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Do a virtually 1H-free birdcage coil for zero echo time MRI without background signal? | MRI of tissues with rapid transverse relaxation can be performed efficiently using the zero echo time (ZTE) technique. At high bandwidths leading to large relative initial radiofrequency (RF) dead times, the method becomes increasingly sensitive to artifacts related to signal stemming from outside the field of view, particularly from the RF coils. Therefore, in this work, a birdcage coil was designed that is virtually free of 1H signal. A transmit-receive birdcage RF coil for MRI of joints at 7T was designed by rigorously avoiding materials containing 1H nuclei, by using purely mechanical connections without glue, and by spoiling of unwanted signal by application of ferromagnetic materials. The coil was tested for residual 1H signal using ZTE phantom and in vivo joint imaging. In standard ZTE imaging, no 1H signal was detected above noise level. Only at extreme averaging, residual signal was observed close to conductors associated with 1H-containing molecules at adjacent glass surfaces. Phantom images with dead times up to 3.8 Nyquist dwells were obtained with only negligible background artifacts. Furthermore, high-quality ZTE images of human joints were acquired. | Because Dutch health care organisations did want to establish well-defined diabetes shared care groups, we investigated the organisation of insulin therapy in general practice in the Netherlands and assessed factors that were associated with providing insulin therapy in type 2 diabetes (DM2) patients. Questionnaire to half of the Dutch general practitioners (GPs) (n=3848). We compared GPs who both start insulin treatment and monitor the dosages with those who always refer patients requiring insulin therapy or only monitor insulin dosages. Total response was 42% (n=1621). 67% of the GPs start insulin therapy in patients with DM2, especially male GPs and those above the age of 40, as well as GPs working in a health centre and those working together with a practice nurse. GPs working in urban regions less often start insulin. The most often mentioned barriers for starting and/or monitoring insulin therapy are lack of knowledge of insulin therapy, lack of time and insufficient financial incentives. |
Do human blastocysts exhibit unique microrna profiles in relation to maternal age and chromosome constitution? | To determine microRNA (miRNA) expression in human blastocysts relative to advanced maternal age and chromosome constitution. Cryopreserved human blastocysts were warmed and underwent a trophectoderm biopsy for comprehensive chromosomal screening. Select blastocysts were then lysed, reverse transcribed, and pre-amplified prior to running real-time PCR. Statistical analysis was performed using an internal constant housekeeping miRNA. Significant microRNA's of interest were then analyzed for their predicted genes and biological pathways. Additional cryopreserved blastocysts were warmed and stained for the SIRT1 protein for validation. Human blastocysts exhibit unique miRNA expression profiles in relation to maternal age and chromosome constitution. miR-93 was exclusively expressed in blastocysts from women in their forties and further up-regulated with an abnormal chromosome complement. Up-regulated miR-93 resulted in an inverse down-regulation of targets like SIRT1, resulting in reduced oxidative defense. | The purpose of this study was to examine energy drink (ED) usage patterns and to investigate the illicit use of prescription stimulants among college students. A sample of 267 undergraduate and graduate students (mean age of 22.48 among stimulant users) from a large midwestern university and its branch campus locations voluntarily participated in the study. Among prescription stimulant users without a valid medical prescription, Mann-Whitney U tests and logistic regression analysis revealed that the frequency of ED use was a significant predictor of the illicit use of prescription stimulants. Moreover, frequency of ED consumption was a significant predictor of the illicit use of prescription stimulant medications, with the odds for using increasing by .06 with each additional day of ED use past 0 day (odds for use = 1.06, P =.008). |
Does dobutamine improve liver function after hemorrhagic shock through induction of heme oxygenase-1? | Induction of heme oxygenase-1 (HO-1) protects the liver against reperfusion injury after hemorrhagic shock. Previous data suggest that the beta(1)-adrenoceptor agonist dobutamine induces HO-1 in hepatocytes. To investigate the functional significance of dobutamine pretreatment for liver function after hemorrhagic shock in vivo. Anesthetized rats received either Ringer's (Vehicle/Shock), 10 microg/kg/min of the beta(1)-adrenoceptor agonist dobutamine (Dob/Shock), or 10 microg/kg/min dobutamine and 500 microg/kg/min of the beta(1)-adrenoceptor antagonist esmolol (Dob/Esmolol/Shock) for 6 h. Hemorrhagic shock was induced thereafter (mean arterial pressure, 35 mm Hg for 90 min). Animals were resuscitated with shed blood and Ringer's. In addition, the HO pathway was blocked after dobutamine pretreatment with 10 micromol/kg tin-mesoporphyrin-IX (Dob/SnMP/Shock) or animals received 100 mg/kg of the carbon monoxide donor dichloromethane (DCM/Shock). Hepatocellular metabolism and liver blood flow were measured by plasma disappearance rate of indocyanine green (PDR(ICG)) as a sensitive marker of liver function. Pretreatment with dobutamine induced HO-1 in pericentral hepatocytes and improved PDR(ICG) (Vehicle/Shock: 11.7 +/- 8.12%/min vs. Dob/Shock: 19.7 +/- 2.46%/min, p = 0.006). Blockade of the HO pathway after preconditioning and the combined pretreatment with dobutamine and esmolol decreased PDR(ICG) (Dob/SnMP/Shock: 12.6 +/- 4.24%/min, p = 0.011; Dob/Esmolol/Shock: 10.2 +/- 4.34%/min, p = 0.008). Pretreatment with a carbon monoxide donor improved PDR(ICG) (DCM/Shock: 18 +/- 3.19%/min, p = 0.022) compared with Vehicle/Shock. | Survivin is an anti-apoptotic protein that has been recently suggested as a predictive marker of joint destruction in adult rheumatoid arthritis. We assessed the presence of extracellular survivin in patients with juvenile idiopathic arthritis (JIA). Survivin levels were assessed in the circulation of 46 patients with JIA and in the age- and gender-matched controls (n=46) having no inflammatory disease, by ELISA. Survivin levels were analyzed with respect to the onset type and the activity of the joint disease. The intensity of inflammation and cartilage turnover was measured as levels of IL-6, serum amyloid A protein (SAA), and cartilage oligomeric matrix protein (COMP), respectively. The levels of extracellular survivin were significantly higher in JIA compared to the controls (p=0.0002). High levels of survivin (above mean + 2SD of the controls) were detected in 8/46 (17% JIA patients. High survivin expression was associated with polyarticular onset, active phase of arthritis. In contrast, survivin was neither related to the levels of IL-6, SAA, nor to COMP. |
Does dNA microarray expression profiling of bladder cancer allow identification of noninvasive diagnostic markers? | There is a need in urological practice to identify new bladder cancer molecular markers to further develop noninvasive diagnostic tests. We analyzed bladder cancer gene expression profiles to determine the relevant differentially expressed genes and whether this differential expression is maintained in urine samples. We collected 55 tissue specimens from a total of 43 patients with bladder cancer and 12 controls, and 49 urine samples from bladder washings from a total of 36 patients with bladder cancer and 13 controls between September 2003 and December 2004. DNA microarrays (GeneChip Human Genome U133 Plus 2.0 Array) were used to identify differentially expressed genes at 3 bladder cancer stages. Selected differentially expressed genes were validated in an independent set of bladder washings by quantitative reverse transcriptase-polymerase chain reaction. Unsupervised cluster analysis of DNA microarray data showed a clear distinction in control vs tumor samples and low vs high grade tumors. Genes with at least 2-fold differential expression in controls vs tumors (2,937 probe sets or 2,295 genes) and in low vs high grade tumors (674 probe sets or 530 genes) were identified and ranked. Gene expression measurements in bladder washings of the 6 most differentially expressed genes in controls vs tumors were confirmed for the 2 over expressed genes tested by quantitative reverse transcriptase-polymerase chain reaction. All 8 selected differentially expressed genes in low vs high grade tumors were confirmed in bladder washing samples. | Ibutilide is a class III antiarrhythmic drug that is used for the cardioversion of atrial arrhythmias, but it can cause torsades de pointes. Amiodarone is also used for the cardioversion of atrial fibrillation and prolongs the QT interval but rarely causes torsades de pointes. The study included 51 consecutive patients with recent onset atrial fibrillation in whom the administration of ibutilide failed to restore sinus rhythm. In those patients we decided to proceed to intravenous administration of amiodarone. The QT intervals were measured on 12-lead ECG. After 11 +/- 5 h of the administration of the amiodarone, 42 patients (82%) were on sinus rhythm. There was no episode of non-sustained torsades de pointes or hypotension that followed the administration of the two antiarrhythmic agents. |
Does quercetin mitigate valinomycin-induced cellular stress via stress-induced metabolism and cell uptake? | Intestinal cells are constantly exposed to luminal toxins. In this study, we investigated the effect of cellular stress caused by valinomycin, which is structurally and functionally similar to the bacterial toxin cereulide, on quercetin metabolism and cellular localization in undifferentiated cells. Coadministration of quercetin and valinomycin (50 μM quercetin/0.05 μM valinomycin) reduced intracellular reactive oxygen species content and increased cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) of Caco-2 cells compared to valinomycin-only (0.05 μM) treatment. Quercertin was effectively metabolized into methyl, glucuronide, and sulfate conjugates, which were mostly secreted into to the culture medium. Three different O-methylated quercetin isomers were detected. Two were exported from the cells and one remained intracellularly. Further, valinomycin caused an increase in the intracellular accumulation of O-methylated quercetin metabolites compared to cells treated only with quercetin. In valinomycin-untreated cells, quercetin and O-methylated quercetin metabolite were localized in the cell membrane, whereas valinomycin treatment resulted in their uptake by the cells. | The relationship between baseline and recurrent vascular events may be important in the targeting of secondary prevention strategies. We examined the relationship between initial event and various types of further vascular outcomes and associated effects of blood pressure (BP)-lowering. Subsidiary analyses of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial that established the benefits of BP-lowering in 6105 patients (mean age 64 years, 30% female) with cerebrovascular disease, randomly assigned to either active treatment (perindopril for all, plus indapamide in those with neither an indication for, nor a contraindication to, a diuretic) or placebo(s). Stroke subtypes and coronary events were associated with 1.5- to 6.6-fold greater risk of recurrence of the same event (hazard ratios, 1.51 to 6.64; P=0.1 for large artery infarction, P<0.0001 for other events). However, 46% to 92% of further vascular outcomes were not of the same type. Active treatment produced comparable reductions in the risk of vascular outcomes among patients with a broad range of vascular events at entry (relative risk reduction, 25%; P<0.0001 for ischemic stroke; 42%, P=0.0006 for hemorrhagic stroke; 17%, P=0.3 for coronary events; P homogeneity=0.4). |
Is l1CAM an independent predictor of poor survival in endometrial cancer - An analysis of The Cancer Genome Atlas ( TCGA )? | L1-cell adhesion molecule (L1CAM) was previously reported to carry a poor prognosis in Stage I, low-risk endometrial cancer (EC). We evaluated the role of L1CAM among all stages and histologies in ECs in The Cancer Genome Atlas (TCGA). Clinical information and RNA-Seq expression data were derived from TCGA uterine cancer cohort. Associations between L1CAM expression and clinical factors were tested with linear and logistic regression. Differences in survival between "high" and "low" expression groups (defined by median expression) of L1CAM were compared using Cox regression analysis, with p-values calculated via log-rank test. Kaplan-Meier curves were tested with the log-rank test. Patient characteristics of 545 primary tumors with RNA-Seq gene expression data were analyzed. Median age was 64years (range 31-90). Stage I, II, III, and IV comprised 62%, 10%, 23%, and 5%, respectively. 75% were endometrioid; 21% serous. Grade 1, 2, and 3 comprised 18%, 22%, and 60%, respectively. Median follow-up was 23.0months. High L1CAM expression was associated with advanced stage (OR 3.2), high grade (OR=6.8), serous histology (OR=16.3), positive cytology (OR=3.5), positive pelvic (OR=21.8) and para-aortic lymph nodes (OR=10.3) (all p≤0.001). High L1CAM was associated with a median overall survival (OS) of 107months, versus not reached for low L1-expressing ECs (HR=3.46, CI 1.97-6.07, p<0.001). On multivariate analysis, L1CAM expression remained an independent prognostic variable in predicting OS in EC. | To investigate whether unstimulated whole saliva flow rate (UFR) and osmolality (Sosm) track changes in hydration status during 48h of restricted fluid intake (RF) or combined fluid and energy restriction (RF+RE). Following the 48h periods, UFR and Sosm were assessed after acute exercise dehydration and rehydration. Thirteen healthy males completed three trials in a randomised order: control (CON) where participants received their estimated energy (12,154+/-230kJ/d: mean+/-S.E.M) and fluid (3912+/-140ml/d) requirements, RF trial where participants received their energy requirements and 193+/-19ml/d water to drink (total fluid 960+/-15ml/d) and RF+RE where participants received 1214+/-25kJ/d and 962+/-16ml/d. After 48h, participants completed 30min of maximal exercise followed by rehydration (0-2h) and refeeding (2-6h). At 48h body mass loss exceeded 3% on RF and RF+RE. UFR decreased during 48h on RF (510+/-122 to 169+/-37microl/min) and RF+RE (452+/-92 to 265+/-53microl/min) and was lower than CON at 48h (441+/-90microl/min: P<0.05). Sosm increased during 48h on RF (54+/-3 to 73+/-5mOsmol/kg) and RF+RE (52+/-3 to 68+/-5mOsmol/kg) and was greater than CON at 48h (52+/-2mOsmol/kg: P<0.05). Unlike UFR, Sosm identified the additional hypohydration associated with exercise (P<0.05) and returned to within 0h values with rehydration. |
Is a genetic variant in primary miR-378 associated with risk and prognosis of hepatocellular carcinoma in a Chinese population? | MiR-378 has been reported to be related to cell survival, tumor growth and angiogenesis and may participate in hepatocellular carcinoma (HCC) development and prognosis. Genetic variants in primary miR-378 (pri-miR-378) may impact miR-378 expression and contribute to HCC risk and survival. This study aimed to assess the associations between a genetic variant in primary miR-378 and HCC susceptibility and prognosis. We conducted a case-control study to analyze the association of rs1076064 in pri-miR-378 with hepatocellular carcinoma risk in 1300 HCC patients with positive hepatitis B virus (HBV) and 1344 HBV carriers. Then, we evaluated the correlation between the polymorphism and hepatocellular carcinoma prognosis in 331 HCC patients at either intermediate or advanced stage without surgical treatment. The variant genotypes of rs1076064 were associated with a decreased HCC risk in HBV carriers [Adjusted odds ratio (OR) = 0.90, 95% confidence intervals (CI) = 0.81-1.00, P = 0.047]. Moreover, HCC patients with the variant genotypes were associated with a better survival [Adjusted hazard ratio (HR) = 0.70, 95% CIs = 0.59-0.83, P<0.0001 in an additive genetic model]. The reporter gene assay showed that the variant G allele of rs1076064 exerted higher promoter activity than the A allele. | To investigate the relationship of electro-parameters and the electroacupuncture sensation (EAS), which is thought to be an important factor for optimal treatment. The frequency steps and compositions of three frequently used electrical stimulations were set when the switch of the electroacupuncture apparatus was turned to the second or third grade of the dense-disperse frequency wave (DD2 and DD3, respectively) or the second grade of the continuous wave (C2). Three groups of patients according to the three electroacupuncture stimulations were divided again into three sub-groups according to the stimulated acupoints: the face acupoint Quanliao (SI 18), the upper-limb acupoint Quchi (LI 11) and the back acupoint Dachangshu (BL 25). The EAS values were measured every 5 min during 30 min electroacupuncture treatments using a visual analogue scale. The frequency compositions of the three electroacupuncture stimulations were 3.3 and 33 Hz, 12.5 and 66.7 Hz, and 3.3 and 3.3 Hz; each frequency step was 30, 54 and 0 Hz, respectively. In each sub-group of the C2 group, the EAS values from 10 to 30 min were significantly weaker than at 0 min. The sensation fluctuations in the DD2 and DD3 groups were different during the 30 min. |
Does inhibition of heme oxygenase-1 protect against tissue injury in carbon tetrachloride exposed livers? | During the metabolism of the hepatotoxin carbon tetrachloride (CCl(4)) by cytochrome P450, heme, and free radicals are released. Heme oxygenase (HO-1) is an enzyme that is induced by heme as well as oxidative stress and has been reported to be involved in mediating protection against toxic liver injury. The purpose of the present study was to specify the role of HO-1 in CCl(4)-hepatotoxicity. We could demonstrate an up-regulation of HO-1 protein in CCl(4)-exposed liver tissue that reaches its maximum after 6 to 12 h, along with intrahepatic leukocyte accumulation and tissue injury. When animals were pretreated with hemin for augmentation of HO-1 expression, CCl(4)-exposure was associated with a reduction of intrahepatic leukocyte accumulation, while inhibition of CCl(4)-induced HO-1 expression by tin protoporphyrin-IX (SnPP-IX) enhanced leukocytic response. Of interest, however, liver morphology, transaminases, and bile flow as parameters of hepatocellular integrity and excretory function did not concur with reduced leukocyte numbers in the hepatic microcirculation, and revealed best organ function and tissue preservation in case of HO-1 inhibition by SnPP-IX. In contrast, hemin-treated CCl(4)-exposed livers demonstrated pathologic enzyme release and cholestasis. | The main complication of Kawasaki disease is the Coronary Artery (CA) involvement and long term follow up of patients depends on the severity of coronary arterial aneurysms, ischemia, and thrombosis. Early diagnosis of these complications can lead to a more desirable outcome for patients. Myocardial ischemia can prolong QT dispersion and increase the risk of cardiac arrhythmias as well as sudden cardiac arrests. Also, T wave peak-to-end (Tp-Te) interval dispersion, which provides a valuable index of transmural dispersion of repolarization, can trigger the arrhythmia. We evaluated the non-corrected QT interval dispersion (QTD) and the corrected QT (QTc) dispersion and measured Tp-Te interval dispersion in 49 Iranian children (28 males and 21 females) with the diagnosis of Kawasaki disease (KD) in the acute phase and 49 age-matched controls in a prospective study from 2009 to 2012. Student's t-test and Pearson correlation were used to analyze the data. All the statistical analyses were performed through the SPSS 16. Besides, P<0.05 was considered as statistically significant. Patients with KD had significantly longer QTc dispersion (0.099±0.055 s versus. 0.040±0.018 s; P<0.001), non-corrected QT dispersion (0.075±0.046 versus 0.042±0.019; P<0.001), and Tp-Te dispersion (0.047±0.054 versus 0.022±0.011; P=0.015). The patients with elevation in white blood cell count (above 15000) had a statistically significant increased in QTD (P=0.011). No significant correlation was found between coronary involvement and repolarization indexes. |
Does prolonged survival follow resection of oesophageal SCC downstaged by prior chemoradiotherapy? | The poor survival rate of surgically treated patients with oesophageal cancer has not improved substantially over the last 25 years, but combined modality therapy has shown early promising results. A prospective study was undertaken to determine the effect of pre-operative synchronous chemoradiotherapy followed by oesophagectomy in 53 patients with squamous cell carcinoma (SCC) of the oesophagus. The patient group was unselected, other than by fitness for surgery. In 25% of patients, complete pathological regression of the tumour was achieved. All but one of the patients in this subgroup had T2 tumours on pre-operative clinical staging and two had evidence of lymph node involvement, but postoperative pathological examination revealed that pre-operative chemoradiotherapy had downstaged their disease to T0N0. There was no hospital mortality in this subgroup and the actuarial 7 year survival was 69%. | Patients with chronic kidney disease (CKD) not requiring dialysis have a high prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency but the relationship between 25(OH)D levels and metabolic syndrome is unknown in this population. This study analyzed stored plasma samples from 495 non-diabetic subjects with severe kidney disease, not yet on dialysis, who participated in the homocysteine in kidney and end stage renal disease study. Metabolic syndrome was defined as the presence of all three of the following: (1) Serum triglycerides ≥ 150 mg/dl or drug treatment for hypertriglyceridemia; (2) serum high density lipoprotein-cholesterol (HDL-C) < 50 mg/dl for women or < 40 mg/dl for men or drug treatment for dyslipidemia; and (3) blood pressure ≥ 130/85 mmHg or drug treatment for hypertension. Multivariate logistic regression models were used to evaluate the cross-sectional association between plasma 25(OH)D levels and metabolic syndrome. The prevalence of metabolic syndrome increased as 25(OH)D levels declined, with the highest prevalence in participants with 25(OH)D levels < 20 ng/ ml. Participants with 25(OH)D levels < 20 ng/ml had a significantly increased risk of metabolic syndrome compared to subjects with levels > 30 ng/ml after adjustment for multiple confounders (OR 2.25, 95% CI 1.25 - 4.07). Plasma 25(OH)D levels were inversely associated with diastolic blood pressure (R = -0.10, p = 0.029) and serum triglyceride levels (R = -0.14, p = 0.002). |
Are in patients with rheumatoid arthritis , Dickkopf-1 serum levels correlated with parathyroid hormone , bone erosions and bone mineral density? | The objective of this study is to compare the serum levels of Dickkopf-1 (DKK1), a natural inhibitor of Wnt signalling, with parathyroid hormone (PTH) and bone involvement in patients with rheumatoid arthritis (RA). This cross-sectional study includes 154 postmenopausal women with RA and 125 healthy controls. DKK1, 25OH vitamin D (25OHD), bone turnover markers, and PTH serum levels were measured by ELISA; lumbar spine and hip bone mineral density (BMD) and the erosion score were obtained. The RA patients and healthy controls were not significantly different in terms of age, body mass index, and 25OHD serum levels. The mean level of DKK1 and PTH were significantly higher in patients with RA than in healthy controls (172±68 [SD] vs. 96±55 pmoL/L, and 30±15 vs 22±11, respectively; p<0.0001). DKK1 serum levels were positively correlated with age (p<0.05) only in the healthy controls, while they were correlated with PTH serum levels only in the RA patients (p<0.0001). Among the RA patients, DKK1 levels adjusted for age, PTH and disease duration were significantly higher in patients with bone erosions (176 vs. 167 pmoL/L, respectively; p<0.05). DKK1 levels adjusted for age and PTH were negatively correlated with total hip BMD (p<0.05). In the RA patients not on treatment with bisphosphonates, DKK1 serum levels positively correlated with C-terminal telopeptides of type I collagene serum levels (p<0.05). | The aim of this study was to measure the effects of above-real-time-training (ARTT) speed and screen resolution on a simulated flight control task. ARTT has been shown to improve transfer to the criterion task in some military simulation experiments. We tested training speed and screen resolution in a project, sponsored by Defence Research and Development Canada, to develop components for prototype air mission simulators. For this study, 54 participants used a single-screen PC-based flight simulation program to learn to chase and catch an F-18A fighter jet with another F-18A while controlling the chase aircraft with a throttle and side-stick controller. Screen resolution was varied between participants, and training speed was varied factorially across two sessions within participants. Pretest and posttest trials were at high resolution and criterion (900 knots) speed. Posttest performance was best with high screen resolution training and when one ARTT training session was followed by a session of criterion speed training. |
Does post t-PA transfer to hub improve outcome of moderate to severe ischemic stroke patients? | Telemedicine offers rural hospitals the ability to treat acute ischemic stroke on site with intravenous tissue plasminogen activator (t-PA). Most patients are subsequently transferred to a hub hospital with a primary stroke center for post t-PA care. There is little evidence that such transfer is beneficial. The purpose of our study is to determine whether the transfer of patients to hub hospitals is beneficial. We retrospectively analyzed data from our prospectively collected cohort in the AR SAVES (Stroke Assistance through Virtual Emergency Support) telestroke network from November 2008 till January 2012. We compared the outcome of patients who were transferred to a "hub" with those who remained at the "spoke" hospital where thrombolysis took place. We stratified patients according to stroke severity using admission NIHSS scores into two groups: patients with mild stroke (NIHSS <8) and those with moderate to severe stroke (NIHSS ≥8). We defined good outcome as a modified Rankin Scale (mRS) score ≤2. Statistical analysis was performed using Fisher's exact test, two-tailed, and significance was considered at p < 0.05. Out of 894 telestroke consultations, 206 patients received thrombolytic therapy; 134 patients had moderate to severe strokes and 160 patients (78%) were transferred to the hub after thrombolytic therapy. The percentage of patients with good outcome at 3 months was similar between patients transferred to hub and those who stayed at the spoke (61% vs. 55%, p = NS). However, when only patients with moderate to severe strokes were analyzed, patients transferred to the hub were more likely to have good outcomes at three months post t-PA (50% versus 24%, p = 0.026). | To investigate changes in advanced glycation end products (AGEs) and their receptor (RAGE) expression in the gastrointestinal (GI) tract in type 2 diabetic rats. Eight inherited type 2 diabetic rats Goto-Kakizak (GK) and ten age-matched normal rats were used in the study. From 18 wk of age, the body weight and blood glucose were measured every week and 2 wk respectively. When the rats reached 32 wk, two-centimeter segments of esophagus, duodenum, jejunum, ileum, and colon were excised and the wet weight was measured. The segments were fixed in 10% formalin, embedded in paraffin and five micron sections were cut. The layer thickness was measured in Hematoxylin and Eosin-stained slides. AGE [N epsilon-(carboxymethyl) lysine and N epsilon-(carboxyethyl)lysine] and RAGE were detected by immunohistochemistry staining and image analysis was done using Sigmascan Pro 4.0 image analysis software. The blood glucose concentration (mmol/L) at 18 wk age was highest in the GK group (8.88 ± 1.87 vs 6.90 ± 0.43, P < 0.001), a difference that continued to exist until the end of the experiment. The wet weight per unit length (mg/cm) increased in esophagus, jejunum and colon from the normal to the GK group (60.64 ± 9.96 vs 68.56 ± 11.69, P < 0.05 for esophagus; 87.01 ± 9.35 vs 105.29 ± 15.45, P < 0.01 for jejunum; 91.37 ± 7.25 vs 97.28 ± 10.90, P < 0.05 for colon). Histologically, the layer thickness of the GI tract was higher for esophagus, jejunum and colon in the GK group [full thickness (μm): 575.37 ± 69.22 vs 753.20 ± 150.41, P < 0.01 for esophagus; 813.51 ± 44.44 vs 884.81 ± 45.31, P < 0.05 for jejunum; 467.12 ± 65.92 vs 572.26 ± 93.60, P < 0.05 for colon]. In esophagus, the AGE and RAGE mainly distributed in striated muscle cells and squamous epithelial cells. The AGE distribution was much stronger in the GK group compared to the normal group both in the striated muscle layer and mucosa layer (immuno-positive area/ total measuring area %: 4.52 ± 0.89 vs 10.96 ± 1.34, P < 0.01 for muscle; 8.90 ± 2.62 vs 22.45 ± 1.26, P < 0.01 for mucosa). No visible difference was found for RAGE distribution between the two groups. In the intestine AGE and RAGE distributed in epithelial cells of villi and crypt. RAGE was also found in neurons in the myenteric and submucosal plexus. The intensity of AGE staining in mucosa of all segments and RAGE staining in neurons in all segments were strongest in the diabetes group. Significant difference for AGE was found in the epithelial cells of villi and crypt in duodenum (immuno-positive area/total measuring area %: 13.37 ± 3.51 vs 37.48 ± 8.43, P < 0.05 for villi; 0.38 ± 0.12 vs 1.87 ± 0.53, P < 0.05 for crypt) and for RAGE in neurons of all segments (e.g., for jejunum: no staining neurons% 0 vs 0, mild 36.0 ± 5.2 vs 28.7 ± 3.5, moderate 53.2 ± 4.8 vs 55.8 ± 5.4, strong 10.7 ± 1.1 vs 15.4 ± 2.0, P < 0.05). In the colon, RAGE was primarily found in neurons in the myenteric and submucosal plexus. It was stronger in the diabetes group than in the normal group (no staining neurons% 6.2 ± 0.2 vs 0.3 ± 0.04, mild 14.9 ± 2.1 vs 17.6 ± 1.5, moderate 53.1 ± 4.6 vs 44.7 ± 4.4, strong 25.6 ± 18 vs 43.6 ± 4.0, P < 0.05). In the rectum, RAGE was primarily found in the mucosa epithelial cells. |
Does chikungunya virus exploit miR-146a to regulate NF-κB pathway in human synovial fibroblasts? | Chikungunya virus causes chronic infection with manifestations of joint pain. Human synovial fibroblasts get infected with CHIKV and could lead to pro-inflammatory responses. MicroRNAs have potentials to regulate the gene expression of various anti-viral and pro-inflammatory genes. The study aims to investigate the role of miR-146a in modulation of inflammatory responses of human synovial fibroblasts by Chikungunya virus. To study the role of miR-146a in CHIKV pathogenesis in human synovial cells and underlying inflammatory manifestations, we performed CHIKV infection in primary human synovial fibroblasts. Western blotting, real-time PCR, luciferase reporter assay, overexpression and knockdown of cellular miR-146a strategies have been employed to validate the role of miR-146a in regulation of pro-inflammatory NF-κB pathway. CHIKV infection induced the expression of cellular miR-146a, which resulted into down-regulation of TRAF6, IRAK1, IRAK2 and increased replication of CHIKV in human synovial fibroblasts. Exogenous expression of miR-146a in human synovial fibroblasts led to decreased expression of TRAF6, IRAK1, IRAK2 and decreased replication of CHIKV. Inhibition of cellular miR-146a by anti-miR-146a restored the expression levels of TRAF6, IRAK1 and IRAK2. Downregulation of TRAF6, IRAK1 and IRAK2 led to downstream decreased NF-κB activation through negative feedback loop. | In this study, we compared the diagnostic performance of the standard SPECT with motion-frozen (MF) myocardial perfusion SPECT (MPS) in obese patients. A total of 90 consecutive obese patients (body mass index, 30.1-46.8, average, 34.3 +/- 3.6; age, 63 +/- 12 y; 30% women) underwent standard supine rest (201)Tl/stress (99m)Tc dual-isotope gated MPS and cardiac catheterization within 3 mo. MF images were obtained by nonlinear warping of cardiac phases to the end-diastolic position. Total perfusion deficit (TPD) was obtained for summed (S-TPD) and motion-frozen (MF-TPD) datasets with sex-specific standard and MF normal limits. The area under the receiver-operating-characteristic (ROC) curve for detection of coronary artery disease (CAD) by MF-TPD was significantly larger than that for S-TPD (0.93 +/- 0.25 vs. 0.88 +/- 0.32, P < 0.05). MF-TPD had higher specificity (77% vs. 55%, P < 0.05) and accuracy (89% vs. 80%, P < 0.05) than did S-TPD. |
Is type 2 angiotensin II receptor downregulated in cardiomyocytes of patients with heart failure? | The human heart expresses type 2 angiotensin (AT(2)) receptor, but the function is poorly defined. In the present study, we investigated (1) the cellular localization of the AT(2) receptor and (2) the relationship between the AT(2) receptor protein expression and the cardiac function of patients with ischemic heart disease. The receptor localization was assessed by immunohistochemistry and the protein expression was quantified by Western blotting in atrial tissues freshly obtained from 22 patients undergoing coronary artery bypass graft surgery (63.0+/-11.0 years old; male ratio, 85%). Prior to the surgery, blood was drawn for determination of atrial-natriuretic hormone level and the left ventricular function was assessed by ultrasound cardiography. The results of immunohistochemistry showed that the AT(2) receptor was localized to cardiomyocytes and was not present in fibroblasts, vascular smooth muscles, or vascular endothelium. Atrial tissues showed various degrees of structural remodeling, but the localization of the AT(2) receptor was not altered in any tissue sections. The amount of the AT(2) receptor was negatively correlated with end-diastolic left ventricular diastolic dimension (r=-0.56, P<0.01), calculated left ventricular mass index (r=-0.51, P<0.02) and the plasma atrial natriuretic peptide (ANP) concentration (r=-0. 62, P<0.01) and positively correlated with left ventricular ejection fraction (r=0.48, P<0.05). | Studies are conflicting regarding the importance of the fluoroquinolone-resistant North American pulsed-field gel electrophoresis type 1 (NAP1) strain in Clostridium difficile infection (CDI) outcome. We describe strain types causing CDI and evaluate their association with patient outcomes. CDI cases were identified from population-based surveillance. Multivariate regression models were used to evaluate the associations of strain type with severe disease (ileus, toxic megacolon, or pseudomembranous colitis within 5 days; or white blood cell count ≥15 000 cells/µL within 1 day of positive test), severe outcome (intensive care unit admission after positive test, colectomy for C. difficile infection, or death within 30 days of positive test), and death within 14 days of positive test. Strain typing results were available for 2057 cases. Severe disease occurred in 363 (17.7%) cases, severe outcome in 100 (4.9%), and death within 14 days in 56 (2.7%). The most common strain types were NAP1 (28.4%), NAP4 (10.2%), and NAP11 (9.1%). In unadjusted analysis, NAP1 was associated with greater odds of severe disease than other strains. After controlling for patient risk factors, healthcare exposure, and antibiotic use, NAP1 was associated with severe disease (adjusted odds ratio [AOR], 1.74; 95% confidence interval [CI], 1.36-2.22), severe outcome (AOR, 1.66; 95% CI, 1.09-2.54), and death within 14 days (AOR, 2.12; 95% CI, 1.22-3.68). |
Do [ Clinical significance of continuous thrombocytopenia in predicting sepsis after severe burn ]? | To explore the relationship between continuous thrombocytopenia and sepsis in patients with severe burns. Clinical data of 148 severely burned patients admitted to our,two burn centers from January 2007 to December 2011 and conforming to the study criteria were retrospectively analyzed. All patients were divided into sepsis group (n =44) and non-sepsis group (n = 104) according to the presence or absence of sepsis within post burn day (PBD) 30. The data of age, gender, total burn area, full-thickness burn area, fluid infusion volume within post burn hour (PBH) 24, plasma concentration of calcium ion on PBD 1, plasma concentration of albumin on PBD 1, platelet count on PBD 1, acute physiology and chronic health evaluation (APACHE) II score on admission, the presence or absence of hypovolemic shock or inhalation injury on admission, the presence or absence of disseminated intravascular coagulation (DIC) within PBH 48, operation or no operation within PBD 3, thrombocytopenia duration within PBD 10, and mortality were statistically compared between two groups to screen the independent risk factors of sepsis. Data were processed with t test, chi-square test, single factor Logistic regression analysis, and multi-factor Logistic regression analysis. Between two groups, there were statistically significant differences in total burn area, full-thickness burn area, plasma concentration of calcium ion on PBD 1, plasma concentration of albumin on PBD 1, APACHE II score on admission, presence or absence of hypovolem- ic shock on admission, presence or absence of inhalation injury on admission, presence or absence of DIC within PBH 48, and mortality (with t values from 2.433 to 4.082, χ2 values from 8. 818 to 31.528, P < 0.05 or P < 0.01). Furthermore, the duration of thrombocytopenia within PBD 10 in sepsis group was (5.2 ± 2.4) d, which was significantly longer than that in non-sepsis group [(2.9 ± 1.9) d, t =6. 189, P <0.01]. There were no statistically significant differences in the other indexes between two groups (with t values from 0.971 to 1. 250, χ2 values respectively 0. 054 and 1.529, P values above 0.05). Single factor and multi-factor Logistic regression analysis indicated that APACHE II score on admission and duration of thrombocytopenia within PBD 10 were closely related to occurrence of sepsis (with odds ratio respectively 1. 140 and 1.569, P values below 0.01). | An understanding of the relationships between the anterior commissure-posterior commissure line (AC-PC), the subthalamic nucleus (STN), and red nucleus (RN) is imperative if these structures are to be used for targeting in deep brain stimulation. Currently, these relationships are incompletely understood and difficult to assess using conventional MRI. We examined the location and relationships of the STN and the RN to the AC-PC line and to each other in order to provide a greater understanding of their utility when targeting the STN, and the consistency of these anatomic relationships when examined using conventional MRI. A total of 52 STN and RN in 26 patients with Parkinson's disease were evaluated on T2-weighted MR images. The anterior and posterior commissures and the border coordinates of the STN and RN were derived using frame coordinates. The distances from the midcommissural point (mcp) to the centers of the STN and RN, the diameters for each nucleus, and the distances between the nuclei were calculated in the x-, y-, and z-axes. The mean AC-PC length was 26.1 +/- 1.3 mm. The distance from the mcp to the center of the STN was 10 +/- 0.7 mm in the x-axis, 0.2 +/- 0.7 mm in the y-axis, and 3.3 +/- 0.9 mm in the z-axis. The distance from the mcp to the center of the RN was 4.7 +/- 0.6 mm in the x-axis, -5.9 +/- 1.0 mm in the y-axis, and 6.1 +/- 1.3 mm in the z-axis. The distance between the STN and RN was 2.3 +/- 0.7 mm in the x-axis, 2.1 +/- 1.0 mm in the y-axis, and -0.2 +/- 1.3 mm in the z-axis. |
Do neo-sex chromosomes in the black muntjac recapitulate incipient evolution of mammalian sex chromosomes? | The regular mammalian X and Y chromosomes diverged from each other at least 166 to 148 million years ago, leaving few traces of their early evolution, including degeneration of the Y chromosome and evolution of dosage compensation. We studied the intriguing case of black muntjac, in which a recent X-autosome fusion and a subsequent large autosomal inversion within just the past 0.5 million years have led to inheritance patterns identical to the traditional X-Y (neo-sex chromosomes). We compared patterns of genome evolution in 35-kilobase noncoding regions and 23 gene pairs on the homologous neo-sex chromosomes. We found that neo-Y alleles have accumulated more mutations, comprising a wide variety of mutation types, which indicates cessation of recombination and is consistent with an ongoing neo-Y degeneration process. Putative deleterious mutations were observed in coding regions of eight investigated genes as well as cis-regulatory regions of two housekeeping genes. In vivo assays characterized a neo-Y insertion in the promoter of the CLTC gene that causes a significant reduction in allelic expression. A neo-Y-linked deletion in the 3'-untranslated region of gene SNX22 abolished a microRNA target site. Finally, expression analyses revealed complex patterns of expression divergence between neo-Y and neo-X alleles. | The reporting of standardized uptake value (SUV) on fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET) in colorectal cancer is becoming common practice, but its clinical utility remains to be determined. This study was designed to compare FDG-PET uptake as measured by SUV with operative findings. A colorectal cancer database was queried to identify patients who underwent FDG-PET scans with reported SUVs followed by exploratory laparotomy within 3 months and compare these results to determine FDG-PET sensitivity. Of 46 patients, 16 (34.8%) were found to be have increased extent of disease intraoperatively than seen on FDG-PET scan. This patient population had a statistically significant decreased mean maximal SUV than the patients whose FDG-PET scan equaled intraoperative findings (P < .025). |
Does mecamylamine attenuate the subjective stimulant-like effects of alcohol in social drinkers? | Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central nicotinic receptor antagonist, reduces the consumption of and preference for alcohol. This study investigated the effect of mecamylamine on the subjective responses to alcohol in humans. It was hypothesized that mecamylamine (7.5 and 15 mg) would attenuate the stimulant-like subjective effects of alcohol (0.8 g/kg) and decrease the self-reported desire to consume additional alcohol beverages. Fourteen male and 13 female nonsmokers participated in 6 laboratory sessions. During each session, subjects received, in randomized order under double-blinded conditions, a capsule containing mecamylamine (7.5 or 15 mg) or placebo followed by a beverage containing alcohol (0.8 g/kg) or placebo. Physiologic and subjective-effect measures were taken at 30-min intervals for 2 hr after beverage consumption. Mecamylamine attenuated the stimulant and euphoric effects of alcohol and reduced the self-reported desire to consume additional alcohol beverages. This effect was most pronounced in men, even though women exhibited greater physiologic reactions to mecamylamine. | To investigate the effectiveness of a suture bridge technique for quadriceps tendon rupture repair in uraemic patients. Between March 2010 and September 2012, 10 uraemic patients (14 sides) with quadriceps tendon rupture were treated with the suture bridge technique. Of them, 8 were male and 2 were female, aged from 30 to 62 years (mean, 54.2 years). The duration of uremia was 3-11 years (mean, 5.5 years): the duration of quadriceps tendon rupture was 5 days to 2 months (median, 12 days). Six cases had a trauma history, and one case had diabetes. The left side was involved in 2 cases, the right side in 4 cases, and both sides in 4 cases. The active range of motion (ROM) of the knees was (115.0 +/- 8.3) degrees in flexion, and (72.5 +/- 21.2) degrees in extension. Lysholm score was 19.5 +/- 16.3. X-ray films showed downward shifting of patella. MRI revealed discontinuity between distal quadriceps tendon and upper pole of patella. The operation time was 30-50 minutes (mean, 40.3 minutes). Primary healing of incision was obtained in all patients without complications. All patients were followed up 12-25 months (mean, 16.3 months). There was no re-rupture of quadriceps tendon or loosening of internal fixation during follow-up. At last follow-up, the active ROM of the knees was (121.0 +/- 7.9) degrees in flexion, showing no significant difference when compared with preoperative one (t = -2.075, P =0.058); the active ROM was (8.2 +/- 6.1) degrees in extension, showing significant difference when compared with preoperative one (t = 11.702, P = 0.000). Lysholm score was 84.6 +/- 12.4, showing significant difference when compared with preoperative score (t = -16.226, P = 0.000). According to the American Knee Society score (KSS), the results were excellent in 4 sides, good in 9 sides, and fair in 1 side, and the total excellent and good rate was 92.9%. At last follow-up, the active ROM of the knee, Lysholm score, and KSS score were significantly better in young patients (< 45 years) than in elder patients (> or = 45 years), and in patients receiving early operation (< 2 weeks) than in patients receiving late operation (> or = 2 weeks) (P < 0.05). |
Does ropivacaine attenuate endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling? | Acute lung injury (ALI) is associated with high mortality due to the lack of effective therapeutic strategies. Mechanical ventilation itself can cause ventilator-induced lung injury. Pulmonary vascular barrier function, regulated in part by Src kinase-dependent phosphorylation of caveolin-1 and intercellular adhesion molecule-1 (ICAM-1), plays a crucial role in the development of protein-/neutrophil-rich pulmonary edema, the hallmark of ALI. Amide-linked local anesthetics, such as ropivacaine, have anti-inflammatory properties in experimental ALI. We hypothesized ropivacaine may attenuate inflammation in a "double-hit" model of ALI triggered by bacterial endotoxin plus hyperinflation via inhibition of Src-dependent signaling. C57BL/6 (WT) and ICAM-1 (-/-) mice were exposed to either nebulized normal saline (NS) or lipopolysaccharide (LPS, 10 mg) for 1 hour. An intravenous bolus of 0.33 mg/kg ropivacaine or vehicle was followed by mechanical ventilation with normal (7 ml/kg, NTV) or high tidal volume (28 ml/kg, HTV) for 2 hours. Measures of ALI (excess lung water (ELW), extravascular plasma equivalents, permeability index, myeloperoxidase activity) were assessed and lungs were homogenized for Western blot analysis of phosphorylated and total Src, ICAM-1 and caveolin-1. Additional experiments evaluated effects of ropivacaine on LPS-induced phosphorylation/expression of Src, ICAM-1 and caveolin-1 in human lung microvascular endothelial cells (HLMVEC). WT mice treated with LPS alone showed a 49% increase in ELW compared to control animals (p = 0.001), which was attenuated by ropivacaine (p = 0.001). HTV ventilation alone increased measures of ALI even more than LPS, an effect which was not altered by ropivacaine. LPS plus hyperinflation ("double-hit") increased all ALI parameters (ELW, EVPE, permeability index, MPO activity) by 3-4 fold compared to control, which were again decreased by ropivacaine. Western blot analyses of lung homogenates as well as HLMVEC treated in culture with LPS alone showed a reduction in Src activation/expression, as well as ICAM-1 expression and caveolin-1 phosphorylation. In ICAM-1 (-/-) mice, neither addition of LPS to HTV ventilation alone nor ropivacaine had an effect on the development of ALI. | The goal of this study was to identify factors that might aid in diagnosis and intraoperative management of hyperparathyroidism. We analyzed biopsy specimens of 242 parathyroids from 159 patients by use of flow cytometry and image cytometry (ICM) for DNA index (DI), defined as the content of nuclear DNA compared with that expected for a DNA diploid standard, for proliferative index (PI), and for ploidy (diploid versus aneuploid or tetraploid). True normal and normal parathyroids from patients with solitary adenomas were uniformly diploid. Abnormal ploidy (aneuploidy or tetraploidy) was identified frequently in adenomas and occasionally in hyperplasias with the exception that multiple endocrine neoplasia (MEN) biopsy specimens were uniformly diploid. DI for adenomas was similar to that for hyperplasias, and DI of both was higher than for normal glands. ICM-DI correlated positively with flow cytometry-DI and patient age and inversely with serum parathyroid hormone. PI was relatively low in all groups but was higher for hyperplasias versus normal parathyroids from patients with solitary adenomas and MEN versus non-MEN. PI correlated inversely with patient age. |
Does oligonol promote anti-aging pathways via modulation of SIRT1-AMPK-Autophagy Pathway? | Oligonol, mainly found in lychee fruit, is an antioxidant polyphenolic compound which has been shown to have anti-inflammatory and anti-cancer properties. The detailed mechanisms by which oligonol may act as an anti-aging molecule have not been determined. In this study, we evaluated the ability of oligonol to modulate sirtuin (SIRT) expression in human lung epithelial (A549) cells. Oligonol was added to A549 cells and reactive oxygen species production, mitochondrial superoxide formation, and p21 protein levels were measured. Signaling pathways activated upon oligonol treatment were also determined by western blotting. Furthermore, the anti-aging effect of oligonol was evaluated ex vivo in mouse splenocytes and in vivo in Caenorhabditis elegans. Oligonol specifically induced the expression of SIRT1, whose activity is linked to gene expression, metabolic control, and healthy aging. In response to influenza virus infection of A549 cells, oligonol treatment significantly up-regulated SIRT1 expression and down-regulated viral hemagglutinin expression. Oligonol treatment also resulted in the activation of autophagy pathways and the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, oligonol-treated spleen lymphocytes from old mice showed increased cell proliferation, and mRNA levels of SIRT1 in the lungs of old mice were significantly lower than those in the lungs of young mice. Additionally, in vivo lethality assay revealed that oligonol extended the lifespan of C. elegans infected with lethal Vibrio cholerae. | Recent studies have suggested that the percent of positive cores in the prostate needle biopsy is a significant predictor of outcome among men undergoing radical prostatectomy or radiation therapy for prostate cancer. We evaluate whether either percent of cores with cancer or percent of cores positive from the most and least involved side of the prostate needle biopsy was associated with a worse outcome among men treated with radical prostatectomy. A retrospective survey of 1,094 patients from the SEARCH Database treated with radical prostatectomy at 4 different equal access medical centers in California between 1988 and 2002 was undertaken. We used multivariate analysis to examine whether total percent of prostate needle biopsy cores with cancer, percent of cores positive from each side of the prostate and other clinical variables were significant predictors of adverse pathology and time to prostate specific antigen (PSA) recurrence following radical prostatectomy. On multivariate analysis serum PSA and percent of positive cores were significant predictors of positive surgical margins, nonorgan confined disease and seminal vesicle invasion. Percent of positive cores (p <0.001), serum PSA (p = 0.008) and biopsy Gleason score (p = 0.014) were significant independent predictors of time to biochemical recurrence. On a separate multivariate analysis that included the variables of total percent of positive cores, percent of positive cores from the most involved side of the biopsy, percent of positive cores from the least involved side of the biopsy and whether the biopsy was positive unilaterally or bilaterally, only the percent of positive cores from the most involved side of the biopsy was a significant independent predictor of PSA failure following radical prostatectomy. Percent of positive cores was used to separate patients into a low risk (less than 34%), intermediate risk (34% to 50%) and high risk (greater than 50%) groups, which provided significant preoperative risk stratification for PSA recurrence following radical prostatectomy (p <0.001). Percent of positive cores cut points were able to further risk stratify men who were at low (p = 0.001) or intermediate (p = 0.036) but not high (p = 0.674) risk for biochemical failure based on serum PSA and biopsy Gleason score. |
Is a genetic variation in the 5 ' flanking region of the UCP3 gene associated with body mass index in humans in interaction with physical activity? | In obese French Caucasian subjects we previously described a silent UCP3 Tyr99Tyr mutation, associated with body mass index. We hypothesised that an unknown polymorphism in the vicinity of the gene could contribute to obesity. Morbidly obese subjects were screened for mutations in 1 kb upstream from the UCP3 gene. Association studies were done between a variant and obesity in 401 morbidly obese and 231 control subjects. We detected three rare genetic variants and one polymorphism: a +5 G-->A in exon 1, a -155 C-->T, a -439 A insertion and a -55 C-->T located 6 bp from the putative TATA box. This variant was in linkage disequilibrium with the Tyr99Tyr polymorphism. Frequencies of the variant allele at the -55 locus were similar in the obese and control groups (0.23 vs 0.21). The -55 polymorphism was associated with BMI in the obese group (p = 0.0031): BMI was higher in TT than in CC or CT patients. Likewise control subjects with a TT genotype had a higher BMI (p = 0.03). In the obese group, homozygosity for this variant is a risk factor for high BMI (odds ratio: 1:75, p = 0.02). Obese patients were divided into tertiles according to physical activity. In the group with a wild C/C genotype, BMI was negatively associated with physical activity (p = 0.015). | This study describes a case of eye burn induced by sodium hypochlorite used as an irrigant during root canal preparation. A 24-year-old female endodontist was using an operating microscope during root canal treatment, and as the root canal was irrigated, the pressure cannula burst and the irrigant (3.5% sodium hypochlorite) came into direct contact with her left eye. She immediately sought ophthalmologic emergency care for pain, redness of the cornea, burning sensation, photophobia, intraocular pressure, and blurred vision. The initial treatment consisted of washing the eye with saline solution and administering analgesic and anti-inflammatory (steroid) medications. One day after the accident, a topical demulcent and hydroxypropyl medication were applied to the eyeball (conjunctiva), the eye was bandaged for 24 hours, and rest was prescribed for 7 days. Eight days later, a corneal ulcer was diagnosed, and antibiotic and anti-inflammatory (steroid) medications were used. Vision was restored without any sequelae 4 weeks after the accident. The endodontist was instructed to apply control medication (Lagricel; Sophia SA, Caracas, Venezuela) for 3 months and to return for ophthalmologic follow-up every 6 months. |
Does pneumoperitoneum with carbon dioxide enhance liver metastases of cancer cells implanted into the portal vein in rabbits? | Little is known about the role of the CO2 pneumoperitoneum on tumor cells that spread from the portal system into the liver during laparoscopic surgery for gastrointestinal malignancies. Therefore, we designed a study to investigate the effect of CO2 pneumoperitoneum on cancer cells implanted in the portal vein in a rabbit model. Immediately after intraportal inoculation of 2.5x10(5) cells of VX2 cancer, the rabbits received either CO2 pneumoperitoneum at a pressure of 10 mm Hg for 30 min (pneumoperitoneum group, n = 14) or laparotomy alone for 30 min (laparotomy group, n = 14). The number (p<0.01) and area of cancer nodules (p = 0.045) on the liver surface on day 17 were greater in the pneumoperitoneum group than in the laparotomy group. The frequency of cancer nodules >3.0 mm in diameter was higher in the pneumoperitoneum group than in the laparotomy group (p<0.001). | The measurement of affective symptoms in older persons who decline cognitively is uncertain. The authors investigated whether mood variability predicts dementia in patients with age-related macular degeneration (AMD). Three-year observational study after a clinical trial. Community follow-up of outpatients ascertained from retina clinics. One hundred sixty patients with AMD. Geriatric Depression Scale (GDS) administered every 2 weeks for 6 months to subjects; Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) administered to subjects' knowledgeable informants. Twenty-three subjects (14.4%) declined cognitively. Age, education, baseline GDS score > or =5, and variability in GDS scores (i.e., fluctuations between adjacent time points) were associated with cognitive decline. For GDS variability, each 1 unit increase in the residual standard deviation (SD) of the GDS increased the risk for cognitive decline by 93% (IDR = 1.92; 95% CI [1.27-2.91]). Thus, subjects with a residual SD of 1 were nearly twice as likely to become demented as subjects with no variability in GDS scores. The risk for subjects with SDs of 2 increased more than threefold (IDR = 3.68; 95% CI [1.61-8.47]). A multiple regression analysis showed that GDS variability was a significant risk factor for dementia after controlling for significant covariates. |
Does sT depression in lead aVL differentiate inferior ST-elevation myocardial infarction from pericarditis? | ST-segment elevation (STE) due to inferior STE myocardial infarction (STEMI) may be misdiagnosed as pericarditis. Conversely, this less life-threatening etiology of ST elevation may be confused for inferior STEMI. We sought to determine if the presence of any ST-segment depression in lead aVL would differentiate inferior STEMI from pericarditis. Retrospective study of 3 populations. Cohort 1 included patients coded as inferior STEMI, cohort 2 included patients with a discharge diagnosis of pericarditis who presented with chest pain and at least 0.5 mm of ST elevation in at least 1 inferior lead. We analyzed the presenting electrocardiogram in both populations, with careful assessment of leads II, III, aVF, and aVL. In addition, we retrospectively studied a third cohort of patients with subtle inferior STEMI (<1-mm STE with occluded artery on catheterization) and assessed the sensitivity of ST depression in lead aVL for this group. Of 154 inferior STEMI patients, 154 had some amount of ST depression in lead aVL (100%; confidence interval, 98%-100%). Of the 49 electrocardiograms in the pericarditis group, all 49 had some inferior STE but none had any ST-segment depression in lead aVL (specificity, 100%; confidence interval, 91%-100%). In the third cohort, there were 272 inferior MIs with coronary occlusion, of which 54 were "subtle." Of these, 49 had some ST depression in lead aVL. | To study the effect of removal of YY1 binding sites within the LCR region of HPV 16 on viral transforming activity. Previously we had generated new plasmids carrying HPV 16 whole genome, which contained naturally occurred mutated LCR sequences. The viral transforming abilities on mouse fibroblasts were evaluated in anchorage-independent assays, while the expression and activity of YY1 protein in fibroblasts were tested with EMSA and luciferase assays. YY1 protein was expressed in mouse fibroblasts C127, with ability for DNA binding and repression on P97 activity. Both HPV 16 wild-type DNA and mutated DNAs were transfected into C127 cells and spread to the soft-agarose mediums after selecting with G 418. The growth numbers of the cells transfected with mutated HPV 16 DNAs were 2-10 fold more than that with wild-type HPV 16 DNA. |
Does a novel dairy product fermented with Propionibacterium freudenreichii improve the riboflavin status of deficient rats? | Riboflavin deficiency is common in many parts of the world, particularly in developing countries. The use of riboflavin-producing strains in the production of dairy products such as fermented milk, yogurt, and cheese is feasible and economically attractive because it would decrease the costs involved during conventional vitamin fortification and satisfy consumer demands for healthier foods. The present study in a rat bioassay assessed the response of administration of yogurt containing a riboflavin-producing strain of Propionibacterium freudenreichii on the riboflavin status of deficient rats. Propionibacterium freudenreichii NIZO B2336 is a spontaneous roseoflavin-resistant mutant derived from P. freudenreichii B374 that produces larger amounts of riboflavin than the parental stain. Rats were fed a riboflavin-deficient diet for 21 d (depletion period), after which this same diet was supplemented with conventional yogurt, yogurt containing the riboflavin-producing strain (B2336), or the parental non-producing strain (B374) and fed to animals for 28 d (repletion period). As controls, rats were fed the same diet with different concentrations of commercial riboflavin. The novel fermented product containing P. freudenreichii B2336, with increased levels of riboflavin, eliminated most physiologic manifestations of ariboflavinosis such as stunted growth, high erythrocyte glutathione reductase activation coefficient values, and hepatomegaly that were observed when using a riboflavin depletion-repletion model, whereas the product fermented with the non-riboflavin-producing strain did not show this beneficial effect. | The aim of this study was to evaluate the postoperative morphine-sparing effects and reduction in pain and secondary mechanical hyperalgesia after preincisional or postincisional epidural administration of a local anesthetic and an opioid compared with a sham epidural control. Patients undergoing major gynecologic surgery by laparotomy were randomly assigned to three groups and studied in a double-blinded manner. Group 1 received epidural lidocaine and fentanyl before incision and epidural saline 40 min after incision. Group 2 received epidural saline before incision and epidural lidocaine and fentanyl 40 min after incision. Group 3 received a sham epidural control (with saline injected into a catheter taped to the back) before and 40 min after incision. All patients underwent surgery with general anesthesia. One hundred forty-one patients completed the study (group 1, n = 45; group 2, n = 49; group 3, n = 47). Cumulative patient-controlled analgesia morphine consumption at 48 h was significantly lower (P = 0.04) in group 1 (89.8 +/- 43.3 mg) than group 3 (112.5 +/- 71.5 mg) but not group 2 (95.4 +/- 60.2 mg), although the hourly rate of morphine consumption between 24 and 48 h after surgery was significantly lower (P < 0.0009) in group 1 (1.25 +/- 0.02 mg/h) than group 2 (1.41 +/- 0.02 mg/h). Twenty-four hours after surgery, the visual analog scale pain score on movement was significantly less intense (P = 0.005) in group 1 (4.9 +/- 2.2 cm) than group 3 (6.0 +/- 2.6 cm) but not group 2 (5.3 +/- 2.5 cm), and the von Frey pain threshold near the wound was significantly higher (P = 0.03) in group 1 (6.4 +/- 0.6 log mg) than in group 3 (6.1 +/- 0.8 log mg) but not group 2 (6.2 +/- 0.7 log mg). |
Is after an episode of acute low back pain , recurrence unpredictable and not as common as previously thought? | Inception cohort study. To provide the first reliable estimate of the 1-year incidence of recurrence in subjects recently recovered from acute nonspecific low back pain (LBP) and to determine factors predictive of recurrence in 1 year. Previous studies provide potentially flawed estimates of recurrence of LBP because they do not restrict the cohort to those who have recovered and are therefore eligible for a recurrence. We identified 1334 consecutive patients who presented to primary care with acute LBP; of these 353 subjects recovered before 6 weeks and entered the current study. The primary outcome measure was recurrence of LBP in the next year. Specifically, an episode of recurrence was defined in 2 ways: recall of recurrence at the 12-month follow-up and report of pain at the 3- or 12-month follow-up. Risk factors for recurrence were assessed at baseline. Pain intensity was assessed at 6 weeks, 3 months, and 12 months and recurrence at 12 months. Factors that could plausibly affect recurrence were chosen a priori and evaluated using a multivariable regression analysis. Recurrence of LBP was found to be much less common than previous estimates suggest, ranging from 24% (95% CI = 20%-28%) using "12-month recall" definition of recurrence, to 33% (95% CI = 28%-38%) using "pain at follow-up" definition of recurrence. However, only 1 factor, previous episode(s) of LBP, was consistently predictive of recurrence within the next 12 months (odds ratio = 1.8-2.0, P = 0.00-0.05). | To test the hypothesis that statins inhibit leptin-induced hypertrophy in cultured neonatal rat cardiomyocytes. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of simvastatin on leptin-induced hypertrophy. Intracellular reactive oxygen species (ROS) levels were determined by using 2',7'-dichlorofluorescein diacetate (DCF-DA) fluorescence. Total intracellular RNA and cell protein content, which serve as cell proliferative markers, were assayed by using propidium iodide (PI) fluorescence and the Bio-Rad DC protein assay, respectively. The cell surface area, an indicator of cell hypertrophy, was quantified by using Leica image analysis software. After 72 h treatment, leptin markedly increased RNA levels, cell surface area, and total cell protein levels in cardiomyocytes, which were significantly inhibited by simvastatin or catalase treatment. ROS levels were significantly elevated in cardiomyocytes treated with leptin for 4 h compared with those cells without leptin treatment. The increase in ROS levels in cardiomyocytes induced by leptin was reversed by treatment with simvastatin and catalase. |
Does the dual mTORC1 and mTORC2 inhibitor PP242 show strong antitumor activity in a pheochromocytoma PC12 cell tumor model? | To assess the activity of mTOR and downstream effector proteins in the mTOR pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) inhibitor (PP242) compared with that of mTOR complex 1 (mTORC1) inhibitor (rapamycin) using a xenograft tumor model. Pheochromocytoma PC12 cell were xenografted into nude mice. Animals were treated with PP242 and rapamycin. Mean tumor volume was compared across groups. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was used to detect apoptosis. Immunoblot analysis was performed to assess mTORC1/2 activity using p-Akt, p-S6, and p-4E-BP1. The expression of the antiapoptotic protein Bcl-2, pro-apoptotic protein Bax, and the mediator of angiogenesis vascular endothelial growth factor were also investigated. The mean tumor volume of PP242 was significantly lower than in other groups. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling results showed that PP242 markedly increased cell apoptosis compared with other groups. Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated p-Akt. We also observed that only PP242, but not rapamycin, significantly reduced Bcl-2 expression and markedly increased Bax expression. Rapamycin decreased vascular endothelial growth factor expression, but not nearly as striking as seen in the PP242 group. | Previous research has demonstrated both greater difficulty in obtaining follow-up appointments and increased likelihood of return visits to the emergency department (ED) for patients with government-funded insurance plans. The purpose of the current study is to determine whether socioeconomic factors, such as race and insurance type, are associated with the frequency of repeat ED visits in pediatric patients with closed fractures. A review of ED visit data over a 2-year period from a statewide hospital discharge database in New York was conducted. Discharges for patients with a unique person identifier in the database age 17 years and younger were examined for an ICD-9 diagnosis of closed upper or lower extremity fracture. Age, sex, race, and insurance type for patients with a return ED visit within 8 weeks for the same fracture diagnosis were compared with those without a return visit using standard univariate statistical tests and logistic regression analyses. Of the 68,236 visits reviewed, the revisit rate was 0.85%. Patients of nonwhite or unidentified race were significantly more likely to have a revisit than white patients (OR, 1.27; P=0.006). Patients with government-funded insurance were significantly more likely to have a revisit than those without government-funded insurance (OR, 1.55; P<0.001). Patients with private insurance were significantly less likely to have a revisit than those without private insurance (OR, 0.72; P=0.001). |
Is [ The common C677T polymorphism in the methylenetetrahydrofolate reductase gene associated with neural tube defects and preeclampsia ]? | To assess whether methylenetetrahydrofolate reductase(MTHFR) gene C677T polymorphism is associated with neural tube defects and preeclampsia. Twenty- four mothers who had given birth to normal children, 27 mothers who had given birth to NTDs children, 120 normal women, and 57 women who had suffered from preeclampsia were genotyped for C677T polymorphism by using PCR/RFLP method. (1) VV genotype frequency in the normal mothers group it was 0.13, while in the NTDs mothers group it was 0.33; mothers with VV genotype were at 3 times increased risk to have a NTDs child, compared with the normal mothers. (2) In the normal women group VV genotype frequency was 0.15, while in the preeclampsia women group it was 0.31; women with VV genotype were at 2.5 times increased risk to have preeclampsia, compared with the normal women. | End-of-life care is designed as response to patients' verbally communicated needs. The concept of dying as a process would allow us to improve care. This concept may combine the needs of the dying, their outburst of emotions, gradual maturation, family processes, acute problems such as decreasing independence, with their inner experience and transformation of perception. In this study we explored dying patients' mode of perception, and deeper reasons for anxiety and existential suffering. Dying inpatients of a major cancer centre treated by an interdisciplinary team were eligible. Psychotherapy records of cancer patients (course, reactions, discussions with nurses and physicians) provided the data. Participant observation and Interpretative Phenomenological Analysis (IPA) was applied. Our data (pilot study N=80/follow-up-study N=600) suggest that patients undergo transition into another state of consciousness beyond anxiety, ego, and pain. Transition appears to have three stages. Anxiety, struggle, denial/acceptance, family processes, and maturation (ie, finding meaning and dignity, coping with trauma) may depend on the transitional process and also hinder or facilitate this transitional process. |
Do donor postextubation hypotension and age correlate with outcome after donation after cardiac death transplantation? | Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. | A hallmark of rheumatoid arthritis (RA) is invasion of the synovial pannus into cartilage, and this process requires degradation of the collagen matrix. The aim of this study was to explore the role of one of the collagen-degrading matrix metalloproteinases (MMPs), membrane type 1 MMP (MT1-MMP), in synovial pannus invasiveness. The expression and localization of MT1-MMP in human RA pannus were investigated by Western blot analysis of primary synovial cells and immunohistochemical analysis of RA joint specimens. The functional role of MT1-MMP was analyzed by 3-dimensional (3-D) collagen invasion assays and a cartilage invasion assay in the presence or absence of tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, or GM6001. The effect of adenoviral expression of a dominant-negative MT1-MMP construct lacking a catalytic domain was also examined. MT1-MMP was highly expressed at the pannus-cartilage junction in RA joints. Freshly isolated rheumatoid synovial tissue and isolated RA synovial fibroblasts invaded into a 3-D collagen matrix in an MT1-MMP-dependent manner. Invasion was blocked by TIMP-2 and GM6001 but not by TIMP-1. Invasion was also inhibited by the overexpression of a dominant-negative MT1-MMP, which inhibits collagenolytic activity and proMMP-2 activation by MT1-MMP on the cell surface. Synovial fibroblasts also invaded into cartilage in an MT1-MMP-dependent manner. This process was further enhanced by removing aggrecan from the cartilage matrix. |
Do initial injury severity and social factors determine ability to deploy after combat-related amputation? | While many recent publications have examined the ability of amputees to return to active duty, it remains largely unknown why few amputees deploy after amputation and many amputees do not. The purpose of this study is to examine what predictor(s) exist for whether or not an amputee will deploy after sustaining a combat-related amputation. All U.S. Service members who sustained major extremity amputations from September 2001 through July 2011 were analysed. Amputation level(s), mechanism of injury, time interval to amputation, age, rank, Physical Evaluation Board (PEB) disposition and ability to deploy after amputation were determined. Deployment information after amputation was obtained for 953 amputees. There were 47 (5%) amputees who deployed. There were no significant differences amongst service branches for the deployment of amputees (p > 0.2). Amputees who underwent their amputation on the same day of their injury were significantly less likely to deploy after amputation than those who had their amputation on the day of injury (p = .01). Deployed amputees had significantly lower Injury Severity Scores than amputees who did not deploy (15.98 vs 20.87, p < 0.01) and officers were significantly (p < .01) more likely to deploy and the average age of amputees who deployed was significantly higher than those who did not (27.5 vs 25.1, p < .01). Lastly, those amputees who sustained a transtibial amputation were significantly more likely to deploy than all other amputation levels (p < .01). Nine out of 19 (47%) Special Forces amputees were able to deploy. | The purpose of our study was to investigate the therapeutic potential of Celecoxib for epithelial ovarian cancer, especially on cellular morphological changes, proliferation invasion and epithelial-mesenchymal transition (EMT). The MTT and transwell assays were performed to evaluate the effect of Celecoxib on proliferation and invasion ability of ovarian cancer cell lines, respectively. Western blot was carried out to detect the expression of epithelial phenotypes, E-cadherin and Keratin, and mesenchymal phenotypes, N-cadherin and Vimentin, as well as p-AKT, p-ERK and ZEB1. ZEB1 small-interfering RNA (siRNA) was used to downregulate the expression of ZEB1 to further inquiring into the downstream of Celecoxib-induced EMT. Cellular morphological assessment revealed that both A2780 and SKOV3 cells gradually appeared in the morphology of mesenchymal cells after Celecoxib treatment. The MTT assay demonstrated that celecoxib had no effect on cell proliferation. Transwell assay showed that Celecoxib significantly increased the cell invasion ability. Western blot data proved that the expression of E-cadherin and keratin was elevated, whereas the expression of N-cadherin and Vimentin was decreased in a dose-dependent manner compared with the untreated cells, the expression of p-AKT, p-ERK and ZEB1 was also obviously elevated. However, ZEB1 siRNA reversed Celecoxib-induced E-cadherin expression and N-cadherin expression, as well as cellular invasiveness. |
Does early childhood television viewing predict explosive leg strength and waist circumference by middle childhood? | The relationship between early childhood television viewing and physical fitness in school age children has not been extensively studied using objective outcome measures. Using a sample of 1314 children from the Québec Longitudinal Study of Child Development, we examine the association between parental reports of weekly hours of television viewing, assessed at 29 and 53 months of age, and direct measures of second grade muscular fitness using performances on the standing long jump test (SLJ) and fourth grade waist circumference. Controlling for many potentially confounding child and family variables, each hour per week of television watched at 29 months corresponded to a .361 cm decrease in SLJ, 95% CI between -.576 and -.145. A one hour increase in average weekly television exposure from 29 to 53 months was associated with a further .285 cm reduction in SLJ test performance, 95% CI between -.436 and -.134 cm and corresponded to a .047 cm increase in waistline circumference, 95% CI between .001 and .094 cm. | OLT is the best alternative for patients with end-stage liver diseases. However, as the need for organs surpasses donor availability, alternatives to OLT are required. LCT could be a useful option versus OLT in several patients even though its low cell-engraftment hampers its efficiency. Endothelial cell barrier is the main obstacle for the implantation of cells into the parenchyma. Our study has focused on the modification of the endothelial barrier with monoclonal antibodies against adhesion molecules in order to increase cell engraftment in a mouse model of liver cell transplantation. Anti-mouse CD54 and anti-mouse CD61 antibodies were administered intrasplenically to healthy mice within 60 min prior to stem cell transplantation. Animals were sacrificed either short term at 2h or middle term seven days after transplantation. Immunohistochemical techniques to detect alkaline phosphatase activity were used to identify the transplanted cells within the liver parenchyma. Anti-CD54 and anti-CD61 administration increases vascular patency and cell engraftment. This represents a 32% and 45% increase, respectively, of engrafted cells compared to the control (p<0.05). |
Do the extent of oesophageal acid exposure overlap among the different gastro-oesophageal reflux disease groups? | Studies have demonstrated that patients with Barrett's oesophagus have the highest oesophageal acid exposure profile, followed by erosive oesophagitis and non-erosive reflux disease patients, but the exact extent of overlap remains unknown. To determine the extent of overlap in oesophageal acid exposure among the different gastro-oesophageal reflux disease groups. A total of 121 patients with gastro-oesophageal reflux disease underwent an upper endoscopy and were classified as having Barrett's oesophagus, erosive oesophagitis and non-erosive reflux disease-all (non-erosive reflux disease-positive and functional heartburn). Subsequently, patients underwent pH testing and overlap in oesophageal acid exposure among the different gastro-oesophageal reflux disease groups was determined. Of those enrolled, 24 had Barrett's oesophagus, 30 erosive oesophagitis and 28 were non-erosive reflux disease-positive. Mean oesophageal acid exposure time was 224.8 +/- 35, 134.3 +/- 21.9 and 141.3 +/- 19.8 min for Barrett's oesophagus, erosive oesophagitis and non-erosive reflux disease-positive respectively. Per cent overlap for total, upright and supine time between non-erosive reflux disease-positive and erosive oesophagitis was 47.4%, 64.7% and 81.8%, between Barrett's oesophagus and erosive oesophagitis was 47.8%, 40.7% and 24%, and between Barrett's oesophagus and non-erosive reflux disease-positive was 31.6%, 37.5% and 20.8% respectively. | Stromal cell-derived factor 1 (SDF-1; CXCL12/pre-B cell growth-stimulating factor) is a dominant chemokine in bone marrow and is known to be involved in inflammatory diseases, including rheumatoid arthritis. However, its role in bone repair remains unknown. The purpose of this study was to investigate the role of SDF-1 and its receptor, CXCR4, in bone healing. The expression of SDF-1 during the repair of a murine structural femoral bone graft was examined by real-time polymerase chain reaction and immunohistochemical analysis. The bone graft model was treated with anti-SDF-1 neutralizing antibody or TF14016, an antagonist for CXCR4, and evaluated by histomorphometry. The functional effect of SDF-1 on primary mesenchymal stem cells was determined by in vitro and in vivo migration assays. New bone formation in an exchanging-graft model was compared with that in the autograft models, using mice partially lacking SDF-1 (SDF-1(+/-)) or CXCR4 (CXCR4(+/-)). The expression of SDF1 messenger RNA was increased during the healing of live bone grafts but was not increased in dead grafts. High expression of SDF-1 protein was observed in the periosteum of the live graft. New bone formation was inhibited by the administration of anti-SDF-1 antibody or TF14016. SDF-1 increased mesenchymal stem cell chemotaxis in vitro in a dose-dependent manner. The in vivo migration study demonstrated that mesenchymal stem cells recruited by SDF-1 participate in endochondral bone repair. Bone formation was decreased in SDF-1(+/-) and CXCR4(+/-) mice and was restored by the graft bones from CXCR4(+/-) mice transplanted into the SDF-1(+/-) femur, but not vice versa. |
Does whole grain rye porridge breakfast improve satiety compared to refined wheat bread breakfast? | Previous studies show that dietary fibre-rich foods with low energy density have a stronger effect on satiety per calorie compared to more energy dense foods. To investigate subjective appetite and voluntary energy intake (24 h) after consumption of rye porridge breakfast and pasta lunch made from whole grain compared to iso-energetic reference meals made from refined cereals: wheat bread breakfast and wheat pasta lunch. In all, 22 healthy subjects, 14 females and 8 males, aged 21-64 years, BMI ranging from 18.7 to 27.5 kg/m(2), participated. A randomised, crossover design was used. Appetite was rated by visual analogue scales (VAS) regularly from just before breakfast (08:00) until bedtime. An ad libitum dinner was served at 16:00. After leaving the clinic and in the morning day 2, subjects recorded foods consumed. Whole grain rye porridge gave a significantly prolonged satiety, lowered hunger and desire to eat (p<0.05 in most point estimates) up to 8 h after consumption compared to the refined wheat bread. The two pasta lunch meals did not vary in their effects on appetite ratings. There was no significant effect on ad libitum energy intake at 16:00 or self-reported energy and macronutrient intake in the evening and breakfast meal on day 2. | Phagocytes, especially monocytes, macrophages, and dendritic cells, play a pivotal role in the innate and adaptive immune responses during sepsis. We have shown that inhibition of histone deacetylase 6 improves survival and increases bacterial clearance in a mouse model of cecal ligation and puncture (CLP). The aim of this study was to determine whether this effect was associated with changes in the number and composition of different blood cell types in the circulation. C57BL/6J mice were subjected to CLP, and 1 h later given an intraperitoneal injection of either Tubastatin A dissolved in dimethyl sulfoxide, or dimethyl sulfoxide only. Sham-operated animals were treated in an identical fashion but not subjected to CLP. Forty-eight hours later, peripheral blood was obtained via cardiac puncture and analyzed using a HemaTrue veterinary hematology analyzer. Tubastatin A administration increased the number of circulating monocytes in the sham-operated and the CLP animals. In comparison with the sham, CLP animals displayed an increase in the granulocyte percentage in white blood cells and decrease in the lymphocyte number and percentage, with a resultant increase in the granulocyte-to-lymphocyte ratio. Treatment of CLP animals with Tubastatin A decreased the granulocyte percentage and restored the lymphocyte number and percentage, which decreased the granulocyte-to-lymphocyte ratio. In the sham animals, Tubastatin A increased red blood cell number, hematocrit, and hemoglobin. This effect was not seen in CLP animals. |
Does pretreatment Gastric Lavage reduce Postoperative Bleeding after Endoscopic Submucosal Dissection for Gastric Neoplasms? | For patients receiving endoscopic submucosal dissection (ESD), there is urgent need pertaining to the prevention of postoperative bleeding. We conducted a retrospective propensity score-matched study that evaluated whether pre-ESD gastric lavage prevents postoperative bleeding after ESD for gastric neoplasms. From September 2002 to October 2015, the 760 consecutive patients receiving ESD for gastric neoplasm were enrolled and data regarding them were retrospectively analyzed. All patients received conventional preventive treatment against delayed bleeding after ESD, including the administration of proton pump inhibitor and preventive coagulation of visible vessels, at the end of the ESD procedure. Pre-ESD risk factors for postoperative bleeding included tumor size and no gastric lavage. Using multivariate analysis tumor size >2.0 cm (HR 2.90, 95% CI 1.65-5.10, p = 0.0002) and no gastric lavage (HR 3.20, 95% CI 1.13-9.11, p = 0.029) were found to be independent risk factors. Next, we evaluated the effect of gastric lavage on the prevention of post-ESD bleeding using a propensity score-matching method. A total of 284 subjects (142 per group) were selected. Adjusted odds ratio of gastric lavage for post-ESD bleeding was 0.25 (95% CI 0.071-0.886, p = 0.032). | Pathologic calcification of articular cartilage in human knees is often associated with advanced age and conditions of osteoarthritis (OA). Coincidently, most studies that have characterized calcification in joint cartilage have examined populations that are aged and presenting with clinical symptoms. Generally, these studies rely upon relatively insensitive plain radiographs or synovial fluid crystal analyses to quantify calcium levels. The purpose of this study was to examine the relationship between cartilage calcification and aging in an unselected donor population of diverse age using highly sensitive calcification imaging. A group of 106 knee blocks were obtained from 56 individual donors (25 females and 31 males, aged 12-74, avg. 50.3 years). Condylar surfaces were graded on a 4-point OA grading scale for cartilage degeneration. The condyles were cut into approximately 7-10mm thick slabs. Using a Faxitron radiography system, high-resolution images were taken of the slabs to specifically image calcification in cartilage. The quantified calcification areas were then analyzed and correlations with both OA grade and age were assessed. Every knee presented some measurable calcification. The relative calcium deposition had a significant positive correlation with age. This same positive correlation was seen between condyles showing grade 1 and 2 changes. OA grades higher than 2 did not present any further significant increase in calcium levels. |
Is macroscopic type a prognostic factor for recurrence-free survival after resection of gastric GIST? | Accurate evaluation of the biological behavior of Gastrointestinal stromal tumor and careful selection of patients with a high risk for tumor recurrence are necessary. In the present study, we analyzed prognostic factors in patients with GIST. A total of 214 patients who had undergone curative resection of a localized primary gastric GIST without adjuvant therapy were enrolled in this retrospective study. Prognostic factors were analyzed. The growth pattern was classified as intramural, endoluminal, exoluminal, or mixed- type. On univariate and multivariate analyses, recurrence was predicted by exoluminal or mixed-type (hazard ratio [HR]=3.7, p=0.043), tumor size of >3.5 cm (HR=7.1, p=0.01), and mitotic rate of >5/50 high-power fields (HR=7.9, p<0.001). | Patients infected with influenza A(H7N9) virus present with acute lung injury (ALI) that is due to severe pneumonia and systemic inflammation. It is often fatal because there are few effective treatment options. Complement activation has been implicated in the pathogenesis of virus-induced lung injury; therefore, we investigated the effect of targeted complement inhibition on ALI induced by H7N9 virus infection. A novel neutralizing specific antihuman C5a antibody (IFX-1) was used. This antibody blocked the ability of C5a to induce granulocytes to express CD11b while not affecting the ability of C5b to form the membrane attack complex. African green monkeys were inoculated with H7N9 virus and treated intravenously with IFX-1. The virus infection led to intense ALI and systemic inflammatory response syndrome (SIRS) in association with excessive complement activation. Anti-C5a treatment in H7N9-infected monkeys substantially attenuated ALI: It markedly reduced the lung histopathological injury and decreased the lung infiltration of macrophages and neutrophils. Moreover, the treatment decreased the intensity of SIRS; the body temperature changes were minimal and the plasma levels of inflammatory mediators were markedly reduced. The treatments also significantly decreased the virus titers in the infected lungs. |
Is cDX2 downregulation associated with poor differentiation and MMR deficiency in colon cancer? | Homeobox genes are often deregulated in cancer and can have both oncogenic and tumor-suppressing potential. The Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor. CDX2 has been implicated in differentiation, proliferation, cell adhesion, and migration. In this study, we investigated CDX2 mRNA and protein expression in relation to the clinicopathological characteristics of colon cancer, including mismatch repair status and recurrence risk. Tumor samples were obtained from colon cancer patients. Biopsies from tumor tissue and normal adjacent tissue were fixed in liquid nitrogen for RNA extraction or in formalin and paraffin embedded (FFPE) for immunohistochemical staining. CDX2 mRNA expression was evaluated by RT-qPCR. FFPE sections were stained for MLH1, MSH2, MSH6, PMS2, and CDX2. A total of 191 patient samples were included in the study and analyzed by immunohistochemistry. Of these samples, 97 were further evaluated by RT-qPCR. There was no significant difference in CDX2 mRNA expression between tumor and normal tissues. CDX2 mRNA expression was significantly lower in right-sided tumors (p<0.05), poorly differentiated tumors (p<0.05), and MMR-deficient tumors (p<0.05). Similarly, CDX2 protein expression was more often low or absent in right-sided tumors (p<0.01), poorly differentiated tumors (p<0.001), and MMR-deficient tumors (p<0.001). Low CDX2 protein or mRNA expression was not associated with recurrence risk. | It is known that enhancement of sympathetic nerve activity based on a decrease in parasympathetic nerve activity is associated with fatigue induced by mental tasks lasting more than 30 min. However, to measure autonomic nerve function and assess fatigue levels in both clinical and industrial settings, shorter experimental durations and more sensitive measurement methods are needed. The aim of the present study was to establish an improved method for inducing fatigue and evaluating the association between it and autonomic nerve activity. Twenty-eight healthy female college students participated in the study. We used a kana pick-out test (KPT) as a brief verbal cognitive task and recorded electrocardiography (ECG) to measure autonomic nerve activity. The experimental design consisted of a 16-min period of ECG: A pre-task resting state with eyes open for 3 min and eyes closed for 3 min, the 4-min KPT, and a post-task resting state with eyes open for 3 min and eyes closed for 3 min. Baseline fatigue sensation, measured by a visual analogue scale before the experiment, was associated with the decrease in parasympathetic sinus modulation, as indicated the by ratio of low-frequency component power (LF) to high-frequency component power (HF), during the KPT. The LF/HF ratio during the post-KPT rest with eyes open tended to be greater than the ratio during the KPT and correlated with fatigue sensation. Fatigue sensation was correlated negatively with log-transformed HF, which is an index of parasympathetic sinus modulation, during the post-KPT rest with eyes open. |
Is reduction of plasma fibrinolytic activity following high-dose cyclophosphamide neutralized in vivo by GM-CSF administration? | GM-CSF has broad clinical applicability as a potent myelopoietic stimulator. However, its function is not restricted to the myelopoietic system and several observations suggest that GM-CSF may interfere with the hemostatic balance. In order to assess whether GM-CSF has any influence on hemostasis, we evaluated some coagulative and fibrinolytic parameters in patients treated with GM-CSF following chemotherapy. Fibrinolytic activity (FA), fibrinogen and D-dimer were evaluated before and after high-dose cyclophosphamide in 6 patients additionally treated with GM-CSF and in 5 control patients; moreover, tissue plasminogen activator (tPA) was assayed in those treated with GM-CSF. Comparative in vitro analysis was performed on cultured endothelial cells before and after exposure to GM-CSF. Control patients showed a significant decrease in plasma FA after chemotherapy compared to basal values (FA/mm2: 15.6 +/- 2.1 at day + 2 and 20.8 +/- 19 at day + 4 vs. 103.8 +/- 64.2 at day 0; p < 0.005); conversely, no FA reduction was observed in GM-CSF-treated subjects. In this latter group a marked increase in tPA antigen was seen, consistent with enhanced FA. No significant changes in plasma D-dimer and fibrinogen values were detected in the two groups. tPA, urokinase-type plasminogen activator, PAI-1 and procoagulant activity were evaluated in vitro on cultured human endothelial cells and found to be unchanged following GM-CSF addition. | To quantify the environmental component of aetiology of overweight and obesity by examining the relationship between the degree of overweight in dogs and cats and the degree of overweight in their owners. Cross-sectional study. Main outcome measures of the owners were weight, height (stature) and BMI. Of the animals, weight and divergence from ideal weight were measured by a veterinarian. Three veterinary clinics in Amsterdam, The Netherlands. Dogs and cats, together with their owners, who visited the veterinary clinic. Dogs and cats had to be older than 1 year, and their owners had to be at least 21 years old. After exclusion, there remained forty-seven pairs of dogs and their owners and thirty-six pairs of cats and their owners. We found a significant relationship between the degree of overweight of dogs and the BMI of their owners (r = 0.31). Correction for length of ownership, gender and age of the animal, and gender, age, education level and activity score of the owner did not materially affect this relationship. However, after correction for the amount of time the dog was being walked each day, this relationship disappeared. No significant relationship was found between the degree of overweight of cats and the BMI of their owners. |
Does silibinin prevent amyloid beta peptide-induced memory impairment and oxidative stress in mice? | Accumulated evidence suggests that oxidative stress is involved in amyloid beta (Abeta)-induced cognitive dysfunction. Silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybum marianum), has been shown to have antioxidative properties; however, it remains unclear whether silibinin improves Abeta-induced neurotoxicity. In the present study, we examined the effect of silibinin on the memory impairment and accumulation of oxidative stress induced by Abeta(25-35) in mice. Aggregated Abeta(25-35) (3 nmol) was intracerebroventricularly administered to mice. Treatment with silibinin (2, 20 and 200 mg.kg(-1), once a day, p.o.) was started immediately after the injection of Abeta(25-35). Locomotor activity was evaluated 6 days after the Abeta(25-35) treatment, and cognitive function was evaluated in a Y-maze and novel object recognition tests 6-11 days after the Abeta(25-35) treatment. The levels of lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the hippocampus were measured 7 days after the Abeta(25-35) injection. Silibinin prevented the memory impairment induced by Abeta(25-35) in the Y-maze and novel object recognition tests. Repeated treatment with silibinin attenuated the Abeta(25-35)-induced accumulation of malondialdehyde and depletion of glutathione in the hippocampus. | Cyclic redistribution of air within the cuff during respiratory pressure changes creates a self-sealing mechanism which allows tracheal sealing, despite tracheal airway pressure being above baseline cuff inflation pressure. The aim of the present study was to investigate the effect of continuous automated cuff pressure regulation on tracheal sealing during cyclic respiratory pressure changes. In vitro tracheal sealing was studied in four different high volume-low pressure (HVLP) tracheal tube cuffs size internal diameter 8.0 and 5.0 mm in combination with a conventional pressure manometer and two different automated pressure controllers (VBM Cuff Controller; Cuff Pressure Control Tracoe). Experiments were performed at 10, 15, 20, and 25 cm H(2)O cuff pressure during intermittent positive pressure ventilation with peak inspiratory pressures of 20 and 25 cm H(2)O. Air leakage was assessed spirometrically. Experiments were performed four times with each tube brand and size with two exemplars of each of the three cuff pressure controllers. Owing to immediate cuff pressure correction, tracheal sealing at cuff pressure below inspiratory pressure was reduced in most of the tracheal tube cuffs, except in those with reduced sealing characteristics when using the Pressure Control Tracoe compared with the conventional pressure manometer and the VBM Cuff Controller. Tracheal sealing with the Pressure Control Tracoe comparable with the other two devices was only achieved at cuff pressures of 20 and 25 cm H(2)O. |
Does serum hepcidin predict uremic accelerated atherosclerosis in chronic hemodialysis patients with diabetic nephropathy? | Hepcidin, as a regulator of body iron stores, has been recently discovered to play a critical role in the pathogenesis of anemia of chronic disease. Atherosclerotic cardiovascular disease is the most common complication and the leading cause of death in chronic hemodialysis (CHD) patients. In the current study, we aimed to explore the relationship between serum hepcidin and uremic accelerated atherosclerosis (UAAS) in CHD patients with diabetic nephropathy (CHD/DN). A total of 78 CHD/DN and 86 chronic hemodialyzed nondiabetic patients with chronic glomerulonephritis (CHD/non-DN) were recruited in this study. The level of serum hepcidin-25 was specifically measured by liquid chromatography-tandem mass spectrometry. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. High serum level of hepcidin-25 was seen in CHD patients. Serum hepcidin-25 in CHD/DN was significantly higher than that in CHD/non-DN patients. Serum hepcidin-25 was positively correlated with ferritin, high-sensitivity C-reactive protein (hs-CRP), TNF-α, and IL-6 in CHD/DN patients. CHD/DN patients exhibited higher common carotid artery intima media thickness (CCA-IMT), hs-CRP, and hepcidin-25 levels than that in CHD/non-DN patients. Moreover, in CHD/DN patients, CCA-IMT was positively correlated with serum hepcidin, hs-CRP, and low-density lipoprotein-cholesterol. On multiple regression analysis, serum hepcidin and hs-CRP level exhibited independent association with IMT in CHD/DN patients. | The diagnostic potential of residual gastric juice for development of naproxen sodium-induced mucosal damage has not been explored. We studied prostaglandin E2 (PGE2) content in residual gastric juice before and after naproxen sodium administration and assessed relationships with endoscopic mucosal damage. Thirty volunteers received the recommended over-the-counter dose (660 mg/day) of naproxen sodium or placebo in this 7-day, double-blind, endoscopically controlled, cross-over study. PGE2 concentration in gastric juice did not increase after placebo; naproxen significantly reduced PGE2 concentration (p < 0.001). In three subjects in whom no endoscopic changes occurred after naproxen administration, PGE2 concentration increased by 14%. In seven subjects who developed hemorrhagic changes, PGE2 concentration declined by 50% (p = 0.08). In 20 subjects who developed numerous hemorrhagic and erosive changes within the antral mucosa, PGE2 concentration declined by 70% (p < 0.001). The starting PGE2 value in subjects with severe mucosal hemorrhagic and erosive changes after naproxen was almost eightfold higher than in subjects who did not develop mucosal damage (p = 0.007) and 67% higher than in subjects with hemorrhagic changes only (p = 0.25). |
Does butyrate modulate oxidative stress in the colonic mucosa of healthy humans? | Butyrate, a short-chain fatty acid produced by colonic microbial fermentation of undigested carbohydrates, has been implicated in the maintenance of colonic health. This study evaluates whether butyrate plays a role in oxidative stress in the healthy colonic mucosa. A randomized, double blind, cross-over study with 16 healthy volunteers was performed. Treatments consisted of daily rectal administration of a 60 ml enema containing 100 mM sodium butyrate or saline for 2 weeks. After each treatment, a blood sample was taken and mucosal biopsies were obtained from the sigmoid colon. In biopsies, the trolox equivalent antioxidant capacity, activity of glutathione-S-transferase, concentration of uric acid, glutathione (GSH), glutathione disulfide and malondialdehyde, and expression of genes involved in GSH and uric acid metabolism was determined. Secondary outcome parameters were CRP, calprotectin and intestinal fatty acid binding protein in plasma and histological inflammatory scores. Butyrate treatment resulted in significantly higher GSH (p<0.05) and lower uric acid (p<0.01) concentrations compared to placebo. Changes in GSH and uric acid were accompanied by increased and decreased expression, respectively, of their rate limiting enzymes determined by RT-PCR. No significant differences were found in other parameters. | Multiple organ failure after deep hypothermic circulatory arrest (DHCA) may occur secondary to endothelial dysfunction and apoptosis. We sought to determine if DHCA causes endothelial dysfunction and apoptosis in brain, kidney, lungs, and other tissues. Anesthetized pigs on cardiopulmonary bypass were: (1) cooled to 18 degrees C, and had their circulation arrested (60 minutes) and reperfused at 37 degrees C for 90 minutes (DHCA, n = 8); or (2) time-matched normothermic controls on bypass (CPB, n = 6). Endothelial function in cerebral, pulmonary, and renal vessels was assessed by vasorelaxation responses to endothelial-specific bradykinin (BK) or acetylcholine (ACh), and smooth muscle-specific nitroprusside. In vivo transcranial vasorelaxation responses to ACh were similar between the two groups. In small-caliber cerebral arteries, endothelial relaxation (BK) was impaired in CPB vs DHCA (maximal 55% +/- 2% [p < 0.05] vs 100% +/- 6%). Pulmonary artery ACh responses were comparable between CPB (110% +/- 10%) and DHCA (83% +/- 6%), but responses in pulmonary vein were impaired in DHCA (109% +/- 3%, p < 0.05) relative to CPB (137% +/- 6%). In renal arteries, endothelial (ACh) responses were impaired in DHCA (71% +/- 13%) relative to CPB (129% +/- 14%). Apoptosis (DNA laddering) occurred primarily in duodenal tissue, with a greater frequency in DHCA (56%, p < 0.05) compared with normothermic CPB (17%) and nonbypass controls (0%). |
Is human adipose tissue cannabinoid receptor 1 gene expression related to fat cell function or adiponectin level? | The cannabinoid receptor 1 gene (CNR1) is implicated in adipocyte function. We investigated human adipose tissue CNR1 mRNA in relation to obesity, clinical and metabolic variables, adipocyte function, and adiponectin (ADIPOQ) levels. We assessed sc fat biopsies from 96 obese and nonobese subjects and omental fat biopsies from 82 obese and nonobese subjects. The sc and omental adipose CNR1 gene expression were similar in obese and nonobese subjects. No association between either sc or omental adipose CNR1 mRNA levels and body mass index, waist circumference, plasma levels of glucose and insulin, lipids, or blood pressure was found. The sc and omental maximal adrenergic lipolytic activation as well as lipolytic adrenoceptor sensitivity were not related to CNR1 gene expression. Lipogenesis in sc adipocytes also showed no association with CNR1 mRNA levels. Finally, no relation was found between adipose CNR1 gene expression and ADIPOQ mRNA, adipose tissue adiponectin secretion, or circulating adiponectin. | Interleukin-6 (IL-6) is a potent immunomodulatory cytokine that may have pathogenetic and prognostic significance in a number of disorders. The objective of this study was to examine the correlation between serum IL-6 levels and phenotypic characteristics, as well as outcome of patients with diffuse large-cell lymphoma (DLCL). Using an enzyme-linked immunosorbent assay (ELISA; lower limit of sensitivity, 0.35 pg/mL), we measured IL-6 levels in frozen sera from 33 healthy controls and 58 untreated patients with DLCL who were enrolled onto a single combination chemotherapy protocol. Serum IL-6 levels were correlated with clinical and laboratory features at diagnosis and with failure-free and overall survival. Serum IL-6 levels in the lymphoma patients (median, 4.37 pg/mL; range, < 0.35 to 110 pg/mL) were significantly higher than in the control group (median, < 0.35 pg/mL; range, < 0.35 to 1.87 pg/mL) (P < .0001). Serum IL-6 levels were higher in patients with B symptoms (P = .012), an elevated beta 2-microglobulin level (> or = 3.0 mg/L) (P = .017), and a poor performance status (P = .02). Direct linear correlations with the erythrocyte sedimentation rate (ESR), platelet count, and total WBC count, and an inverse linear correlation with the serum albumin level, were observed (all P < .02). Patients with elevated serum IL-6 levels had inferior failure-free (P = .042) and overall survival (P = .05) compared with those with normal serum IL-6 levels. |
Does post-ischemic hypothermia ameliorate ischemic brain damage but not post-ischemic audiogenic seizures in rats? | The objective of this study was to describe a pattern of recovery and histological nerve cell loss in Sprague-Dawley rats exposed to severe brain ischemia and to compare it to that of Wistar rats. Ether- and ketamine-anesthetized Sprague-Dawley rats were exposed to 3, 5, 6 and 10 min of normothermic severe brain ischemia (4 groups) induced by hypotension and neck compression. In group No. 5, the brain temperature was rapidly lowered, after 10 min of ischemia, to 30 degrees C during 45-50 min of recirculation. Wistar rats (group No. 6) served as controls (10-min normothermic ischemia). In Sprague-Dawley (S-D) rats, post-ischemic audiogenic seizures (PAS) increased with the duration of ischemia and reached 86% (6/7 rats), after 10 min of ischemia. Mortality rate was high (50% = 7/14 rats). No seizure activity was observed after 10 min of ischemia in 6 Wistar (W) rats, and all survived. In the S-D rats, 10 min of ischemia produced histopathological damage in all brain regions examined, except in the thalamus. Damage was less severe in the W rats. Post-ischemic hypothermia ameliorated hippocampal and cortical nerve cell damage, but had no effect on the incidence of PAS activity and mortality. In W rats, hippocampal nerve cell loss was much less severe than in the S-D rats and cortical damage was not observed. | Low rates of compliance with quality measures for inflammatory bowel disease (IBD) have been reported for US gastroenterologists. We assessed the influence of quality improvement (QI) education on compliance with physician quality reporting system (PQRS) measures for IBD and measures related to National Quality Strategy (NQS) priorities. Forty community-based gastroenterologists participated in the QI study; 20 were assigned to educational intervention and control groups, respectively. At baseline, randomly selected charts of patients with moderate-to-severe ulcerative colitis were retrospectively reviewed for the gastroenterologists' performance of 8 PQRS IBD measures and 4 NQS-related measures. The intervention group participated in a series of accredited continuing medical education (CME) activities focusing on QI. Follow-up chart reviews were conducted 6 months after the CME activities. Independent t tests were conducted to compare between-group differences in baseline-to-follow-up rates of documented compliance with each measure. The analysis included 299 baseline charts and 300 follow-up charts. The intervention group had significantly greater magnitudes of improvement than the control group for the following measures: assessment of IBD type, location, and activity (+14 %, p = 0.009); influenza vaccination (+13 %, p = 0.025); pneumococcal vaccination (+20 %, p = 0.003); testing for latent tuberculosis before anti-TNF-α therapy (+10 %, p = 0.028); assessment of hepatitis B virus status before anti-TNF-α therapy (+9 %, p = 0.010); assessment of side effects (+17 %, p = 0.048), and counseling patients about cancer risks (+13 %, p = 0.013). |
Is polymorphism within the glutathione S-transferase P1 gene associated with increased susceptibility to childhood malignant diseases? | Glutathione S-transferases (GSTs) are involved in the metabolism of carcinogens and anticancer drugs. Functional polymorphisms exist in at least three genes that code for the GSTs, such as the GSTM1 and GSTT1 gene deletions or the A-G transition within the GSTP1 gene, which represents distinct GSTP1a and GSTP1b alleles. In the present case-control study, we aimed at estimation of the relationship between the GSTM1, GSTT1, and GSTP1 genotypes and the susceptibility to various types of childhood malignancies and the early relapses of diseases. Using the polymerase chain reaction on the DNA extracted from peripheral blood leukocytes, we identified the GSTM1, GSTT1, and GSTP1 genotypes in 234 children at the initial stage of a childhood malignancy as well as in 460 age-and sex-matched healthy subjects who served as controls. The follow-up period for the effects of the anticancer therapy ranged from 11 to 43 months. Compared to the controls, a significant increase in the frequency of the GSTP1b/GSTP1b genotype (odds ratio (OR) 5.7; 95% confidence limit (CL) from 2.4 to 13.8; Pearsons Chi-square P = 0.0001) was detected in the children with neoplasms. The GSTM1 and GSTT1 genotypes did not show any correlation with the risk of the de novo diagnosed neoplasms. During the observation, 62 children (26%) were found to be present with a local or disseminated recurrence of the diseases. The analysis indicated a trend in increasing risk of relapse for carriers of the GSTP1a allele (OR = 3.29; 95% CL from 0.73 to 14.67 P = 0.03). | Distension of the ischemic region has been related to an increased incidence of spontaneous ventricular arrhythmias following coronary occlusion. This study analyzed whether regional ischemic distension predicts increased ventricular fibrillation inducibility after coronary occlusion in swine. In 18 anesthetized, open-chest pigs, the left anterior descending coronary artery was ligated for 60 min. Myocardial segment length in the ischemic region was monitored by means of ultrasonic crystals. Programmed stimulation was applied at baseline and then continuously between 10 and 60 min after coronary occlusion. Coronary occlusion induced a rapid increase in end-diastolic length in the ischemic region, which reached 109.4% (0.9%) of baseline values 10 min after occlusion (P<.001). On average, 6.6 (0.5) stimulation protocols were completed and 5.4 (0.6) ventricular fibrillation episodes induced between 10 and 60 min of coronary occlusion. Neither baseline serum potassium levels nor the size of the ischemic region were significantly related to ventricular fibrillation inducibility. In contrast, the increase in end-diastolic length 10 min after coronary occlusion was associated directly (r=0.67; P=.002) with the number of induced ventricular fibrillation episodes and inversely (r=-0.55; P=.018) with the number of extrastimuli needed for ventricular fibrillation induction. |
Is neddylation and deneddylation of CUL-3 required to target MEI-1/Katanin for degradation at the meiosis-to-mitosis transition in C. elegans? | SCF (Skp1-Cullin-F-box) complexes are a major class of E3 ligases that are required to selectively target substrates for ubiquitin-dependent degradation by the 26S proteasome. Conjugation of the ubiquitin-like protein Nedd8 to the cullin subunit (neddylation) positively regulates activity of SCF complexes, most likely by increasing their affinity for the E2 conjugated to ubiquitin. The Nedd8 conjugation pathway is required in C. elegans embryos for the ubiquitin-mediated degradation of the microtubule-severing protein MEI-1/Katanin at the meiosis-to-mitosis transition. Genetic experiments suggest that this pathway controls the activity of a CUL-3-based E3 ligase. Counteracting the Nedd8 pathway, the COP9/signalosome has been shown to promote deneddylation of the cullin subunit. However, little is known about the role of neddylation and deneddylation for E3 ligase activity in vivo. Here, we identified and characterized the COP9/signalosome in C. elegans and showed that it promotes deneddylation of CUL-3, a critical target of the Nedd8 conjugation pathway. As in other species, the C. elegans signalosome is a macromolecular complex containing at least six subunits that localizes in the nucleus and the cytoplasm. Reducing COP9/signalosome function by RNAi results in a failure to degrade MEI-1, leading to severe defects in microtubule-dependent processes during the first mitotic division. Intriguingly, reducing COP9/signalosome function suppresses a partial defect in the neddylation pathway; this suppression suggests that deneddylation and neddylation antagonize each other. | To evaluate the superiority of transcutaneous oxygen pressure (TcPO2) before, during and after peripheral transluminal angioplasty (PTA) in comparison with ankle brachial index (ABI) in patients with diabetes. 40 consecutive patients with diabetes treated by PTA where included. This study shows results before, during and after PTA and their progression for 8 weeks. The TcPO2 increased from 28.11 ± 8.1 to 48.03 ± 8.4 mmHg, 8 weeks after PTA (p < 0.001). The ABI increased from 0.48 ± 0.38 to 0.77 ± 0.39 after PTA (p < 0.001). After PTA, the stenosis of the vessel decreased from 58.33 ± 20.07% to 21.87 ± 13.57% (p < 0.001). TcPO2 was determined in all the patients, but ABI could not be determined in all patients. Furthermore, we determined patients with "false negatives" with an improvement in ABI and "false positives" in 12.5% of patients. Additionally, in this study, we monitored TcPO2 while performing PTA, revealing variations in each phase of the radiological procedure. |
Is migraine related to an increased risk of Parkinson 's disease : A population-based , propensity score-matched , longitudinal follow-up study? | The association between migraine and Parkinson's disease (PD) remains controversial. The purpose of the present population-based, propensity score-matched follow-up study was to investigate whether migraineurs are at a higher risk of developing PD. A total of 41,019 subjects aged between 40 and 90 years with at least two ambulatory visits with a diagnosis of migraine in 2001 were enrolled in the migraine group. A logistic regression model that included age, sex, pre-existing comorbidities and socioeconomic status as covariates was used to compute the propensity score. The non-migraine group consisted of 41,019 propensity score-matched, randomly sampled subjects without migraine. The PD-free survival rate were estimated using the Kaplan-Meier method. Stratified Cox proportional hazard regression was used to estimate the effect of migraine on the risk of developing PD. During follow-up, 148 subjects in the migraine group and 101 in the non-migraine group developed PD. Compared to the non-migraine group, the hazard ratio of PD for the migraine group was 1.64 (95% confidence interval: 1.25-2.14, p = 0.0004). The PD-free survival rate for the migraine group was significantly lower than that for the non-migraine group (p = 0.0041). | Transfusion of packed erythrocytes stored for a long duration is associated with increased pulmonary arterial pressure and vascular resistance. Prolonged storage decreases erythrocyte deformability, and older erythrocytes are rapidly removed from the circulation after transfusion. The authors studied whether treating stored packed ovine erythrocytes with NO before transfusion could prevent pulmonary vasoconstriction, enhance erythrocyte deformability, and prolong erythrocyte survival after transfusion. Ovine leukoreduced packed erythrocytes were treated before transfusion with either NO gas or a short-lived NO donor. Sheep were transfused with autologous packed erythrocytes, which were stored at 4°C for either 2 ("fresh blood") or 40 days ("stored blood"). Pulmonary and systemic hemodynamic parameters were monitored before, during, and after transfusion. Transfused erythrocytes were labeled with biotin to measure their circulating lifespan. Erythrocyte deformability was assessed before and after NO treatment using a microfluidic device. NO treatment improved the deformability of stored erythrocytes and increased the number of stored erythrocytes circulating at 1 and 24 h after transfusion. NO treatment prevented transfusion-associated pulmonary hypertension (mean pulmonary arterial pressure at 30 min of 21 ± 1 vs. 15 ± 1 mmHg in control and NO-treated packed erythrocytes, P < 0.0001). Washing stored packed erythrocytes before transfusion did not prevent pulmonary hypertension. |
Does quantitation of HIV-1 RNA in plasma predict outcome after seroconversion? | To investigate the relation between the quantity of human immunodeficiency virus type 1 (HIV-1) RNA in plasma and the risk for the acquired immunodeficiency syndrome (AIDS) or a decline in the CD4+ T-cell count after seroconversion. Prospective study. 62 homosexual men with documented HIV-1 seroconversion. University outpatient setting. Clinical status, CD4+ T-cell counts, and plasma and serum samples were obtained every 6 months. Human immunodeficiency virus RNA in plasma was quantitated with a branched-DNA (bDNA) assay. Serum samples were assayed for neopterin, beta 2-microglobulin, and immune complex dissociated HIV-1 p24 antigen. 18 of 62 (29%) men developed AIDS; 21 (34%) had a significant decline in the CD4+ T-cell count without AIDS; and 23 (37%) had a stable CD4+ T-cell count. For each participant, HIV-1 RNA results were categorized into one of four groups: 1) detection of HIV-1 RNA (> 1 x 10(4) genome equivalents/mL [Eq/mL]) in all samples; 2) detection in most samples (> or = 50%); 3) detection in fewer than 50% of samples; and 4) detection in none of the samples. Detection of HIV-1 RNA in all or most samples was strongly associated with AIDS (16 of 18 patients) and a decline in the CD4+ T-cell count (13 of 21 patients) compared with a stable CD4+ T-cell count (4 of 23 patients; P < 0.001). Conversely, the absence of HIV-1 RNA (< 1 x 10(4) Eq/mL) in all or most samples was associated with stable CD4+ T-cell counts (19 of 23 patients) and a lower risk for AIDS or decline in the CD4+ T-cell count (10 of 39 patients; P < 0.001). In multivariate analysis of all laboratory values at the seroconversion visit, a plasma HIV-1 RNA level greater than 1 x 10(5) Eq/mL was the most powerful predictor of AIDS (odds ratio, 10.8; P = 0.01). | Brain-derived neurotrophic factor (BDNF) has been found in the intestinal tract of a variety of species. Its effects on visceral hyperalgesia have been examined to some degree, but limited studies have focused on gut motility. The aim of the present study was to investigate the effects of BDNF on gut motility of mice. Longitudinal muscle (LM) strips were prepared from mice ileum and distal colon. The motility of gut was evaluated by the contraction of LM strips, which was recorded by a polyphisograph in vitro. Firstly, the roles of substance P (SP), calcitonin gene-related peptide (CGRP), and acetylcholine (ACh) on the contraction of LM strips were clarified. Then the exogenous BDNF was administered, and the alterations of SP/CGRP/ACh-induced contractions of the muscle strips were explored. Finally, heterozygous BDNF(+/-) mice and antibody of TrkB were introduced to investigate the role of endogenous BDNF on the SP/CGRP/ACh-induced gut motility. SP (10(-8)-10(-6) mol L(-1)), CGRP (10(-8)-10(-7) mol L(-1)) and ACh (10(-8)-10(-6) mol L(-1)) dose-dependently caused the contraction of LM strips from ileum and distal colon, while the excitatory effect of CGRP was preceded by a transient inhibition. But 10(-6) mol L(-1) CGRP inhibited the contraction of LM strips. Pretreatment with exogenous BDNF (10(-8) mol L(-1)) remarkably enhanced the contraction of LM strips induced by SP (10(-9)-10(-7) mol L(-1)) and CGRP (10(-8)-10(-9) mol L(-1)). However, exogenous BDNF couldn't affect the contraction induced by ACh (10(-9)-10(-7) mol L(-1)). The excitatory effects of SP (10(-8)-10(-6) mol L(-1)) and CGRP (10(-8)-10(-7) mol L(-1)) on the contractions of LM strips from ileum and distal colon were significantly attenuated in BDNF(+/-) mice compared with those in BDNF(+/+) mice, while no difference of the effects of ACh (10(-8)-10(-6) mol L(-1)) on LM strips was observed between BDNF(+/-) mice and BDNF(+/+) mice. The monoclonal antibody of TrkB (TrkB-Ab) dramatically attenuated the excitatory effects of SP and CGRP on the contractions of LM strips, without affecting the excitatory effects of ACh. |
Is simple radiographic assessment of bone quality associated with loss of surgical fixation in patients with proximal humeral fractures? | This study aimed to determine if the ratio of cortical thickness to shaft diameter of the humerus, as measured on a simple anterior-posterior shoulder radiograph, is associated with surgical fixation failure. 64 consecutive fractures in 63 patients (mean age 66.1 years, range 35-90) operated with surgical fixation between March 2011 and July 2014 using PERI-LOC locking plate and screws (Smith and Nephew, UK) were identified. Predictors of bone quality were measured from preoperative radiographs, including ratio of the medial cortex to shaft diameter (medial cortical ratio, MCR). Loss of fixation (displacement, screw cut out, or change in neck-shaft angle >4 degrees) was determined on follow-up radiographs. Loss of fixation occurred in 14 patients (21.9%) during the follow up. Patients were older in the failure group 72.8 vs. 64.2 years (p=0.007). The MCR was significantly lower in patients with failed fixation 0.170 vs 0.202, p=0.019. Loss of fixation is three times more likely in patients with a MCR <0.16 (41% vs. 14%, p=0.015). Increased fracture parts led to increased failure rate (p=0.0005). | Exposure to aeroallergens induces eosinophilic airway inflammation in patients with asthma and allergic airway diseases. The circulating number of eosinophils in peripheral blood is relatively small, leading us to hypothesize that bone marrow needs to be engaged quickly to meet the demands of the tissues. To investigate the communication between the lungs and bone marrow, we used acute allergen exposure and airway inflammation models in mice. Gene-deficient mice and cytokine reporter mice as well as in vitro cell culture models were used to dissect the mechanisms. Naïve BALB/c mice produced increased numbers of eosinophil precursors and mature eosinophils in the bone marrow when their airways were exposed to a common fungal allergen, Alternaria alternata. Expression of IL-5 and IL-33 increased rapidly in the lungs, but not in the bone marrow. Sera from allergen-exposed mice promoted eosinophilopoiesis in bone marrow cells from naïve mice, which was blocked by anti-IL-5 antibody. Mice deficient in the IL-33 receptor ST2 (i.e., Il1rl1(-/-) mice) were unable to increase their serum levels of IL-5 and allergen-induced eosinophilopoiesis in the bone marrow after allergen exposure. Finally, group 2 innate lymphoid cells (ILC2s) in the lungs showed robust expression of IL-5 after Alternaria exposure. |
Does elevated serum lactate correlate with intracranial hemorrhage in neonates treated with extracorporeal life support? | To correlate the initial and maximal lactate levels with the occurrence of intracranial hemorrhage (ICH) and survival in patients treated with extracorporeal life support (ECLS). Retrospective chart review. Pediatric intensive care unit. Eighty-two neonatal patients placed on ECLS for respiratory failure due to sepsis, meconium aspiration, or persistent pulmonary hypertension of the newborn. The initial lactate level measured within 6 hours of initiating ECLS and the maximal lactate level measured throughout the ECLS course were collected. Lactate levels were described as mean lactate +/- SE (mM). Head ultrasound reports and survival were reviewed. Platelet counts and activated clotting times (ACTs) were examined. The mean initial and maximal lactate levels were higher in ECLS patients who developed ICH (initial: 10 +/- 1.7 mM vs 6.4 +/- 0.8 mM, p = .05 and maximal: 12.4 +/- 2.5 mM vs 7.9 +/- 0.8 mM, p = .04). Initial and maximal lactate levels were also elevated in nonsurvivors (initial: 11.7 +/- 3 mM vs 6.4 +/- 0.7 mM, p = .01 and maximal: 14.8 +/- 3.3 mM vs 7.8 +/- 0.8 mM, P < .01). Platelet counts and ACT did not differ in patients with and without ICH. | The study objective was to evaluate variations in genes implicated in antidepressant mechanism of action for association with response to duloxetine treatment in major depressive disorder (MDD). We assessed response over 6 weeks in 250 duloxetine-treated Caucasian patients in a randomized, double-blind study of patients with MDD. Single nucleotide polymorphisms (SNPs) were genotyped in 19 candidate genes selected based on evidence for involvement in antidepressant mechanism of action. Primary analysis examined baseline to end point reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score, using a set-based test for association for each gene. Follow-up analyses examined individual SNPs within any significant gene for association with reduction in HAMD17 and 30-item Inventory of Depressive Symptomatology-Clinician Rated (IDS-C-30). After correction for multiple comparisons, only COMT was associated with change in HAMD17 (experiment wide p = .018). Peak association was detected with rs165599 (p = .006), which accounted for approximately 3% of variance in HAMD17 change and >4% of variance in IDS-C-30 change (p = .001). The least-squared mean change (SE) in HAMD17 score by rs165599 genotype was -10.8 (1.2), -8.7 (.6), and -6.5 (.7) for patients with GG, GA, and AA genotypes, respectively. For SNPs in serotonin 2A receptor (HTR2A) previously associated with citalopram response, including rs7997012, no significant evidence of association with duloxetine response was identified. |
States diet quality , risk factors and access to care among low-income uninsured American adults in states expanding Medicaid vs. expanding under the affordable care act? | The Affordable Care Act (ACA) Medicaid expansion varies in availability across states. We compared characteristics of low-income uninsured residents in both Medicaid nonexpanding and expanding states with respect to their dietary quality, health risk factors, and access to care. Data from the 2007-2012 National Health and Nutrition Examination Survey was matched with the Kaiser Family Foundation Medicaid expansion data. Bivariate and multivariate regressions were estimated to assess differences across expanding and non-expanding states. The non-expansion group had a lower Healthy Eating Index score (41.8 vs. 44.1, p-value=0.006), a higher Body Mass Index (29.9 vs. 28.9, p-value=0.032), higher obesity prevalence (41% vs. 33%, p-value=0.007), and lower asthma prevalence (14.8% vs. 19.7%, p-value=0.037) compared with the expansion group. | To explore morphological or electrophysiological evidence for the presence of endolymphatic hydrops (EH) in guinea pig cochleae in the first 3 months after cochlear implantation. Dummy silastic electrodes were implanted atraumatically into the basal turn of scala tympani via a cochleostomy. Round window electrocochleography (ECochG) was undertaken prior to and after implantation. Animals survived for 1, 7, 28 or 72 days prior to a terminal experiment, when ECochG was repeated. The cochleae were imaged using micro-CT after post-fixing with osmium tetroxide to reveal the inner ear soft tissue structure. EH was assessed by visual inspection at a series of frequency specific places along the length of the cochlea, and the extent to which Reissner's membrane departed from its neutral position was quantified. Tissue response volumes were calculated. Using ECochG, the ratio of the summating potential to the action potential (SP/AP ratio) was calculated in response to frequencies between 2 and 32 kHz. There was minimal evidence of electrode trauma from cochlear implantation on micro-CT imaging. Tissue response volumes did not change over time. EH was most prevalent 7 days after surgery in implanted ears, as determined by visual inspection. Scala media areas were increased, as expected in cases of EH, over the first month after cochlear implantation. SP/AP ratios decreased immediately after surgery, but were elevated 1 and 7 days after implantation. |
Does nonuniform strut distribution correlate with more neointimal hyperplasia after sirolimus-eluting stent implantation? | Little is known about causes of intimal hyperplasia (IH) after sirolimus-eluting stent (SES) implantation. Intravascular ultrasound was performed in 24 lesions with intra-SES restenosis and a comparison group of 25 nonrestenotic SESs. To assess stent strut distribution, the maximum interstrut angle was measured with a protractor centered on the stent, and the visible struts were counted and normalized for the number of stent cells. In SES restenosis patients, minimum lumen site was compared with image slices 2.5, 5.0, 7.5, and 10.0 mm proximal and distal to this site. The minimum lumen site had a smaller IVUS lumen area at follow-up (2.7+/-0.9 versus 6.2+/-1.9 mm2; P<0.01), larger maximum interstrut angle (135+/-39 degrees versus 72+/-23 degrees; P<0.01), larger IH area (3.4+/-1.5 versus 0.6+/-1.1 mm2; P<0.01) and thickness (0.7+/-0.3 versus 0.1+/-0.2 mm; P<0.01) at maximum interstrut angle, and fewer stent struts (4.9+/-1.0 versus 6.0+/-0.5; P<0.01) even when normalized for the number of stent cells (0.78+/-0.15 versus 0.97+/-0.07; P<0.01). Compared with nonrestenotic SES, the restenosis lesions also had a smaller minimal lumen area, larger IH area, thicker IH at maximum interstrut angle, fewer stent struts, and larger maximum interstrut angle. Multivariate analysis identified the number of visualized stent struts normalized for the number of stent cells and maximum interstrut angle as the only independent IVUS predictor of IH cross-sectional area (P<0.01 and P<0.01), minimum lumen area (P<0.01 and P<0.01), and IH thickness (P<0.01 and P<0.01). | 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. |
Is obesity associated with worse overall survival in women with low-grade papillary serous epithelial ovarian cancer? | The objective of this study was to evaluate prognostic risk factors for survival in women with low-grade serous epithelial ovarian cancer (LGSC). A multicenter retrospective analysis of patients with LGSC was conducted. Potential epidemiologic risk factors evaluated included obesity, age, parity, race, smoking, oral contraceptive pill and/or hormonal replacement therapy use, and previous hysterectomy or surgery on fallopian tubes and/or ovaries. Additional factors included stage, extent of debulking, residual disease, and disease status. Eighty-one patients were identified, and pathologic diagnosis was independently confirmed. Median age at diagnosis was 56 years (range, 21-86 years). Thirty-four percent were obese, and 80% had optimally debulked disease. Forty-six percent were alive, 14% with disease, whereas 25% were dead of disease, 2% died of intercurrent disease, and 27% had an unknown status. In a univariate analysis, optimal surgical debulking was associated with improved progression-free survival (P = 0.01), disease-specific survival (P = 0.03), and overall survival (OS) (P < 0.001) and body mass index with worse OS (P = 0.05). On multivariate analysis, obesity (hazard ratio, 2.8; 95% confidence interval, 1.05-7.3; P = 0.04) and optimal tumor debulking (hazard ratio, 0.05; 95% confidence interval, 0.008-0.29; P = 0.001) were a significant predictor of OS. | Animal models have shown histamine to be released from the skin during the acute phase of a burn injury. The role of histamine during the early phase of thermal injuries in humans remains unclear. The objectives of this trial were to study histamine release in human skin during the acute phase of a standardized thermal injury in healthy volunteers. Histamine concentrations in human skin were measured by skin microdialysis technique. Microdialysis fibers were inserted into the dermis in the lower leg in male healthy volunteers. A standardized superficial thermal injury was elicited by a heating thermode (49 degrees C) applied to the skin for 5 min. Histamine in dialysate was analyzed for up to 2 h after the injury using two different analytical methods. Spectrofluorometric assay of histamine showed no histamine release in separate studies using 2-min samples over 20 min (n = 6) and 5-10-min samples over 120 min (n = 8). The histamine values were at the limits of the quantification limit of the spectrofluorometric assay. Confirmatory studies using a sensitive radioimmunoassay confirmed no histamine release within the first hour of a thermal injury (baseline 11.6 +/- 1.8 nM vs. post-burn values of 14.8 +/- 1.8 nM, n = 8). |
Does intraurethral stimulation for reflex bladder activation depend on stimulation pattern and location? | Reflex bladder excitation has been demonstrated by stimulation of the pudendal nerve and several of its distal branches. However, excitation parameters have not been consistent and the relationship to anatomical locations within the urethra has not been fully investigated. An improved understanding of the lower urinary tract neurophysiology will improve human studies and neuroprosthetic device development. Intraurethral stimulation was performed in nine cats at near isovolumetric bladder volumes before and/or after spinalization. Bladder excitability profiles were obtained for lower (2 Hz) and higher (33 Hz) frequency stimuli along the urethra between the bladder neck and external meatus. Higher frequency stimuli were excitable at all urethral locations prior to spinalization but only excitable in the middle and distal urethra after spinalization. Lower frequency stimuli were excitable at proximal and middle locations before spinalization but not excitable at any location after spinalization. In most evaluations, bursting pulse stimulation patterns evoked greater bladder pressures than the dominant continuous frequency (2 or 33 Hz). | Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective follow-up study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence free survival. Two sample sets of high-risk primary breast cancer patients participating in a randomised national trial investigating the effectiveness of high-dose chemotherapy were analysed. Sera in set I (n = 63) were analysed by surface enhanced laser desorption ionisation time-of-flight mass spectrometry (SELDI-TOF MS) for biomarker finding. Initial results were validated by analysis of sample set II (n = 371), using one-dimensional gel-electrophoresis. In sample set I, the expression of a peak at mass-to-charge ratio 9198 (relative intensity <or= 20 or > 20), identified as haptoglobin (Hp) alpha-1 chain, was strongly associated with recurrence free survival (global Log-rank test; p = 0.0014). Haptoglobin is present in three distinct phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2), of which only individuals with phenotype Hp 1-1 or Hp 2-1 express the haptoglobin alpha-1 chain. As the expression of the haptoglobin alpha-1 chain, determined by SELDI-TOF MS, corresponds to the phenotype, initial results were validated by haptoglobin phenotyping of the independent sample set II by native one-dimensional gel-electrophoresis. With the Hp 1-1 phenotype as the reference category, the univariate hazard ratio for recurrence was 0.87 (95% CI: 0.56 - 1.34, p = 0.5221) and 1.03 (95% CI: 0.65 - 1.64, p = 0.8966) for the Hp 2-1 and Hp 2-2 phenotypes, respectively, in sample set II. |
Is hER-2 expression prognostic in osteosarcoma ; a Children 's Oncology Group prospective biology study? | Since the initial reports of human epidermal growth factor receptor 2 (HER-2) expression as being prognostic in osteosarcoma, numerous small studies varying in the interpretation of the immunohistochemical (IHC) staining patterns have produced conflicting results. The Children's Oncology Group therefore embarked on a prospective biology study in a larger sample of patients to define in osteosarcoma the prognostic value of HER-2 expression using the methodology employed in the initial North American study describing an association between HER-2 expression and outcome. The analytic patient population was comprised of 149 patients with newly diagnosed osteosarcoma, 135 with localized disease and 14 with metastatic disease, all of whom had follow up clinical data. Paraffin embedded material from the diagnostic biopsy was stained with CB11 antibody and scored by two independent observers. Correlation of HER-2 IHC score and demographic variables was analyzed using a Fisher's exact test and correlation with survival using a Kaplan-Meier analysis. No association was found with HER-2 status and any of the demographic variables tested including the presence or absence of metastatic disease at diagnosis. No association was found between HER-2 status and either event free survival or overall survival in the patients with localized disease. | To determine the role of repetitive endocardial focal activations and Purkinje fibers in the maintenance of long duration ventricular fibrillation (LDVF, VF>1 minute) in canine hearts in vivo. The study was conducted in electrophysiological laboratory of Shanghai Ruijin hospital from July 2010 to August 2012. A 64-electrode basket was introduced through a carotid artery into the left ventricle (LV) of 11 beagle dogs for global endocardial electrical mapping. In the Lugol's solution group (n=5), the subendocardium was ablated by washing with Lugol's solution. In the control group, (n=6) saline was used for ablation. Before and after saline or Lugol ablation, we determined QRS duration and QT/QTc interval in sinus rhythm (SR). We also measured the activation rates in the first 2 seconds of each minute during 7 minutes of VF for each group. If VF terminated spontaneously in less than 7 minutes, the VF segments used in activation rate analysis were reduced accordingly. At the beginning of VF there was no difference between the groups in the activation rate. However, after 1 minute of LDVF the Lugol's solution group had significantly slower activation rate than the control group. In the control group, all episodes of LDVF (6/6) were successfully sustained for 7 minutes, while in the Lugol's solution group 4/5 episodes of LDVF spontaneously terminated before 7 minutes (4.8±1.4 minutes) (P=0.015). In the control group, at 5.1±1.3 minutes of LDVF, a successive, highly organized focal LV endocardial activation pattern was observed. During this period, activations partly arose in PF and spread to the working ventricular myocardium. Mapping analysis showed that these events were consistent with repetitive endocardial focal activations. No evidence of similar focal activations was observed in the Lugol's solution group. |
Is high density lipoprotein cholesterol associated with serum cortisol in older people? | To determine the associations between serum cortisol and HDL cholesterol, other lipoprotein lipids and cardiovascular risk factors, carotid atherosclerosis, and clinical heart disease in older people. A cross-sectional, observational, ancillary study of the Cardiovascular Health Study (CHS). A total of 245 community-dwelling people, 65 to 89 years old, were recruited consecutively for a 2-month period from the CHS cohort in Forsyth County, North Carolina. Cortisol was measured by radioimmunoassay in serum collected between 7:00 and 10:00 AM after an overnight fast. Cortisol levels were correlated with lipoprotein lipids, insulin, glucose, body mass index, waist-hip ratio, prevalent coronary heart disease, hypertension, diabetes, and carotid atherosclerosis by B-mode ultrasound. Serum cortisol was correlated negatively (r = -.24) with body mass index and waist-hip ratio (r = -.16) but was not related significantly to fasting insulin or glucose. Cortisol was not associated significantly with triglyceride and low density lipoprotein cholesterol but showed a positive correlation (r = .21) with high density lipoprotein cholesterol. The relationship between cortisol and high density lipoprotein cholesterol persisted after adjustment for gender, body mass index, waist-hip ratio, cigarette and alcohol use, triglyceride level, and diabetes. There was a trend toward a negative correlation between cortisol and measures of carotid atherosclerosis, but no significant relationship was indicated between cortisol and prevalent coronary heart disease, hypertension, or diabetes. | To explore the role of SCF/c-Kit signaling in the invasion of bladder cancer T24 cells. Western blotting was used to detect the expression of c-Kit and PI3K pathway activation stimulated by stem cell factor (SCF) in T24 cells. The invasiveness of T24 cells before and after SCF stimulation and Wortmannin (aspecific PI3K inhibitor) treatment was evaluated using Transwell invasion assay (direct and indirect counting methods). T24 cells expressed c-Kit protein and showed obvious Akt phosphorylation after stimulation with SCF (1 ng/ml) for 24 h. Compared to the control group, SCF stimulation (1 ng/ml) caused a greater number of T24 cells to migrate through the polycarbonate film (P<0.01), and this effect was blocked by the application of Wortmannin before the stimulation. |
Is neutrophil migration towards C5a and CXCL8 prevented by non-steroidal anti-inflammatory drugs via inhibition of different pathways? | Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to induce PG-independent anti-inflammatory actions. Here, we investigated the role of three different NSAIDs (naproxen, ibuprofen and oxaprozin) on neutrophil responses to CXCL8 and C5a. Human neutrophils were isolated from healthy volunteers by dextran and Ficoll-Hypaque density gradients. Neutrophils were pre-incubated with different concentrations (1-100 µM) of NSAIDs or kinase inhibitors. Neutrophil degranulation into supernatants was tested by elisa and zymography. Neutrophil chemotaxis was determined using Boyden chambers. F-actin polymerization was determined by Alexa-Fluor 488-conjugated phalloidin fluorescent assay. Integrin expression was assessed by flow cytometry. The phosphorylation of intracellular kinases was studied by Western blot. Pretreatment with NSAIDs did not affect neutrophil degranulation, but inhibited neutrophil migration and polymerization of F-actin, in response to CXCL8 and C5a. Pretreatment with different NSAIDs prevented C5a-induced integrin (CD11b) up-regulation, while only ibuprofen reduced CXCL8-induced CD11b up-regulation. Pre-incubation with naproxen or oxaprozin, but not ibuprofen, inhibited the PI3K/Akt-dependent chemotactic pathways. Both endogenous (released in cell supernatants) or exogenous (added to cell cultures) PGE2 did not affect C5a- or CXCL8-induced activities. Short-term incubation with NSAIDs did not affect neutrophil PGE2 release. | Subclinical thyroid conditions, defined by normal thyroxin (T4) but abnormal thyroid-stimulating hormone (TSH) levels, may be associated with cardiovascular and metabolic risk. More recently, TSH levels within the normal range have been suggested to be associated with metabolic syndrome and cardiovascular risk. This work studies the linearity of the relationship between metabolic syndrome and TSH across the euthyroid range. We studied 3533 male participants of the Aragon Workers' Health Study (AWHS) with normal TSH and free T4 levels, across quintiles of these variables, after adjusting for age, alcohol intake, and smoking. Compared with the lowest TSH quintile, the odds ratios for metabolic syndrome at the higher quintiles, which indicate lower thyroid function, were 1.34 (1.04, 1.73), 1.56 (1.21, 2.01), 1.57 (1.22, 2.03), and 1.71 (1.32, 2.21). The lowest free T4 quintile also showed an odds ratio of 1.49 (1.16, 1.90) with respect to the highest quintile. In addition, spline models showed departures from linearity: the risk of metabolic syndrome mostly increases at TSH values below the median (sample half-closest to subclinical hyperthyroidism). Interestingly, glucose also increases with TSH primarily below the median TSH, diastolic blood pressure shows similar changes across the entire TSH range, whereas body mass index, triglycerides, and high-density lipoprotein (HDL)-cholesterol change only at the highest normal TSH values, which are associated with lower free T4 concentration. |
Are matrix metalloproteinase-1 and -9 promoter polymorphisms associated with an increased risk of uterine leiomyomas in a Japanese population? | Matrix metalloproteinases (MMPs) play an important role in modeling and remodeling the extracellular matrix in leiomyomas. Hence, we investigated whether associations exist between leiomyomas and promoter polymorphisms in the MMP-1 and MMP-9 genes in a Japanese population. We compared the distribution of polymorphisms in the promoter regions of MMP-1 (-1607 1G/2G) and MMP-9 (-1562 C/T) in 267 leiomyoma patients and 184 control patients using polymerase chain reaction-fragment-length polymorphism (PCR-RFLP) analysis. The allele frequencies of the MMP-1 -1607 2G and MMP-9 -1562 T polymorphisms were 74.6% and 18.6% in leiomyoma patients, and 71.3% and 18.6% in control patients, respectively. No significant differences in allele frequencies or genotype distributions were found between leiomyoma and control patients. Moreover, no associations were found between MMP-1 and MMP-9 genotypes and leiomyoma size or a family history of the condition. | This study investigated whether off-pump coronary bypass graft operations on the beating heart under normothermic conditions reduces the systemic oxidative stress and inflammatory reaction seen in patients operated under cardiopulmonary bypass (CPB). A cardiac stabilizer (Octopus Tissue Stabilizer; Medtronic Inc, Minneapolis, MN) was used to perform the coronary anastomoses on the normothermic beating heart with or without CPB. Serial blood samples were taken at various intervals. Plasma was analyzed for several oxidative stress and inflammatory markers. Significant increases from prior anesthesia values of lipid hydroperoxides (190% at 4 hours), protein carbonyls (250% at 0.5 hours) and nitrotyrosine (510% at 0.5 hours) were seen in the CPB group, but they were abolished or significantly reduced in the off-pump group. Complement C3a and elastase levels were rapidly increased upon the institution of CPB, and this was followed by increases in IL-8, TNF-alpha, and sE-selectin. In contrast, the rise of these factors was blunted in patients operated without CPB. |
Is nonadherence with ambulatory saliva sampling associated with biased salivary testosterone estimates? | Nonadherence with scheduled saliva sampling, as encountered in ambulatory settings, can bias the estimation of salivary cortisol concentrations. This study is the first to estimate if such nonadherence is also associated with biased salivary testosterone concentration estimates. Using a standard ambulatory saliva-sampling protocol, we instructed pregnant women to collect saliva samples on two consecutive days at awakening, 1100h, 1500h, 2000h, and 2200h. We estimated testosterone concentrations in the saliva samples and participants' actual sampling times with an electronic medication event-monitoring system. We classified a saliva sample as adherent if it was sampled within a specific time window relative to its scheduled sampling time. We used a mixed-model analysis to distinguish between trait (number of adherent saliva samples per participant) and state (adherence status of a specific sample) adherence. We included 60 pregnant women in this study. Seventy-five percent (448 of 600) of the scheduled samples indicated adherence with the sampling schedule. Participants' trait adherence was associated with their diurnal profiles of salivary testosterone estimates; that is, adherent participants had higher salivary testosterone estimates compared with nonadherent participants, F(1,58)=5.41, p=0.023, Cohen's d=0.67. The state adherence of a sample was associated with the salivary testosterone estimate of the related sample, F(1,469)=4.48, p=0.035, Cohen's d=0.20, with delayed sampling associated with lower salivary testosterone estimates. | Biochar is a solid coproduct of biomass pyrolysis, and soil amended with biochar has been shown to enhance the productivity of various crops and induce systemic plant resistance to fungal pathogens. The aim of this study was to explore the ability of wood biochar to induce resistance to the root-knot nematode (RKN) Meloidogyne graminicola in rice (Oryza sativa cv. Nipponbare) and examine its histochemical and molecular impact on plant defense mechanisms. A 1.2 % concentration of biochar added to the potting medium of rice was found to be the most effective at reducing nematode development in rice roots, whereas direct toxic effects of biochar exudates on nematode viability, infectivity or development were not observed. The increased plant resistance was associated with biochar-primed H2O2 accumulation as well as with the transcriptional enhancement of genes involved in the ethylene (ET) signaling pathway. The increased susceptibility of the Ein2b-RNAi line, which is deficient in ET signaling, further confirmed that biochar-induced priming acts at least partly through ET signaling. |
Does hypothermia protect and Prolongs the Tolerance Time of Retinal Ganglion Cells against Ischemia? | Hypothermia has been shown to be neuroprotective in the therapy of ischemic stroke in the brain. To date no studies exist on the level of the inner retina and it is unclear if hypothermia would prolong the ischemic tolerance time of retinal ganglion cells, which are decisive in many ischemic retinopathies. Bovine eyes were enucleated and stored either at 21°C or 37°C for 100 or 340 minutes, respectively. Afterwards the globes were dissected, the retina was prepared and either the spontaneous ganglion cell responses were measured or the retina was incubated as an organotypic culture for additional 24 hours. After incubation the retina was either processed for histology (H&E and DAPI staining) or real-time PCR (Thy-1 expression) was performed. Hypothermia prolonged ganglion cell survival up to 340 minutes under ischemic conditions. In contrast to eyes kept at 37°C the eyes stored at 21°C still showed spontaneous ganglion cell spiking (56.8% versus 0%), a 5.8 fold higher Thy-1 mRNA expression (not significant, but a trend) and a preserved retinal structure after 340 minutes of ischemia. | Esophageal squamous cell carcinoma (ESCC) and colorectal neoplasms (CRNs) share risk factors. We aimed to investigate whether the CRN risk is increased in ESCC patients. ESCC patients who underwent a colonoscopy within 1 year of diagnosis were retrospectively analyzed. Patients were matched 13 by age, gender, and body mass index to asymptomatic controls. CRN was defined as the histological confirmation of adenoma or adenocarcinoma. Advanced CRN was defined as any of the following ≥3 adenomas, high-grade dysplasia, villous features, tumor ≥1 cm, or adenocarcinoma. The risk factors for both CRN and advanced CRN were evaluated by univariate and multivariate analyses. Sixty ESCC patients were compared with 180 controls. The ESCC group had significantly higher numbers of CRNs (odds ratio [OR], 2.311; 95% confidence interval [CI], 1.265 to 4.220; p=0.006) and advanced CRNs (OR, 2.317; 95% CI, 1.185 to 4.530; p=0.013). Significant risk factors for both CRN and advanced CRN by multivariate analysis included ESCC (OR, 2.157, 95% CI, 1.106 to 4.070, p=0.024; and OR, 2.157, 95% CI, 1.045 to 4.454, p=0.038, respectively) and older age (OR, 1.068, 95% CI, 1.032 to 1.106, p<0.001; and OR, 1.065, 95% CI, 1.024 to 1.109, p=0.002, respectively). |
Does hemodynamic disturbed flow induce differential DNA methylation of endothelial Kruppel-Like Factor 4 promoter in vitro and in vivo? | Hemodynamic disturbed flow (DF) is associated with susceptibility to atherosclerosis. Endothelial Kruppel-Like Factor 4 (KLF4) is an important anti-inflammatory atheroprotective transcription factor that is suppressed in regions of DF. The plasticity of epigenomic KLF4 transcriptional regulation by flow-mediated DNA methylation was investigated in vitro and in arterial tissue. To recapitulate dominant flow characteristics of atheroprotected and atherosusceptible arteries, human aortic endothelial cells were subjected to pulsatile undisturbed flow or oscillatory DF containing a flow-reversing phase. Differential CpG site methylation was measured by methylation-specific polymerase chain reaction, bisulfite pyrosequencing, and restriction enzyme-polymerase chain reaction. The methylation profiles of endothelium from disturbed and undisturbed flow sites of adult swine aortas were also investigated. In vitro, DF increased DNA methylation of CpG islands within the KLF4 promoter that significantly contributed to suppression of KLF4 transcription; the effects were mitigated by DNA methyltransferase (DNMT) inhibitors and knockdown of DNMT3A. Contributory mechanisms included DF-induced increase of DNMT3A protein (1.7-fold), DNMT3A enrichment (11-fold) on the KLF4 promoter, and competitive blocking of a myocyte enhancer factor-2 binding site in the KLF4 promoter near the transcription start site. DF also induced DNMT-sensitive propathological expression of downstream KLF4 transcription targets nitric oxide synthase 3, thrombomodulin, and monocyte chemoattractant protein-1. In support of the in vitro findings, swine aortic endothelium isolated from DF regions expressed significantly lower KLF4 and nitric oxide synthase 3, and bisulfite sequencing of KLF4 promoter identified a hypermethylated myocyte enhancer factor-2 binding site. | To examine relationships among demographic variables, healthcare system distrust, lung cancer stigma, smoking status, and timing of medical help-seeking behavior in individuals with symptoms suggestive of lung cancer after controlling for ethnicity, socioeconomic status, and social desirability. Descriptive, cross-sectional, correlational study. Outpatient oncology clinics in Louisville, KY. 94 patients diagnosed in the past three weeks to six years with all stages of lung cancer. Self-report, written survey packets were administered in person followed by a semistructured interview to assess symptoms and timing characteristics of practice-identified patients with lung cancer. Timing of medical help-seeking behavior, healthcare system distrust, lung cancer stigma, and smoking status. Lung cancer stigma was independently associated with timing of medical help-seeking behavior in patients with lung cancer. Healthcare system distrust and smoking status were not independently associated with timing of medical help-seeking behavior. |
Does seroprevalence of alphavirus antibodies in a cross-sectional study in southwestern Tanzania suggest endemic circulation of chikungunya? | To date, Alphavirus infections and their most prominent member, chikungunya fever, a viral disease which first became apparent in Tanzania in 1953, have been very little investigated in regions without epidemic occurrence. Few data exist on burden of disease and socio-economic and environmental covariates disposing to infection. A cross-sectional seroprevalence study was undertaken in 1,215 persons from Mbeya region, South-Western Tanzania, to determine the seroprevalence of anti-Alphavirus IgG antibodies, and to investigate associated risk factors. 18% of 1,215 samples were positive for Alphavirus IgG. Seropositivity was associated with participant age, low to intermediate elevation, flat terrain and with IgG positivity for Rift Valley fever, Flaviviridae, and rickettsiae of the spotted fever group. When comparing the geographical distribution of Alphavirus seropositivity to that of Rift Valley fever, it was obvious that Alphaviruses had spread more widely throughout the study area, while Rift Valley fever was concentrated along the shore of Lake Malawi. | In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between cells and surrounding matrix; however, its role in liver development and regeneration is undefined. Polysialic acid (polySia), a unique posttranslational modifier of NCAM, is produced by the enzymes, ST8SiaII and ST8SiaIV, and weakens NCAM interactions. The role of polySia with NCAM synthesizing enzymes ST8SiaII and ST8SiaIV were examined in HPCs in vivo using the choline-deficient ethionine-supplemented and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet models of liver injury and regeneration, in vitro using models of proliferation, differentiation, and migration, and by use of mouse models with gene defects in the polysialyltransferases (St8sia 2+/-4+/-, and St8sia2-/-4-/-). We show that, during liver development, polySia is required for the correct formation of bile ducts because gene defects in both the polysialyltransferases (St8sia2+/-4+/- and St8sia2-/-4-/- mice) caused abnormal bile duct development. In normal liver, there is minimal polySia production and few ductular NCAM+ cells. Subsequent to injury, NCAM+ cells expand and polySia is produced by DRs/HPCs through ST8SiaIV. PolySia weakens cell-cell and cell-matrix interactions, facilitating HGF-induced migration. Differentiation of HPCs to hepatocytes in vitro results in both transcriptional down-regulation of polySia and cleavage of polySia-NCAM. Cleavage of polySia by endosialidase (endoN) during liver regeneration reduces migration of DRs into parenchyma. |
Is hyperhomocysteinemia sufficient to cause preeclampsia in an animal model : the importance of folate intake? | The objective of our study was to determine whether methylenetetrahydrofolate reductase (Mthfr)-deficient mice develop preeclampsia (PE). Mice were placed on a normal or low-folate/high-methionine (LF/HM) diet to assess the impact of mild and severe homocysteinemia. Blood pressure and proteinuria were measured throughout gestation in Mthfr-deficient and control mice on both diets, by radiotelemetry and by determining the urinary albumin/creatinine ratio by enzyme-linked immunosorbent assay, respectively. Although Mthfr-deficient mice have endothelial dysfunction, they do not develop hypertension or proteinuria during gestation. The LF/HM diet induced proteinuria, growth restriction, and a decrease in the number of pups per litter in all mice without any effect on the placenta. | Constitutive activation of the signal transducer and activator of transcription 3 (Stat3) has been detected in various human cancers and has been linked to tumor development and progression. Oncogenic Stat3 signaling results in induction of specific target genes, among which survivin is implicated in the proliferation and survival of cancer cells. Targeting of Stat3 constitutive expression by the nonsteroidal antiinflammatory drug (NSAID) sulindac has been demonstrated to exert antineoplastic effects in oral squamous cell carcinoma cells in vitro and in vivo. The expression and functional role of Stat3 and survivin was evaluated in 2 salivary gland adenocarcinoma cell lines (HSY and HSG). In addition, the effects of the NSAID sulindac and other cyclooxygenase (COX) inhibitors on Stat3 and survivin expression and on cell proliferation and apoptosis of HSY and HSG cells were analyzed. Messenger RNA and protein expression of Stat3 and survivin was detected in HSY and HSG cell lines. Treatment of these cells with siRNA against Stat3 or survivin inhibited cell proliferation and induced apoptosis. Moreover, Stat3 siRNA treatment down-regulated the protein and mRNA expression of survivin, and survivin forced expression partially reversed the antineoplastic effects of Stat3 siRNA treatment. Treatment of HSY and HSG cells with the NSAID sulindac, but not other COX inhibitors, induced significant decreases in cell proliferation and increases in apoptosis, accompanied by down-regulation of Stat3 and survivin expression. In contrast, survivin forced expression or transfection with constitutively active Stat3 attenuated the effects of sulindac on cell growth and apoptosis. |
Is glycemic variability evaluated by continuous glucose monitoring system associated with the 10-y cardiovascular risk of diabetic patients with well-controlled HbA1c? | The present study aimed to identify the relationship between glycemic variability (GV) and the 10-y risk of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) patients with good glycemic control. Two-hundred forty consecutive T2DM patients (HbA1c≤7.0%) without CVD were included to calculate the 10-y CVD risk by Framingham risk score (FRS), and divided into 3 groups: low-risk group (FRS≤10%), intermediate-risk group (>10%, ≤20%) and high-risk group (>20%). Inter-group differences of GV were determined by comparing the SD of blood glucose (SDBG), mean amplitudes of glycemic excursion (MAGE), and mean of daily differences (MODD) gathered from 72-h continuous glucose monitoring system. The levels of SDBG and MAGE significantly increased along with the raises of 10-y CVD risk of T2DM patients (p<0.01). FRS was positively correlated with age, systolic blood pressure, SDBG and MAGE (r=0.717, 0.525, 0.509 and 0.485 respectively, p<0.01), while negatively correlated with the level of HDL-C (r=-0.348, p<0.01). Furthermore, multivariate logistic regression analysis confirmed that increased MAGE [OR: 1.623(1.198-2.316), p<0.001] and patients with high urine albumin excretion rates [OR: 1.743(1.247-2.793), p<0.001] were independent predictors for high 10-y CVD risk. | RNA-binding motif protein 19 (RBM19, NCBI Accession # NP_083038) is a conserved nucleolar protein containing 6 conserved RNA recognition motifs. Its biochemical function is to process rRNA for ribosome biogenesis, and it has been shown to play a role in digestive organ development in zebrafish. Here we analyzed the role of RBM19 during mouse embryonic development by generating mice containing a mutation in the Rbm19 locus via gene-trap insertion. Homozygous mutant embryos failed to develop beyond the morula stage, showing defective nucleologenesis, activation of apoptosis, and upregulation of P53 target genes. A unique feature of RBM19 is its localization to the cytoplasm in morula stage-embryos, whereas most other nucleolar proteins are localized to the nucleolar precursor body (NPB). The nucleoli in the Rbm19 mutant embryos remain immature, yet they can carry out rRNA synthesis. The timing of developmental arrest occurs after expression of the inner cell mass markers OCT3/4 and NANOG, but prior to the specification of trophectoderm as reflected by CDX2 expression. |
Is soft drink consumption associated with depressive symptoms among adults in China? | Research evidence supports a positive link between soft drinks and depressive symptoms. However, data thus far are only from Caucasian populations. We investigated whether high levels of consumption of soft drinks were associated with the depressive symptoms among adults in China. A cross-sectional survey was conducted with 3667 adults in Tianjin, China. Dietary intake was assessed using a valid self-administered food frequency questionnaire, and depressive symptoms were assessed with the Zung Self-Rating Depression Scale (SDS), cut-off point of 40, 45 or 50 indicating elevated depressive symptoms. The prevalence of elevated depressive symptoms was 7.6% (SDS ≥50). After adjustments for potentially confounding factors, the odds ratios (95% confidence interval) of having elevated depressive symptoms by increasing levels of soft drink consumption were 1.00, 1.43 (1.01, 2.01) and 2.00 (1.15, 3.37) (p for trend <0.01). Similar relations were observed when SDS ≥40 or 45 were used as a definition of depressive symptoms. | The aim of this study is to evaluate if it is necessary to remove all the radioactive sentinel lymph nodes (SLNs) not seen on lymphoscintigraphy in order to accurately stage breast cancer patients. From March 1999 to March 2006, SLN biopsy was performed in 461 patients. All patients were only injected with radioisotope. Lymphoscintigraphy was performed in all the patients. The mean number of SLNs removed was 2.1 (range 1-15). The SLN was positive in 133 patients (28.8%). Lymphoscintigraphy accurately predicted the number of SLNs identified intraoperatively in 243 patients (52.7%). In 175 patients (37.9%) there were more SLNs identified intraoperatively than were seen on lymphos cintigraphy. In 11 (6.2%) of these 175 patients, additional SLNs identified intraoperatively harboured metastasis. Type of injection, need for a second injection, tumour location and age were not identified as statistically significantly associated with additional positive SLNs identified intraoperatively and not seen on lymphoscintigraphy. |
Is hypertrophic cardiomyopathy due to sarcomeric gene mutations characterized by impaired energy metabolism irrespective of the degree of hypertrophy? | We investigated cardiac energetics in subjects with mutations in three different familial hypertrophic cardiomyopathy (HCM) disease genes, some of whom were nonpenetrant carriers without hypertrophy, using phosphorus-31 magnetic resonance spectroscopy. Familial hypertrophic cardiomyopathy is caused by mutations in sarcomeric protein genes. The mechanism by which these mutant proteins cause disease is uncertain. A defect of myocyte contractility had been proposed, but in vitro studies of force generation have subsequently shown opposing results in different classes of mutation. An alternative hypothesis of "energy compromise" resulting from inefficient utilization of adenosine triphosphate (ATP) has been suggested, but in vivo data in humans with genotyped HCM are lacking. The cardiac phosphocreatine (PCr) to ATP ratio was determined at rest in 31 patients harboring mutations in the genes for either beta-myosin heavy chain, cardiac troponin T, or myosin-binding protein C, and in 24 controls. Transthoracic echocardiography was used to measure left ventricular (LV) dimensions and maximal wall thickness. The PCr/ATP was reduced in the HCM subjects by 30% relative to controls (1.70 +/- 0.43 vs. 2.44 +/- 0.30; p < 0.001), and the reduction was of a similar magnitude in all three disease-gene groups. The PCr/ATP was equally reduced in subjects with (n = 24) and without (n = 7) LV hypertrophy. | Accumulation of tumor-infiltrating mast cells (MCs) predicts poor survival in several cancers after resection. However, its effect on the prognosis of patients with colorectal liver metastases (CRLM) is not known. Our retrospective study included 135 patients who underwent potentially curative resection for CRLM between 2001 and 2010. Expression of tryptase, MAC387, CD83, and CD31, which are markers for MCs, macrophages, mature dendritic cells, and vascular endothelial cells, respectively, was determined via immunohistochemistry of resected tumor specimens. The relationship between immune cell infiltration and long-term outcome was investigated. The median follow-up time was 48.4 months for all patients and 57.5 months for survivors. Overall survival (OS) rates at 1, 3, and 5 years were 91.0, 62.4, and 37.4 %, respectively. Five-year disease-free survival (DFS) and OS rates were 21.6 and 38.1 %, respectively, in patients with high MC infiltration, and 42.6 and 55.6 %, respectively, in patients with low MC infiltration (p < 0.01 for both DFS and OS). Infiltration of other types of immune cells did not correlate with survival. Multivariate analyses indicated that hypoalbuminemia and high peritumoral MC infiltration were significant predictors of unfavorable OS. |
Are low serum 25-hydroxyvitamin d concentrations associated with increased risk for melanoma and unfavourable prognosis? | Low vitamin D status (serum 25(OH)D concentration) is associated with increased incidence and unfavourable outcome of various types of cancer. However, there are limited data on influence of serum 25(OH)D on risk and prognosis of malignant melanoma. Basal serum 25(OH)D concentrations were retrospectively analyzed in a cohort of melanoma patients (n = 324) and healthy controls (n = 141). We tested the hypothesis that serum 25(OH)D concentrations are predictive of melanoma risk, thickness of primary melanomas, and overall survival (OS). Median serum 25(OH)D concentrations were significantly lower (p = 0.004) in melanoma patients (median = 13.6 ng/ml) as compared to controls (median = 15.6 ng/ml). Primary tumors of patients with low serum 25(OH)D concentrations (<10 ng/ml) had significantly (p = 0.006) greater Breslow thickness (median: 1.9 mm) as compared to patients with higher levels (>20 ng/ml; median: 1.00 mm). Patients with 25(OH)D serum concentrations in the lowest quartile had inferior overall survival (median: 80 months) comparing with the highest quartile (median: 195 months; p = 0.049). | To describe technical challenges encountered using the Ovation endograft for abdominal aortic aneurysms and suggest tips and maneuvers for successful management. Deployment of the Ovation's unsupported main body is often associated with the anteroposterior arrangement of the limb gates instead of the usual side-by-side configuration, rendering contralateral catheterization challenging. Successful catheterization of the contralateral limb can be confirmed by lateral deviation of the ipsilateral stiff guidewire caused by balloon inflation within the contralateral limb. Moreover, failure to cannulate the contralateral limb gate due to persistent impingement of the guidewire or compromise of the inflated rings can be overcome using the transbrachial antegrade approach. |
Do uremic toxins adsorbed by AST-120 promote tubular hypertrophy and interstitial fibrosis in nephrectomized rats? | Uremic toxins have been shown to promote glomerular hypertrophy. The present study was performed to elucidate the relation between uremic toxins and tubulointerstitial changes. Sixty male Sprague-Dawley rats underwent 2/3 nephrectomy (Nx; n = 30) and 4/5 Nx (n = 30). Experiments were initiated 2 weeks after surgery, and were performed over an 8-week period. Half of each group (Nx-A) was administered 1 g/day of an oral carbonaceous adsorbent, AST-120, with pair-feeding, and the other half (Nx-C) served as controls. All rats were sacrificed at week 8 after a clearance study. The shortest diameter of proximal tubules (PTD) and interstitial fibrosis area (IFA) at week 8 in 2/3 Nx-A rats was significantly decreased compared to that in 2/3 Nx-C rats (similar body weights, systolic blood pressures, glomerular filtration rates, and urinary protein excretion levels). The values of PTD and IFA, glomerular filtration rate and urinary protein excretion level at week 8 in 4/5 Nx-A rats were significantly decreased compared to those in 4/5 Nx-C rats (similar body weights and systolic blood pressures). | Previous work has demonstrated a link between restricted sleep and risk indicators for cardiovascular and metabolic disease, such as levels of cortisol, lipids, and glucose. The present study sought to identify relations between polysomnographic measures of disturbed sleep (frequency of arousals from sleep, total sleep time, and sleep efficiency) and a number of such indicators. A second purpose was to relate the number of arousals to mood, stress, work characteristics, and other possible predictors in daily life. Twenty-four people (10 men, 14 women; mean age 30 years), high vs. low on burnout, were recruited from a Swedish IT company. Polysomnographically recorded sleep was measured at home before a workday. Blood pressure, heart rate, morning blood sample, and saliva samples of cortisol were measured the subsequent working day. They were also recorded for diary ratings of sleep and stress, and a questionnaire with ratings of sleep, stress, work conditions, and mood was completed. A stepwise regression analysis using sleep parameters as predictors brought out number of arousals as the best predictor of morning cortisol (serum and saliva), heart rate, systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein (HDL)-, low-density lipoprotein (LDL)-cholesterol, and LDL/HDL-ratio. Work stress/unclear boundaries between work and leisure time was the best predictor of arousals among the stress variables. |
Is high free fatty acid level associated with recurrent stroke in cardioembolic stroke patients? | To determine whether the plasma level of free fatty acid (FFA) could be associated with recurrent stroke in cardioembolic (CE) stroke patients. We analyzed data from 669 acute ischemic stroke patients and examined the association between FFA concentration and recurrent stroke in CE stroke patients compared with non-CE stroke patients. The baseline plasma FFA concentration (mEq/L) was approximately 1.5-fold higher in CE stroke patients (1.01 ± 0.63) than in non-CE stroke patients (0.72 ± 0.51). Multivariate logistic analysis showed that an increased level of FFA was significantly associated with CE stroke (hazard ratio [HR] 2.124, confidence interval [CI] 1.492-3.024). During the mean follow-up period of 25.4 months, a total of 56 (8.4%) patients experienced a stroke recurrence. The recurrence rate did not differ between patients with CE (10.5%) and non-CE (8.0%) stroke (p = 0.396). In CE stroke patients, an elevated baseline FFA concentration was independently associated with stroke recurrence (HR 2.711, CI 1.056-6.959). However, there was no association between FFA and stroke recurrence in non-CE stroke patients. | To determine whether mitomycin C suppresses aqueous humor formation in cynomolgus monkeys. Three monkeys received subconjunctival injections (50 microL) in four quadrants bilaterally, one eye receiving mitomycin C (0.5 mg/mL) and the other receiving distilled water. Seven monkeys underwent 360 degrees conjunctival peritomy bilaterally and episcleral application of mitomycin C-soaked (0.5 mg/mL) cellulose sponges for 5 minutes in all four quadrants unilaterally. Aqueous humor flow was measured fluorophotometrically 1 and 3 days, and 1, 2, and 4 weeks after subconjunctival injection; and 3 days and 1, 2, 3, and 4 weeks after episcleral application. There was no change in aqueous flow in either eye and no difference between eyes following subconjunctival injection. Aqueous flow was reduced by 8% +/- 7% (mean +/- SEM), 20% +/- 3% (P < .01), 9% +/- 10%, and 0% +/- 4% compared with contralateral controls 1, 2, 3, and 4 weeks, respectively, after episcleral application of mitomycin C. |
Is fertilization rate an independent predictor of implantation rate? | To determine whether fertilization rate serves as a biological assay, reflects oocyte quality, and may be used to help predict patient implantation rate. Retrospective cohort study. Academic center. Couples undergoing 3603 in vitro fertilization (IVF) cycles from 2001 to 2007. None. We compared the implantation rate among cycles with high versus low fertilization rate. Univariate analyses were performed to determine the association of implantation rate with potential confounding variables: age, day-3 follicle-stimulating hormone level, day-3 estradiol level, antral follicle count, oocyte number, cycle attempts, embryo grading, and number of embryos transferred. Multivariate analysis was then performed to determine whether the fertilization rate remained an independent predictor. Cutoffs for fertilization rate were 50% for intracytoplasmic sperm injection (ICSI) and 75% for conventional insemination. Higher ICSI fertilization was statistically significantly associated with the implantation rate (25.2% vs. 17.8 %). After adjusting for variables associated with implantation rate, fertilization rate for ICSI remained a strong independent predictor of implantation. Higher conventional insemination fertilization was statistically significantly associated with implantation (32.1% vs. 25.7%) and remained a statistically significant predictor after adjustment. | Work status is a valid indicator of post burn health. There is limited information on this issue after work-related burn injury. To investigate long-term health- and work status after work-related burns. Eighty-six former patients treated for severe work-related burn injuries an average of 9.0 years previous to follow-up were questioned about their present work status. They were also assessed with the Burn Specific Health Scale-Brief (BSHS-B) and a pain scale adopted from the abbreviated Burn Specific Health Scale. At follow-up 71 (83%) of the former patients were working, nine (10%) were on sick leave or had a disability pension, and six (7%) were unemployed. Those who were not working reported a poorer outcome in three of the BSHS-B psychosocial domains (Body Image, Affect and Interpersonal Relationships) and in two of the BSHS-B physical domains (Treatment Regimens and Work). They also reported significantly more pain. |
Is ultrasonographic endometrial thickness measurement predictive for treatment response in simple endometrial hyperplasia without atypia? | We sought to determine the predictors of treatment response in simple endometrial hyperplasia without atypia. We prospectively treated 67 women with simple endometrial hyperplasia without atypia who were administered cyclic oral medroxyprogesterone acetate 10 mg/day for 12 days of luteal phase for 3 months and underwent control endometrial sampling after treatment. All subjects were evaluated in terms of age, gravidity, parity, body mass index (BMI), menstrual cycle, endometrial thickness, uterine fibroids, ovarian cysts, serum CA 125 levels, systemic disorders and cigarette smoking. All parameters were used to predict treatment success. Persistent hyperplasia was observed in 11 subjects. Endometrial thickness was significantly correlated with treatment failure (r=0.293, p=0.015). In ROC analysis, endometrial thickness was found to be predictive for persistent hyperplasia (area under curve: 0.724, P=0.019). Optimal cut off value was calculated to be 16.5 mm with 64% sensitivity, 72% specificity and 91% negative predictive value. The number of persistent hyperplasia in women with and without endometrial thickness greater than 16.5 mm was significantly different (7/23 vs. 4/45, p=0.029). Odds ratio of endometrial thickness higher than 16.5 mm for treatment failure was 4.4 (95% CI, 1.2-17.4, p=0.03). | To determine the in vivo neutralizing activities of anti-interleukin-6 (IL-6) antibody on survival rate and host defense in a clinically relevant model of infection. Prospective, randomized, experimental animal study. University and Shriners Burns Institute research laboratories. Two hundred seventy-six adult, female Balb/c mice. Balb/c mice were treated with 10 micrograms of antimurine IL-6 antibody, nonspecific murine immunoglobulin G (IgG), or placebo at 2, 4, or 8 hrs after they underwent bacterial challenge by gavage of 10(10) Escherichia coli and thermal injury. The survival rate was determined. The number of viable translocated bacteria, the total amount of translocation, and the percentage of bacteria that survived were also studied in different tissues. Survival rate after burn and gavage was significantly improved in animals treated with antimurine IL-6 antibody at 2 and 4 hrs but not at 8 hrs after injury compared with control animals treated with nonspecific IgG or saline. The IL-6 serum concentration was significantly lower after burn and gavage in the animals treated 2 and 4 hrs after injury compared with nontreated animals. Better killing of translocated bacteria was observed in the tissues of animals treated with antimurine IL-6 antibody 2 hrs after injury. |
Is cT pulmonary angiography the first-line imaging test for acute pulmonary embolism : a survey of US clinicians? | Our aim is to document current imaging practices for diagnosing acute pulmonary embolism (PE) among physicians practicing in the United States and explore factors associated with these practices. Between September 2004 and February 2005, we surveyed by mail 855 physicians selected at random from membership lists of three professional organizations. Physicians reported their imaging practices and experiences in managing patients with suspected acute PE during the preceding 12 months. Completed questionnaires were received from 240 of 806 eligible participants (29.8%) practicing in 44 states: 86.7% of respondents believed that computed tomographic pulmonary angiography (CTPA) was the most useful imaging procedure for patients with acute PE compared with 8.3% for ventilation-perfusion (V-P) scintigraphy and 2.5% for conventional pulminary angiography (PA). After chest radiography, CTPA was the first imaging test requested 71.4% of the time compared with V-P scintigraphy (19.7%) and lower-limb venous ultrasound (5.8%). Participants received indeterminate or inconclusive results 46.4% of the time for V-P scintigraphy, 10.6% of the time for CTPA, and 2.2% of the time for PA. CTPA was available around the clock to 88.3% of participants compared with 53.8% for V-P scintigraphy and 42.5% for PA. A total of 68.6% of respondents received CTPA results in 2 hours or less (vs 37.5% for V-P scintigraphy and 22.9% for PA). CTPA also provided an alternative diagnosis to PE or showed other significant abnormalities 28.5% of the time, and these findings frequently altered management. | The fetal programming hypothesis suggests that intrauterine stimuli can induce metabolic changes in offspring, increasing the disease risk in adulthood. Periodontal disease may enhance serum cytokine levels. Cytokines such as tumor necrosis factor-alpha (TNF-α) have been associated with reduced glucose transporter type 4 (GLUT4) expression, decreased protein kinase B (Akt) phosphorylation, and insulin resistance. This study aimed to evaluate GLUT4 content, and Akt serine phosphorylation status in the gastrocnemius skeletal muscle (GSM), glycemia, insulinemia and change in body weight in offspring of rats with periodontal disease. Female Wistar rats were distributed into a control group (CN) and an experimental periodontal disease group (PD), in which a ligature was placed around the mandibular first molars. Seven days after ligature placement, both groups were mated with normal male rats. The ligatures remained throughout pregnancy until weaning, after which the male offspring were distributed into groups: CN-o, control rat offspring; and PD-o, periodontal disease rat offspring. The body weight from 0 to 75days of age was measured. At 75days, the glycemia, insulinemia, TNF-α levels, Akt serine phosphorylation, and GLUT4 content in the GSM were measured in the offspring. The PD-o group showed a low birth weight (LBW), unchanged glycemia, increased insulinemia, insulin resistance, increased TNF-α levels, decreased Akt serine phosphorylation status, and reduced GLUT4 content in the plasma membrane and translocation index after insulin stimulation. |
Is stromal transforming growth factor-beta 1 crucial for reinforcing the invasive potential of low invasive cancer? | Tumour cells alter the characteristics of the adjacent stroma to create a supportive microenvironment during cancer progression. In vitro and in vivo experiments were carried out to verify the role of stromal TGF-β1 in reinforcing of the invasive potential in low invasive cancer. Isolated NF or CAF was co-cultured with low invasive HSC-2 cells to evaluate whether stromal TGF-β1 induced PDPN expression by Transwell invasion and influenced tumour growth in orthotopic xenografts. Stimulation by TGF-β1 promoted PDPN expression and Transwell invasion through SMAD signalling as well as activation of Src, P38 mitogen activated protein kinase and extracellular regulated kinase 1/2. PDPN induction was TβRII-dependent. Tumour growth of HSC-2 OSCC in a mouse xenograft was intensified in the tumour CAF microenvironment. | Cognitive decline is part of the long-term outcome for many individuals with bipolar disorder (BD). The ε4 allele (APOE*4) of apolipoprotein E (APOE) is a well-established risk factor for dementia in Alzheimer's disease (AD). However, its contribution to the risk of cognitive deterioration in BD has not yet been determined. Our aim was to analyze the APOE genotype association with cognitive status in a sample of older adults with BD and compare this to the association in individuals with AD, individuals with mild cognitive impairment (MCI), and healthy controls. Participants (n = 475) were allocated to four groups: individuals with BD (n = 77), those with AD (n = 211), those with MCI (n = 43), and healthy controls (n = 144) according to clinical and neuropsychological assessment. APOE was genotyped by real-time polymerase chain reaction. Tukey's honest significant difference test and Pearson's chi-squared test were used to compare diagnostic groups. Subjects with BD were similar to controls with respect to the distribution of the APOE genotype (p = 0.636) and allele frequencies (p = 0.481). Significant differences were found when comparing the AD group to the BD group or to controls (APOE genotype: p < 0.0002; allele frequencies: p < 0.001). APOE*4 was significantly increased in the AD group when compared to the BD group (p = 0.031) and controls (p < 0.0001). The cognitively impaired BD subgroup (Mini-Mental State Examination below the cutoff score and/or neuropsychological assessment compatible with MCI) had a statistically significant higher frequency of APOE*2 compared to the AD group (p = 0.003). |
Is coronary endothelial dysfunction associated with an increased risk of cerebrovascular events? | Stroke, mainly attributable to atherothrombotic disease, represents a leading cause of disability and death in the Western world. Endothelial dysfunction, which is considered a key factor in atherogenesis, is associated with an increased risk of cardiovascular events. However, the magnitude of the association between coronary endothelial dysfunction (CED) and cerebrovascular events is unknown. This study was performed to investigate the association between CED and cerebrovascular events. We studied 503 patients without obstructive coronary artery disease (CAD) who underwent coronary endothelial function testing by intracoronary acetylcholine infusion. Patients were divided according to the presence (n=305) or absence (n=198) of CED, and medical records were examined for the occurrence of ischemic or hemorrhagic stroke or transient ischemic attack either before (prevalent) or after (incident) coronary endothelial function testing. Among the study population, a total of 25 cerebrovascular events were documented, 22 in patients with CED (15 prevalent) and 3 in patients without (all prevalent) (P=0.008). Multivariable logistic regression, which included traditional cerebrovascular disease-related risk factors, identified the presence of CED as the single strongest factor associated with cerebrovascular events (OR, 4.32; 95% CI, 1.26 to 14.83). Kaplan-Meier analysis indicated that patients with CED had a significantly higher cumulative cerebrovascular event rate than those without (P=0.04). | To determine whether follicle curetting at the time of oocyte retrieval increases oocyte yield. Retrospective review of all patients who underwent oocyte retrieval from July 1, 2003 to June 30, 2005. Number of oocytes retrieved. retrieval time, number of cryopreserved embryos, pregnancy rates, and incidence of ovarian hyperstimulation syndrome. There were no differences in patient demographics, antral follicle count, cycle stimulation characteristics, fertilization rates, embryo quantity or quality, embryo cryopreservation rates, clinical pregnancy rates, live birth rates, or ovarian hyperstimulation syndrome between the groups. Retrievals that utilized curetting took three minutes longer. Follicle curetting significantly increased the number of oocytes retrieved, 13.9 +/- 0.6 compared to 11.4 +/- 0.6 oocytes without curetting (P = 0.003). The quantity of mature oocytes was also increased with curetting (10.3 +/- 0.5 versus 8.4 +/- 0.5, P = 0.006). |
Is vascular endothelial dysfunction in cyclosporine-treated rat aortas associated with serum total homocysteine levels? | Elevation of serum total homocysteine (tHcy) is considered to contribute to endothelial cell dysfunction, which is considered to be the initial event in posttransplant vascular disease. We sought to investigate whether an association existed between serum tHcy levels and vascular endothelial function during cyclosporine (CsA) treatment. Endothelium-dependent and -independent relaxation responses (to acetylcholine [ACh] and sodium nitroprusside [SNP]) were determined on thoracic aortae from CsA-treated rats (5 mg kg/d, subcutaneously, for 14 days). A correlation analysis was performed between ACh responses and tHcy levels. CsA decreased the responses to ACh and the pD(2) values of the concentration-response curves compared with controls (P < .05). Responses to SNP and serum tHcy levels were unchanged among the groups. tHcy negatively correlated with the ACh pD(2) values among control (r = -0.69; P < .05) and vehicle (r = -0.73; P < .05) groups, indicating that the increase in tHcy was associated with decreased sensitivity to ACh. In CsA-treated rats, no association was observed between these parameters. Also, no correlation was noted between CsA concentrations and tHcy levels. | MiR-93 was observed in various types of cancers. This study is to investigate a role of miR-93 in the carcinogenesis of HCC. The expression of miR-93 in HepG2 cells and prima-ry human hepatocytes (PHHC) was measured by RT-PCR. HepG2 cells were transfected with miR-93 inhibitor or negative control. The cell proliferation was determined by using the CellTiter 96® Aqueous One Solution Cell Proliferation Assay kit. The migration and clonogenicity in vitro were measured by cell migration assay, colony formation analysis and anchorage-in-dependent growth assay. The apoptosis and cell cycle were detected by flow cytometry analysis. The mRNA and protein levels of transforming growth factor-beta type II receptor (TGFBR2) and integrin beta8 (ITGB8)were evaluated by RT-PCR and western blot analysis. MiR-93 was upregulated in HepG2 cells compared with PHHC and inhibition of miR-93 significantly suppressed HepG2 cell proliferation, migration and col-ony formation. The expressions of TGFBR2 and ITGB8 were upregulated when miR-93 was inhibited. |
Are aGT gene polymorphisms ( M235T , T174M ) associated with coronary heart disease in a Chinese population? | The angiotensinogen (AGT) gene has been shown to be involved in the development of coronary heart disease (CHD). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to clarify the associations between AGT polymorphisms and CHD risk among the Chinese population. Published literature from PubMed, the China National Knowledge Infrastructure and Wanfang Data were searched. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a fixed- or random-effects model. Fourteen studies (2540 cases and 2173 controls) for M235T polymorphism and five studies (655 cases and 815 controls) for T174M polymorphism were included in the meta-analyses. The results showed that M235T polymorphism was significantly associated with CHD risk under a recessive model (OR=1.65, 95% CI 1.22-2.25). There was also significant association between T174M polymorphism and CHD risk under a homogeneous co-dominant model (OR= 4.20, 95% CI 1.90-9.29) and a recessive model (OR=4.15, 95% CI 1.88-9.15). Further sensitivity analyses confirmed the significant association. | Monocyte-derived dendritic cells (DCs) play important roles in the immune response against infections and malignancies. Human herpesvirus 6 (HHV-6) infects monocytes and is reactivated in immunodeficient patients. To clarify the mechanisms of HHV-6-induced immunodeficiency, we investigated the effect of HHV-6 infection on differentiation of monocytes to DCs. Monocytes were inoculated with or without HHV-6 and then allowed to differentiate to myeloid DCs in culture medium containing granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. The expression of cell surface molecules on DCs and the capacity of the DCs for antigen capture were examined by flow cytometric analysis. Alteration of antigen-presenting capacity induced by HHV-6 infection was examined. The morphology of HHV-6-infected monocyte-derived DCs was distinctly different from that of the DCs derived from mock-infected monocytes. Although expression levels of DC-associated surface antigens, including CD80, CD83, and CD86, were significantly higher on HHV-6-infected monocyte-derived DCs than on DCs derived from mock-infected monocytes, antigen-presenting capacity was significantly lower in the former group. Addition of culture supernatant of HHV-6-infected monocytes resulted in suppression of the T-lymphocyte proliferative response, and anti-IL-10 neutralizing antibody partly inhibited this suppressive effect. The antigen-presenting capacity of DCs generated from a patient with severe HHV-6 reactivation was significantly lower than that of DCs generated from the same patient in the recovery phase. |
Does deoxycholate promote survival of breast cancer cells by reducing the level of pro-apoptotic ceramide? | At physiologic concentration in serum, the bile acid sodium deoxycholate (DC) induces survival and migration of breast cancer cells. Here we provide evidence of a novel mechanism by which DC reduces apoptosis that is induced by the sphingolipid ceramide in breast cancer cells. Murine mammacarcinoma 4T1 cells were used in vitro to determine apoptosis and alteration of sphingolipid metabolism by DC, and in vivo to quantify the effect of DC on metastasis. We found that DC increased the number of intestinal metastases generated from 4T1 cell tumors grafted into the fat pad. The metastatic nodes contained slowly dividing cancer cells in immediate vicinity of newly formed blood vessels. These cells were positive for CD44, a marker that has been suggested to be expressed on breast cancer stem cells. In culture, a subpopulation (3 +/- 1%) of slowly dividing, CD44+ cells gave rise to rapidly dividing, CD44- cells. DC promoted survival of CD44+ cells, which was concurrent with reduced levels of activated caspase 3 and ceramide, a sphingolipid inducing apoptosis in 4T1 cells. Z-guggulsterone, an antagonist of the farnesoid-X-receptor, obliterated this anti-apoptotic effect, indicating that DC increased cell survival via farnesoid-X-receptor. DC also increased the gene expression of the vascular endothelial growth factor receptor 2 (Flk-1), suggesting that DC enhanced the initial growth of secondary tumors adjacent to blood vessels. The Flk-1 antagonist SU5416 obliterated the reduction of ceramide and apoptosis by DC, indicating that enhanced cell survival is due to Flk-1-induced reduction in ceramide. | Telomerase preserves telomere length and structure, preventing cellular senescence, which is associated with alteration of the chromosomal ends. We hypothesized that telomerase activity is altered in peripheral blood mononuclear cells (PBMCs) of hemodialysis (HD) patients. To investigate this hypothesis as well as the relationship between telomerase and inflammation, we measured the activity of this reverse transcriptase as well as the level of several inflammatory markers in PBMCs and serum of an end-stage renal failure (ESRF) population and a non-renal-failure group of subjects. In PBMCs isolated from 42 HD and 39 non-renal-failure subjects of the same age (51.0 +/- 12.4 and 51.4 +/- 12.1 years, respectively) telomerase activity was measured using PCR-ELISA; the method was based on the telomeric repeat amplification protocol. Telomerase activity in PBMCs was detected in 18 (42.9%) HD and 28 (71.8%) non-renal-failure subjects (p = 0.013). Among positive subjects, percent telomerase activity in PBMCs was significantly higher in non-renal- failure (117 +/- 112 %) than in HD (47.6 +/- 57.1 %) subjects (p = 0.008). Detectable telomerase activity was lower in long-term than in short-term HD patients (13.3 +/- 8.9 vs. 75.0 +/- 64.8%, respectively, p = 0.015). Although higher in HD group, inflammatory indexes (C-reactive protein, interleukin-6, IL-6, soluble IL-6 and soluble gp130) were not correlated to telomerase activity in PBMCs. |
Does a Live Vector Expressing HPV16 L1 generate an Adjuvant-Induced Antibody Response In-vivo? | The association between human papillomavirus (HPV) infections and cervical cancer has suggested the design of prophylactic and therapeutic vaccines against genital warts. The HPV capsid has made of two L1 and L2 coat proteins that have produced late in viral infections. Regarding to the recent studies, two commercial prophylactic vaccines have based on L1 viral like particles (VLPs) could strongly induce antibody responses, and protect human body from HPV infections. However, the use of these HPV vaccines has hindered due to their high cost and some limitations. Currently, among various vaccination strategies, live vector-based vaccines have attracted a great attention. Herein, a non-pathogenic strain of the protozoan organism known as Leishmania tarentolae has utilized to induce potent humoral immunity in mice model. At first, cloning of HPV16 L1 gene into Leishmania expression vector has performed and confirmed by PCR and digestion with restriction enzymes. The promastigotes of Leishmania tarentolae (L.tar) have transfected with linearized DNA construct by electroporation. Protein expression has analyzed by SDS-PAGE and western blotting. Then, the immunogenicity of leishmania expressing L1 protein (L.tar-L1) has assessed in mice model. Our data has indicated that subcutaneous immunization of mice with the recombinant L.tar-L1 has led to enhance the levels of IgG1 and lgG2a in comparison with control groups. Furthermore, there was no significant increase in antibody levels between two and three times of immunizations. | 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). |
Do adhesion molecule CD146 and its soluble form correlate well with carotid atherosclerosis and plaque instability? | Intraplaque neovascularization and foam cell infiltration contribute to the development of unstable plaque, leading to thromboembolism and stroke. Cell adhesion molecules (CAMs) have been reported to be involved in the progression of atherosclerosis and plaque vulnerability. The aim of this study was to assess the association of adhesion molecule CD146 with carotid plaque instability. We collected forty atherosclerotic plaques from 40 patients undergoing carotid endarterectomy. The clinical information of each patient was obtained, and the plaque morphology and characteristics were examined by the ultrasound. The CD146 expressions of the plaques were graded by using semiquantitative scales. The serum level of soluble form of CD146 was detected by enzyme-linked immunosorbent assay (ELISA). CD146 expression was mainly on the intraplaque blood vessels and infiltrated macrophages. The CD146 expression was strongly correlated with the matrix metalloproteinase-9(MMP-9)expressions (P < 0.001) in the plaques. Soluble CD146 (sCD146) was also elevated in patients with atherosclerotic plaques. There was significant correlation between the increased CD146 expression and sCD146 level (P = 0.0057). sCD146 correlated well with serum MMP-9 (P < 0.0044), IL-6 (P = 0.0044) and high sensitivity C-reactive protein (hsCRP) (P = 0.005). | A randomized clinical trial from Great Britain suggested a possible beneficial effect of acetylsalicylate in the prevention of radiation-induced bowel toxicity. Olsalazine is an orally administered drug designed to deliver 5-aminosalicylate to the large bowel with minimal systemic absorption. A randomized clinical trial was undertaken to assess the effectiveness of olsalazine in preventing acute diarrhea in patients receiving pelvic radiation therapy. Patients receiving pelvic radiation therapy were randomized, in double-blind fashion, to olsalazine 250 mg, two capsules twice daily, or an identical appearing placebo, two capsules twice daily. Patients were then evaluated weekly during radiation therapy for the primary study endpoint, diarrhea, as well as rectal bleeding, abdominal cramping, and tenesmus. The study was closed early, after entry of 58 evaluable patients, when a preliminary analysis showed excessive diarrhea in patients randomized to olsalazine. The incidence and severity of diarrhea were worse in patients randomized to olsalazine (p = 0.0036). Sixty percent of the patients randomized to olsalazine experienced Grade 3 or 4 diarrhea compared to only 14% randomized to placebo. There was also a trend toward higher incidence and greater severity of abdominal cramping in patients who were randomized to olsalazine (p = 0.084). |
Is helicobacter pylori associated with anaemia in Latin America : results from Argentina , Brazil , Bolivia , Cuba , Mexico and Venezuela? | To investigate the association between Helicobacter pylori infection and anaemia. Six cross-sectional studies. H. pylori infection was assessed by the [13C]urea breath test using MS or IR analysis. Hb was measured for all countries. Ferritin and transferrin receptors were measured for Argentina, Bolivia, Mexico, and Venezuela. Health services in Argentina, Brazil and Mexico or public schools in Bolivia, Cuba and Venezuela. In Argentina, 307 children aged 4-17 years referred to a gastroenterology unit; in Bolivia, 424 randomly selected schoolchildren aged 5-8 years; in Brazil, 1007 adults (157 men, 850 women) aged 18-45 years attending thirty-one primary health-care units; in Cuba, 996 randomly selected schoolchildren aged 6-14 years; in Mexico, seventy-one pregnant women in their first trimester attending public health clinics; in Venezuela, 418 children aged 4-13 years attending public schools. The lowest prevalence of H. pylori found was among children in Argentina (25.1%) and the highest in Bolivia (74.0%). In Bolivia, Cuba and Venezuela children showed similar prevalence of H. pylori infection as in Brazilian and Mexican adults (range 47.5% to 81.8%). Overall anaemia prevalence was 11.3% in Argentina, 15.4% in Bolivia, 20.6% in Brazil, 10.5% in Cuba and 8.9% in Venezuela. Adjusted analyses allowing for confounding variables showed no association between H. pylori colonization and anaemia in any study. Hb, ferritin and transferrin receptor levels were also not associated with H. pylori infection in any country. | Although up to 30% of men who undergo radical prostatectomy for clinically organ-confined prostate cancer will relapse with disseminated disease, currently it is not possible to predict these patients. Androgen receptor (AR) immunoreactivity in stromal and epithelial compartments of tumor foci was evaluated by video image analysis in 53 radical prostatectomy specimens. Kaplan-Meier and Cox Regression analyses were used to determine whether AR immunostaining was related to rate and risk of relapse, respectively. Ninety-eight percent (52/53) of the tumors contained AR positive malignant epithelial cells. Kaplan-Meier analysis indicated that patients with high AR levels (>64% AR positive nuclear area) in the malignant epithelial cells or low AR levels (<or=45% AR positive nuclear area) in the peritumoral stroma cells, were more likely to relapse earlier following radical prostatectomy. The shortest time to relapse and the highest relapse rate was for patients with both high AR in the malignant epithelial cells and low AR in the peritumoral stromal cells. |
Does pOSSUM predict decreased overall survival in curative resection for colorectal cancer? | Poor condition at operation determined by the physiologic POSSUM score is related to postoperative mortality and morbidity of colorectal cancer surgery. This study was designed to analyze the relationship between condition of patients with colorectal cancer at operation and long-term overall survival. A total of 542 patients survived a radical resection for Stages I, II, or III colorectal cancer. Physiologic POSSUM score at surgery, exclusive of age, was calculated for all patients. Mean physiologic POSSUM score was used as cutoff point to determine low-risk and high-risk group patients. A Cox proportional hazard analysis was performed to study the effect of low-risk and high-risk group on overall survival and to identify independent risk factors. Five-year overall survival was significantly higher in low-risk group patients than in high-risk group patients (low-risk group 66.6 percent vs. high-risk group 48.5 percent; P < 0.001). Differences in overall survival also were found when patients in Stages I, II, and III were analyzed separately. Risk factors for overall survival were advanced stage of disease, poor tumor differentiation, mucinous adenocarcinoma, older than age 70 years, and poor condition of the patient at time of operation. | Rheumatoid arthritis (RA) is the most common autoimmune disease in the word, affecting 1% of the population. Long-term prognosis in RA was greatly improved following the introduction of highly effective medications such as methotrexate (MTX). Despite the importance of this drug in RA, 8%-16% of patients must discontinue the treatment because of adverse effects. Last decade, we developed a promising new nanocarrier as a drug-delivery system, lipid-core nanocapsules. The aim of the investigation reported here was to evaluate if methotrexate-loaded lipid-core nanocapsules (MTX-LNC) reduce proinflammatory and T-cell-derived cytokines in activated mononuclear cells derived from RA patients and even in functional MTX-resistant conditions. We also aimed to find out if MTX-LNC would reduce inflammation in experimentally inflammatory arthritis at lower doses than MTX solution. Formulations were prepared by self-assembling methodology. The adjuvant arthritis was induced in Lewis rats (AIA) and the effect on edema formation, TNF-α levels, and interleukin-1 beta levels after treatment was evaluated. Mononuclear cells obtained from the synovial fluid of RA patients during articular infiltration procedures were treated with MTX solution and MTX-LNC. For in vitro experiments, the same dose of MTX was used in comparing MTX and MTX-LNC, while the dose of MTX in the MTX-LNC was 75% lower than the drug in solution in in vivo experiments. Formulations presented nanometric and unimodal size distribution profiles, with D[4.3] of 175±17 nm and span of 1.6±0.2. Experimental results showed that MTX-LNC had the same effect as MTX on arthritis inhibition on day 28 of the experiment (P<0.0001); however, this effect was achieved earlier, on day 21 (P<0.0001), by MTX-LNC, and this formulation had reduced both TNF-α (P=0.001) and IL-1α (P=0.0002) serum levels by the last day of the experiment. Further, the MTX-LNC were more effective at reducing the cytokine production from mononuclear synovial cells than MTX. |
Does adenoviral vector expressing CYLD augment antitumor activity of TRAIL by suppression of NF-kappaB survival signaling in hepatocellular carcinoma? | CYLD is a tumor suppressor gene related to cylindroma and is negative regulator of NF-kappaB. However, antitumor effect of CYLD has not been reported. The activation of NF-kappaB induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) renders hepatocellular carcinoma (HCC) resistant to TRAIL-mediated cell apoptosis. Here we described that the adenoviral vector expressing CYLD (Ad/hTERT-CYLD) augmented the cytotoxicity of TRAIL in HCC cells by negatively regulating NF-kappaB activity since CYLD could reverse the ubiquitination of TNF receptor-associated factor 2 (TRAF2) and interact with the IkappaB kinasegamma (IKKgamma). The combined treatment of Ad/hTERT-CYLD and a conditionally replicating adenovirus carrying TRAIL gene (ZD55-TRAIL) induced rapid and potent apoptosis in HCC cells, characterized by activation of caspase-3, caspase-8, PARP and the reduction of X-linked inhibitor of apoptosis protein (XIAP). In animal study, the combined treatment could eradicate the BEL7404 xenograft tumors. In contrast, treatment with Ad/hTERT-CYLD or ZD55-TRAIL alone achieved less antitumor effect. | To determine whether activin A concentrations are altered in chronic fetal hypoxemia and intrauterine fetal growth restriction (IUGR). In vivo animal experimental model. Department of Physiology, Monash University. Chronically catherised fetal sheep in late pregnancy. Chronic fetal hypoxia and IUGR were experimentally induced by single umbilical artery ligation (SUAL) in catheterised fetal sheep. Maternal and fetal blood samples and amniotic fluid (AF) samples were collected during surgery and thereafter on alternate days, until the time of delivery for analyte measurement. Fetal blood gas parameters were measured daily. Plasma and AF was used to analyse activin A, prostaglandin E2 (PGE2) and cortisol and fetal blood gas analysis was undertaken in whole blood. SUAL produced asymmetric IUGR and non-acidaemic chronic fetal hypoxia and resulted in preterm labour (129 [3] days). AF activin A concentrations were 10-fold higher in the SUAL group than in controls whereas levels in the fetal and maternal circulations were similar between groups. |
Does diagnostic ultrasound combined with glycoprotein IIb/IIIa-targeted microbubbles improve microvascular recovery after acute coronary thrombotic occlusions? | The high mechanical index (MI) impulses from a diagnostic ultrasound transducer may be a method of recanalizing acutely thrombosed vessels if the impulses are applied only when microbubbles are channeling through the thrombus. In 45 pigs with acute left anterior descending thrombotic occlusions, a low-MI pulse sequence scheme (contrast pulse sequencing) was used to image the myocardium and guide the delivery of high-MI (1.9 MI) impulses during infusion of either intravenous platelet-targeted microbubbles or nontargeted microbubbles. A third group received no diagnostic ultrasound and microbubbles. All groups received half-dose recombinant prourokinase, heparin, and aspirin. Contrast pulse sequencing examined replenishment of contrast within the central portion of the risk area and guided the application of high-MI impulses. Angiographic recanalization rates, resolution of ST-segment elevation on ECG, and wall thickening were analyzed. Pigs receiving platelet-targeted microbubbles had more rapid replenishment of the central portion of the risk area (80% versus 40% for nontargeted microbubbles; P=0.03) and higher epicardial recanalization rates (53% versus 7% for prourokinase alone; P=0.01). Replenishment of contrast within the risk area (whether with platelet-targeted microbubbles or nontargeted microbubbles) was associated with both higher recanalization rates and even higher rates of ST-segment resolution (82% versus 21% for prourokinase alone; P=0.006). ST-segment resolution occurred in 6 pigs (40%) treated with microbubbles who did not have epicardial recanalization, of which 5 had recovery of wall thickening. | Reactive oxygen species (ROS) induced by exogenous toxicants are suggested to be involved in carcinogenesis by oxidative modification of DNA. 8-Hydroxyl-2-deoxyguanosine (8-OHdG) has been considered as a reliable biomarker for oxidative DNA damage both in vivo and in vitro studies. But the effect of smoking on oxidative damage has not yet been fully elucidated. Wistar rats were exposed to cigarette smoke at concentrations of 20 and 60 % for 30 min, twice/day for 45 weeks. Then the histopathology of lung tissues, levels of ROS, 8-OHdG, and total antioxidant (T-AOC), expression of DNA repair enzymes, e.g. 8-oxyguaine DNA glycosylase (OGG1), and MutThomolog 1 (Oxidized Purine Nucleoside Triphosphatase, MTH1) were determined in urine, peripheral blood lymphocytes, and lung tissue. The results showed that long-term cigarette smoke exposure can cause obvious damages of lung tissue in rats. In addition, a significant and cigarette smoke concentration-dependent increase in ROS and 8-OHdG were observed compared with the non-exposed control rats. In contrast, the expression of OGG1 and MTH1, and T-AOC levels were obviously decreased after long-term exposure to cigarette smoke. |
Does ultra-deep targeted sequencing of advanced oral squamous cell carcinoma identify a mutation-based prognostic gene signature? | Patients with advanced oral squamous cell carcinoma (OSCC) have heterogeneous outcomes that limit the implementation of tailored treatment options. Genetic markers for improved prognostic stratification are eagerly awaited. Herein, next-generation sequencing (NGS) was performed in 345 formalin-fixed paraffin-embedded (FFPE) samples obtained from advanced OSCC patients. Genetic mutations on the hotspot regions of 45 cancer-related genes were detected using an ultra-deep (>1000×) sequencing approach. Kaplan-Meier plots and Cox regression analyses were used to investigate the associations between the mutation status and disease-free survival (DFS). We identified 1269 non-synonymous mutations in 276 OSCC samples. TP53, PIK3CA, CDKN2A, HRAS and BRAF were the most frequently mutated genes. Mutations in 14 genes were found to predict DFS. A mutation-based signature affecting ten genes (HRAS, BRAF, FGFR3, SMAD4, KIT, PTEN, NOTCH1, AKT1, CTNNB1, and PTPN11) was devised to predict DFS. Two different resampling methods were used to validate the prognostic value of the identified gene signature. Multivariate analysis demonstrated that presence of a mutated gene signature was an independent predictor of poorer DFS (P = 0.005). | The objective was to examine effects of gonadal hormone manipulation on aortic diameter and macrophage infiltration in rodents during abdominal aortic aneurysm (AAA) formation. Experiment 1: 17-beta estradiol and testosterone pellets were implanted in male (ME) and female (FT) rats. No pellet was implanted in shams (MES, FTS). Experiment 2: Testes and ovaries were removed from males (MO) and females (FO), respectively. No organs were removed from shams (MOS, FOS). Experiment 3: Male and female rats were orchiectomized and oophorectomized, respectively. Four weeks post-castration, testosterone (MOT) and 17-beta estradiol (FOE) pellets were implanted. Shams underwent castration, but no pellet was implanted (MOTS, FOES). All rats underwent infrarenal aortic infusion with elastase postimplantation/postcastration. Diameters were measured on postoperative d 14. Tissue was stained for macrophages by immunohistochemistry. Diameter (P = 0.046) and macrophage counts (P = 0.014) decreased in ME compared with shams, but not in females treated with testosterone (FT). Diameter (P = 0.019) and macrophage infiltration (P = 0.024) decreased in MO compared with shams, but not in FO. Diameter increased in MOT compared with MOTS (P = 0.033), but decreased in FOE compared with FOES (P = 0.002). Macrophages decreased in FOE compared with FOES (P = 0.002). |
Is combined use of noninvasive tests useful in the initial diagnostic approach to a child with suspected inflammatory bowel disease? | To assess the effectiveness of the combined use of fecal calprotectin (FC), anti-Saccharomyces cerevisiae antibody (ASCA), perinuclear staining antineutrophil antibody (pANCA), small intestinal permeability test (IP), and bowel wall ultrasonography measurement (BWUS) in the diagnostic work-up of children with suspected inflammatory bowel disease (IBD). All children referred for initial assessment of possible IBD were eligible. Patients with symptoms or signs (right-lower quadrant mass, perianal disease, or hematochezia) mandating a complete work-up for IBD were excluded. All enrolled patients underwent a clinical, laboratory, radiographic, and endoscopic evaluation including biopsy examinations. The immunoglobulin (Ig)G and IgA ASCA, IgG pANCA, FC, IP, and BWUS were tested in all patients at the initial assessment. A final diagnosis of IBD was made in 27 patients: 17 Crohn disease and 10 ulcerative colitis. Eighteen children had other gastrointestinal diagnoses (8 functional bowel disorders, 5 food allergy-mediated diseases, 4 infectious enterocolitis, 1 familial Mediterranean fever). In patients with simultaneous abnormal values of FC, BWUS, and ASCA/pANCA, the estimated probability of having IBD was 99.47%. Patients with negative results on all tests had a 0.69% of probability of IBD. | In breast cancer, distinct expression profiles of microRNAs (miRNAs) have been associated with molecular subgroups and clinicopathological characteristics, implicating a diagnostic and prognostic role of miRNAs. However, the biological functions of deregulated miRNAs in tumor progression are not yet completely defined. In this study, we investigated the function of miR-18a in regulating breast cancer metastasis through the hypoxia-inducible factor 1α (HIF1A)-dependent hypoxic response. An orthotopic metastatic breast cancer xenograft model (MDA-MB-231 cells) was used to identify miRNAs associated with spontaneous lung metastasis. The function of miR-18a in regulating HIF1A expression, as well as cellular responses to hypoxia and metastasis, were then studied in vitro and in vivo by assessing ectopic miR-18a expression or miR-18a inhibition. miRNA-mRNA interactions (AGO2 immunoprecipitation and 3' untranslated region Luciferase reporter assays), gene expression (quantitative PCR and microarray), cell migration and invasion, and cell growth were assessed under normoxic or hypoxic conditions, complemented by orthotopic xenograft of tumor cells to the mammary fat pad to investigate the effect of modulating miR-18a expression on primary tumor growth and lung metastasis. Last, clinically relevant correlations between miR-18a, HIF1A, hypoxia-responsive gene expression and distant metastasis-free survival (DMFS) were assessed using published expression array breast tumors data sets. miRNAs encoded by the MIR17HG gene were downregulated in lung metastases compared to primary tumors. Ectopic expression of miR-18a, a MIR17HG family member, in a metastatic variant of MDA-MB-231 cells reduced primary tumor growth and lung metastasis, whereas miR-18a inhibition in the parental cells promoted tumor growth and lung metastasis. We identified HIF1A as a direct target of miR-18a. Modulating miR-18a expression significantly affected hypoxic gene expression, cell invasiveness and sensitivity to anoikis and hypoxia in vitro in a HIF1A-dependent manner. Analysis of previously published data revealed that higher expression of HIF1A and a panel of hypoxic genes is associated with shorter DMFS interval in patients with basal-like breast tumors, and that, within this subtype, miR-18a expression is inversely correlated with hypoxic gene expression. Together, these data support a role of miR-18a in repressing distant metastasis through a HIF1A-dependent pathway. |
Is day-to-day variation in iron status indexes similar for most measures in elderly women with and without rheumatoid arthritis? | To determine the day-to-day variation in biochemical measures of iron status in a group of elderly women with rheumatoid arthritis compared with a group of healthy elderly women. Venous blood samples were collected from each subject on 3 nonconsecutive days during a 2-week study period; subjects had fasted overnight. Variability in hemoglobin level, hematocrit value, serum iron concentration, total iron-binding capacity, transferrin saturation, serum ferritin concentration, and plasma transferrin receptor level was determined. Two groups of women, one with rheumatoid arthritis (n=10) and another that was apparently healthy (n=10). Variance component analysis was used to estimate the biological variation (sigma square day) and analytic variation (sigma square rep) for each iron index. The coefficient of variation (CV) for each variance component was calculated: coefficient of biological variation = CV day, coefficient of analytic variation = CV rep, and coefficient of a single future determination = CV fd. The CV rep for all iron indexes was smaller than the CV day in both groups. The CV day was considerably higher for serum iron concentration and for transferrin saturation than for the other indexes in both groups (16.6% and 16.6% in healthy subjects and 33.6% and 28.2%, respectively, in subjects with rheumatoid arthritis). The higher CV day for serum iron concentration and transferrin saturation translated into a higher CV fd for these indexes. Because of the higher variance for these two indexes, more sampling days were required for reliable estimates. CV day and CV fd for plasma transferrin receptor level were relatively low. | This study was designed to examine whether or not adenovirus-mediated gene transfer of C-type natriuretic peptide (CNP) can prevent coronary restenotic changes after balloon injury in pigs in vivo. Gene therapy to prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) might be useful but requires a method applicable for in vivo gene delivery into the coronary artery as well as the efficient vector encoding a potent antiproliferative substance. We tested whether the adenovirus-mediated gene transfer of CNP by use of an infiltrator angioplasty balloon catheter (IABC) might prevent the coronary restenotic changes after balloon injury. Balloon angioplasty was performed in the left anterior descending and the left circumflex coronary artery in pigs. Immediately after the balloon injury, adenovirus solution encoding either CNP (AdCACNP) or beta-galactosidase (AdCALacZ) gene was injected with IABC into the balloon-injured coronary segments. Expression of CNP was assessed by immunohistochemical staining and cyclic guanosine 3',5'-monophosphate (cGMP) measurement. Coronary restenotic changes were evaluated by both angiographic and histological examinations. CNP was highly expressed in the media and the adventitia of the coronary artery at the AdCACNP-transfected but not at the AdCALacZ-transfected segment. In the AdCALacZ-transfected segment, vascular cGMP levels tended to be reduced as compared with the untreated segment, whereas in the AdCACNP-transfected segment, vascular cGMP levels were restored. Angiographic coronary stenosis was significantly less at the AdCACNP-transfected than at the AdCALacZ-transfected segment. Histological examination revealed that this was achieved primarily by the marked inhibition of the geometric remodeling of the coronary artery by the CNP gene transfer. |
Is inspiratory muscle strength a determinant of maximum oxygen consumption in chronic heart failure? | 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. | Adolescent intermittent alcohol exposure (AIE) has profound effects on neuronal function. We have previously shown that AIE causes aberrant hippocampal structure and function that persists into adulthood. However, the possible contributions of astrocytes and their signaling factors remain largely unexplored. We investigated the acute and enduring effects of AIE on astrocytic reactivity and signaling on synaptic expression in the hippocampus, including the impact of the thrombospondin (TSP) family of astrocyte-secreted synaptogenic factors and their neuronal receptor, alpha2delta-1 (α2δ-1). Our hypothesis is that some of the influences of AIE on neuronal function may be secondary to direct effects on astrocytes. We conducted Western blot analysis on TSPs 1 to 4 and α2δ-1 from whole hippocampal lysates 24 hours after the 4th and 10th doses of AIE, then 24 days after the last dose (in adulthood). We used immunohistochemistry to assess astrocyte reactivity (i.e., morphology) and synaptogenesis (i.e., colocalization of pre- and postsynaptic puncta). Adolescent AIE reduced α2δ-1 expression, and colocalized pre- and postsynaptic puncta after the fourth ethanol (EtOH) dose. By the 10th dose, increased TSP2 levels were accompanied by an increase in colocalized pre- and postsynaptic puncta, while α2δ-1 returned to control levels. Twenty-four days after the last EtOH dose (i.e., adulthood), TSP2, TSP4, and α2δ-1 expression were all elevated. Astrocyte reactivity, indicated by increased astrocytic volume and area, was also observed at that time. |
Do sLCO1B1 gene polymorphisms influence plasma rifampicin concentrations in a South Indian population? | To determine the effect of SLCO1B1 gene polymorphisms (rs11045819, rs4149032 and rs4149033) on rifampicin (RMP) concentrations in adult tuberculosis (TB) patients from south India. We genotyped adult TB patients for three SLCO1B1 gene polymorphisms-rs11045819, rs4149032 and rs4149033-and compared 2-h post-dosing RMP concentrations of the different genotypes for each of the polymorphisms. Plasma RMP was determined using high-performance liquid chromatography. Genotyping was performed using direct sequencing. Among the 256 study patients, minor allele frequencies were respectively 0.01 (A), 0.46 (C) and 0.07 (A) for rs11045819, rs4149032 and rs4149033 polymorphisms; genotype distributions followed Hardy-Weinberg equilibrium. RMP concentrations did not significantly differ between the different genotypes of the three polymorphisms. | Stem cells derived from the dental pulp of human exfoliated deciduous teeth (SHEDs) have unique neurogenic properties that could be potentially exploited for therapeutic use. The importance of paracrine SHED signaling for neuro-regeneration has been recognized, but the exact mechanisms behind these effects are presently unknown. In the present study, we investigated the neuro-protective potential of exosomes and micro-vesicles derived from SHEDs on human dopaminergic neurons during oxidative stress-induced by 6-hydroxy-dopamine (6-OHDA). ReNcell VM human neural stem cells were differentiated into dopaminergic neurons and treated with 100 μmol/L of 6-OHDA alone or in combination with exosomes or micro-vesicles purified by ultracentrifugation from SHEDs cultivated in serum-free medium under two conditions: in standard two-dimensional culture flasks or on laminin-coated micro-carriers in a bioreactor. Real-time monitoring of apoptosis was performed with the use of time-lapse confocal microscopy and the CellEvent Caspase-3/7 green detection reagent. Exosomes but not micro-vesicles derived from SHEDs grown on the laminin-coated three-dimensional alginate micro-carriers suppressed 6-OHDA-induced apoptosis in dopaminergic neurons by approximately 80% throughout the culture period. Strikingly, no such effects were observed for the exosomes derived from SHEDs grown under standard culture conditions. |
Does the transcription factor Ap-1 regulate monkey 20α-hydroxysteroid dehydrogenase promoter activity in CHO cells? | Monkey 20α-hydroxysteroid dehydrogenase (20α-HSD) is a catabolic enzyme responsible for converting progesterone into biologically inactive 20α-hydroxyprogesterone, thereby playing a key role in the estrous cycle or pregnancy and allowing ovulation and parturition to occur in most mammalian animals. Monkey 20α-HSD was highly abundant in ovarian and placental tissues during the pre-ovulation and pre-parturition phase and was primarily localized in the syncytiotrophoblast of the placenta. In this study, we focused on the molecular characterization of the monkey 20α-HSD promoter region by conducting reporter assays in Chinese hamster ovary (CHO) K1 cells. A reporter assay using constructs of various lengths of the 5'-flanking region (-890-Luc, -513-Luc, -306-Luc, -273-Luc, and -70-Luc) revealed that a region corresponding to the activator protein 1 (Ap-1) located between -281 and -274 bp was essential for the transcriptional activity. Absence of the Ap-1 site in -273-Luc dramatically decreased the transcription levels to the control levels. When the reporter constructs were co-transfected with Ap-1 (Jun) and specificity protein (Sp-1) genes, the transcription activities of the constructs increased with the exception of -273 and -70, while that of the double construct was reduced compared to that of Ap-1 alone. Furthermore, mutational analysis demonstrated that a putative Ap-1 site played an important role in the expression of the reporter gene. These findings were confirmed by EMSA examining the interactions of the protein Ap-1 in a nuclear extract from CHO-K1 cells and the expression levels of the Ap-1 transcription factor in pre-parturition placenta and CHO-K1 cells. Although mut-1 and mut-2 of Ap-1 bound with nuclear extracts from CHO-K1 cells, the transcriptional activity of mut-3 was almost completely suppressed. | We aimed to evaluate risk factors for ventilator-associated pneumonia (VAP) due to Acinetobacter baumannii (AbVAP) in critically ill patients. This was a prospective observational study conducted in an intensive care unit (ICU) of a district hospital (6 beds). Consecutive patients were eligible for enrolment if they required mechanical ventilation for >48 hours and hospitalization for >72 hours. Clinical, microbiological, and laboratory parameters were assessed as risk factors for AbVAP by univariate and multivariate analysis. 193 patients were included in the study. Overall, VAP incidence was 23.8% and AbVAP, 11.4%. Previous hospitalization of another patient with Acinetobacter baumannii infection was the only independent risk factor for AbVAP (OR (95% CI) 12.016 (2.282-19.521) P < 0.001). ICU stay (25 ± 17 versus 12 ± 9 P < 0.001), the incidence of other infections (OR (95% CI) 9.485 (1.640-10.466) P = 0.002) (urinary tract infection, catheter related infection, and bacteremia), or sepsis (OR (95% CI) 10.400 (3.749-10.466) P < 0.001) were significantly increased in patients with AbVAP compared to patients without VAP; no difference was found with respect to ICU mortality. |
Is emergency Department Ultrasound a Sensitive Detector of Solid Organ Injury? | To estimate the sensitivity and specificity of emergency department (ED) ultrasound for the detection of solid organ injury following blunt abdominal trauma. A prospective cohort study performed in the ED of an urban Level I trauma center on patients who sustained blunt abdominal trauma. Following initial standard trauma evaluation, patients underwent a secondary ultrasound examination performed specifically to identify injury to the liver or spleen, followed by computed tomography (CT) scan of the abdomen. Ultrasound examinations were performed by emergency medicine residents or attending physicians experienced in the use of ultrasound for detecting hemoperitoneum. Ultrasonographers prospectively determined the presence or absence of liver or spleen injury. CT findings were used as the criterion standard to evaluate the ultrasound results. From July 1998 through June 1999, 152 patients underwent secondary ultrasound examination and CT. Of the 152 patients, nine (6%) had liver injuries and 10 (7%) had spleen injuries. Ultrasound correctly detected only one of the liver injuries for a sensitivity of 11% (95% CI: 0%-48%) and a specificity of 98% (95% CI: 94%-100%). Ultrasound correctly detected eight spleen injuries for a sensitivity of 80% (95% CI: 44%-98%) and a specificity of 99% (95% CI: 95%-100%). | Circadian rhythms in mammals depend upon the cyclic oscillations of transcriptional/translational feedback loops in pacemaker cells of the suprachiasmatic nucleus. The rise and fall of clock-related proteins is a function of synthesis and degradation, the latter involving phosphorylation by casein kinase Iepsilon and delta. Earlier studies by our lab described the actions of a selective CKIepsilon/delta inhibitor, PF-670462, on circadian behavior in rats; the present work extended these studies to a diurnal species, Cynomolgus monkeys. General cage activity was used to estimate the circadian rhythms of eight telemeterized monkeys under baseline conditions and following s.c. doses of PF-670462. |
Does quantification of SLIT-ROBO transcripts in hepatocellular carcinoma reveal two groups of genes with coordinate expression? | SLIT-ROBO families of proteins mediate axon pathfinding and their expression is not solely confined to nervous system. Aberrant expression of SLIT-ROBO genes was repeatedly shown in a wide variety of cancers, yet data about their collective behavior in hepatocellular carcinoma (HCC) is missing. Hence, we quantified SLIT-ROBO transcripts in HCC cell lines, and in normal and tumor tissues from liver. Expression of SLIT-ROBO family members was quantified by real-time qRT-PCR in 14 HCC cell lines, 8 normal and 35 tumor tissues from the liver. ANOVA and Pearson's correlation analyses were performed in R environment, and different clinicopathological subgroups were pairwise compared in Minitab. Gene expression matrices of cell lines and tissues were analyzed by Mantel's association test. Genewise hierarchical clustering revealed two subgroups with coordinate expression pattern in both the HCC cell lines and tissues: ROBO1, ROBO2, SLIT1 in one cluster, and ROBO4, SLIT2, SLIT3 in the other, respectively. Moreover, SLIT-ROBO expression predicted AFP-dependent subgrouping of HCC cell lines, but not that of liver tissues. ROBO1 and ROBO2 were significantly up-regulated, whereas SLIT3 was significantly down-regulated in cell lines with high-AFP background. When compared to normal liver tissue, ROBO1 was found to be significantly overexpressed, while ROBO4 was down-regulated in HCC. We also observed that ROBO1 and SLIT2 differentiated histopathological subgroups of liver tissues depending on both tumor staging and differentiation status. However, ROBO4 could discriminate poorly differentiated HCC from other subgroups. | The immune system changes with age. In this study we characterized immune changes by performing immunologic screening profiles on ageing individuals. This study was performed at Akdeniz University, in the Faculty of Medicine, Department of Immunology. Healthy volunteers consisted of a younger group (22 donors) and an older group (45 individuals). All subjects had no serious health problems (i.e. chronic heart, lung, liver or immunological diseases) and were taking no prescribed medications. Flow cytometry analysis was used to evaluate CD3, CD4, CD8, CD16, CD19, CD28, CD40, CD45, CD56, CD80, CD86, CTLA-4 and ELISA for IL-1 beta, IL-2, IL-6, IL-10, IFN-gamma, TNF-alpha expression In addition, NK activity and induced cytokine expression (by bioassay and ELISA, respectively) were evaluated. No statistical differences were observed between the two groups in expression of CD3, CD8, CD19, CD80, CD86, CD16, CD 56, or CD28. A higher frequency of expression of CD4, CTLA-4, CD40, and CD45 was seen in older subjects by comparison with younger subjects. Cytokine profiles expressed by stimulated monocytes and lymphocytes from the two groups showed no difference in IL-1 beta, IL-2, IL-6, IL-10, TNF-alpha, and IFN-gamma production levels. |
Is inverse association of testosterone and the metabolic syndrome in men consistent across race and ethnic groups? | Low sex hormone levels have been associated with the metabolic syndrome (MetS). Our objective was to determine whether the association between sex hormone levels and MetS varies by race/ethnicity among men and to investigate the relationship of sex hormones and individual components of MetS. We conducted a population-based observational survey. A multistage stratified design was used to recruit a random sample of 2301 racially/ethnically diverse men age 30-79 yr. Blood samples were obtained on 1899 men. Analyses were conducted on 1885 men with complete data on total testosterone (T), free T, and SHBG. There were no interventions. MetS was defined using a modification of the Adult Treatment Panel III guidelines. The association between MetS and sex hormone levels was assessed using odds ratios and 95% confidence intervals estimated using logistic regression models. A strong inverse association was observed, in both bivariate and multivariate analyses, between hormone levels and MetS. The odds of MetS increased about two-fold with a 1 sd decrease in hormone levels. The association between sex hormones and MetS was statistically significant across racial/ethnic groups. Although the magnitude of this association was largest among White men, racial/ethnic differences were not statistically significant. The strength of the association of sex hormones with individual components of MetS varied; stronger associations were observed with waist circumference and dyslipidemia and more modest associations with diabetes and elevated blood sugar. | Glioblastoma multiforme (GBM) is a highly malignant human brain neoplasm with limited therapeutic options. GBMs display a deregulated apoptotic pathway with high levels of the antiapoptotic Bcl-2 family of proteins and overt activity of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Therefore, combined interference of the PI3K pathway and the Bcl-2 family of proteins is a reasonable therapeutic strategy. ABT-263 (Navitoclax), an orally available small-molecule Bcl-2 inhibitor, and GDC-0941, a PI3K inhibitor, were used to treat established glioblastoma and glioblastoma neurosphere cells, alone or in combination. Although GDC-0941 alone had a modest effect on cell viability, treatment with ABT-263 displayed a marked reduction of cell viability and induction of apoptotic cell death. Moreover, combinatorial therapy using ABT-263 and GDC-0941 showed an enhanced effect, with a further decrease in cellular viability. Furthermore, combination treatment abrogated the ability of stem cell-like glioma cells to form neurospheres. ABT-263 and GDC-0941, in combination, resulted in a consistent and significant increase of Annexin V positive cells and loss of mitochondrial membrane potential compared with either monotherapy. The combination treatment led to enhanced cleavage of both initiator and effector caspases. Mechanistically, GDC-0941 depleted pAKT (Serine 473) levels and suppressed Mcl-1 protein levels, lowering the threshold for the cytotoxic actions of ABT-263. GDC-0941 decreased Mcl-1 in a posttranslational manner and significantly decreased the half-life of Mcl-1 protein. Ectopic expression of human Mcl-1 mitigated apoptotic cell death induced by the drug combination. Furthermore, GDC-0941 modulated the phosphorylation status of BAD, thereby further enhancing ABT-263-mediated cell death. |
Does the Density of Interstitial Cells of Cajal be Diminished in Choledochal Cysts? | Interstitial cells of Cajal (ICC) have been shown to be present in the extrahepatic biliary tract of animals and humans. However, ICC distribution in choledochal cysts (CC) has not been investigated. A study was conducted to investigate the distribution of ICC in the extrahepatic biliary tract, including CC, in pediatric human specimens. The specimens were divided into two main groups as gallbladders and common bile ducts. Gallbladders were obtained from the cholelithiasis, CC operations and autopsies. Common bile ducts were obtained from autopsies. Tissues were stained using c-kit immunohistochemical staining. ICC were assessed semi-quantitatively by applying morphological criteria and were counted as the number of cells/0.24 mm(2) in each area under light microscopy. A total of 35 gallbladders and 14 CC were obtained from operations. Ten gallbladders plus common bile ducts were obtained from autopsies. The mean numbers of ICC in the gallbladders of cholelithiasis and the gallbladders of CC were 12.2 ± 4.9 and 5.3 ± 1.2, respectively (p = 0.003). The mean numbers of ICC in the common bile ducts and CC were 9.8 ± 2.9 and 3.4 ± 1.4, respectively (p = 0.001). | The benefits of intravenous tissue-plasminogen activator (tPA) in acute ischemic stroke are time-dependent. Emergency medical services (EMS) hospital prenotification of an incoming patient with potential stroke may provide a means of reducing evaluation and treatment times and improving treatment rates; yet, available data are limited. We examined 371 988 patients with acute ischemic stroke transported by EMS and enrolled in Get With The Guidelines-Stroke from April 1, 2003, to March 31, 2011. Prenotification occurred in 249 197 (67.0%) of EMS-transported patients. Among eligible patients arriving by 2 hours, patients with EMS prenotification were more likely to be treated with tPA within 3 hours (82.8% versus 79.2%, absolute difference +3.5%, P<0.0001, the National Institutes of Health Stroke Scale-documented cohort; 73.0% versus 64.0%, absolute difference +9.0%, P<0.0001, overall cohort). Patients with EMS prenotification had shorter door-to-imaging times (26 minutes versus 31 minutes, P<0.0001), shorter door-to-needle times (78 minutes versus 80 minutes, P<0.0001), and shorter symptom onset-to-needle times (141 minutes versus 145 minutes, P<0.0001). In multivariable and modified Poisson regression analyses accounting for the clustering of patients within hospitals, use of EMS prenotification was independently associated with greater likelihood of door-to-imaging times ≤25 minutes, door-to-needle times for tPA ≤60 minutes, onset-to-needle times ≤120 minutes, and tPA use within 3 hours. |
Does meniscal transection rather than excision increase pain behavior and structural damage in experimental osteoarthritis in mice? | To evaluate pain behavior and structural damage in mice subjected to either meniscal transection or removal. Mice (10/group) were subjected to transection of the medial collateral and anterior cruciate ligaments (ACLT/MCLT) followed by either transection (meniscotomy) or removal (meniscectomy) of the medial meniscus. A control group was subjected only to transection of the ligaments. Pain was assessed using the electronic pressure-meter paw test. Cell influx, measured in joint exudates, and joint histopathology were assessed after 49 days. Four other groups subjected to meniscotomy received indomethacin, the inducible nitric oxide synthase (iNOS) inhibitor 1400W, morphine or the vehicles. Both meniscotomy and meniscectomy groups displayed persistent and significant increase in pain behavior as compared to controls, being significantly more severe in the former. Cell influx was more intense in the meniscotomy as compared to the meniscectomy group. Structural damage at the tibia, but not at the femur, was also more severe in the meniscotomy group. Indomethacin and 1400W partially but significantly reduced pain whereas morphine abrogated pain behavior in meniscotomized mice. | The mechanisms underlying the initiation of sustained ventricular tachycardia (VT) have not been fully elucidated. The extent to which reentry, abnormal automaticity, and triggered activity play a role in VT differs depending on the etiology of left ventricular dysfunction. By analyzing electrograms from implantable cardioverter defibrillator (ICD), we sought to determine whether there were differences in VT initiation patterns between patients with ischemic and nonischemic cardiomyopathy. We analyzed ICD electrograms in patients with ejection fractions < 40% who had sustained VT over a 27-month period. The trigger for VT onset was classified as a ventricular premature beat (VPB), supraventricular tachycardia, or of "sudden onset." The baseline cycle length, VT cycle length, coupling interval, and prematurity ratio were recorded for each event. The prematurity ratio was calculated as the coupling interval of the VT initiator divided by the baseline cycle length. Sixty-three VT events in 14 patients met the inclusion criteria. A VPB initiated the VT in 58 episodes (92%), 1 episode (2%) was initiated by a supraventricular tachycardia, and 4 episodes (6%) were sudden onset. The prematurity ratio was significantly higher (P < 0.05) in patients with ischemic cardiomyopathy (0.751 +/- 0.068) as compared to patients with nonischemic cardiomyopathy (0.604 +/- 0.139). |
Does tetramethylpyrazine protect lymphocytes from radiation-induced apoptosis through nuclear factor-κB? | Radiation induces an important apoptosis response in irradiated organs. The objective of this study was to investigate the radioprotective effect of tetramethylpyrazine (TMP) on irradiated lymphocytes and discover the possible mechanism of protection. Lymphocytes were pretreated for 12 h with TMP (25-200 μmol·L(-1)) and then exposed to 4 Gy radiation. Cell apoptosis and the signaling pathway were analyzed. Irradiation increased cell death, DNA fragmentation, activated caspase activation and cytochrome c translocation, downregulated B-cell lymphoma 2 (Bcl-2) and up-regulated Bcl-2-associated X protein (Bax). Pretreated with TMP significantly reversed this tendency. Several anti-apoptotic characteristics of TMP, including the ability to increase cell viability, inhibit caspase-9 activation, and upregulate Bcl-2 and down-regulate Bax in 4Gy-irradiated lymphocytes were determined. Signal pathway analysis showed TMP could translate nuclear factor-κB (NF-κB) from cytosol into the nucleus. | Most adolescents and young adults (AYAs) with type 1 diabetes struggle with diabetes self-management and exhibit suboptimal glycemic control. This study examined two models of association between illness representations, a modifiable predictor of suboptimal outcomes, and adherence and glycemic control in AYAs with type 1 diabetes. Ninety-nine AYAs (ages 15-20 years) completed measures of illness representations and adherence at two visits. Blood glucose monitoring frequency and haemoglobin A1c were obtained via chart review. Relationships were examined using structural equation modelling. Illness representations accounted for a significant proportion of the variance in blood glucose monitoring frequency (ΔR2 = .23, p < .01) and adherence to emergency precautions at Time 1 (ΔR2 = .07, p = .03). Illness representations also accounted for significant variance in blood glucose monitoring frequency (ΔR2 = .08, p = .01), adherence to recommendations for insulin and food (ΔR2 = .08, p = .02) and exercise (ΔR2 = .10, p < .01), and adherence to emergency precautions (ΔR2)= .16, p < .01) at Time 2. |
Is serum cytokeratin-19 fragment ( Cyfra 21-1 ) a prognostic indicator for epithelial ovarian cancer? | Cytokeratin 19 is significant for indicating cancer cells, and Cyfra 21-1 is a fragment of cytokeratin 19. This retrospective study was designed to define the prognostic value of serum Cyfra 21-1 in epithelial ovarian cancers (EOC). Serum Cyfra 21-1 concentration was obtained from 42 patients with EOC prior to treatment. Various prognostic aspects were examined using univariable and multivariable analyses. The standard serum marker cancer antigen 125 was measured simultaneously and compared in this analysis. Serum levels of both Cyfra 21-1 and cancer antigen 125 were associated with positive retroperitoneal lymph nodes and platinum resistance; higher levels of Cyfra 21-1 (3.0 ng/mL as the cut-off) were associated with shorter disease-free survival (16 months vs. 28 months, p = 0.001) and overall survival (29 months vs. 41 months, p = 0.007) than lower levels. Further univariable analysis showed that Cyfra 21-1, poor differentiation, and retroperitoneal lymph node metastasis were related to platinum resistance and mortality. Multivariable analysis indicated retroperitoneal lymph node metastasis and serum Cyfra 21-1 were independent risk factors for both disease-free survival and overall survival. | Chronic ethanol use is known to disrupt normal sleep rhythms, but the cellular basis for this disruption is unknown. An important contributor to normal sleep patterns is a low-threshold calcium current mediated by T-type calcium channels. The T-type calcium current underlies burst responses in thalamic nuclei that are important to spindle propagation, and we recently observed that this current is sensitive to acute low doses of ethanol. We used a combination of current clamp and voltage clamp recordings in an in vitro brain slice preparation of the dorsal lateral geniculate nucleus (LGN) of macaque monkeys that have chronically self-administered ethanol to determine whether chronic ethanol exposure may affect T-type currents. Current clamp recordings from the LGN of ethanol naive macaques showed characteristic burst responses. However, recordings from the LGN in macaques that self-administered ethanol revealed a significant attenuation of bursts across a range of voltages (n=5). Voltage clamp recordings from control LGN neurons (n=16) and neurons (n=29) from brain slices from chronically drinking macaques showed no significant differences (P>0.05) in T-type current kinetics or in the membrane resistance of the thalamic cells between the two cohorts. However, mean T-type current amplitude measured in the chronically drinking animals was reduced by 31% (P<0.01). |
Is hepatitis B core-related antigen assay useful for monitoring the antiviral effects of nucleoside analogue therapy? | The clinical significance of the hepatitis B virus core-related antigen (HBcrAg) assay in monitoring the antiviral effects of lamivudine is reviewed. The HBcrAg assay simultaneously measured serum levels of hepatitis B core (HBc) and e (HBe) antigens using monoclonal antibodies which recognize common epitopes of these two denatured antigens. Although serum HBcrAg levels correlated linearly with those of hepatitis B virus (HBV) DNA in natural course, the decrease in HBcrAg was significantly slower than in HBV DNA after initiation of lamivudine administration. We analyzed the clinical significance of HBV DNA and HBcrAg levels to predict the occurrence of lamivudine resistance. HBV DNA measurement may be useful to identify patients who are at high risk of developing lamivudine resistance, and HBcrAg measurement may help to detect patients who are at low risk of drug resistance. The measurement of HBcrAg was also found to be a useful prognosticator for reactivation of hepatitis after cessation of lamivudine administration. | Retinal vascular disease represents a major cause for vision loss in the Western world. Recent research has shown that neuronal and vascular damage are closely related in retinal disease. Ciliary neurotrophic factor (CNTF) is a well-studied neurotrophic factor that is currently being tested in clinical trials for the treatment of retinal degenerative diseases and macular telangiectasia. However, little is known about its effect on retinal vasculature. In this study, we investigate the effects of CNTF in retinal neovascular disease using the mouse model of oxygen-induced retinopathy (OIR). Newborn pups were exposed to 75% oxygen from postnatal day (P)7 to P12 and subsequently returned to room air. Ciliary neurotrophic factor was injected intravitreally at OIR P12 and the vaso-obliterated and neovascular areas were quantified at OIR P17. Immunohistochemistry, RNA, and protein analysis were used to identify CNTF-responsive cells. In vitro experiments were performed to analyze the effect of CNTF on endothelial and astroglial cells. In the OIR model, CNTF facilitated capillary regrowth and attenuated preretinal neovascularization in a dose-dependent manner. The protective effect of CNTF was mediated via activation of the JAK/STAT3/SOCS3 signaling pathway. Immunohistochemical studies identified endothelial cells among others as CNTF-responsive cells in the retina. In vitro studies confirmed the anti-angiogenic effect of CNTF on endothelial cell sprouting. |
Does weight gain reveal dramatic increases in skeletal muscle extracellular matrix remodeling? | In animal models of obesity, chronic inflammation and dysregulated extracellular matrix remodeling in adipose tissue leads to insulin resistance. Whether similar pathophysiology occurs in humans is not clear. The aim of this study was to test whether 10% weight gain induced by overfeeding triggers inflammation and extracellular matrix remodeling (gene expression, protein, histology) in skeletal muscle and sc adipose tissue in humans. We also investigated whether such remodeling was associated with an impaired metabolic response (hyperinsulinemic-euglycemic clamp). Twenty-nine free-living males were fed 40% over their baseline energy requirements for 8 weeks. Ten percent body weight gain prompted dramatic up-regulation of a repertoire of extracellular matrix remodeling genes in muscle and to a lesser degree in adipose tissue. The amount of extracellular matrix genes in the muscle were directly associated with the amount of lean tissue deposited during overfeeding. Despite weight gain and impaired insulin sensitivity, there was no change in local adipose tissue or systemic inflammation, but there was a slight increase in skeletal muscle inflammation. | FEV6 can be used as a convenient alternative to FVC. The aim of this study was to determine an alternative to the fixed cutoff points of FEV1/FVC <0.70 suitable for FEV1/FEV6 in primary care. Pulmonary function testing was conducted on volunteers recruited from 4 community centers in Xi'an, China, between July and August 2012. Participants underwent 3 FVC maneuvers. The maneuver with the best FEV1 was retained. FVC, FEV1, and FEV6 were measured by portable spirometer. The receiver operating characteristic curves that corresponded to the optimal combination of sensitivity and specificity for FEV1/FEV6 were determined. A kappa test was used to compare the agreement between FEV1/FVC and FEV1/FEV6. The positive predictive value and negative predictive value were also calculated. A total of 767 volunteers participated in this study, of whom 297 were male and 470 were female. Considering FEV1/FVC <0.70 as the accepted standard for COPD, the area under the curve was 98% (P < .001), and the FEV1/FEV6 cutoff, corresponding to the greatest sum of sensitivity and specificity, was 0.72. For the total population, the FEV1/FEV6 sensitivity, specificity, positive predictive value, and negative predictive value were 96.9, 98.8, 95.8, and 99.2%, respectively. The agreement between the 2 cutoff points was excellent, and the kappa value was 0.954. |
Is bFGF release dependent on flow conditions in experimental vein grafts? | Basic Fibroblastic Growth Factor (bFGF) is a powerful mitogen for smooth muscle cells and has been implicated in the genesis of Myointimal hyperplasia. The aim of this study was to determine the release of bFGF by veins in different haemodynamic conditions. Laboratory animal study. In 39 Lewis rats, a 1 cm long segment of inferior vena cava was inserted at the level of the abdominal aorta. The segments of inferior vena cava were obtained from syngenic Lewis rats. Arterial Vein Grafts (AVG) were harvested after 4 weeks (AVG 4) and 12 weeks (AVG 12). In 16 animals the arterial vein grafts were explanted 4 weeks after the initial operation and reimplanted (Reimplanted Vein Grafts: RVG) in syngenic Lewis rats as venous-venous bypass grafts at the level of the left iliac vein and harvested after 2 weeks (RVG 2) and 8 weeks (AVG 8). The tissue was studied in organ culture in a serum-free system for (1) release of bFGF (immunoassay) and (2) mitogenic activity of the conditioned media. Scanning electron and light microscopy studies were also performed. bFGF release by veins increased significantly (p < 0.01) when veins were inserted in the arterial circulation, and decreased significantly (p < 0.01) when grafts were reimplanted in the venous system. bFGF release (ng/cm2): [Formula: see text] | Young children with sickle cell disease (SCD) are at risk for cognitive delay. In addition to biologic risk factors associated with SCD, environmental factors contribute to cognitive dysfunction within this cohort. We completed a single-arm, prospective cohort study. Children with SCD between the ages of 3 and 36 months and their caregivers were followed between October 2010 and December 2013. The aim was to describe the role of a home visitation model, the home environment, and socioeconomic status in the development of young children with SCD. Primary outcome measures were the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and the Home Observation for Measurement of the Environment (HOME). We hypothesized that the home visitation model, Parents as Teachers Thirty-five participants had at least two PAT visits and BSID-III assessments. Mean scores within all five subtests of the BSID-III improved between enrollment and exit, with significant changes within cognitive (P = 0.016) and expressive language (EL) domains (P = 0.002). Multivariate modeling found the HOME score associated with the exit results of the cognitive domain. |
Is nQO1 gene rs1800566 variant associated with risk for multiple sclerosis? | A possible role of oxidative stress in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis has been suggested. The detoxification enzyme NAD(P)H dehydrogenase, quinone 1 (NQO1) has been found up-regulated in MS lesions. A previous report described an association between the SNP rs1800566 in the NQO1 gene and the risk for MS in the Greek population. The aim of this study was to replicate a possible influence of the. SNP rs1800566 in the NQO1 gene in the risk for MS in the Spanish Caucasian population. We analyzed allelic and genotypic frequency of NQO1 rs1800566 in 290 patients with MS and 310 healthy controls, using TaqMan Assays. NQO1 rs1800566 allelic and genotypic frequencies did not differ significantly between MS patients and controls, and were unrelated with age of onset of MS, gender, and clinical type of MS. | To describe the long-term outcomes from a completed, multi-institutional phase 4 registry trial using the Contura multilumen balloon (CMLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer. Three hundred forty-two evaluable patients were enrolled by 23 institutions between January 2008 and February 2011. All patients received 34 Gy in 10 fractions, delivered twice daily. Rigorous target coverage and normal tissue dose constraints were observed. The median follow-up time was 36 months (range, 1-54 months). For the entire patient cohort of 342 patients, 10 patients experienced an ipsilateral breast tumor recurrence (IBTR). Eight of these IBTR were classified as true recurrences/marginal miss (TRMM), and 2 were elsewhere failures (EF). Local recurrence-free survival was 97.8% at 3 years. For the entire cohort, 88% of patients had good to excellent overall cosmesis. The overall incidence of infection was 8.5%. Symptomatic seroma was reported in only 4.4% of patients. A separate analysis was performed to determine whether improved outcomes would be observed for patients treated at high-volume centers with extensive brachytherapy experience. Three IBTR were observed in this cohort, only 1 of which was classified as a TRMM. Local recurrence-free survival at high-volume centers was 98.1% at 3 years. Overall cosmetic outcome and toxicity were superior in patients treated at high-volume centers. In these patients, 95% had good to excellent overall cosmesis. Infection was observed in only 2.9% of patients, and symptomatic seroma was reported in only 1.9%. |
Does tolcapone addition improve Parkinson 's disease associated nonmotor symptoms? | Addition of catechol-O-methyltransferase inhibitors to a conventional levodopa/dopadecarboxylase inhibitor regimen improves motor symptoms in patients with Parkinson's disease. Optimizing dopamine substitution is also beneficial for nonmotor features. To investigate the efficacy of supplemental tolcapone intake on nonmotor symptoms. A total of 125 levodopa-treated patients additionally took tolcapone in this observational trial. Initially and following 4 weeks of tolcapone intake, the neurologist scored with Unified Parkinson's Disease Rating Scale parts I, II, IV, the nonmotor symptoms scale for Parkinson's disease and recorded the off time. The patients rated themselves with the EuroQuol, its visual analogue scale and the nonmotor screening questionnaire. Caregivers reported the daily duration of care giving. All scores improved except for Unified Parkinson's Disease Rating Scale part IV and domains 4, 5 and 8 of the nonmotor symptoms scale for Parkinson's disease. | Regeneration and tolerance factor (RTF) has been recently suggested to contribute to the control of fetal-ablating immunity at the maternal-fetal interface through the induction of T helper 2 (Th2)-dominated response. The protein consists of a membrane-associated domain and an extracellular portion which is proteolitically cleaved to yield a soluble peptide. In humans, it has been shown to be expressed by invading cytotrophoblasts and decidual lymphoid cells, to be increased on peripheral blood B lymphocytes during a normal gestation and on circulating natural killer cells during unsuccessful pregnancies. However, the expression of RTF in other cell types and, specifically, in non-hematopoietic maternal cells of the human uterus has not been characterized in detail. Thus, we have specifically studied the expression and modulation of the cytokine in human endometrium obtained in different phases of the cycle and in early pregnancy. The 20 kDa extracellular domain of RTF has been localized by immunohistochemical method and Western blot analysis. Levels of RTF messenger RNA (mRNA) in basal and stimulated conditions have been evaluated by semiquantitative reverse transcription-polymerase chain reaction. The extracellular domain of RTF could be detected in both the glandular epithelium and stroma with diffuse distribution in both cycling endometrium and first trimester decidua. Both cycling and pregnant endometrium expressed the gene for RTF but mRNA levels resulted significantly increased in secretory phase-endometrial stromal cells when compared to proliferative phase samples. Inflammatory cytokines, interleukin-1beta and tumour necrosis factor alpha were able to directly increase endometrial RTF mRNA expression. |
Is remnant lipoprotein cholesterol homogenous assay ( RemL-C ) closely associated with very-low-density lipoprotein remnants : comparison with the immunoseparation assay? | Remnant-like particle-cholesterol (RLP-C) is recognized as a risk factor for cardiovascular disease. As an alternative to the immunoseparation assay widely used for the measurement of RLP-C, a new remnant lipoprotein-C homogenous assay (RemL-C) is available. In light of its homogeneity as an assay method, we speculated that this homogeneous assay (RemL-C) is closely associated with very-low-density lipoprotein(VLDL) remnant including intermediate-density lipoprotein(IDL). We examined the characteristics of the homogeneous assay for reacting with VLDL remnants. VLDL1, VLDL2, and IDL were separated by ultracentrifugation in the fasting serum of subjects including hypertriglyceridemia and uremic patients usually having higher levels of remnants. While RemL-C and RLP-C were mainly recovered in VLDL1 and both assays were strongly correlated with serum TG and VLDL1, the RemL-C assay was more closely correlated with VLDL2 and IDL levels than the RLP-C assay. RemL-C levels were significantly correlated with IDL-C, whereas RLP-C levels had only borderline associations with IDL-C (r= 0.56 Vs. 0.31). | Although in vitro studies have determined that the activation of mitogen-activated protein (MAP) kinases is crucial to the activation of transcription factors and regulation of the production of proinflammatory mediators, the roles of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in acute lung injury have not been elucidated. Saline or lipopolysaccharide (LPS, 6 mg/kg of body weight) was administered intratracheally with a 1-hour pretreatment with SP600125 (a JNK inhibitor; 30 mg/kg, IO), or PD98059 (an MEK/ERK inhibitor; 30 mg/kg, IO). Rats were sacrificed 4 hours after LPS treatment. SP600125 or PD98059 inhibited LPS-induced phosphorylation of JNK and ERK, total protein and LDH activity in BAL fluid, and neutrophil influx into the lungs. In addition, these MAP kinase inhibitors substantially reduced LPS-induced production of inflammatory mediators, such as CINC, MMP-9, and nitric oxide. Inhibition of JNK correlated with suppression of NF-kappaB activation through downregulation of phosphorylation and degradation of IkappaB-alpha, while ERK inhibition only slightly influenced the NF-kappaB pathway. |
Does matrix metalloproteinase-9 deletion rescue auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome? | Sensory processing deficits are common in autism spectrum disorders, but the underlying mechanisms are unclear. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism. Electrophysiological responses in humans with FXS show reduced habituation with sound repetition and this deficit may underlie auditory hypersensitivity in FXS. Our previous study in Fmr1 knockout (KO) mice revealed an unusually long state of increased sound-driven excitability in auditory cortical neurons suggesting that cortical responses to repeated sounds may exhibit abnormal habituation as in humans with FXS. Here, we tested this prediction by comparing cortical event related potentials (ERP) recorded from wildtype (WT) and Fmr1 KO mice. We report a repetition-rate dependent reduction in habituation of N1 amplitude in Fmr1 KO mice and show that matrix metalloproteinase-9 (MMP-9), one of the known FMRP targets, contributes to the reduced ERP habituation. Our studies demonstrate a significant up-regulation of MMP-9 levels in the auditory cortex of adult Fmr1 KO mice, whereas a genetic deletion of Mmp-9 reverses ERP habituation deficits in Fmr1 KO mice. Although the N1 amplitude of Mmp-9/Fmr1 DKO recordings was larger than WT and KO recordings, the habituation of ERPs in Mmp-9/Fmr1 DKO mice is similar to WT mice implicating MMP-9 as a potential target for reversing sensory processing deficits in FXS. Together these data establish ERP habituation as a translation relevant, physiological pre-clinical marker of auditory processing deficits in FXS and suggest that abnormal MMP-9 regulation is a mechanism underlying auditory hypersensitivity in FXS. | A double-lumen catheter (DLC) is used as a temporary blood access in emergency haemodialysis and continuous haemodialysis. There are various reports concerning thrombosis related to use of DLC and other catheters. The objective of this study is to assess the incidence of venous thrombosis when using DLC in patients undergoing blood purification. Method. Forty-eight Japanese patients, hospitalized in the Saitama Medical University hospital from December 2004 to April 2005, who had DLC insertion as a temporary blood access for blood purification. The existence of a thrombus was determined using ultrasonography, before catheter insertion, and every 2 days after insertion up to 3 weeks. At the time of DLC insertion, general blood tests including plasma D-dimer, and serum C-reactive protein (CRP) were performed. When DLC was removed, plasma D-dimer and serum CRP were measured. In 30 of 48 (62.5%) patients with DLC insertion as a temporary blood access for haemodialysis, venous thrombi with diameters>1.1 mm were detected by venous ultrasonography. No predictive factors were recognized except an increase in plasma D-dimer that was significantly higher in the patients with venous thrombus. The changes in plasma D-dimer were 3.54 (SE 0.8) microg/dl in patient with thrombus, and 0.29 (0.30) microg/dl in patient without thrombus (P=0.004). |
Is high-fat but not sucrose intake essential for induction of dyslipidemia and non-alcoholic steatohepatitis in guinea pigs? | Non-alcoholic fatty liver disease (NAFLD) and dyslipidemia are closely related. Diet plays an important role in the progression of these diseases, but the role of specific dietary components is not completely understood. Therefore, we investigated the role of dietary sucrose and fat/cholesterol on the development of dyslipidemia and NAFLD. Seventy female guinea pigs were block-randomized (based on weight) into five groups and fed a normal chow diet (control: 4 % fat), a very high-sucrose diet (vHS: 4 % fat, 25 % sucrose), a high-fat diet (HF: 20 % fat, 0.35 % cholesterol), a high-fat/high-sucrose diet (HFHS: 20 % fat, 15 % sucrose, 0.35 % cholesterol) or a high-fat/very high-sucrose diet (HFvHS: 20 % fat, 25 % sucrose, 0.35 % cholesterol) for 16 and 25 weeks. All three high-fat diets induced dyslipidemia with increased concentrations of plasma cholesterol (p < 0.0001), LDL-C (p < 0.0001) and VLDL-C (p < 0.05) compared to control and vHS. Contrary to this, plasma triglycerides were increased in control and vHS compared to high-fat fed animals (p < 0.01), while circulating levels of free fatty acids were even between groups. Histological evaluation of liver sections revealed non-alcoholic steatohepatitis (NASH) with progressive inflammation and bridging fibrosis in high-fat fed animals. Accordingly, hepatic triglycerides (p < 0.05) and cholesterol (p < 0.0001) was increased alongside elevated levels of alanine and aspartate aminotransferase (p < 0.01) compared to control and vHS. | An event-related brain potential (ERP) study investigated how different processing stages involved in face identification are reflected by ERP modulations, and how stimulus repetitions and attentional set influence such effects. ERPs were recorded in response to photographs of familiar faces, unfamiliar faces, and houses. In Part I, participants had to detect infrequently presented targets (hands), in Part II, attention was either directed towards or away from the pictorial stimuli. The face-specific N170 component elicited maximally at lateral temporal electrodes was not affected by face familiarity. When compared with unfamiliar faces, familiar faces elicited an enhanced negativity between 300 and 500 ms ('N400f') which was followed by an enhanced positivity beyond 500 ms post-stimulus ('P600f'). In contrast to the 'classical' N400, these effects were parietocentrally distributed. They were attenuated, but still reliable, for repeated presentations of familiar faces. When attention was directed to another demanding task, no 'N400f' was elicited, but the 'P600f' effect remained to be present. |
Does pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 attenuate angiotensin II/salt-induced aortic remodeling? | To test the hypothesis that pharmacological plasminogen activator inhibitor (PAI)-1 inhibition protects against renin-angiotensin-aldosterone system-induced cardiovascular injury, the effect of a novel orally active small-molecule PAI-1 inhibitor, PAI-039, was examined in a mouse model of angiotensin (Ang) II-induced vascular remodeling and cardiac fibrosis. Uninephrectomized male C57BL/6J mice were randomized to vehicle subcutaneus, Ang II (1 mug/h) subcutaneous, vehicle+PAI-039 (1 mg/g chow), or Ang II+PAI-039 during high-salt intake for 8 weeks. Ang II caused significant medial, adventitial, and aortic wall thickening compared with vehicle. PAI-039 attenuated Ang II-induced aortic remodeling without altering the pressor response to Ang II. Ang II increased heart/body weight ratio and cardiac fibrosis. PAI-039 did not attenuate the effect of Ang II on cardiac hypertrophy and increased fibrosis. The effect of PAI-039 on Ang II/salt-induced aortic remodeling and cardiac fibrosis was comparable to the effect of genetic PAI-1 deficiency. Ang II increased aortic mRNA expression of PAI-1, collagen I, collagen III, fibronectin, osteopontin, monocyte chemoattractant protein-1, and F4/80; PAI-039 significantly decreased the Ang II-induced increase in aortic osteopontin expression at 8 weeks. | Extranodal natural killer/T-cell lymphoma (NKTCL) is a clinically heterogeneous disease with a poor prognosis, requiring risk-stratified management in affected patients. Recently, tumor microenvironment including regulatory T cells (Tregs) has been implicated as a prognostic marker in certain types of lymphoma. We collected 64 NKTCL cases and numerically quantified the amount of tumor-infiltrating FOXP3-positive Tregs by automated slide scanning and image analysis program after immunohistochemical staining using anti-FOXP3 antibody. Patients were able to be classified into two end groups by their level of Tregs. Twenty-eight (44%) patients had Tregs <50/0.40 mm(2), while 36 (56%) had Tregs > or =50/0.40 mm(2) within the tumor. The decreased number of Tregs (<50/0.40 mm(2)) was more common in patients with poor performance status or in those presented in non-upper aerodigestive tract. However, the level of Tregs was not associated with other prognostic factors, including stage, lactate dehydrogenase level, International Prognostic Index, and NKTCL Prognostic Index. Importantly, patients with increased numbers of Tregs (> or =50/0.40 mm(2)) showed prolonged overall and progression-free survival (P = 0.0005 and P = 0.0079, respectively). The number of FOXP3-positive Tregs was an independent prognostic factor (P = 0.001) by multivariate analysis. |
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