammation, and may thereby affect the risk of malignity. Hence, genetic variations that modify the function of P-glycoprotein may be associated with the risk of colorectal cancer (CRC). We have previously found an association between the MDR1 intron 3 G-rs3789243-A polymorphism and the risk of CRC in a Danish study population. The aim of this study was to investigate if this MDR1 polymorphism was associated with risk of colorectal adenoma (CA) and CRC in the Norwegian population. Using a case-control design, the association between the MDR1 intron 3 G-rs3789243-A polymorphism and the risk of colorectal carcinomas and adenomas in the Norwegian population was assessed in 167 carcinomas, 990 adenomas, and 400 controls. Genotypes were determined by allelic discrimination. Odds ratio (OR) and 95 confidence interval (95% CI) were estimated by binary logistic regression. No association was found between the MDR1 polymorphism (G-rs3789243-A) and colorectal adenomas or cancer. Carriers of the variant allele of MDR1 intron 3 had odds ratios (95% CI) of 0.97 (0.72-1.29) for developing adenomas, and 0.70 (0.41-1.21) for colorectal cancer, respectively, compared to homozygous wild type carriers. |
Does ischemic preconditioning attenuate renal ischemia-reperfusion injury by inhibiting activation of IKKbeta and inflammatory response? | Renal ischemia-reperfusion (I/R) injury is a major cause of acute renal failure (ARF). The transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated as a key mediator of reperfusion injury. Activation of NF-kappaB is dependent upon the phosphorylation of its inhibitor, IkappaB, by the specific inhibitory kappaB kinase (IKK) subunit, IKKbeta. We hypothesized that ischemic preconditioning (IPC) reduces acute renal damage following I/R injury by inhibiting activation of IKKbeta. As neutrophil gelatinase-associated lipocalin (NGAL), an early predictive biomarker of acute kidney injury, is regulated by NF-kappaB, we approached the relationship between NGAL and IKKbeta. Thirty male Sprague-Dawley rats were randomly divided into 3 groups after right kidney nephrectomy. Group A rats were sham-operated controls. Group B rats were 45-min ischemic in the left renal artery while Group C rats were pre-treated with 3 cycles of 2-min ischemia and 5-min reperfusion. All the rats were sacrificed at 24 h after reperfusion. We harvested kidneys and serum to do further analysis, including histological and functional parameters, expressions of NGAL and IKKbeta in renal tissues. Compared with rats subjected to I/R injury, pre-treated rats had a significant decrease in serum creatinine level (Scr) and tubulointerstitial injury scores (Scr, 86.79 +/- 12.98 vs. 205.89 +/- 19.16 mircomol/l, p < 0.01; tubulointerstitial injury scores, 1.3 +/- 0.48 vs. 3.8 +/- 0.79, p < 0.01). In addition, expressions of IKKbeta (0.95 +/- 0.21 vs. 1.74 +/- 0.17, p < 0.05) and NGAL (1.71 +/- 0.032 vs. 2.66 +/- 0.078, p < 0.05) at renal tubule in pre-treated rats were attenuated significantly compared with rats subjected to ischemia-reperfusion injury. Moreover, our study showed that IKKbeta and NGAL were in positive correlation (R = 0.965 > R(0.01)(30) = 0.448, p < 0.01). | Breast cancer is the leading cause of cancer deaths in women world-wide. In low and middle income countries, where there are no population-based mammographic screening programmes, late presentation is common, and because of inadequate access to optimal treatment, survival rates are poor. Mammographic screening is well-studied in high-income countries in western populations, and because it has been shown to reduce breast cancer mortality, it has become part of the healthcare systems in such countries. However the performance of mammographic screening in a developing country is largely unknown. This study aims to evaluate the performance of mammographic screening in Malaysia, a middle income country, and to compare the stage and surgical treatment of screen-detected and symptomatic breast cancer. A retrospective review of 2510 mammograms performed from Jan to Dec 2010 in a tertiary medical centre is carried out. The three groups identified are the routine (opportunistic) screening group, the targeted (high risk) screening group and the diagnostic group. The performance indicators of each group is calculated, and stage at presentation and treatment between the screening and diagnostic group is analyzed. The cancer detection rate in the opportunistic screening group, targeted screening group, and the symptomatic group is 0.5 %, 1.25 % and 26 % respectively. The proportion of ductal carcinoma in situ is 23.1 % in the two screening groups compared to only 2.5 % in the diagnostic group. Among the opportunistic screening group, the cancer detection rate was 0.2 % in women below 50 years old compared to 0.65 % in women 50 years and above. The performance indicators are within international standards. Early-staged breast cancer (Stage 0-2) were 84.6 % in the screening groups compared to 61.1 % in the diagnostic group. |
Do [ Clinical study on continuous plasma filtration absorption treatment for burn sepsis ]? | To observe the therapeutic effects of continuous plasma filtration absorption (CPFA) treatment on burn sepsis. Thirty burn patients with sepsis hospitalized in Beijing Fengtai You'anmen Hospital from July 2009 to October 2012 were treated by CPFA for twice besides routine treatment. The blood samples were collected at five sites (A, B, C, D, and E, respectively) of blood purification equipment before and after CPFA, before and after hemoabsorption, and before hemofiltration. The plasma levels of TNF-α, IL-1β, IL-6, IL-10, interleukin-1 receptor antagonist (IL-1RA), soluble tumor necrosis factor receptor (sTNFR) I , and sTNFR-II from sites A, C, and E were determined with ELISA before CPFA was performed for the first time, and those from sites B and D were determined with ELISA after CPFA was performed for the first time. Plasma levels of the above-mentioned cytokines from sites A and B were determined with ELISA before CPFA and after CPFA was performed for the second time. The data of plasma levels of IL-1βP3, IL-1RA, sTNFR-I, sTNFR-II, and TNF-α before CPFA and after CPFA was performed for the second time were collected for calculation of the ratios of IL-1RA to IL-1β and sTNFR-I plus sTNFR-II to TNF-α. The expression rate of human leukocyte antigen DR (HLA-DR) on the CD14 positive monocytes, acute physiology and chronic health evaluation (APACHE) II score, body temperature, pulse, respiratory rate, and leukocyte count of patients were evaluated or recorded before CPFA and after CPFA was performed for the second time. Patients'condition was observed. Data were processed with paired t test. The plasma levels of TNF-α, IL-1β, IL-6 and IL-10 from site B after CPFA was performed for the second time were significantly lower than those from site A before CPFA was performed for the first time (with t values respectively 7.05, 5.23, 4.73, 2.37, P values below 0.01). After CPFA was performed for the first time, the plasma levels of TNF-α, IL-1β, and IL-6 from site D were significantly lower than those from site C before CPFA was performed for the first time (with t values respectively 5.48, 2. 17, 1.78, P < 0.05 or P <0.01). The plasma levels of all cytokines were close between site B after CPFA was performed for the first time and site E before CPFA was performed for the first time (with t values from 0.04 to 1.05, P values above 0.05). The plasma levels of TNF-α, IL-1β, and IL-6 from site B after CPFA was performed for the second time were significantly lower than those from site A before CPFA was performed for the second time (with t values from 1.87 to 5.93, P <0.05 or P <0.01). The ratios of IL-1RA to IL-1β and sTNFR-I plus sTNFR-II to TNF-α, and expression rate of HLA-DR were increased significantly after CPFA was performed for the second time as compared with those before CPFA (with t values from 3.99 to 7. 80, P values below 0.01). APACHE II score after CPFA was performed for the second time was 11 ± 6, which was lower than that before CPFA (22 ± 7, t =4.63, P <0.01). After CPFA was performed for the second time, body temperature, pulse, and respiratory rate of patients were improved (with t values from 1.95 to 3.55, P values below 0.05) , and the leukocyte count was significantly decreased (t =4.36, P <0.01) as compared with those before CPFA. All patients survived and were discharged with length of stay of (27 ± 31) d, and no adverse effects occurred during CPFA treatment. | Asymmetric cell division (ACD) is a key process that allows different cell types to be generated at precisely defined times and positions. In Drosophila, neural precursor cells rely heavily on ACD to generate the different cell types in the nervous system. A conserved protein machinery that regulates ACD has been identified in Drosophila, but how this machinery acts to allow the establishment of differential cell fates is not entirely understood. To identify additional proteins required for ACD, we have carried out an in vivo live imaging RNAi screen for genes affecting the asymmetric segregation of Numb in Drosophila sensory organ precursor cells. We identify Banderuola (Bnd), an essential regulator of cell polarization, spindle orientation, and asymmetric protein localization in Drosophila neural precursor cells. Genetic and biochemical experiments show that Bnd acts together with the membrane-associated tumor suppressor Discs-large (Dlg) to establish antagonistic cortical domains during ACD. Inhibiting Bnd strongly enhances the dlg phenotype, causing massive brain tumors upon knockdown of both genes. Because the mammalian homologs of Bnd and Dlg are interacting as well, Bnd function might be conserved in vertebrates, and it might also regulate cell polarity in higher organisms. |
Does disordered eating behavior and mental health correlate among treatment seeking obese women? | Previous research has suggest that obesity is associated with increased risk for psychopathological disorders, however, little is known about which obese patients are most vulnerable to psychopathological disorders. We therefore investigated 126 treatment-seeking obese women to describe eating disorder pathology and mental health correlates, and to identify disordered eating behaviors that may place obese at increased risk for psychopathological disorders. The Structured Clinical Interview for DSM-IV (SCID) was used to identify Eating Disorders (ED). A battery of psychological tests, including the Anxiety Scale Questionnaire (ASQ,) Clinical Depression Questionnaire (CDQ), Eating Disorder Inventory-2 (EDI-2) Eating Attitudes Test-26 (EAT-26) scales and structured clinical interview were administered to all the patients. We analyzed the link between psychopathological disorders and eating attitudes by using both multiple regression analysis and non-parametric correlation. Disordered eating behaviors and emotional behavioral aspects related to Anorexia Nervosa, such as ineffectiveness, are strongly linked to the depression and anxiety in obese subjects. No correlation was found between psychopathological disorders and age or anthropometric measurements. | To investigate by immunohistochemical observation the effects of amniotic membrane (AM) patching on myofibroblastic differentiation and matrix metalloproteinase (MMP) expression in the corneal stroma after an alkali burn in vivo. A corneal alkali burn was made by placing a circular piece of filter paper containing 1 N NaOH on the central cornea of rabbits. Burning was done unilaterally in each rabbit. Immediately after the wounding, in the AM group, AM was sutured onto the cornea and removed on day 1. Rabbits with no AM patching were controls. On day 14, corneas were excised and immunohistochemical observation was carried out using antibodies against alpha-smooth muscle actin (alpha-SMA), vimentin, MMP-1, MMP-2, MMP-9, and membrane-type1 (MT1)-MMP. Observation after Masson trichrome staining was also performed. In the AM group, alpha-SMA positive cells were noticeably fewer, and MMP-2, MMP-9, and MT1-MMP expression was clearly inhibited. Also, collagen fibers were more regularly arranged than in control eyes. The more proximate the cells were to the epithelial side, the fewer alpha-SMA-positive cells were observed in the AM group. |
Are human bocaviruses commonly found in stools of hospitalized children without causal association to acute gastroenteritis? | Human bocaviruses (HBoVs) may be grouped into respiratory (HBoV1) and enteric (HBoV2-4) types. We examined this association of HBoV types and clinical symptoms in 955 children who had acute gastroenteritis (AGE, n = 172), acute respiratory tract infection (ARTI, n = 545) or symptoms of both (n = 238). Both nasal swab and stool specimens were studied for such patients. HBoV1 DNA was detected in 6.2 % of patients with ARTI and 9.2 % of patients with symptoms of both ARTI and AGE, but in only 1.7 % of patients with AGE alone. In about one half of the cases, HBoV1 was detected concomitantly in nasal swab and stool samples. HBoV2 was found in stool samples of patients with AGE (5.8 %), ARTI (5.1 %) and symptoms of both (5.5 %) but only rarely in nasal swabs. HBoV3 was found in the stools, but not in nasal swabs, in 0.6, 1.1 and 0.8 % of patients with, respectively, AGE, ARTI and both. HBoV4 was not found. All but one HBoV-positive stool sample of AGE patients contained a known gastroenteritis virus (rotavirus, norovirus, sapovirus, astrovirus or enteric adenovirus) that was probably responsible for the symptoms of the respective case. Sera of 30 HBoV-positive patients were available, and IgM antibodies for HBoVs were found in ten cases and HBoV DNA in eight of these. | It has been recognized for almost a decade that concentrations of signaling androgens sufficient to activate the androgen receptor are present in castration-resistant prostate cancer tissue. The source of these androgens is highly controversial, with three competing models proposed. We, therefore, wished to determine the androgenic potential of human benign and malignant (hormone-naïve and treated) prostate tissue when incubated with various precursors and examine concomitant changes in enzyme expression. Freshly harvested prostate tissue [benign, hormone-naïve, and hormone-refractory prostate cancer (HRPC)] was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by gas chromatography-mass spectroscopy. Changes in the expression of androgen synthetic and/or degradative enzymes were determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset. Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signaling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone-refractory compared with hormone-naïve cancer. Consistent with this, gene set enrichment analysis of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publicly available expression dataset. Importantly, we found no evidence to support a significant contribution from either the "backdoor" or "5-α dione" pathway. |
Is serum vitamin D associated with non-alcoholic fatty liver disease in Chinese males with normal weight and liver enzymes? | Considering the characterization of vitamin D deficiency as a risk factor of ectopic fat deposition, the association of serum 25-hydroxy vitamin D3 [25(OH)D3] levels with non-alcoholic fatty liver disease (NAFLD) was evaluated in Chinese men with normal body mass index (BMI) and enzyme markers of liver function. A total of 514 participants (22 to 79 years old) with normal BMI and liver enzymes were identified for analysis. Abdominal ultrasound was performed to diagnose NAFLD, and the fatty liver index (FLI) was calculated to quantify liver steatosis. Serum 25(OH)D3 levels were determined by an electrochemiluminescence immunoassay. Among the entire study population, the mean levels of serum 25(OH)D3 were 15.32±5.77 ng/mL. However, when serum 25(OH)D3 levels were compared between non-NAFLD subjects (n=438) and NAFLD subjects (n=76), the latter showed significantly lower levels (15.65±5.89 ng/mL vs 13.46±4.65 ng/mL, P=0.002). In addition, serum 25(OH)D3 levels were found to be significantly correlated with FLI after adjustment for age and BMI (r=-0.108, P=0.014). Logistic regression showed that serum 25(OH)D3 levels were independently correlated with NAFLD (OR: 0.937, 95% CI: 0.884-0.993, P=0.028). Furthermore, stepwise regression analysis revealed that serum 25(OH)D3 levels were inversely associated with FLI (β=-0.055, P=0.040). | Classical conditioning of the eyeblink reflex is a simple form of motor learning which depends on the integrity of the cerebellum. Acquisition of conditioned eyeblink responses is markedly reduced in patients with cerebellar disorders. Noninvasive transcranial direct current stimulation (tDCS) has been reported to modify the excitability of the cerebellar cortex. The aim of the study was to assess whether acquisition of conditioned eyeblink responses (CR) is altered by cerebellar tDCS. A standard delay conditioning paradigm with a 540 ms tone as conditioned stimulus (CS) coterminating with a 100 ms air puff as unconditioned stimulus (US) was used in a total of 30 healthy subjects (18 female, 12 male, mean age 23.4 ± 1.9 years). One hundred paired CS-US trials and 30 extinction CS alone trials were given. tDCS (2 mA intensity, ramp like onset) was applied over the right cerebellar hemisphere ipsilaterally to the US during the acquisition phase. Subjects were randomly assigned to three groups (n = 10) using anodal, cathodal or sham stimulation. The investigator as well as the participants was blinded to the stimulation modality. CR acquisition was significantly enhanced by anodal tDCS (mean total CR incidence 73.4 ± 25.2%) and significantly reduced by cathodal stimulation (12.6 ± 17.2%) compared to sham stimulation (43.8 ± 24.1%). During anodal tDCS CR onset occurred significantly earlier, that is mean onset of responses was shifted closer to CS onset. |
Is focal S100A4 protein expression an independent predictor of development of metastatic disease in cystectomized bladder cancer patients? | The prognosis of patients with apparently localized, operable, muscle-invasive bladder cancer depends to a large extent on the presence or absence of subclinical, microscopic distant metastases at the time of surgery. Expression of the S100A4 protein has been shown to correlate with the risk of metastasis in both animal tumour-model systems and clinical investigations in other tumour types. The purpose of the present study was to investigate the prognostic potential of S100A4 protein expression for predicting distant metastatic relapse in muscle-invasive bladder cancer. We analyzed 108 consecutive patients, treated for transitional cell bladder cancer with preoperative radiotherapy and cystectomy. Pretherapeutic biopsies of the bladder tumours were investigated for immunohistochemical expression of S100A4 protein and results, along with clinical and histopathological data, compared with the pattern of relapses over a 10+ yr follow-up period. Focal S100A4 protein expression emerged as the only significant independent predictor of distant metastatic relapse and distant metastasis-free survival in multivariate analysis. | The physicochemical and biological characteristics of electronegative low-density lipoprotein (LDL) (LDL(-)) from type 2 diabetic patients (DM2), before and after insulin therapy, were studied. Total LDL was subfractionated in LDL(+) (native LDL) and LDL(-) by anion-exchange chromatography. The proportion of LDL(-) was increased in plasma from DM2 patients compared to control subjects (13.8 +/- 4.6% versus 6.1 +/- 2.5, P < 0.05) and was not modified after glycemic optimization (14.0 +/- 5.9%). LDL(-) from DM2 patients presented similar differential characteristics versus LDL(+) than LDL(-) from controls; that is, decreased apoB and oxidizability, and increased triglyceride, nonesterified fatty acids (NEFA), apoE, apoC-III, platelet-activating factor (PAF) acetylhydrolase activity and aggregability. No difference in particle size, antioxidants, malondialdehyde (MDA), fructosamine or glycated low-density lipoprotein (gLDL) was observed between LDL subfractions. Concerning differences between LDL subfractions isolated from DM2 and from control subjects, the former showed increased MDA, fructosamine and gLDL proportion and decreased LDL size and antioxidant content. The only effect of glycemic optimization was a decrease in fructosamine and gLDL in LDL(+) from DM2 subjects. LDL(-) from DM2 patients presented low binding affinity to the low-density lipoprotein receptor (LDLr) in cultured fibroblasts compared to LDL(+) and two- to threefold increased ability to release interleukin-8 (IL-8) and monocyte chemotactic protein 1 (MCP-1) in endothelial cells. |
Is which the optimal bowel preparation for colonoscopy - a meta-analysis? | To assess which bowel preparation agent is most effective. A search of randomized trials between January 1990 and July 2005 was obtained, using MEDLINE and PubMed databases, and the Cochrane Central Register of Controlled Trials. Meta-analysis was performed using the Forest plot review. Sodium phosphate (NaP) was more effective in bowel cleansing than polyethylene glycol (PEG) - odds ratio 0.75 (95%CI: 0.65-0.88; P = 0.0004); and sodium picosulphate (SPS) - odds ratio 0.52 (95%CI: 0.34-0.81; P = 0.004). PEG and SPS were comparable in bowel cleansing ability, odds ratio 1.69 (95%CI: 0.92-3.13; P = 0.09). NaP was more easily completed by patients compared to PEG, odds ratio 0.16 (95%CI: 0.09-0.29; P < 0.00001). More patients were able to complete SPS than PEG, but this was not statistically significant - odds ratio 0.56 (95%CI: 0.28-1.13; P = 0.11). NaP and PEG were comparable in terms of adverse events, odds ratio 0.98 (95%CI: 0.82-1.17; P = 0.81), although NaP resulted in more asymptomatic hypokalaemia and hyperphosphataemia. NaP and SPS appeared to have similar incidence of adverse events. PEG resulted in more adverse events than SPS, odds ratio 3.82 (95%CI: 1.60-9.15; P = 0.003). | Endoplasmic reticulum (ER) stress exerts myocardial oxidative stress, apoptosis, and contractile anomalies, although the precise interplay between ER stress and apoptosis remains elusive. This study was designed to examine the impact of the cysteine-rich free radical scavenger metallothionein on ER stress-induced myocardial contractile defect and underlying mechanisms. Wild-type friendly virus B and transgenic mice with cardiac-specific overexpression of metallothionein were challenged with the ER stress inducer tunicamycin (1 mg/kg, intraperitoneal, 48 h) prior to the assessment of myocardial function, oxidative stress, and apoptosis. Our results revealed that tunicamycin promoted cardiac remodeling (enlarged left ventricular end systolic/diastolic diameters with little changes in left ventricular wall thickness), suppressed fractional shortening and cardiomyocyte contractile function, elevated resting Ca(2+), decreased stimulated Ca(2+) release, prolonged intracellular Ca(2+) clearance, and downregulated sarco(endo)plasmic reticulum Ca(2+)-ATPase levels, the effects of which were negated by metallothionein. Treatment with tunicamycin caused cardiomyocyte mitochondrial injury, as evidenced by decreased mitochondrial membrane potential (∆Ѱm, assessed by JC-1 staining), the effect of which was negated by the antioxidant. Moreover, tunicamycin challenge dramatically facilitated myocardial apoptosis as manifested by increased Bax, caspase 9, and caspase 12 protein levels, as well as elevated caspase 3 activity. Interestingly, metallothionein transgene significantly alleviated tunicamycin-induced myocardial apoptosis. |
Is non-neural tyrosine hydroxylase , via modulation of endocrine pancreatic precursors , required for normal development of beta cells in the mouse pancreas? | Apart from transcription factors, little is known about the molecules that modulate the proliferation and differentiation of pancreatic endocrine cells. The early expression of tyrosine hydroxylase (TH) in a subset of glucagon(+) cells led us to investigate whether catecholamines have a role in beta cell development. We studied the immunohistochemical characteristics of TH-expressing cells in wild-type (Th (+/+) ) mice during early pancreas development, and analysed the endocrine pancreas phenotype of TH-deficient (Th (-/-) ) mice. We also studied the effect of dopamine addition and TH-inhibition on insulin-producing cells in explant cultures. In the mouse pancreas at embryonic day (E)12.5-E13.5, the ∼10% of early glucagon(+) cells that co-expressed TH rarely proliferated and did not express the precursor marker neurogenin 3 at E13.5. The number of insulin(+) cells in the Th (-/-) embryonic pancreas was decreased as compared with wild-type embryos at E13.5. While no changes in pancreatic and duodenal homeobox 1 (PDX1)(+)-progenitor cell number were observed between groups at E12.5, the number of neurogenin 3 and NK2 homeobox 2 (NKX2.2)-expressing cells was reduced in Th (-/-) embryonic pancreas, an effect that occurred in parallel with increased expression of the transcriptional repressor Hes1. The potential role of dopamine as a pro-beta cell stimulus was tested by treating pancreas explants with this catecholamine, which resulted in an increase in total insulin content and insulin(+) cells relative to control explants. | Viral pathogens have not generally been regarded as important causes of severe hospital-acquired pneumonia (HAP), except in patients with hematologic malignancy or transplant recipients. We investigated the role and distribution of viruses in adult with severe HAP who required intensive care. From March 2010 to February 2012, adult patients with severe HAP required admission to the intensive care unit (ICU), 28-bed medical ICU in a tertiary care hospital, were prospectively enrolled. Respiratory viruses were detected using multiplex reverse-transcription polymerase chain reaction and/or shell vial culture. A total of 262 patients were enrolled and 107 patients (40.8%) underwent bronchoscopic BAL for etiologic diagnosis. One hundred and fifty-six patients (59.5%) had bacterial infections and 59 patients (22.5%) had viral infections. Viruses were detected in BAL fluid specimens of 37 patients (62.7%, 37/59). The most commonly identified viruses were respiratory syncytial virus and parainfluenza virus (both 27.1%, 16/59), followed by rhinovirus (25.4%, 15/59), and influenza virus (16.9%, 10/59). Twenty-one patients (8.0%, 21/262) had bacterial-viral coinfections and Staphylococcus aureus was the most commonly coexisting bacteria (n = 10). Viral infection in non-immunocompromised patients was not uncommon (11.1%, 16/143), although it was not as frequent as that in immunocompromised patients (36.4%, 43/119). Non-immunocompromised patients were significantly older than immunocompromised patients and had significantly higher rates of underlying chronic obstructive pulmonary disease, tuberculous destroyed lung and chronic kidney disease. The 28 day mortalities of patients with bacterial infections, viral infections and bacterial-viral coinfections were not significantly different (29.5%, 35.6% and 19.0%, respectively; p = 0.321). |
Does geopropolis from Melipona scutellaris decrease the mechanical inflammatory hypernociception by inhibiting the production of IL-1β and TNF-α? | The pharmacological activity of geopropolis collected by stingless bees (important and threatened pollinators), a product widely used in folk medicine by several communities in Brazil, especially in the Northeast Region, needs to be studied. The aim of this study was to evaluate the antinociceptive activity of Melipona scutellaris geopropolis (stingless bee) using different models of nociception. The antinociceptive activity of the ethanolic extract of geopropolis (EEGP) and fractions was evaluated using writhing induced by acetic acid, formalin test, carrageenan-induced hypernociception, and quantification of IL-1β and TNF-α. The chemical composition was assessed by quantification of total flavonoids and phenolic compounds. EEGP and its hexane and aqueous fractions showed antinociceptive activity. Both EEGP and its aqueous fraction presented activity in the mechanical inflammatory hypernociception induced by the carrageenan model, an effect mediated by the inhibition of IL-1β and TNF-α. The chemical composition of EEGP and its hexane and aqueous fractions showed a significant presence of phenolic compounds and absence of flavonoids. | Monocytes are cellular components of wound repair, arteriogenesis, and atherogenesis. Vascular endothelial growth factor (VEGF)-A and placental growth factor recruit monocytes to sites of arteriogenesis via stimulation of VEGF receptor-1 (VEGFR-1). The chemotactic response of monocytes to VEGF-A is attenuated in individuals with diabetes mellitus (DM). This VEGF resistance correlates with impaired collateral growth. The aim of this study is to elucidate the molecular basis of VEGF resistance and impaired monocyte response in DM. Phosphorylation of Akt, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) could be stimulated with either placental growth factor-1 or VEGF-A in monocytes from non-DM but not DM individuals. In contrast, formyl-methionyl-leucyl-phenylalanine caused a comparable activation of these molecules in both DM and non-DM monocytes. Baseline phosphorylation of Akt, p38, and ERK1/2 was significantly elevated in monocytes from DM compared with non-DM subjects. Of note, H(2)O(2) activated Akt, p38, and ERK1/2 in non-DM monocytes ex vivo. Protein tyrosine phosphatases had stronger oxidative modifications in monocytes from DM than from non-DM individuals, which reflects functional protein tyrosine phosphatase inhibition, similar to that seen after H(2)O(2) challenge. Overall, protein tyrosine phosphatase and protein tyrosine phosphatase-1B activity were reduced in DM monocytes. DM monocytes revealed higher expression of the receptor for advanced glycation end products. Stimulation with advanced glycation end products ligands resulted in activation of non-DM monocytes and inhibition of VEGFR-1-mediated chemotaxis. The elevated baseline phosphorylation/activation of Akt, p38, and ERK1/2 in DM monocytes likely causes the resistance to further stimulation with specific stimuli such as VEGF-A, revealing a molecular explanation of the DM-related signal transduction defect. |
Does [ Tiam1 expression correlate with the biological behavior of human colorectal carcinoma cells ]? | To investigate whether the Tiam1 gene expression enhances the invasive and metastatic capabilities of colorectal carcinoma cells. Endogenous expression of Tiam1 in five colorectal carcinoma cell lines was investigated by RT-PCR. Tiam1/C1199HA cDNA was transfected into HT29, a colorectal carcinoma cell line without endogenous Tiam1 expression. RNA and protein expression of Tiam1 gene in the transfectants were detected by RT-PCR, immunohistochemistry and Western blot respectively. The biological behaviors of the transfectants were investigated by MTT and in-vitro invasion assays. Tiam1 gene was highly expressed in LoVo and SW620 cells. Low level expression was seen in HCT116 and SW480 and no expression was found in HT29. Transfection of Tiam1 significantly increased the proliferation of HT29 cells along with markedly enhanced in-vitro invasion and metastasis. | Erectile dysfunction (ED) and atherosclerotic cardiovascular disease (ASCVD) share many common risk factors, and vascular ED is a marker for increased ASCVD risk. Low 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with increased ASCVD risk, but less is known regarding the relationship of low 25(OH)D with ED. We determined whether 25(OH)D deficiency is associated with ED independent of ASCVD risk factors. We performed cross-sectional analyses of 3390 men aged ≥20 years free of ASCVD who participated in NHANES 2001-2004. Serum 25(OH)D was measured by the DiaSorin radioimmunoassay; deficiency was defined as levels <20 ng/ml (<50 nmol/L). Self-reported ED, assessed by a single validated question, was defined as men who reported being "never" or "sometimes able" to maintain an erection. We assessed the relationship between 25(OH)D deficiency and ED prevalence using adjusted Poisson regression methods. After accounting for NHANES sampling, the weighted prevalence of 25(OH)D deficiency and of ED were 30% and 15.2%, respectively. 25(OH)D levels were lower in men with vs. those without ED (mean 22.8 vs 24.3 ng/mL, respectively; p = 0.0005). After adjusting for lifestyle variables, comorbidities, and medication use, men with 25(OH)D deficiency had a higher prevalence of ED compared to those with levels ≥30 ng/ml (Prevalence Ratio 1.30, 95% CI 1.08-1.57). |
Does trichostatin A inhibit Retinal Pigmented Epithelium Activation in an In Vitro Model of Proliferative Vitreoretinopathy? | Proliferative vitreoretinopathy (PVR) is a blinding disorder that develops after a retinal tear or detachment. Activation of the retinal pigmented epithelium (RPE) is implicated in PVR; however, the mechanisms leading to enhanced RPE proliferation, migration, and contraction remain largely unknown. This study utilized an in vitro model of PVR to investigate the role of acetylation in RPE activation and its contribution to the progression of this disease. ARPE-19 cells, primary cultures of porcine RPE, and induced pluripotent stem cell-derived RPE (iPS-RPE) were utilized for cellular and molecular analyses. Cells treated with transforming growth factor beta 2 (TGFβ2; 10 ng/mL) alone or in the presence of the broad-spectrum histone deacetylase (HDAC) inhibitor, trichostatin A (TSA; 0.1 μM), were assessed for contraction and migration through collagen contraction and scratch assays, respectively. Western blotting and immunofluorescence analysis were performed to assess α-smooth muscle actin (α-SMA) and β-catenin expression after TGFβ2 treatment alone or in combination with TSA. TGFβ2 significantly increased RPE cell contraction in collagen matrix and this effect was inhibited in the presence of TSA (0.1 μM). In agreement with these data, immunofluorescence analysis of TSA-treated iPS-RPE wounded monolayers revealed decreased α-SMA as compared with control. Scratch assays to assess wound healing revealed TSA inhibited TGFβ2-mediated iPS-RPE cell migration. | Environmental and socio-demographic factors can influence the variation of the human sex ratio at birth (SRB = the ratio of males to males plus females). In particular, findings of seasonal, parental education, birth order, and maternal age effects on the SRB are not always in agreement, and a number of works report minimal variation. Here, we investigated the seasonality of SRB in academic and non-academic mothers employed at the University of Vienna, and who gave birth between 1963 and 2000 (n = 1932 births). All data were available from an anonymous employee database. Both groups, academic and non-academic mothers do not differ between their overall SRB. In academic mothers the SRB is significantly (P = 0.004) increased during the springtime and decreased during the summertime. Although in non-academic mothers the trend is comparable, it is far less pronounced and not significant (P = 0.345). When a multiple logistic model was applied to the data of academic mothers the only significant influencing factor on the SRB is the season, while birth order of children and mothers' age at childbirth has no effect. None of the three independent variables influence the SRB in non-academic mothers. These findings suggest a more flexible SRB rate in academic mothers than in non-academics within the seasons. |
Does whole Rye Consumption improve Blood and Liver n-3 Fatty Acid Profile and Gut Microbiota Composition in Rats? | Whole rye (WR) consumption seems to be associated with beneficial health effects. Although rye fiber and polyphenols are thought to be bioactive, the mechanisms behind the health effects of WR have yet to be fully identified. This study in rats was designed to investigate whether WR can influence the metabolism of n-3 and n-6 long-chain fatty acids (LCFA) and gut microbiota composition. For 12 weeks, rats were fed a diet containing either 50% WR or 50% refined rye (RR). The WR diet provided more fiber (+21%) and polyphenols (+29%) than the RR diet. Fat intake was the same in both diets and particularly involved similar amounts of essential (18-carbon) n-3 and n-6 LCFAs. The WR diet significantly increased the 24-hour urinary excretion of polyphenol metabolites-including enterolactone-compared with the RR diet. The WR rats had significantly more n-3 LCFA-in particular, eicosapentanoic (EPA) and docosahexanoic (DHA) acids-in their plasma and liver. Compared with the RR diet, the WR diet brought significant changes in gut microbiota composition, with increased diversity in the feces (Shannon and Simpson indices), decreased Firmicutes/Bacteroidetes ratio and decreased proportions of uncultured Clostridiales cluster IA and Clostridium cluster IV in the feces. In contrast, no difference was found between groups with regards to cecum microbiota. The WR rats had lower concentrations of total short-chain fatty acids (SCFA) in cecum and feces (p<0.05). Finally, acetate was lower (p<0.001) in the cecum of WR rats while butyrate was lower (p<0.05) in the feces of WR rats. | Therapeutic intervention during the early stages of an intracerebral hemorrhage (ICH) might have value in improving clinical outcomes. During the 73-site International Recombinant Activated Factor VII Intracerebral Hemorrhage Trial, CT techniques were used to monitor the change in hematoma volume in response to treatment. The use of CT imaging technology served 3 functions: to provide accurate measurements of the change in hematoma volume, intraventricular volume (IVH), and edema volume; to evaluate the use of CT scans as a predictor of patient outcomes; and to demonstrate that hematoma volume can serve as a surrogate marker for ICH clinical progression. The multicenter clinical trial received institutional review board approval and obtained informed consent from the patient or a legally acceptable representative (waived in a few cases of incapacity, according to local and national regulations). CT scans were used to quantify volumes of hemorrhage and to monitor evolution over a 72-hour period in patients with ICH treated with placebo or 40, 80, or 160 microg/kg of recombinant activated factor VII (rFVIIa). CT image data were transmitted digitally to an imaging laboratory and analyzed by 2 readers masked to patient and treatment data, by using Analyze software, a fully integrated toolkit for interactive display, processing, and measurement of biomedical image data. The use of this software enabled the evaluation of intraclass variability of CT scan interpretations. Interpretations of ICH and IVH volumes of CT scans in patients treated in this study showed minimal intraclass variability. Variability was greatest for interpretations of edema volume. |
Does calcium sensing receptor promote cardiac fibroblast proliferation and extracellular matrix secretion? | Calcium-sensing receptor (CaR) acts as a G protein coupled receptor that mediates the increase of the intracellular Ca(2+) concentration. The expression of CaR has been confirmed in various cell types, including cardiomyocytes, smooth muscle cells, neurons and vascular endothelial cells. However, whether CaR is expressed and functions in cardiac fibroblasts has remained unknown. The present study investigated whether CaR played a role in cardiac fibroblast proliferation and extracellular matrix (ECM) secretion, both in cultured rat neonatal cardiac fibroblasts and in a model of cardiac hypertrophy induced by isoproterenol (ISO). Immunofluorescence, immunohistochemistry and Western blot analysis revealed the presence of CaR in cardiac fibroblasts. Calcium and calindol, a specific activator of CaR, elevated the intracellular calcium concentration in cardiac fibroblasts. Pretreatment of cardiac fibroblasts with calhex231, a specific inhibitor of CaR, U73122 and 2-APB attenuated the calindol- and extracellular calcium-induced increase in intracellular calcium ([Ca(2+)]i). Cardiac fibroblast proliferation and migration were assessed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), cell count and the cell scratch assay. ECM production was detected by expression of matrix metalloproteinase-3 and -9 (MMP-3 and -9). Activation of CaR promoted cardiac fibroblast proliferation and migration and ECM secretion. More importantly, calhex231, suppressed cardiac fibroblast proliferation and migration and MMP-3 and -9 expression. To further investigate the effect of CaR on cardiac fibrosis, a model of ISO-induced cardiac hypertrophy was established. Pretreatment with calhex231 prevented cardiac fibrosis and decreased the expression of MMP-3 and -9 expression. | Crohn's disease is a heterogeneous inflammatory bowel disease. The impact of age at diagnosis on the clinical course of patients varies widely as reported in the Western literature. Using the Vienna Classification, we seek to determine whether young Crohn's disease patients in an Asian population followed a different clinical course than old patients. The case records of 100 Crohn's disease patients who were treated at the Inflammatory Bowel Disease Center, Singapore General Hospital, were studied retrospectively. The age group and location of disease and behavior according to the Vienna classification were determined at diagnosis. A1 group (age <40 years) defined as "young" and A2 group (age > or =40) defined as "old" contained 65 and 35 patients, respectively. Median age for the young group was 27.4 years and that for the old group was 52.6 years. Of the young patients, 66.7% flared at least once compared with 28.6% of the old patients, odds ratio of 5.0 (P < 0.001). Young patients were more likely to be steroid dependent (20.0% of A1 versus 8.6% of A2, P = 0.14), received azathioprine (38.5% of A1 versus 5.7% of A2, P < 0.001) and experienced complications (31% of A1 versus 20% of A2, P = 0.25)-numerically higher rates that did not reach statistical significance. There was no significant difference between the age groups for the location and behavior of disease as well as requirement for surgery. |
Does a pepper MSRB2 gene confer drought tolerance in rice through the protection of chloroplast-targeted genes? | The perturbation of the steady state of reactive oxygen species (ROS) due to biotic and abiotic stresses in a plant could lead to protein denaturation through the modification of amino acid residues, including the oxidation of methionine residues. Methionine sulfoxide reductases (MSRs) catalyze the reduction of methionine sulfoxide back to the methionine residue. To assess the role of this enzyme, we generated transgenic rice using a pepper CaMSRB2 gene under the control of the rice Rab21 (responsive to ABA protein 21) promoter with/without a selection marker, the bar gene. A drought resistance test on transgenic plants showed that CaMSRB2 confers drought tolerance to rice, as evidenced by less oxidative stress symptoms and a strengthened PSII quantum yield under stress conditions, and increased survival rate and chlorophyll index after the re-watering. The results from immunoblotting using a methionine sulfoxide antibody and nano-LC-MS/MS spectrometry suggest that porphobilinogen deaminase (PBGD), which is involved in chlorophyll synthesis, is a putative target of CaMSRB2. The oxidized methionine content of PBGD expressed in E. coli increased in the presence of H2O2, and the Met-95 and Met-227 residues of PBGD were reduced by CaMSRB2 in the presence of dithiothreitol (DTT). An expression profiling analysis of the overexpression lines also suggested that photosystems are less severely affected by drought stress. | Exclusion of macroprolactinaemia, a well-recognised interference, as the cause of hyperprolactinaemia is essential to avoid potential misdiagnosis and mismanagement of patients. We have derived gender-specific serum total and post-polyethylene glycol (PEG) precipitation monomeric reference ranges for the recently re-standardised Abbott Architect prolactin assay. Prolactin was measured in serum samples obtained from males (n=49) and females (n=52) using the current Abbott Architect immunoassay pre- and post-PEG precipitation. Gender-specific reference ranges were derived for total and monomeric (post-PEG) prolactin. Routine patients' samples (n=175) with a serum total prolactin >700 mIU/L were screened for macroprolactinaemia to assess classification compared with our previous post-PEG precipitation percentage recovery-based approach. Reference ranges for serum total prolactin were 58-419 mIU/L (male) and 63-561 mIU/L (female). Male and female monomeric prolactin reference ranges were 32-309 mIU/L and 39-422 mIU/L, respectively. Mean (SD) post-PEG percentage recovery of the IS 84/500 prolactin standard was 80 (2.3)%. Of 175 patients' samples screened for macroprolactinaemia, 149 had monomeric prolactin concentrations (median monomeric prolactin=1035 mIU/L; median recovery=83%) above the gender-specific reference range. Monomeric prolactin concentrations (median monomeric prolactin=162 mIU/L; median recovery=20%) in the remaining 26 were within the reference ranges. One patient classified as macroprolactin positive and another classified as macroprolactin negative would not have been identified as such using the previous recovery-based approach. |
Does hIV Distal Neuropathic Pain be Associated with Smaller Ventral Posterior Cingulate Cortex? | Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller. HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images. Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain. | In the absence of facilities and expertise for laparoscopic bile duct exploration (LBDE), most patients with suspected ductal calculi undergo preoperative endoscopic duct clearance. Intraoperative cholangiography (IOC) is not performed at the subsequent laparoscopic cholecystectomy. This study aimed to investigate the rate of successful duct clearance after simple transcystic manipulations. This prospective study investigated 1,408 patients over 13 years in a unit practicing single-session management of biliary calculi. For the great majority, IOC was attempted. Abnormalities were dealt with by flushing of the duct, glucagon injection, Dormia basket trawling, choledochoscopic transcystic exploration, or choledochotomy. Of 1,056 cholangiograms performed (75%), 287 were abnormal (27.2%). Surgical trainees, operating under supervision, successfully performed 24% of all cholangiograms. Of 396 patients admitted with biliary emergencies, 94.1% had abnormal cholangiograms. Of the 287 patients with abnormal IOCs, 9.4% required no intervention, 18% were clear after glucagon and flushing, and 13% were cleared using Dormia basket trawling under fluoroscopy. A total of 95 patients required formal LBDE, and 2 required postoperative endoscopic retrograde cholangiopancreatography (ERCP). No postoperative ERCP for retained stones was required after simple transcystic manipulation. Eight conversions occurred, one during a transcystic exploration. Follow-up evaluation continued for as long as 6 years in some cases. Two patients had recurrent stones after LBDE and a clear postoperative tube cholangiogram. |
Do budesonide and formoterol inhibit inflammatory mediator production by bronchial epithelial cells infected with rhinovirus? | Rhinoviruses (RVs) are responsible for the majority of acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations. RVs infect the lower airways and induce the production of pro-inflammatory and remodelling-associated mediators. Budesonide (BUD) and formoterol (FORM) synergize in controlling asthma and COPD exacerbations; however, their effects on virus-induced inflammation and remodelling are less known. We investigated whether BUD and FORM synergize in suppressing RV-induced inflammation and remodelling in the airways. In vitro models of RV infection of BEAS-2B and primary normal human bronchial epithelial (NHBE) cells were used. We assessed the effects of individual and combined drugs administered post-infection, at a clinically relevant concentration range (10(-6)-10(-10) m), on the production of CCL5, CXCL10, CXCL8, IL-6 and the remodelling-associated VEGF and bFGF, using ELISA and RT-PCR. BUD effectively suppressed RV-mediated induction of all mediators studied, in a concentration-dependent manner. FORM alone suppressed the production of CXCL8 and bFGF. The combination of BUD and FORM had concentration-dependent, additive or synergistic effects in the suppression of RV-induced CCL5, CXCL8 and CXCL10 in both cell types as well as VEGF in NHBE only. Combination treatment also resulted in an enhanced suppression of RV-induced IL-6, and CCL5 at the mRNA level as compared with BUD or FORM alone. | Both Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD) might increase the risk of suicidal behavior. The aim of this study was to assess the relationship between personality dimensions specifically involved in suicidal vulnerability and PMS/PMDD. We collected data from 232 women consecutively hospitalized after a suicide attempt. We examined the relationship between impulsivity, aggressiveness/hostility, hopelessness, trait anger, affect intensity, emotional lability, and PMS/PMDD. Notably, we created an algorithm from the shortened Premenstrual Assessment form in order to assess PMDD status. The proportions of PMS and PMDD among female suicide attempters were 50% and 23% respectively. Women with PMS or PMDD were more likely to endorse most of these personality traits to than those without even after controlling for potential confounders. We found an impulsive-aggressive pattern of personality in women with PMS or PMDD, independently from the time of the menstrual cycle. Interestingly, trait anger remained associated with both PMS and PMDD independently of every other personality traits. The higher the anger level, the higher the risk was to suffer from both PMS and PMDD. |
Is second measurement of morning systolic blood pressure more closely associated with albuminuria? | It is important to control blood pressure as well as to control blood glucose for the prevention of diabetic nephropathy. However, to our knowledge, there are no reports investigating which blood pressure, including morning, evening and clinic, is more closely associated with albuminuria and whether one measurement is sufficient or not in patients with Type 2 diabetes. We measured morning, evening and clinic blood pressure and compared the area under the curve (AUC) of blood pressure for urinary albumin excretion equal to or more than 30 mg/g creatinine using receiver-operating characteristic curve analyses and odds ratio for albuminuria defined as urinary albumin excretion equal to or more than 30 mg/g creatinine in 858 patients with Type 2 diabetes. Odds ratio (95% confidence interval (CI)) of morning, evening and clinic systolic blood pressure for albuminuria was 1.034 (1.024 - 1.044), 1.033 (1.023 - 1.043) and 1.013 (1.055 - 1.021), respectively (p < 0.001 in all), and AUC of morning, evening and clinic systolic blood pressure was 0.644 (0.628 - 0.700) (p < 0.001 vs. clinic), 0.660 (0.623 - 0.696) (p < 0.001 vs. clinic) and 0.597 (0.559 - 0.636), respectively. AUC of the second morning systolic blood pressure was greater than the first (p = 0.033). | 17β-Hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours. An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry. Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19-0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54-2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients. |
Does helicobacter pylori eradication prevent recurrence after simple closure of perforated duodenal ulcer? | Evidence remains inconclusive as to whether eradication of Helicobacter pylori prevents ulcer relapse after simple closure of a perforated duodenal ulcer. This study was conducted to determine the effect of H. pylori eradication using a quadruple drug regimen along with a probiotic on ulcer recurrence after perforation closure. A total of 93 patients who had presented with perforated duodenal ulcer and had a simple closure of a duodenal perforation comprised the study group. Three months postoperatively, patients who were found to be positive for H. pylori infection (n = 60) were administered quadruple therapy consisting of omeprazole, clarithromycin, amoxicillin and colloidal bismuth subcitrate for 10 days along with the probiotic Lactobacillus sporogenes for 14 days. Diagnosis of H. pylori was carried out by urease test and histology. Patients were followed for 18 months. Recurrence of ulcer was analyzed for correlation with H. pylori status. Of 60 patients who received H. pylori eradication therapy, 53 were available for subsequent follow up. H. pylori eradication was achieved in 43/53 (81.1%) patients. The ulcer recurrence in the eradicated group was 18.6% (8/43) compared to 70% (7/10) in the noneradicated group (P = 0.003). | The conversion of cortisol (F) to cortisone (E) is catalyzed by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). Children suffering from chronic renal failure (CRF) have a decreased activity of 11beta-HSD2 contributing to increased arterial blood pressure. The objective was to investigate whether a normal conversion of F to E is achieved after renal transplantation (TX) in children. Fifteen children with CRF, 17 children with steroid-free immunosuppression after TX, and 18 healthy controls (CO) were enrolled. The activity of 11beta-HSD2 in plasma was calculated using the ratio of F/E determined by tandem mass spectrometry, the ratio of tetrahydrocortisol (THF) +5alpha-tetrahydrocortisol (5alphaTHF) in urine determined by gas chromatography/mass spectrometry, and the ratio of (THF +5alphaTHF)/tetrahydrocortisone (THE) in urine determined by tandem mass spectrometry. The F/E ratio (mean +/- S.D./S.E.M.) was significantly higher in CRF and TX (5.6 +/- 1.9/0.6, 7.12 +/- 3.1/0.9) than in CO (1.18 +/- 0.2/0.03, P < 0.0001) groups. The (THF + 5alphaTHF)/THE ratio in CRF (1.19 +/- 1.1/0.5) and TX (1.19 +/- 0.1/0.5) groups was significantly higher than in controls (0.21 +/- 0.05/0.18, P < 0.0001). Positive correlations between plasma and urinary ratios (P = 0.0004. R(2) = 0.73 in CRF, P = 0.0013, R(2) = 0.56 in TX, P < 0.0001, R(2) = 0.66 in CO) were found, whereas significant correlations between F/E or (THF + 5alphaTHF)/THE ratios and blood pressure, the number of antihypertensive drugs taken or creatinine clearance could not be found. |
Are plasma PCSK9 levels significantly modified by statins and fibrates in humans? | Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men. Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6x vs 1.5x, respectively at 10 muM), while fenofibrate did not induce changes in either. | . We aimed to evaluate the effectiveness of a multifaceted intervention, targeting staff-patient communication, in improving emergency department patient satisfaction. We undertook a pre- and post-intervention study in a university-affiliated emergency department, over a 12-month period. The intervention included communication workshops, a patient education film, and a patient liaison nurse. At the patient level, the patient liaison nurse ensured optimal staff-patient community communication and played a role in staff communication education. The intervention was evaluated using patient surveys (containing general and communication-specific satisfaction items scored out of 100), complaint rates, and patient liaison nurse activity data. A total of 321 and 545 patients returned questionnaires in the pre- and post-intervention periods, respectively. Significant improvements were observed in patients' perceptions of being 'informed about delays' [score difference, 5.3; 95% confidence interval (CI), 0.6-10.0], that 'staff cared about them as a person' (difference, 4.4; 95% CI, 0.7-8.1), the overall emergency department facility assessment (difference, 3.9; 95% CI, 0.4-7.5) and overall emergency department care (difference, 3.8; 95% CI, 0.3-7.3). Non-significant improvements were seen in all other satisfaction items. In the post-intervention period, there was a 22.5% (95% CI, 14.6-32.8) decrease in the number of complaints received and a decrease in the complaint rate of 0.7 (95% CI, -0.3 to 1.6) complaints per 1000 patients. The patient liaison nurse activities included orientation of the patient including (i) explanation of tests, procedures, and delays; (ii) communication with a range of hospital staff; and (iii) general comfort measures including analgesia quality control. |
Does apelin stimulate myosin light chain phosphorylation in vascular smooth muscle cells? | Physiological roles of apelin and its specific receptor APJ signaling were investigated in vascular smooth muscle cells (VSMCs). The present study determined whether apelin activates myosin light chain (MLC), a major regulatory event in initiating smooth muscle contraction. To assess MLC activation, we performed Western blot and immunohistochemical studies using an antibody against the phospho-MLC. In VSMCs, apelin induces the phosphorylation of MLC in a concentration-dependent manner with a peak at 2 minutes. Pretreatment of VSMCs with pertussis toxin abolishes the apelin-induced phosphorylation of MLC. Inhibition of protein kinase C (PKC) with GF-109203X markedly attenuated the apelin-induced MLC phosphorylation. In addition, methylisobutyl amiloride, a specific inhibitor of the Na+/H+ exchanger (NHE), and KB-R7943, a potent inhibitor for the reverse mode of the Na+/Ca2+ exchanger (NCX), significantly suppressed the action of apelin. In wild-type mice, apelin phosphorylates MLC in vascular tissue, whereas it had no response in APJ-deficient mice by Western blot and immunohistochemistry. Apelin-induced phosphorylation of MLC was accompanied with myosin phosphatase target subunit phosphorylation. | The incidence of thyroid cancer is increasing. As such, the number of survivors is rising, and it has been shown that their quality of life (QOL) is worse than expected. Using results from the North American Thyroid Cancer Survivorship Study (NATCSS), a large-scale survivorship study, we aim to compare the QOL of thyroid cancer survivors to the QOL of survivors of other types of cancer. The NATCSS assessed QOL overall and in four subcategories: physical, psychological, social, and spiritual well-being using the QOL-Cancer Survivor (QOL-CS) instrument. Studies that used the QOL-CS to evaluate survivors of other types of cancers were compared to the NATCSS findings using two-tailed t tests. We compared results from NATCSS to QOL survivorship studies in colon, glioma, breast, and gynecologic cancer. The mean overall QOL in NATCSS was 5.56 (on a scale of 0-10, where 10 is the best). Overall QOL of patients with thyroid cancer was similar to that of patients with colon cancer (mean 5.20, p = 0.13), glioma (mean 5.96, p = 0.23), and gynecologic cancer (mean 5.59, p = 0.43). It was worse than patients surveyed with breast cancer (mean 6.51, p < 0.01). |
Does direct current reduce wound edema after full-thickness burn injury in rats? | To observe the effect of 4 and 40 microA direct current (DC) on edema formation after burn injury in rats. Silver-nylon wound dressings were used as either anodes (-) or cathodes (+) on 20% total body surface area full-thickness scalds in anesthetized male Sprague-Dawley rats. Untreated burned rats and rats treated with silver-nylon dressings without current were used as controls. Immediately applied, continuous DC reduced burn edema by 17 to 48% at different times up to 48 hours postburn (p < 0.001). Neither reversal of electrode polarity nor change in current density had any significant effect on the results of treatment. Starting treatment during the first 8 hours postburn produced the least edema accumulation, but the reduction was significant even when DC was applied 36 hours afterburn. If started immediately after injury, treatment had to be continued a minimum of 8 hours to be most effective. | To study serum levels of placental protein 14 (PP14) in relation to endometrial function in women with a history of habitual abortion. Prospective study. Departments I and II of Obstetrics and Gynecology, University Central Hospital of Helsinki, Helsinki, Finland. Fifty patients (26 primary and 24 secondary habitual aborters) and 38 controls without a history of abortion studied during a regular cycle. Habitual aborters as a whole or when subgrouped into those with normal cycles (n = 40) or with a luteal phase defect (LPD; n = 10) and control women demonstrated a distinct increase in PP14 levels from late follicular to late luteal phases. In the luteal phase, serum PP14 levels were lower in the patients than in the controls (27.2 +/- 3.1 versus 48.5 +/- 10.1 micrograms/L), but the differences in PP14 levels between habitual aborters with or without LPD was not significant (16.3 +/- 4.3 versus 29.9 +/- 3.7 micrograms/L). |
Does patatin-related phospholipase pPLAIIIδ influence auxin-responsive cell morphology and organ size in Arabidopsis and Brassica napus? | The members of the patatin-related phospholipase subfamily III (pPLAIIIs) have been implicated in the auxin response. However, it is not clear whether and how these genes affect plant and cell morphogenesis. Here, we studied the roles of the patatin-related phospholipase pPLAIIIδ in auxin-responsive cell morphology and organ size in Arabidopsis and Brassica napus. We show that overexpression of pPLAIIIδ inhibited longitudinal growth but promoted transverse growth in most organs of Arabidopsis and Brassica napus. Compared to wild-type plants, pPLAIIIδ-KO plants exhibited enhanced cell elongation in hypocotyls, and pPLAIIIδ-OE plants displayed broadened radial cell growth of hypocotyl and reduced leaf pavement cell polarity. For the hypocotyl phenotype in pPLAIIIδ mutants, which resembles the "triple response" to ethylene, we examined the expression of the ACS and ACO genes involved in ethylene biosynthesis and found that ACS4 and ACS5 were up-regulated by 2.5-fold on average in two OE lines compared with WT plants. The endogenous auxin distribution was disturbed in plants with altered pPLAIIIδ expression. pPLAIIIδ-OE and KO plants exhibited different sensitivities to indole-3-acetic acid-promoted hypocotyl elongation in both light and dark conditions. Gene expression analysis of auxin-induced genes in the dark showed that OE plants maintained a higher auxin response compared with WT and KO plants after treatment with 1 μM IAA for 12 h. Following treatment with 10 μM IAA for 30 min in the light, early auxin-induced genes were significantly up-regulated in two OE plant lines. | To examine the relationship between and impact of spontaneous bacteria peritonitis (SBP) and renal failure requiring dialysis in waitlisted liver transplant (LT) candidates. Renal failure is a common and severe complication in cirrhotic patients with SBP. Approximately one-third of patients with SBP develop renal failure despite treatment of infection. However, the incidence of renal failure requiring dialysis in LT waitlisted patients who have developed SBP is unknown. The high mortality observed in this group has also raised debate about resource utilization in the care of these patients. Data from the United Network for Organ Sharing Standard Transplant and Research files were collected retrospectively between 1994 and 2012. The primary endpoint measured was first time initiation of dialysis while on the LT wait list. Secondary endpoints included waitlist time and mortality on wait list. A total of 42,085 patients were included. SBP at time of listing was diagnosed in 2,352 patients (5.6%) and first time initiation of dialysis while on the wait list occurred in 2,367 patients (6.2%). Unadjusted OR for requiring dialysis for patients listed with SBP was 1.66 (p < 0.001). When controlled for age, gender, BMI, diabetes mellitus, baseline creatinine, MELD score, serum albumin at listing, the adjusted OR for dialysis was 1.24 (p = 0.007) in waitlisted patients with SBP. Patients with SBP at time of listing had a mean waitlist time 142.1 d vs. 198.7 d in non-SBP patients (p < 0.001). |
Is prehydration effective for rapid control of recalcitrant atopic dermatitis? | Skin care remains a key component in atopic dermatitis (AD) management; there are no data available guiding optimal bathing recommendations. This study aims to determine whether 15-minute to 20-minute baths followed by topical corticosteroid application (prehydration therapy) are effective for clearing moderate to severe AD. In the Oregon Health & Science University outpatient dermatology clinic, a retrospective review was done of the health records of patients with AD seen first between January 1, 2007, and December 31, 2011, who were then reevaluated within 1 to 3 weeks of starting the therapy. Qualifying patients underwent the prehydration regimen and were reevaluated. The primary outcome was therapeutic response using the Investigators' Global Assessment Scale. Secondary outcomes were measured using the dynamic Treatment Response Scale. Of 110 distinct electronic records, 35 patients were excluded. At the initial visit, 75 patients were evaluated with the Investigators' Global Assessment Scale. Forty-eight patients (64%) were severe, and 27 patients (36%) were moderate. All subjects began prehydration therapy followed by topical corticosteroid. At follow-up visit in 1 to 3 weeks when using the patient's or provider's assessment of treatment response, 59 patients (79%) had marked improvement, and 3 patients (4%) were clear. | Unloading of the rodent heart activates the fetal gene program, decreases peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARalpha-regulated gene expression (MCAD), and induces cardiomyocyte atrophy. NF-kappaB regulates the fetal gene program and PPARalpha-regulated gene expression during cardiac hypertrophy and induces atrophy in skeletal muscle. Our objective was to test the hypothesis that NF-kappaB is the regulator for activation of the fetal gene program, for downregulation of PPARalpha and PPARalpha-regulated gene expression, and for cardiomyocyte atrophy in the heart subjected to mechanical unloading. Activation of the inhibitory kappa B kinase beta (IKKbeta)/NF-kappaB pathways were measured in the heterotopically transplanted rat heart using Western blotting of total and phospho-IKKbeta and using transcription factor ELISA's for the five members of the NF-kappaB family (p65 (Rel A), p105/p50, c-Rel, RelB, and p100/p52). In loss of function experiments, we transplanted hearts of p105/p50 knockout mice into wildtype mice and compared changes in gene expression and cardiomyocyte size with wildtype hearts transplanted into wildtype mice. Total and phospho-IKKbeta levels significantly increased in the transplanted heart seven days after surgery. The activation of IKKbeta was paralleled by increased DNA binding activity of p65 and p105/p50. Mechanical unloading induced myosin heavy chain beta expression and decreased cardiomyocyte size in hearts of both wildtype and p105/p050 knockout animals. In contrast, the downregulation of PPARalpha and MCAD was significantly attenuated or prevented in the hearts of p105/p50 knockout mice. |
Do silent polymorphisms in the RYR1 gene modify the phenotype of the p.4898 I > T pathogenic mutation in central core disease : a case report? | Central core disease is a congenital myopathy, characterized by presence of central core-like areas in muscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is caused by mutations in the human ryanodine receptor gene (RYR1), which encodes a calcium-release channel. Since the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three 'hot spots', with particular attention to the C-terminal region. Recent next-generation sequencing methods are now identifying multiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult. In a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a new case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1 gene identified two different missense mutations: c.14256 A > C polymorphism in exon 98 and c.14693 T > C in exon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed because patient's daughter, mother and sister carried only the exon 98's mutation, a synonymous variant that was subsequently found in the frequency of 013-0,05 of alleles. Further next generation sequencing study of the whole RYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and 8 polymorphisms in heterozygosis. | Our laboratory has demonstrated that significantly more cell-mediated immunosuppression occurs after full laparotomy than after either anesthesia control or carbon dioxide (CO2) pneumoperitoneum. We further demonstrated that the postoperative immunosuppression is related to the length of the incision. Other investigators believe that the immunosuppression observed after laparotomy is caused by peritoneal exposure to small amounts of lipopolysaccharide found in circulating air. They believe that the better-preserved immune function associated with laparoscopic surgery results from the avoidance of air contamination of the peritoneal cavity. To investigate this hypothesis, we determined and compared postoperative lymphocyte proliferation rates after (a) laparotomy in room air, (b) laparotomy in a CO2 chamber, (c) CO2 insufflation in a murine model, and (d) anesthesia alone. Female C3H/He mice (n = 21) were divided randomly into four groups: (a) anesthesia control, (b) air laparotomy, (c) CO2 laparotomy, and (d) CO2 insufflation. The control mice underwent no procedure. The group 2 animals underwent a full midline incision (xiphoid to pubis) and exposure to room air for 20 min and then were clipped closed. The group 3 mice underwent a full midline incision in a sealed CO2 chamber for 20 min, and the group 4 mice insufflation with CO2 gas at 4 to 6 mm Hg for 20 min. Splenocytes were harvested from all the animals on day 2 after the interventions. Lymphocyte proliferation then was assessed using the nonradioactive colorimetric MTS/PMS system 72 h after concanavalin-A stimulation. There was no significant difference in lymphocyte proliferation between the air and CO2 laparotomy groups. Lymphocyte proliferation in the anesthesia control and CO2 insufflation groups was significantly higher than in both the air laparotomy (p<0.05) and CO2 laparotomy (p<0.05) groups (p values by Tukey-Kramer test). There was no significant difference between the anesthesia control and CO2 pneumoperitoneum groups. |
Is radiologic evidence that hypothalamic gliosis associated with obesity and insulin resistance in humans? | To use quantitative magnetic resonance imaging (MRI) to test whether mediobasal hypothalamic (MBH) gliosis is associated with obesity and insulin resistance in humans. Sixty-seven participants underwent a fasting blood draw and MRI. Cases with radiologic evidence of MBH gliosis (N = 22) were identified as the upper tertile of left MBH T2 relaxation time and were compared to controls (N = 23) from the lowest tertile. In a separate postmortem study, brain slices (N = 10) through the MBH were imaged by MRI and stained for glial fibrillary acidic protein (GFAP). In all participants, longer T2 relaxation time in the left MBH was associated with higher BMI (P = 0.01). Compared with controls, cases had longer T2 relaxation times in the right MBH (P < 0.05), as well as higher BMI (P < 0.05), fasting insulin concentrations (P < 0.01), and HOMA-IR values (P < 0.01), adjusted for sex and age. Elevations in insulin and HOMA-IR were also independent of BMI. In the postmortem study, GFAP staining intensity was positively associated with MBH T2 relaxation time (P < 0.05), validating an MRI-based method for the detection of MBH gliosis in humans. | Chronic urticaria is one of the perplexing problems faced by clinicians. There are a few reports associating house dust mite sensitivity with chronic urticaria, based upon the patient's history as well as intradermal skin testing and in vitro analysis. To investigate the possible association between house dust mite sensitivity and chronic urticaria. In this case control study three groups of patients were enrolled. Group I: Chronic urticaria (73 subjects). Group II: Chronic urticaria with collateral allergic disorders (49 subjects). Group III: Normal subjects without chronic urticaria or other allergies (25 subjects). All the patients underwent skin prick testing with antigens of the house dust mite, Dermatophagoides pteronyssinus (DP) and Dermatophagoides farinae (DF), with positive and negative controls. Among the patients with chronic urticaria, 78/122 (64%) patients had skin sensitivity to house dust mites. Out of these, 39/73 (53%) had chronic urticaria alone and 39/49 (79%) had chronic urticaria with other associated allergies. Among the normal control subjects, 7/25(28%) reacted positively to house dust mites. |
Do biphasic chromatin structure and FISH signals in reflect intranuclear order? | One of the two parental allelic genes may selectively be expressed, regulated by imprinting, X-inactivation or by other less known mechanisms. This study aims to reflect on such genetic mechanisms. Slides from short term cultures or direct smears of blood, bone marrow and amniotic fluids were hybridized with FISH probes singly, combined or sequentially. Two to three hundred cells were examined from each preparation. | Fluticasone propionate is a potent inhaled corticosteroid that is effective in improving pulmonary function and symptoms in patients with asthma. To evaluate the effects of fluticasone propionate on quality of life in patients with severe asthma requiring oral corticosteroids. A total of 96 patients with severe asthma participated in a randomized, double-blind, placebo-controlled, parallel-group, oral steroid-sparing study. Patients received fluticasone propionate aerosol, 750 or 1000 micrograms bid, or placebo for 16 weeks; 91 of these patients continued in a 1-year open-label study, in which everyone initially received fluticasone propionate, 1000 micrograms bid. At regular intervals, patients completed the Medical Outcomes Study Short Form-36 (SF-36), a general health status questionnaire measuring eight dimensions of quality of life, plus one question on change in health from the previous year. Compared with the US population, patients scored significantly lower at baseline for five of eight SF-36 dimensions (P < .01). After 16 weeks, patients receiving fluticasone propionate, 1000 micrograms, improved significantly (P < or = .02) in physical functioning, role-physical, general health, and change in health, compared with the placebo group. After 1 year of open-label treatment with fluticasone propionate, these improvements were maintained. SF-36 scores in the placebo group during the double-blind period either worsened or remained unchanged; however, when these patients were switched to fluticasone propionate during the open-label period, their SF-36 scores also improved. Forced expiratory volume in 1 second (FEV1) at the end of the double-blind period was positively correlated with mean quality of life scores on physical functioning, role-physical, vitality, social functioning, and change-in-health status. |
Is p-gp activity a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines , but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients? | AVE9633 is a new immunoconjugate comprising a humanized monoclonal antibody, anti-CD33 antigen, linked through a disulfide bond to the maytansine derivative DM4, a cytotoxic agent and potent tubulin inhibitor. It is undergoing a phase I clinical trial. Chemoresistance to anti-mitotic agents has been shown to be related, in part, to overexpression of ABC proteins. The aim of the present study was to investigate the potential roles of P-gp, MRP1 and BCRP in cytotoxicity in AVE9633-induced acute myeloid leukaemia (AML). This study used AML cell lines expressing different levels of P-gp, MRP1 or BCRP proteins and twenty-five samples from AML patients. Expression and functionality of the transporter protein were analyzed by flow cytometry. The cytotoxicity of the drug was evaluated by MTT and apoptosis assays. P-gp activity, but not MRP1 and BCRP, attenuated AVE9633 and DM4 cytotoxicity in myeloid cell lines. Zosuquidar, a potent specific P-gp inhibitor, restored the sensitivity of cells expressing P-gp to both AVE9633 and DM4. However, the data from AML patients show that 10/25 samples of AML cells (40%) were resistant to AVE9633 or DM4 (IC(50) > 500 nM), and this was not related to P-gp activity (p-Value: 0.7). Zosuquidar also failed to re-establish drug sensitivity. Furthermore, this resistance was not correlated with CD33 expression (p-Value: 0.6) in those cells. | Laparoscopic ventral hernia repair (LVHR) is associated with shorter hospitalization and lower complication rates compared to open ventral hernia repair. We sought to determine if hernia-related factors, such as defect size and re-operative status correlate with postoperative complications, operative times and length of stay (LOS). The study is a retrospective review of 30-day perioperative outcomes following LVHR in 91 patients who underwent surgery at a single institution from August 2009 through June 2012. A single surgeon performed all procedures. Indications for surgery were recurrent incisional hernia in 33 % of patients and primary incisional or ventral abdominal hernias in the rest. Coated polyester mesh with an average size of 348 cm(2) (±214; range 113-1,036) was used. Mean operative time was 132 min (±66.1; range 53-412). The mean LOS was 4.0 days (±3.5; range 1-22). Complications occurred in 13 patients for overall morbidity of 16.5 % and no mortality. There was one recurrence in 30 days (1.1 %). Patients who had a surgery >120 min or a LOS >1 day were statistically more likely to have multiple hernias, larger defect sizes (>40 cm(2)), larger mesh sizes (>300 cm(2)) or a history of recurrent hernia (P < 0.05). No other clinical or demographic variable evaluated in this study correlated with operative time or LOS. |
Does altered expression of methylenetetrahydrofolate reductase modify response to methotrexate in mice? | Folates provide one-carbon units for nucleotide synthesis and methylation reactions. A common polymorphism (677C-->T) in methylenetetrahydrofolate reductase (MTHFR) encodes an enzyme with reduced activity. Response to the antifolate methotrexate (MTX) may be modified in 677TT individuals because MTHFR converts nonmethylated folates, used for thymidine and purine synthesis, to 5-methyltetrahydrofolate, used in homocysteine remethylation to methionine. To study potential interactions between MTHFR activity and MTX, we examined the impact of decreased and increased MTHFR expression on MTX response in mice. Mthfr-deficient (Mthfr and Mthfr) and wild-type (Mthfr) mice were injected with MTX or saline and assessed for hematological parameters (hematocrit, hemoglobin, red, and white blood cell numbers), plasma homocysteine, nephrotoxicity, hepatotoxicity, and splenic 2'-deoxyuridine 5'-triphosphate/2'-deoxythymidine 5'-triphosphate ratios. MTHFR-overexpressing transgenic mice (MTHFR-Tg) were generated, metabolites and folate distributions were measured, and response to MTX was assessed. MTX-treated Mthfr and Mthfr mice displayed hyperhomocysteinemia and decreased hematocrit, hemoglobin, and red blood cell numbers compared with wild-type animals. Mthfr mice also showed increased nephrotoxicity and hepatotoxicity. MTHFR-Tg mice were generated and confirmed to have increased levels of MTHFR with altered distributions of folate and thiols in a tissue-specific manner. After MTX treatment, MTHFR-Tg mice exhibited the same decreases in hematological parameters as Mthfr-deficient mice, and significantly decreased thymidine synthesis (higher 2'-deoxyuridine 5'-triphosphate/2'-deoxythymidine 5'-triphosphate ratios) compared with wild-type mice, but they were protected from MTX-induced hyperhomocysteinemia. | This study investigated whether anxiety, fear of pain, or pain catastrophizing were predictive of pain-related outcomes after induced delayed onset muscle soreness (DOMS) at the shoulder. Healthy participants (19 males and 23 females) were eligible for participation if they had (a) no history of neck or shoulder pain, (b) no sensory or motor impairments of the upper-extremity, (c) not regularly participating in upper-extremity weight training, (d) not currently or regularly taking pain medication, and (e) no history of upper-extremity surgery. Participants completed self-report measures for fear of pain, pain catastrophizing, and anxiety. Then, participants underwent a standard fatigue protocol to induce DOMS in the shoulder external rotator muscles. Participants were reassessed 24 hours after DOMS induction on clinical and evoked pressure pain reports, muscle force production, self-report of upper-extremity disability, and kinesiophobia. Stepwise regression models considered sex, anxiety, pain intensity, fear of pain, and pain catastrophizing as outcome predictors. Fear of pain alone explained 16% (P=0.008) of the variance in clinical pain and 10% (P=0.047) evoked pressure pain intensity. Clinical pain intensity alone explained 11% (P<0.031) of the variance in muscle force production. Clinical pain intensity and fear of pain explained 50% (P<0.001) of the variance in upper-extremity disability, whereas fear of pain and sex accounted for 26% (P=0.005) of the variance in kinesiophobia. |
Is self-reported physical activity in smoking pre-cessation a protective factor against relapse for all? | In recent years, the relationship between physical activity (PA) and smoking cessation has been increasingly studied. However, very few studies have investigated the possible protective role of PA on smoking relapse on the long term. This study evaluated the impact of self-reported PA in precessation on smoking relapse. Other variables evaluated included measures of dependence, socio-demographic factors and smoking-related variables. Several possible interactions between PA and well identified factors influencing smoking relapse rate were also explored. After the initial consultation, 345 smokers were consecutively recruited in a smoking-cessation unit. Smoking abstinence was collected regularly during consultation or by phone calls. PA was measured with the International Physical Activity Questionnaire short form. Cox proportional hazard model was performed to determine factors associated with smoking relapse. Among the initial sample, 227 adults were included in the survival analysis. After adjustment for potential cofounders, PA was not associated with smoking relapse. Self-efficacy level, absence of professional activity, previous attempts to quit and alcohol use disorders were associated with relapse. Secondary analysis showed a statistically significant effect of an interaction term for PA and antidepressant use on reducing smoking relapse (HR = .81, 95% CI: .66-.99). | Whether the round window membrane (RWM) is permeable to iodine-based contrast agents (IBCA) is unknown; therefore, our goal was to determine if IBCAs could diffuse through the RWM using CT volume acquisition imaging. Imaging of hydrops in the living human ear has attracted recent interest. Intratympanic (IT) injection has shown gadolinium's ability to diffuse through the RWM, enhancing the perilymphatic space. Four unfixed human cadaver temporal bones underwent intratympanic IBCA injection using three sequentially studied methods. The first method was direct IT injection. The second method used direct RWM visualization via tympanomeatal flap for IBCA-soaked absorbable gelatin pledget placement. In the third method, the middle ear was filled with contrast after flap elevation. Volume acquisition CT images were obtained immediately postexposure, and at 1-, 6-, and 24-hour intervals. Postprocessing was accomplished using color ramping and subtraction imaging. After the third method, positive RWM and perilymphatic enhancement were observed with endolymph sparing. Gray scale and color ramp multiplanar reconstructions displayed increased signal within the cochlea compared with precontrast imaging. The cochlea was measured for attenuation differences compared with pure water, revealing a preinjection average of -1,103 HU and a postinjection average of 338 HU. Subtraction imaging shows enhancement remaining within the cochlear space, Eustachian tube, middle ear epithelial lining, and mastoid. |
Are the coiled coils of cohesin conserved in animals , but not in yeast? | The SMC proteins are involved in DNA repair, chromosome condensation, and sister chromatid cohesion throughout Eukaryota. Long, anti-parallel coiled coils are a prominent feature of SMC proteins, and are thought to serve as spacer rods to provide an elongated structure and to separate domains. We reported recently that the coiled coils of mammalian condensin (SMC2/4) showed moderate sequence divergence (approximately 10-15%) consistent with their functioning as spacer rods. The coiled coils of mammalian cohesins (SMC1/3), however, were very highly constrained, with amino acid sequence divergence typically <0.5%. These coiled coils are among the most highly conserved mammalian proteins, suggesting that they make extensive contacts over their entire surface. Here, we broaden our initial analysis of condensin and cohesin to include additional vertebrate and invertebrate organisms and multiple species of yeast. We found that the coiled coils of SMC1/3 are highly constrained in Drosophila and other insects, and more generally across all animal species. However, in yeast they are no more constrained than the coils of SMC2/4 and Ndc80/Nuf2p, suggesting that they are serving primarily as spacer rods. | Serum calcium (Ca) and inorganic phosphate (Pi) concentrations and calcium-phosphate product (CPP) levels are positively associated with worse outcomes in patients with chronic kidney disease, but there are few data for Pi or Ca and none for CPP in patients with chronic heart failure (CHF). Unselected, consecutive patients with CHF (left ventricular ejection fraction, LVEF ≤45%) were enrolled in a prospective observational study for the occurrence of hospitalisation and mortality. Blood samples were collected at the time of recruitment and analysed immediately. Patients (n = 713) were on contemporary optimal treatment and mean (standard error, SE) follow-up was 765 (18.9) days. Mean (SE) Ca was 2.29 (0.004) mmol/l. Median (interquartile range, IQR) Pi was 1.11 (0.98-1.23) mmol/l and median CPP 2.53 (2.21-2.88) mmol(2)/l(2). LVEF correlated inversely with Ca, natural log-transformed (Ln)Pi, and LnCPP. There was no difference in CPP between classes of symptom severity or diabetes status. Ca and LnCPP (but not LnPi) were associated with total mortality. Ca was significantly associated with progressive HF and non-cardiovascular death but not with sudden death. Binary logistic regression analyses showed that LnPi and LnCPP were associated with risk of hospitalisation. |
Does chair design affect how older adults rise from a chair? | To determine how modifications of key chair design aspects, such as seat height, posterior seat tilt, backrest recline, seat compressibility, and armrest placement, affect how older adults rise from a chair and the seating comfort they experience. Cross-sectional comparison. Congregate housing facility and university laboratory. Two groups of volunteers, Old (n = 29, mean age 84) and Young (n = 21, mean age 23). Analysis of time to rise, body motion (determined by use of digitized videotaping), and self-reported difficulty when subjects rose from a variety of controlled chair settings thought to represent important chair design specifications encountered by older adults. Subjects also reported their comfort while being seated in these settings. Lowered seat height, increased posterior seat tilt and backrest recline, and perhaps increased seat compressiblity cause increased time to rise, increased body motion, and increased self-reported ratings of rise difficulty in both Young and Old groups. Under the most challenging conditions, the effect appears to be stronger in the Old than in the Young: a few Old were unable to rise, and the Old took disproportionately longer to rise and used disproportionately greater neck motion (P generally < 0.001) compared with the Young. Arm rest placement did not alter rise performance or ratings significantly. The conditions in which rise difficulty increases or decreases do not correspond exactly to conditions in which comfort increases or decreases. Some aspects that increase rise difficulty, such as tilt/recline and seat compressiblity, may also increase comfort. | HIV-1 envelope glycoprotein gp120 (gp120) is considered as one of the major virulent proteins responsible for the involvement of the cardiovascular system. Autophagy as a form of self maintenance plays important roles in cell survival and death. HIV-1 gp120 is reported to induce autophagy in a variety of cells. However, the effect of gp120 on autophagy in cardiomyocytes has not been reported. This study aimed to test our hypothesis that gp120 could induce autophagy in cardiomyocytes. Rat cardiomyocyte H9c2 cells were treated with gp120 (100 ng/ml) in vitro for 4h, 1 day and 7 days. The autophagy related proteins were analyzed by Western blot and the autophagosomes were analyzed by confocal microscopy. The autophagic proteins and autophagosomes were markedly increased in the H9c2 cells after 4h of gp120 treatment. Furthermore, gp120 induced autophagic proteins and autophagosomes were significantly inhibited by the N-methyl-d-aspartic acid (NMDA) receptor inhibitor MK801, c-Jun N-terminal kinase (JNK) inhibitor SP600125, and the class III phosphoinositide 3-kinase (PI3K) inhibitor 3-methyladenine (3-MA), while there was no change in the cells pretreated with the CXCR4 antagonist AMD3100. In addition, no apparent cell death was observed in the cardiomyocytes treated with gp120 for up to 7 days. |
Does [ Curcumin promote apoptosis of esophageal squamous carcinoma cell lines through inhibition of NF-kappaB signaling pathway ]? | Activation of NF-kappaB signaling pathway plays a critical role in the initiation and progression of carcinogenesis. However, the role of NF-kappaB pathway in esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. Studies have shown that curcumin possesses anti-infection and anti-oxidation effects. This study was to evaluate whether curcumin could induce apoptosis through inhibition of NF-kappaB signaling pathway in ESCC cells. Expressions of pIkappaBalpha and Bcl-2 were detected using Western blott after incubation of ESCC cells with curcumin (50 micromol/L) at different time points. Apoptosis and the number of viable ESCC cells were analyzed using flow cytometry and MTT, respectively, after the treatment of curcumin, 5-FU, or the combination of curcumin and 5-FU. In two ESCC cell lines, EC9706 and Eca109,curcumin inhibited IkappaBalpha phosphorylation and Bcl-2 in a time-dependent manner; curcumin alone increased cell apoptosis (P<0.05), and the effect became more prominent when it was combined with 5-FU (P<0.05); curcumin plus 5-FU exerted a stronger inhibition effect on cell proliferation than curcumin alone (P<0.05) or 5-FU alone (P<0.05). | We investigated the relationship between preoperative psychological state and postoperative confusion in elderly drinkers. We studied 81 male patients, ranging in age from 65 to 80 years, who were scheduled to undergo total hip arthroplasty and total knee arthroplasty. The patients were divided into two groups; non-drinkers and patients who drank 25 g or more of alcohol daily. All patients were given a neuropsychological screening evaluation, including a Mini-Mental State test, the Japanese version of the State-Trait Anxiety Inventory (STAI), a depression scale test, and evaluation of a history of aggression and postoperative confusion. Postoperative confusion during the first 72 h after the end of the operation occurred in 7 of the 50 non-drinkers (14%) and in 11 of the 31 drinkers (35%) (P = 0.01). There were no significant differences in STAI (state anxiety and trait anxiety), Mini-Mental State, and depression scale scores between the non-drinkers and drinkers, or between patients with and without postoperative confusion. All 8 patients who had a history of aggression developed postoperative confusion. There was no significant difference in the incidence of postoperative confusion between drinkers who did not have a history of aggression and non-drinkers. |
Is mast cell activation characterized by upregulation of a functional anaphylatoxin C5a receptor? | Mast cells (MC) are key effector cells of allergic diseases and resistance to helminthic parasites and induce or amplify diverse innate and adaptive immune responses. The signals controlling MC mobilization during inflammation are not fully understood. Since anaphylatoxins are attractive candidates as MC chemoattractants, we investigated expression and function of anaphylatoxin receptors in murine MC. Precursor cell-derived MC cultured with IL-3 in the presence or absence of SCF did not express significant amounts of surface C5a receptor (C5aR) or C3a receptor (C3aR). MC required approximately 4 h of stimulation with Ag (DNP-albumin, following preincubation with IgE anti-DNP), ionomycin, or PMA to enable a strong chemotactic response towards C5a, paralleled by a distinct C5aR upregulation. Likewise, C5a induced intracellular calcium fluxes solely in activated MC. In contrast, C3a proved to be a weak MC chemotaxin and unable to increase intracellular calcium. Primary peritoneal MC did not express detectable amounts of anaphylatoxin receptors, however, similar to precursor cell-derived MC, stimulation with Ag or ionomycin for 4 h induced a prominent surface expression of C5aR whereas C3aR remained undetectable. | Left ventricular hypertrophy (LVH) is common in patients with autosomal dominant polycystic kidney disease (ADPKD). Although insulin resistance contributes to cardiac hypertrophy, the relationship between insulin resistance and LVH in patients with ADPKD has not been previously studied. We performed M-mode and color Doppler echocardiography on 176 family members (106 patients and 70 healthy relatives) from 16 families with polycystic kidney disease type 1 (PKD1). Left ventricular mass index (LVMI) was calculated using the Penn equation and corrected for body surface area. Fasting insulin and glucose concentrations were measured and insulin resistance was evaluated by means of the homeostasis model assessment. In multivariate regression analysis, insulin resistance was significantly associated with LVMI in healthy relatives (P < 0.01) and patients with PKD1 (P < 0.05) independent of age, weight, systolic blood pressure, and albuminuria. |
Does beta-catenin mediate the apoptosis induction effect of celastrol in HT29 cells? | We evaluated the apoptosis induction effects of celastrol in human colorectal cancer cell line HT29 in WNT/beta-catenin pathway. HT29 cells were treated with various concentrations (10-100μM) for 24h, MTT assay was performed to examine the effect of celastrol on growth inhibition of HT29 cells. Beta-catenin siRNA was used for transfection of cells. Cell apoptosis was detected through both DNA laddering analysis and Tdt-mediated dUTP nick end labeling (TUNEL) assay. Western blot analysis and real-time reverse transcription polymerase chain reaction technologies were applied to assess the expression level of c-Myc, Bax, and Bcl-2 in HT29 cells. Treatment of HT29 cells with celastrol resulted in a growth inhibition effect, and the IC(50) value was 56μM. Celastrol induced HT29 cells apoptosis, and increased the nuclear translocation of beta-catenin. Apoptosis induction effects of celastrol were significantly attenuated by beta-catenin siRNA transfection. Beta-catenin siRNA markedly increased mRNA and protein levels of c-Myc compared with control siRNA. Beta-catenin siRNA significantly inhibited the expression of Bax and Bcl-2 in celastrol-treated HT29 cells. | Glucocorticoids (GCs), including the synthetic GC derivate dexamethasone, are widely used as immunomodulators. One of the numerous side effects of dexamethasone therapy is hypertension arising from reduced release of the endothelium-derived vasodilator nitric oxide (NO). Herein, we described the role of dexamethasone and its glucocorticoid receptor (GR) in the regulation of NO synthesis in vitro using the mouse myocardial microvascular endothelial cell line, MyEND. GC treatment caused a firm decrease of extracellular NO levels, whereas the expression of endothelial NO synthase (eNOS) was not affected. However, GC application induced an impairment of tetrahydrobiopterin (BH4 ) concentrations as well as GTP cyclohydrolase-1 (GTPCH-1) expression, both essential factors for NO production upstream of eNOS. Moreover, dexamethasone stimulation resulted in a substantially decreased GR gene and protein expression in MyEND cells. Importantly, inhibition of proteasome-mediated proteolysis of the GR or overexpression of an ubiquitination-defective GR construct improved the bioavailability of BH4 and strengthened GTPCH-1 expression and eNOS activity. |
Does timosaponin A3 induce hepatotoxicity in rats through inducing oxidative stress and down-regulating bile acid transporters? | To investigate the mechanisms underlying the hepatotoxicity of timosaponin A3 (TA3), a steroidal saponin from Anemarrhena asphodeloides, in rats. Male SD rats were administered TA3 (100 mg·kg(-1)·d(-1), po) for 14 d, and the blood and bile samples were collected after the final administration. The viability of a sandwich configuration of cultured rat hepatocytes (SCRHs) was assessed using WST-1. Accumulation and biliary excretion index (BEI) of d8-TCA in SCRHs were determined with LC-MS/MS. RT-PCR and Western blot were used to analyze the expression of relevant genes and proteins. ROS and ATP levels, and mitochondrial membrane potential (MMP) were measured. F-actin cytoskeletal integrity was assessed under confocal microscopy. TA3 administration in rats significantly elevated the total bile acid in serum, and decreased bile acid (BA) component concentrations in bile. TA3 inhibited the viability of the SCRHs with an IC50 value of 15.21±1.73 μmol/L. Treatment of the SCRHs with TA3 (1-10 μmol/L) for 2 and 24 h dose-dependently decreased the accumulation and BEI of d8-TCA. The TA3 treatment dose-dependently decreased the expression of BA transporters Ntcp, Bsep and Mrp2, and BA biosynthesis related Cyp7a1 in hepatocytes. Furthermore, the TA3 treatment dose-dependently increased ROS generation and HO-1 expression, decreased the ATP level and MMP, and disrupted F-actin in the SCRHs. NAC (5 mmol/L) significantly ameliorated TA3-induced effects in the SCRHs, whereas mangiferin (10-200 μg/mL) almost blocked TA3-induced ROS generation. | Early parenthood is a time of chronic sleep disturbance and also of heightened depression risk. Poor sleep quality has been identified both as a predictor of postpartum depressive symptoms and as a consequence. This study sought to clarify causal pathways linking sleep and postpartum depression via longitudinal path modeling. Sleep quality at 6 months postpartum was hypothesized to exacerbate depressive symptoms from 1 month through 1 year postpartum in both mothers and fathers. Within-couple associations between sleep and depression were also tested. Data were drawn from a low-income, racially and ethnically diverse sample of 711 couples recruited after the birth of a child. Depressive symptoms were assessed at 1, 6, and 12 months postpartum, and sleep was assessed at 6 months postpartum. For both partnered mothers and fathers and for single mothers, depressive symptoms at 1 month postpartum predicted sleep quality at 6 months, which in turn predicted depressive symptoms at both 6 and 12 months. Results held when infant birth weight, breastfeeding status, and parents' race/ethnicity, poverty, education, and immigration status were controlled. Mothers' and fathers' sleep quality and depressive symptoms were correlated, and maternal sleep quality predicted paternal depressive symptoms both at 6 and at 12 months. |
Are stimulation of the subthalamic nucleus in Parkinson 's disease : cognitive and affective changes linked to the motor outcome? | Subthalamic nucleus deep brain stimulation (STN0 DBS) is a widely performed surgical treatment in PD. However, the relationship between motor results and cognitive/behavioural modifications is unclear. This study investigated the correlation patterns of the motor, cognitive and behavioural consequences of STN DBS with respect to positioning of the active contact. Fifty-eight consecutive PD patients having undergone STN DBS were assessed pre-operatively and 12 months after surgery. Motor, cognitive and behavioural results were neither correlated to each other nor linked to the position of the active contact. Three patients with a history of pre-operative, dopaminergic psychosis or post-surgical confusion became demented. Age and a distant history of depression were associated with the occurrence of post-surgical depression. | Transfusion of red blood cells (RBCs) is a daily medical procedure. Erythrocyte concentrates (ECs) can be stored up to 56 days at 4 °C in saline additive solution mainly composed of adenine and sugar. Such nonphysiological conditions induce the occurrence of storage lesions, such as alterations of metabolism, protein oxidation, and deterioration of rheological properties. Their accumulation tends to decrease the main EC therapeutic property, that is, the oxygenation capacity. Protein carbonylation is a marker of oxidative stress and aging, and its occurrence during RBC storage was earlier characterized as a time-dependent and cellular compartment dependent modification. Three ECs from independent donations were followed. The carbolynome was here characterized in soluble and membrane extracts (n-dodecyl β-D-maltoside-based extraction buffer) of RBCs stored for 6, 27, and 41 days, through biotin hydrazide derivatization, biotin-avidin affinity purification, SDS-PAGE separation, and LC-MS/MS analyses. A total of 142 and 20 proteins were identified as carbonylated in soluble and membrane extracts, respectively. Particularly, a time-dependent evolution of 26.8% of the soluble carbonylome was observed. |
Does novel clomiphene `` stair-step '' protocol reduce time to ovulation in women with polycystic ovarian syndrome? | The objective of the study was to determine the efficacy of a novel "stair-step" clomiphene protocol in women with polycystic ovarian syndrome (PCOS) who do not respond to 50 mg clomiphene. This was a retrospective analysis at an academic fertility center. The stair-step protocol is performed as follows: 50 mg clomiphene for 5 days, ultrasonography on days 11-14. If unresponsive, immediately begin 100 mg clomiphene for 5 days and repeat ultrasound in 1 week. If still unresponsive, begin 150 mg clomiphene for 5 days and repeat the ultrasound in 1 week. Stair-step cycles were compared with published historical clomiphene outcomes for women who were nonresponsive. The time to ovulation was 32-53 days less with the stair-step protocol compared with a traditional regimen. The dose-dependent ovulation rate was 64% at 100 mg with the stair-step protocol compared with 22% with a traditional regimen. | To investigate the protective effect of melatonin on liver after intestinal ischemia-reperfusion injury in rats. One hundred and fifty male Wistar rats, weighing 190-210 g, aged 7 wk, were randomly divided into melatonin exposure group, alcohol solvent control group and normal saline control group. Rats in the melatonin exposure group received intraperitoneal (IP) melatonin (20 mg/kg) 30 min before intestinal ischemia-reperfusion (IR), rats in the alcohol solvent control group received the same concentration and volume of alcohol, and rats in the normal saline control group received the same volume of normal saline. Serum samples were collected from each group 0.5, 1, 6, 12, and 24 h after intestinal IR. Levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured with an auto-biochemical analyzer. Serum TNF-alpha was tested by enzyme-linked immunosorbent assay (ELISA). Malondialdehyde (MDA) in liver was detected by colorimetric assay. Pathological changes in liver and immunohistochemical straining of ICAM-1 were observed under an optical microscope. The levels of ALT measured at various time points after intestinal IR in the melatonin exposure group were significantly lower than those in the other two control groups (P < 0.05). The serum AST levels 12 and 24 h after intestinal IR and the ICAM-1 levels (%) 6, 12 and 24 h after intestinal IR in the melatonin exposure group were also significantly lower than those in the other two control groups (P < 0.05). |
Do prevalence of pseudobulbar affect symptoms and clinical correlates in nursing home residents? | Pseudobulbar affect (PBA) is a neurological disorder of emotional expression, characterized by uncontrollable episodes of crying or laughing in patients with certain neurological disorders affecting the brain. The purposes of this study were to estimate the prevalence of PBA in US nursing home residents and examine the relationship between PBA symptoms and other clinical correlates, including the use of psychopharmacological medications. A retrospective study was conducted between 2013 and 2014 with a convenience sample of residents from nine Michigan nursing homes. Chronic-care residents were included in the "predisposed population" if they had a neurological disorder affecting the brain and no evidence of psychosis, delirium, or disruptive behavior (per chart review). Residents were screened for PBA symptoms by a geropsychologist using the Center for Neurologic Study-Lability Scale (CNS-LS). Additional clinical information was collected using a diagnostic evaluation checklist and the most recent Minimum Data Set 3.0 assessment. Of 811 residents screened, complete data were available for 804, and 412 (51%) met the criteria for the "predisposed population." PBA symptom prevalence, based on having a CNS-LS score ≥13, was 17.5% in the predisposed population and 9.0% among all nursing home residents. Those with PBA symptoms were more likely to have a documented mood disorder and be using a psychopharmacological medication, including antipsychotics, than those without PBA symptoms. | Our previous study demonstrated that prolonged cold preservation promoted neointima formation and remodeling but delayed the subsequent arteriosclerosis of rat abdominal aorta grafts. The mechanisms of this phenomenon remain obscure. In this study, we investigated whether stromal cell derived factor-1 (SDF-1) could play a role in recruiting stem cells to repair and remodel the damaged intima of abdominal aorta grafts. Male Spague-Dawley rats received abdominal aorta grafts from male Wistar rats. Hematoxylin and eosin staining was performed to assess the structure of graft aortas by measuring the neointimal thickness. Immunohistochemical staining detected SDF-1 expression. RT-PCR demonstrated the expression of CXCR4, the only known natural receptor of SDF-1 expression on stem cells. The neointimal thickness of the SDF-1 antibody-treated group was inconspicuous; a significant relationship existed between the expression of SDF-1 and the neointimal thickness of the grafts. Furthermore, no CXCR4 was detected in normal abdominal aortas, but it was observed in the grafted abdominal aorta. |
Is glucose intolerance predicted by low insulin secretion and high glucagon secretion : outcome of a prospective study in postmenopausal Caucasian women? | To study the pathophysiological importance of changes in insulin sensitivity and islet function over time for alterations in glucose tolerance in a randomly selected large group of non-diabetic women aged 57-59 years over a 3-year period. At baseline and at the 3-year follow-up, glucose tolerance (WHO 75 g oral glucose), insulin sensitivity (euglycaemic, hyperinsulinaemic clamp) and insulin and glucagon secretion (2 to 5-min responses to 5 g i.v. arginine at fasting, 14 and > 25 mmol/l glucose) were measured. At baseline, women with impaired glucose tolerance (IGT, n = 28) had lower insulin sensitivity (p = 0.048) than normal women (NGT, n = 58). The arginine-induced insulin responses (AIR) were inversely associated with insulin sensitivity (r > or = -0.55, p < 0.001). When related to the 3-year follow-up, the baseline product of AIR at 14 mmol/l glucose times insulin sensitivity, insulin effect index (IE) (r = -0.40, p < 0.001) and the arginine-induced glucagon response at 14 mmol/l glucose (AGR, r = 0.28, p = 0.009) both correlated with follow-up 2-h glucose. In a multiple regression model, baseline 2-h glucose, insulin effect index and arginine-induced glucagon response independently predicted 2-h glucose at follow-up (total r = 0.668, p < 0.001). Furthermore, delta insulin sensitivity (i. e. follow-up minus baseline) correlated with delta insulin secretion (r = -0.30, p = 0.006), whereas delta glucagon secretion correlated with delta2-h glucose (r = 0.30, p = 0.006) over the 3 years. In a multiple regression, alterations in 2-h glucose over the 3 years were independently determined by changes in fasting insulin and glucagon secretion (r = 0.424, p < 0.001). | Biological evidence reported in the literature supports the role of CELSR1 as being essential for valvular function in murine lymphatics. Yet thus far, there have been no variants in CELSR1 associated with lymphatic dysfunction in humans. In this report, a rare early inactivating mutation in CELSR1 is found to be causal for non-syndromic, lower extremity lymphedema in a family across three generations. Near-infrared fluorescence lymphatic imaging shows that instead of being propelled within the lumen of well-defined lymphatic vessels, lymph moved in regions of both legs in an unusual fashion and within sheet-like structures. |
Is toll-like receptor-4 message up-regulated in lipopolysaccharide-exposed rat lung pericytes? | Pericytes are multifunctional, polymorphic perivascular cells that lie within the microvessel basal lamina, are located on the abluminal side of endothelial cells, and are thought to play a regulatory role in capillary leak observed in sepsis. Toll-Like receptor 4 (TLR-4) has been implicated as the proximal transmembrane receptor for the LPS/CD 14 complex during the activation of lipopolysacharide (LPS)-induced sepsis. It is our hypothesis that TLR-4 is present on lung pericytes and is up-regulated in response to LPS. Rat microvascular lung pericytes were isolated and cultured. Cells from passage 3-5 were used and treated with LPS (control, 10 ng/mL, and 100 ng/mL) for 18 h. Immunostaining and immunoblotting were performed to detect the presence of CD-14, TLR-2, and TLR-4. Real-time polymerase chain reaction was used to analyze the presence and quantity of mRNA for CD-14, TLR-2, and TLR-4. Immunostaining and immunoblotting revealed the presence of CD-14, TLR-2, and TLR-4 in pericytes from each treatment group, and real-time polymerase chain reaction confirmed the presence of mRNA for CD-14, TLR-2, and TLR-4. An increase in the mRNA was observed in CD-14, TLR-2, and TLR-4 in the presence of increasing LPS 4 h after treatment. At 18 h after LPS treatment, a decrease in mRNA was noted. | Menopausal reduction in estrogen causes increased adipose accumulation, leading many to turn to dietary supplements to prevent and treat such changes. Enhanced adipose mobilization stimulated by some supplements can increase the risk of non-alcoholic fatty liver disease (NAFLD). Cytoprotective and anti-obesity compounds may prevent the lipotoxicity associated with mobilization. A phytochemical blend was tested in aged, ovariectomized rats. Rats were given the AIN-93M basal diet or a diet containing varying doses of phytochemicals with 2.4 IU/g vitamin D [diet 1: 1000 mg/kg genistein (G); diet 2: 500 mg/kg (G), 200 mg/kg resveratrol (R), and 1000 mg/kg quercetin (Q); diet 3: 1000 mg/kg (G), 400 mg/kg (R), and 2000 mg/kg (Q)]. Serum free fatty acids and hepatic triglycerides were elevated with diets 2 and 3. Despite this increase, the phytochemical blends did not increase apoptotic, cell repair, or remodeling gene expression. The highest phytochemical dose prevented increases in serum alanine aminotransferase. |
Does exosomal transfer of miR-30a between cardiomyocytes regulate autophagy after hypoxia? | Recent studies have indicated a protective role of physiological autophagy in ischemic heart disease. However, the underlying mechanisms of autophagy regulation after ischemia are poorly understood. Exosomes are nano-sized vesicles released from cells that play critical roles in mediating cell-to-cell communication through the transfer of microRNAs. In this study, we observed that miR-30a was highly enriched in exosomes from the serum of acute myocardial infarction (AMI) patients in vivo and culture medium of cardiomyocytes after hypoxic stimulation in vitro. We also found that hypoxia inducible factor (HIF)-1α regulates miR-30a, which efficiently transferred via exosomes between cardiomyocytes after hypoxia. Inhibition of miR-30a or release of exosomes increased the expression of the core autophagy regulators beclin-1, Atg12, and LC3II/LC3I, which contributed to maintaining the autophagic response in cardiomyocytes after hypoxia. Taken together, the present study showed that exosomes from hypoxic cardiomyocytes regulate autophagy by transferring miR-30a in a paracrine manner, which revealed a new pathway of autophagy regulation that might comprise a promising strategy to treat ischemic heart disease. | We aimed to study fecal calprotectin in Scottish children with inflammatory bowel disease (IBD) and compare its diagnostic accuracy with blood parameters. Stool samples from 48 Scottish children (29 males, 19 females) had calprotectin measured at IBD diagnosis. The median age at diagnosis was 11.2 years (interquartile range [IQR] 8.7-13.0 years). There were 33 patients with Crohn's disease, 5 with ulcerative colitis, and 10 with IBD type unspecified. IBD was diagnosed by standard criteria. Calprotectin was measured using a commercially available kit (PhiCal Test) and 47/48 patients had comparative blood results available at diagnosis. The fecal calprotectin concentrations were raised in 96% (46/48) of patients studied. The median calprotectin value was 750 microg/g (IQR 235.8-1251 microug/g). In comparison with standard blood tests, 32/45 (71.1%) had abnormal erythrocyte sedimentation rate, 19/38 (50.0%) had abnormal C-reactive protein, 29/46 (63.0%) had raised platelets, 12/45 (26.7%) had hypoalbuminemia, and 38/46 (82.6%) had abnormal hemoglobin. We identified 7/47 (14.9%) patients with raised calprotectin at diagnosis who did not have any abnormalities detected in the blood tests performed. All 48 patients (100%) had at least 1 abnormal blood test and/or raised calprotectin at diagnosis. |
Is the GH response to low-dose bolus growth hormone-releasing hormone ( GHRH ( 1-29 ) NH2 ) attenuated in patients with longstanding post-irradiation GH insufficiency? | Previous studies have suggested that post-irradiation GH insufficiency results from a loss of GHRH secretion, since many patients were able to release GH following exogenous GHRH stimulation. However, supramaximal doses of GHRH were used and the response may decline with time after radiotherapy. We re-evaluated the GHRH dose-response curve in patients post cranial irradiation and in controls. Randomized controlled study. Five adult male long-term survivors of childhood brain tumours (median age 21.8 years (18.4-26.7); 13.7 years (11.4-15.7) post-radiotherapy, >30Gy) and five matched controls were studied. An intravenous bolus of GHRH(1-29)NH(2) was administered in doses at the lower (0.05 microg/kg) and upper (0.15 microg/kg) range of the dose-response curves for young males, as well as the standard supramaximal dose (1. 0 microg/kg). GH was measured before stimulation, every 2min for the first hour and every 5min for the second hour. All studies were conducted in a random fashion. Significantly lower peak and area under the curve (AUC) GH concentrations occurred in the irradiated group using 0.15 microg/kg (median peak Irradiated, 4. 5mU/l vs median Controls, 37.4mU/l; P<0.01) and 1.0 microg/kg (median peak Irradiated, 4.8mU/l vs median Controls, 15.2mU/l; P<0. 05) GHRH(1-29)NH(2). In irradiated subjects there was an incremental rise in GH output with increasing doses of GHRH(1-29)NH(2 )(median AUC: 122mU/l.min vs 179mU/l.min vs 268mU/l.min; P=0.007) reflecting altered pituitary sensitivity and reduced responsiveness. | To compare rates of pelvic inflammatory disease (PID) among women who did and did not receive an intrauterine device (IUD) the day they sought emergency contraception (EC) or pregnancy testing. Women, 15 to 45 years of age, who sought EC or pregnancy testing from an urban family planning clinic completed surveys at the time of their clinic visit (August 22, 2011, to May 30, 2013) and 3 months after their clinic visit. The surveys assessed contraceptive use and symptoms, testing, and treatment for sexually transmitted infections (STI) and PID. We reviewed the medical records of participants who reported IUD placement within 3 months of enrollment and abstracted de-identified electronic medical record (EMR) data on all women who sought EC or pregnancy testing from the study clinic during the study period. During the study period, 1,060 women visited the study clinic; 272 completed both enrollment and follow-up surveys. Among survey completers with same-day IUD placement, PID in the 3 months after enrollment was not more common (1/28 [3.6%]; 95% CI, 0%-10.4%) than among women who did not have a same-day IUD placed (11/225 [4.9%]; 95% CI, 2.7%-8.6%; p = .71). Chart review and EMR data similarly showed that rates of PID within 3 months of seeking EC or pregnancy testing were low whether women opted for same-day or delayed IUD placement. |
Is irisin Associated with Urotensin II and Protein Energy Wasting in Hemodialysis Patients? | Irisin is a newly identified myokine which can promote energy expenditure. Urotensin II (UII) is identified as the most potent mammalian vasoconstrictor to date. Previous studies showed that UII can aggravate insulin resistance while irisin alleviate insulin resistance. Through this study, it is our aim to elucidate if UII can induce insulin resistance and also have an association with the irisin level in hemodialysis (HD) patients. One hundred and twenty-eight patients on maintenance hemodialysis treatment and forty healthy subjects were enrolled in this study. Blood irisin concentrations and UII concentrations were measured by ELISA and RIA respectively. The body composition was analyzed by bioelectrical impedance. The serum irisin levels and UII levels were both significantly lower in HD patients in comparison to that of the healthy subjects. The serum irisin levels were lower in HD patients with protein energy wasting than those of the patients without protein energy wasting. The independent determinants of circulating Ln (irisin) (the natural logarithm of irisin) were UII lean body mass and patients with protein energy wasting. | The objective of this study was to compare the effect of air abrasion (KCP 2000), acid etching (37% phosphoric acid), and the combination of both procedures on the shear bond strength and microleakage of a light-cured pit-and-fissure sealant to the enamel of human primary molar teeth. Noncarious extracted human primary molars were randomly divided into 4 groups in preparation for enamel bonding. The enamel surface was treated as follows for each group: (1) group 1 (control group); (2) group 2 (acid etch group); (3) group 3 (KCP [Kinetic Cavity Preparation System] group); and (4) group 4 (KCP and acid etch group). Delton, a light-cured pit-and-fissure sealant, was then applied to the occlusal surface after conditioning. The bonded specimens were maintained in distilled water at 37 degrees C+/-2 degrees C for 7 days, after which they were subjected to thermocycling followed by shear bond testing. Microleakage was determined by immersing the prepared teeth in 50% silver nitrate dye followed by sectioning and calculation of dye penetration. The mean shear bond strength of the KCP+acid etch group exhibited nearly 50% higher bond strength than the acid etch group (P<.01). In addition, specimens bonded to enamel conditioned only with acid etch exhibited bond strengths that were nearly twice that of those conditioned with the KCP system alone. No significant difference was noted between the air abrasion and control groups. |
Are guideline-concordant weight-loss programs in an urban area uncommon and difficult to identify through the internet? | To determine the reliability of Internet-based information on community-based weight-loss programs and grade their degree of concordance with 2013 American Heart Association, American College of Cardiology, and The Obesity Society weight-management guidelines. An online search was conducted for weight-loss programs in the Maryland-Washington, DC-Virginia corridor. Content analysis was performed to abstract program components from their websites, and then 80 programs were randomly selected for a telephone survey to verify this information. Reliability of Internet information was determined in comparison with telephone interview responses. Of the 191 programs, 1% were graded as high, 8% as moderate, and 91% as low with respect to guideline concordance based on website content. Fifty-two programs participated in the telephone survey (65% response rate). Program intensity, diet, physical activity, and use of behavioral strategies were underreported on websites as compared to description of these activities during the phone interview. Within the subsample, 6% of programs were graded as high based on website information, whereas 19% were graded as high after the telephone interview. | BAF312 (Siponimod) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. This drug is currently undergoing clinical trials for the treatment of secondary progressive multiple sclerosis (MS). Here, we investigated the effects of BAF312 on isolated astrocyte and microglia cultures as well as in slice culture models of demyelination. Mouse and human astrocytes were treated with S1PR modulators and changes in the levels of pERK, pAkt, and calcium signalling as well as S1PR1 internalization and cytokine levels was investigated using Western blotting, immunochemistry, ELISA and confocal microscopy. Organotypic slice cultures were prepared from the cerebellum of 10-day-old mice and treated with lysophosphatidylcholine (LPC), psychosine and/or S1PR modulators, and changes in myelination states were measured by fluorescence of myelin basic protein and neurofilament H. BAF312 treatment of human and mouse astrocytes activated pERK, pAKT and Ca(2+) signalling as well as inducing S1PR1 internalization. Notably, activation of S1PR1 increased pERK and pAKT in mouse astrocytes while both S1PR1 and S1PR3 equally increased pERK and pAKT in human astrocytes, suggesting that the coupling of S1PR1 and S1PR3 to pERK and pAKT differ in mouse and human astrocytes. We also observed that BAF312 moderately attenuated lipopolysaccharide (LPS)- or TNFα/IL17-induced levels of IL6 in both astrocyte and microglia cell cultures. In organotypic slice cultures, BAF312 reduced LPC-induced levels of IL6 and attenuated LPC-mediated demyelination. We have shown previously that the toxic lipid metabolite psychosine induces demyelination in organotypic slice cultures, without altering the levels of cytokines, such as IL6. Importantly, psychosine-induced demyelination was also attenuated by BAF312. |
Does a linoleate-enriched cheese product reduce low-density lipoprotein in moderately hypercholesterolemic adults? | To test the effect of substituting a modified-fat cheese product into the diets of hypercholesterolemic adults. A 4-month, randomized, double-blind, crossover substitution trial. General community outpatient study. Twenty-six healthy adult volunteers (17 men, 9 women) with moderate hypercholesterolemia (total cholesterol > 5.69 mmol/L but < 7.24 mmol/L). Daily substitution of 100 g of cheese, either partial skim-milk mozzarella or modified-fat (vegetable oil) mozzarella cheese product, into participants' normal diets. Participants consumed an assigned cheese for 2 months, at which time they crossed over to consume the other study cheese. Plasma lipid and apolipoprotein levels were measured at baseline and at 2 and 4 months after initiation of the study. Compliance was assessed by body weight and by biweekly dietary records and interviews. No differences in weight or in the amount or type of calories consumed were found during the study. No statistically significant changes in lipid values resulted from consumption of mozzarella cheese. Modified-fat cheese substitution resulted in a decreased low-density lipoprotein cholesterol level when compared with levels at both baseline (-0.28 mmol/L; 95% Cl, -0.14 to -0.42 mmol/L) and during consumption of the skim-milk mozzarella cheese (-0.38 mmol/L; 95% Cl, -0.2 to -0.70 mmol/L). Findings for total cholesterol were similar. High-density lipoprotein cholesterol, plasma triglyceride, and apolipoprotein A-l and B-100 levels were unaltered. Both sexes responded similarly. | Historically, fever, pneumonia, and sepsis after trauma are ascribed to pain and poor pulmonary toilet. No evidence supports that assertion however, and no known biologic mechanisms link injury to infection. Our studies show that injured tissues release mitochondria (MT). Mitochondrial damage-associated molecular patterns (mtDAMPs) however can mimic bacterial pathogen-associated danger molecules and attract neutrophils (PMN). We hypothesized that mtDAMPs from traumatized tissue divert neutrophils from the lung, causing susceptibility to infection. Anesthetized rats (6-10 per group) underwent pulmonary contusion (PC) by chest percussion. When modeling traumatic MT release, some rats had MT isolated from the liver (equal to 5% liver necrosis) injected intraperitoneally (IPMT). Negative controls had PC plus buffer intraperitoneally. Positive controls underwent PC plus cecal ligation and puncture. At 16 hours, bronchoalveolar and peritoneal lavages were performed. Bronchoalveolar lavage fluid (BALF) and peritoneal lavage fluid were assayed for PMN count, albumin, interleukin β, (IL-β), and CINC-1. Assays were normalized to blood urea nitrogen to calculate absolute concentrations. PC caused alveolar IL-1β and CINC production and a 34-fold increase in BALF neutrophils. As expected, IPMT increased peritoneal IL-1β and CINC and attracted PMN to the abdomen. However, remarkably, IPMT after PC attenuated BALF cytokine accumulation and decreased BALF PMN. Cecal ligation and puncture had no direct effect on BALF PMNs but, like IPMT, blunted BALF leukocytosis after PC. |
Is bradycardia during therapeutic hypothermia associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest? | Comatose patients resuscitated after out-of-hospital cardiac arrest receive therapeutic hypothermia. Bradycardia is frequent during therapeutic hypothermia, but its impact on outcome remains unclear. We explore a possible association between bradycardia during therapeutic hypothermia and neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. Retrospective cohort study, from January 2009 to January 2011. University hospital medical and cardiac ICUs. One hundred eleven consecutive comatose out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. Patients treated with standardized treatment protocol after cardiac arrest. All out-of-hospital cardiac arrest patients' records were reviewed. Hemodynamic data were obtained every fourth hour during the first days. The patients were in temperature target range (32-34°C) 8 hours after out-of-hospital cardiac arrest and dichotomized into bradycardia and nonbradycardia groups depending on their actual heart rate less than or equal to 60 beats/min or more than 60 beats/min at that time. Primary endpoint was Cerebral Performance Category score at hospital discharge. More nonbradycardia group patients received epinephrine during resuscitation and epinephrine and norepinephrine in the early in-hospital period. They also had lower base excess at admission. Survival rate with favorable outcome was significantly higher in the bradycardia than the nonbradycardia group (60% vs 37%, respectively, p = 0.03). For further heart rate quantification, patients were divided into quartiles: less than or equal to 49 beats/min, 50-63 beats/min, 64-77 beats/min, and more than or equal to 78 beats/min, with respective proportions of patients with good outcome at discharge of 18 of 27 (67%), 14 of 25 (56%), 12 of 28 (43%), and 7 of 27 (26%) (p = 0.002). Patients in the lowest quartile had significantly better outcome than the higher groups (p = 0.027), whereas patients in the highest quartile had significantly worse outcome than the lower three groups (p = 0.013). | A laboratory study was conducted to evaluate the influence of cocultivation of toxigenic Fusarium (F.) and Alternaria (A.) fungi with respect to growth and mycotoxin production. Fusarium culmorum Fc13, Fusarium graminearum Fg23 and two Alternaria tenuissima isolates (At18 and At220) were simultaneously or consecutively co-incubated on wheat kernels in an in vitro test system. Fungal biomass was quantified by determining ergosterol content. Three Fusarium toxins (DON, NIV and ZON) and three Alternaria toxins (AOH, AME and ALT) were analysed by a newly developed HPLC/MS/MS method. In simultaneous cocultures, the fungal biomass was enhanced up to 460% compared with individual cultures; Alternaria toxins were considerably depressed down to <5%. Combining At18 and At220 with Fg23 inhibited the toxin production of both fungal partners. In contrast, Fc13 increased its DON and ZON production in competitive interaction with both A. strains. |
Is elevated estimated arterial age associated with metabolic syndrome and low-grade inflammation? | Arterial age can be estimated from equations relating arterial stiffness to age and blood pressure in large cohorts. We investigated whether estimated arterial age (eAA) was elevated in patients with the metabolic syndrome and/or known cardiovascular disease (CVD), which factors were associated with eAA and whether eAA added prognostic information. In 1993, 2366 study participants, 41, 51, 61, and 71 years old, had traditional cardiovascular risk factors and carotid-femoral pulse wave velocity (cfPWV) measured. Risk groups were identified based on known CVD and components of metabolic syndrome, Systematic COronary Risk Evaluation, or Framingham risk score. From age, mean blood pressure, and cfPWV, eAA and estimated cfPWV (ePWV) were calculated. In 2006, the combined cardiovascular endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for ischemic heart disease was registered. cfPWV and ePWV increased with ageing and cardiovascular risk (all P < 0.001), but ePWV increased more with ageing than cfPWV. The difference between eAA and chronological age was associated with male sex (β = 0.14), higher heart rate (β = 0.16 both P < 0.001), fasting glucose (β = 0.08) soluble urokinase plasminogen activator receptor (β = 0.06, both P < 0.01), and known CVD (β = 0.06, P < 0.05) independently of age, SBP, and heart rate. Independently of Systematic COronary Risk Evaluation, eAA (hazard ratio = 1.20, P < 0.01) predicted CEP, but not as accurately as ePWV (hazard ratio = 1.58, P < 0.001) and cfPWV (hazard ratio = 1.32, P < 0.001) among apparently healthy study participants. | Rhesus macaque and human preimplantation embryos display similar rates of chromosomal abnormalities. The aim of this study was to determine whether embryos developing from MI oocytes that mature post-retrieval display more chromosomal anomalies than those embryos that are generated from oocytes that are at MII at the time of retrieval. Rhesus macaque oocytes were obtained after hormonal ovarian stimulation. Immediately after retrieval, the oocytes were classified according to their maturational status. Following in vitro fertilization, Day 3 embryos with good morphology and development derived from oocytes maturing post-retrieval and those from oocytes that were mature at the time of retrieval were cytogenetically assessed using a five-color fluorescent in situ fluorescent hybridization assay developed for rhesus macaque chromosomes homologous to human chromosomes 13, 16, 18, X and Y. Blastomeres from 53 embryos were analyzed. Of the 27 embryos that developed from oocytes that were mature at collection, 18 embryos were chromosomally normal (66.7%), while from the 26 embryos that developed from oocytes that matured post-retrieval, only 9 embryos were chromosomally normal (34.6%). |
Does acute High-Intensity Intermittent Aerobic Exercise reduce Plasma Angiopoietin-Like 2 in Patients With Coronary Artery Disease? | Circulating levels of angiopoietin-like 2 (ANGPTL2), a proinflammatory and proatherogenic protein, are elevated in patients with coronary artery disease (CAD). We hypothesized that high-intensity intermittent exercise (HIIE), known to be beneficial in patients with CAD, would reduce circulating ANGPTL2 levels. Plasma levels of ANGPTL2 were measured before and 20 minutes, 24 hours, and 72 hours after an acute exercise session in a crossover study comparing HIIE to moderate-intensity continuous exercise (MICE) in 14 patients with CAD and 20 age-matched and 20 young healthy controls. Pre-exercise ANGPTL2 levels were 3-fold higher in patients with CAD than in age-matched controls (P < 0.05) and correlated negatively with Vo2max/lean body mass (P < 0.0001). In healthy controls, ANGPTL2 levels were low and not affected by HIIE or MICE. In patients with CAD, ANGPTL2 levels decreased significantly by 41% after 20 minutes of HIIE, a reduction that was maintained after 24 and 72 hours (P < 0.05). In contrast, although ANGPTL2 levels decreased by 47% after 20 minutes of MICE, they increased by 104% after 24 hours and returned to baseline values after 72 hours (P < 0.05). A negative correlation was observed between this increase in ANGPTL2 levels and the mean rate-pressure product (heart rate × systolic blood pressure; index of myocardial O2 consumption) measured during MICE, suggesting that subclinical ischemia might promote ANGPTL2 expression. | In mice, the farnesoid X receptor is involved in bacterial translocation, which can result in spontaneous bacterial peritonitis in patients with cirrhosis. We investigated if polymorphisms in the farnesoid X receptor gene influence the risk for spontaneous bacterial peritonitis. Laboratory and clinical data of 293 cirrhotic patients with ascites and 226 healthy controls were prospectively collected. The rs56163822, rs11110390 and rs12313471 polymorphisms of the farnesoid X receptor were determined. 115 (39%) patients had spontaneous bacterial peritonitis. Distribution of all farnesoid X receptor genotypes matched the Hardy-Weinberg equilibrium. Patients with spontaneous bacterial peritonitis had a higher frequency of the rs56163822 GT genotype (7.0%) than patients without (1.7%, OR=4.4, p=0.02). This genotype was confirmed as predictor of spontaneous bacterial peritonitis by binary logistic regression analysis (OR=6.8, p=0.018). |
Are small acute increases in serum creatinine associated with decreased long-term survival in the critically ill? | Long-term outcomes after acute kidney injury (AKI) are poorly described. We hypothesized that one single episode of minimal (stage 1) AKI is associated with reduced long-term survival compared with no AKI after recovery from critical illness. A prospective cohort of 2,010 intensive care unit (ICU) patients admitted to the ICU between years 2000 and 2009 at a provincial tertiary care hospital. Development of AKI was determined according to the KDIGO classification and mortality up to 10 years after ICU admission was recorded. Of the 1,844 eligible patients, 18.4% had AKI stage 1, 12.1% had stage 2, 26.5% had stage 3, and 43.0% had no AKI. The 28-day, 1-year, 5-year, and 10-year survival rates were 67.1%, 51.8%, 44.1%, and 36.3% in patients with mild AKI, which was significantly worse compared with the critically ill patients with no AKI at any time (P < 0.01). The unadjusted 10-year mortality hazard ratio was 1.53 (95% confidence interval, 1.2-2.0) for 28-day survivors with stage 1 AKI compared with critically ill patients with no AKI. Adjusted 10-year mortality risk was 1.26 (1.0-1.6). After propensity matching stage 1 AKI with no AKI patients, mild AKI was still significantly associated with decreased 10-year survival (P = 0.036). | In rats, oral oleoyl-estrone (OE) decreases food intake and body lipid content. The aim of this study was to determine whether OE treatment affects the energy metabolism of pregnant rats and eventually, of their pups; i.e. changes in normal growth patterns and the onset of obesity after weaning. Pregnant Wistar rats were treated with daily intragastric gavages of OE in 0.2 ml sunflower oil from days 11 to 21 of pregnancy (i.e. 10 nmol oleoyl-estrone/g/day). Control animals received only the vehicle. Plasma and hormone metabolites were determined together with variations in cellularity of adipose tissue. Treatment decreased food intake and lowered weight gain during late pregnancy, mainly because of reduced adipose tissue accumulation in different sites. OE-treated pregnant rats' metabolic pattern after delivery was similar to that of controls. Neonates from OE-treated rats weighed the same as those from controls. They also maintained the same growth rate up to weaning, but pups from OE-treated rats slowed their growth rate afterwards, despite only limited differences in metabolite concentrations. |
Are sarcopenic obesity and myosteatosis associated with higher mortality in patients with cirrhosis? | Obesity is frequently associated with cirrhosis, and cirrhotic patients may develop simultaneous loss of skeletal muscle and gain of adipose tissue, culminating in the condition of sarcopenic obesity. Additionally, muscle depletion is characterized by both a reduction in muscle size and increased proportion of muscular fat, termed myosteatosis. In this study, we aimed to establish the frequency and clinical significance of sarcopenia, sarcopenic obesity and myosteatosis in cirrhotic patients. We analysed 678 patients with cirrhosis. Sarcopenia, sarcopenic obesity and myosteatosis were analysed by CT scan using the third lumbar vertebrae skeletal muscle and attenuation indexes, using previously validated gender-and body mass index-specific cutoffs. Patients were predominately men (n = 457, 67%), and cirrhosis aetiology was hepatitis C virus in 269 patients (40%), alcohol in 153 (23%), non-alcoholic steatohepatitis/cryptogenic in 96 (14%), autoimmune liver disease in 55 (8%), hepatitis B virus in 43 (6%), and others in 5 patients (1%). Sarcopenia was present in 292 (43%), 135 had sarcopenic obesity (20%) and 353 had myosteatosis (52%). Patients with sarcopenia (22 ± 3 vs. 95 ± 22 months, P < 0.001), sarcopenic obesity (22 ± 3 vs. 95 ± 22 months, P < 0.001), and myosteatosis (28 ± 5 vs. 95 ± 22 months, P < 0.001) had worse median survival than patients without muscular abnormalities. By multivariate Cox regression analysis, both sarcopenia [hazard ratio (HR) 2.00, 95% confidence interval (CI) 1.44-2.77, P < 0.001], and myosteatosis (HR 1.42, 95% CI 1.02-1.07, P = 0.04) were associated with mortality. | Pectins are one of the main components of plant cell walls. They are secreted to the wall as highly methylesterified forms that can be de-esterified by pectin methylesterases (PMEs). The degree of methylesterification of pectins changes during development, PMEs are involved in the cell wall remodeling that occurs during diverse plant developmental processes. Nevertheless, the functional meaning of pectin-related wall remodeling in different cell types and processes remains unclear. In vivo, the microspore follows the gametophytic pathway and differentiates to form the pollen grain. In vitro, the microspore can be reprogrammed by stress treatments becoming a totipotent cell that starts to proliferate and follows the embryogenic pathway, a process known as microspore embryogenesis. To investigate if the change of developmental programme of the microspore towards embryogenesis involves changes in pectin esterification levels, which would cause the cell wall remodeling during the process, in the present study, dynamics of PME expression and degrees of pectin esterification have been analysed during microspore embryogenesis and compared with the gametophytic development, in Brassica napus. A multidisciplinary approach has been adopted including BnPME gene expression analysis by quantitative RT-PCR, fluorescence in situ hybridization, immuno-dot-blot and immunofluorescence with JIM5 and JIM7 antibodies to reveal low and highly-methylesterified pectins. The results showed that cell differentiation at advanced developmental stages involved induction of BnPME expression and pectin de-esterification, processes that were also detected in zygotic embryos, providing additional evidence that microspore embryogenesis mimics zygotic embryogenesis. By contrast, early microspore embryogenesis, totipotency and proliferation were associated with low expression of BnPME and high levels of esterified pectins. |
Do progestins in the hippocampus of female rats have antiseizure effects in a pentylenetetrazole seizure model? | Progestins can have profound effects on seizure processes. However, the effects and mechanisms of progestins to modulate seizures have not been systematically investigated. The present studies were designed to characterize the effects of progestins to modulate pentylenetetrazole (PTZ)-induced seizures in female rats. In Experiment 1, ictal activity and plasma and hippocampal progesterone (P) and 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) levels of proestrous rats were compared with those of diestrous and ovariectomized (ovx) rats. Experiments 2 and 3 examined effects of ovx and replacement with vehicle, P, or 3alpha,5alpha-THP, systemically (Experiment 2) or to the hippocampus (Experiment 3) on seizures and plasma and hippocampal P and 3alpha,5alpha-THP concentrations. Proestrous rats had reduced ictal activity and increased levels of P and 3alpha,5alpha-THP in plasma and hippocampus compared with diestrous or ovx rats (Experiment 1). Rats administered systemic P or 3alpha,5alpha-THP had significantly reduced ictal activity and increased plasma and hippocampal P and 3alpha,5alpha-THP levels compared with vehicle-administered rats (Experiment 2). Administration of P or 3alpha,5alpha-THP to the hippocampus of ovx rats significantly reduced seizure activity and increased hippocampal, but not plasma, levels of P and 3alpha,5alpha-THP compared with vehicle administration (Experiment 3). | To investigate the significance of respiratory muscle weakness in chronic heart failure and its relation both to maximum oxygen consumption during cardiopulmonary exercise testing and to skeletal muscle (quadriceps) strength. Seven healthy men aged 54.9 (SEM 4.3) years and 20 men with chronic heart failure aged 61.4 (1.6) years (P = 0.20) with radionuclide left ventricular ejection fraction of 25.4 (3.0)%. Mouth pressures during maximum static inspiratory effort (PImax) at functional residual capacity (FRC) and residual volume (RV) were measured in all subjects and taken as indices of inspiratory muscle strength. Similarly, mouth pressures during maximum static expiratory effort (PEmax) at FRC and total lung capacity (TLC) were taken as indices of expiratory muscle strength. Cardiopulmonary exercise testing was performed in all subjects. All controls and 15 heart failure patients also had their right quadriceps muscle strength measured. There was respiratory muscle weakness in heart failure patients, with reduction of PImax at FRC (59.7) (6.3) v 85.6 (9.6) cm H2O, P = 0.045), PEmax at FRC (94.8 (6.2) v 134.6 (9.1) cm H2O, P = 0.004), and PEmax at TLC (121.7 (8.5) v 160.7 (13) cm H2O, P = 0.028). PImax at RV was also reduced but this did not reach statistical significance (77.3 (6.6) v 89.3 (13) cm H2O, P = 0.44). There was also significant weakness of the right quadriceps muscle (308.5 (22) v 446.2 (28) N, P = 0.001). PImax at both FRC and RV correlated with maximum oxygen consumption (r = 0.59, P = 0.006, and r = 0.45, P = 0.048 respectively) but not PEmax. There was, however, no significant correlation between PImax and right quadriceps strength. |
Do human embryonic stem cell-derived neural precursor transplants in collagen scaffolds promote recovery in injured rat spinal cord? | Several studies have reported functional improvement after transplantation of in vivo-derived neural progenitor cells (NPC) into injured spinal cord. However, the potential of human embryonic stem cell-derived NPC (hESC-NPC) as a tool for cell replacement of spinal cord injury (SCI) should be considered. We report on the generation of NPC as neural-like tubes in adherent and feeder-free hESC using a defined media supplemented with growth factors, and their transplantation in collagen scaffolds in adult rats subjected to midline lateral hemisection SCI. hESC-NPC were highly expressed molecular features of NPC such as Nestin, Sox1 and Pax6. Furthermore, these cells exhibited the multipotential characteristic of differentiating into neurons and glials in vitro. Implantation of xenografted hESC-NPC into the spinal cord with collagen scaffold improved the recovery of hindlimb locomotor function and sensory responses in an adult rat model of SCI. Analysis of transplanted cells showed migration toward the spinal cord and both neural and glial differentiation in vivo. | Alterations in serum lipids and an increased risk of myocardial infarction have been associated with HIV-1 infection and its treatment. Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy in frozen plasma samples from participants in the Multicenter AIDS Cohort Study. The effects of HIV-1 infection, antiretroviral therapy, and other factors on median particle concentrations were examined using quantile regression. Fasted samples were tested from 1082 men, including 609 HIV-seronegative and 473 HIV-1-infected men. Compared with HIV-seronegative men, HIV-1-infected men on antiretroviral therapy had an atherogenic phenotype with higher numbers of very low density lipoprotein and small low-density lipoprotein particles and lower numbers of high-density lipoprotein and large low-density lipoprotein particles. HIV-infected, antiretroviral-naive men had significantly lower high-density lipoprotein and small low-density lipoprotein particle concentrations compared with the HIV-seronegative men. Among men on antiretroviral therapy, the atherogenic phenotype was most pronounced in men with a good clinical status. |
Are ovarian stem cells always accompanied by very small embryonic-like stem cells in adult mammalian ovary? | Existing dogma that a female is born with fixed number of eggs was challenged by the detection of stem cells in adult mammalian ovary. Data has accumulated in support of ovarian stem cells (OSCs) proliferation, maintenance in culture, formation of germ cell nests and differentiation into oocytes and primordial follicle assembly using different strategies. Flow cytometry analysis identified >8 μm OSCs which are DDX1 positive and are considered equivalent to spermatogonial stem cells (SSCs) in testis. Analysis of both ovarian and testicular smears obtained after enzymatic digestion has led to the identification of an additional stem cell population termed very small embryonic-like stem cells (VSELs). VSELs and OSCs/SSCs differ from each other in their size and OCT-4 expression. VSELs express pluripotent markers including nuclear OCT-4 whereas OSCs/SSCs express cytoplasmic OCT-4 suggesting a differentiated state. VSELs can be studied by flow cytometry as small sized cells which are LIN-/CD45-/Sca-1+. We have reported 0.02 ± 0.008, 0.03 ± 0.017 and 0.08 ± 0.03 % of total cells as VSELs in normal, chemoablated and after FSH treatment to chemoablated mouse ovary. | Adverse drug reactions (ADRs) associated with anti-tuberculosis (anti-TB) drug regimens have considerable impact on anti-TB treatment, potentially leading to unsuccessful outcomes. Nevertheless, the risk factors that play a role in anti-TB drug-induced ADRs are not well established. It is well documented that genetic polymorphisms in drug-metabolizing enzymes (DMEs) result in considerably complex variability in anti-TB drug disposition. In addition, the impact of pharmacogenetic variation on the metabolism of anti-TB drugs may be modifiable by environmental exposure. Thus, an assessment of pharmacogenetic variability combined with biomarkers of environmental exposure may be helpful for demonstrating the effect of the gene-environment interaction on susceptibility to ADRs induced by anti-TB drug therapy. The aim of the study was to investigate the impact of the interaction between environmental risk factors and pharmacogenetic polymorphisms in four common DMEs--N-acetyltransferase 2 (arylamine N-acetyltransferase) [NAT2], glutathione S-transferase theta 1 [GSTT1], glutathione S-transferase mu 1 [GSTM1], and cytochrome P450 2E1 [CYP2E1]--on commonly reported ADRs to first-line anti-TB drugs in 129 patients receiving homogeneous TB treatment. TB patients monitored during drug treatment were divided into subgroups according to the presence or absence of ADRs. Additionally, the patients' clinical and demographic characteristics were collected in order to identify the environmental factors that are potential triggers for ADRs induced by anti-TB drug treatment. Pharmacogenetic variability was determined by gene sequencing, TaqMan® assays, or polymerase chain reaction. The findings of this study suggest that the NAT2 slow acetylator haplotype, female sex, and smoking are important determinants of susceptibility to ADRs induced by anti-TB drugs. Patients carrying multiple, but not single, polymorphisms in the NAT2, GSTM1, GSTT1, and CYP2E1 genes were found to have an increased risk of ADRs, as revealed by gene-gene interaction analysis. Moreover, we also identified meaningful gene-environment interaction models that resulted in the highest levels of ADR risk. |
Does atrial natriuretic peptide suppress endothelin gene expression and proliferation in cardiac fibroblasts through a GATA4-dependent mechanism? | Atrial natriuretic peptide (ANP) is a hormone that has both antihypertrophic and antifibrotic properties in the heart. We hypothesized that myocyte-derived ANP inhibits endothelin (ET) gene expression in fibroblasts. We have investigated the mechanism(s) involved in the antiproliferative effect of ANP on cardiac fibroblasts in a cell culture model. We found that cardiac myocytes inhibited DNA synthesis in co-cultured cardiac fibroblasts as did treatment with the ET-1 antagonist BQ610. The effect of co-culture was reversed by antibody directed against ANP or the ANP receptor antagonist HS-142-1. ANP inhibited the expression of the ET-1 gene and ET-1 gene promoter activity in cultured fibroblasts. The site of the inhibition was localized to a GATA-binding site positioned between -132 and -135 upstream from the transcription start site. GATA4 expression was demonstrated in cardiac fibroblasts, GATA4 bound the ET-1 promoter both in vitro and in vivo, and siRNA-mediated knockdown of GATA4 inhibited ET-1 expression. ET-1 treatment resulted in increased levels of phospho-serine(105) GATA4 in cardiac fibroblasts and this induction was partially suppressed by co-treatment with ANP. | Sit-to-stand tasks are commonly facilitated by modifying the initial position of the center of mass relative to the feet. It was hypothesized that modifications in the center of mass trajectory during sit-to-stand tasks altered the total body momentum at seat departure and redistributed the lower extremity net joint moments. Between-task within-subject comparison was employed using a robust statistical method to accommodate for small sample size. Six individuals performed four sit-to-stand tasks with systematic modifications in the initial center of mass position by varying the orientation of the lower extremity segments. The momentum of the center of mass and lower extremity net joint moments were quantified and compared. Reducing the horizontal center of mass displacement significantly reduced horizontal total body momentum required at seat departure. Sit-to-stand tasks initiated with more horizontal shank and thigh positions required significantly greater knee and hip extensor net joint moments than those with more vertical shank and thigh positions. Sit-to-stand tasks initiated with vertical shank positions also required significantly greater hip extensor net joint moments as compared to those with more horizontal shank orientations. |
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