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Is the response to bronchodilators in adults predictive of bronchial-hyperreactivity? | In some subjects with suspected asthma who have normal spirometry, administration of bronchodilators (BD) improves expiratory flow rates. The predictive value of this phenomenon in adults is not known. To evaluate the predictive value of the response to BD for bronchial hyper-responsiveness (BHR) using the metacholine challenge test (MCT). Patients and methods. The study population included 62 non-smoking adult patients (41.9% women) 29.5 +/- 15.5 years of age (range 18-64 years) with suspected asthma with normal spirometry that underwent MCT within 1 week. The response to BD (200 mu g inhaled salbutamol) was compared between subjects with positive and negative MCT using cutoff levels of provocative concentrations of metacholine causing a 20% decrease in forced expiratory volume in 1 second (FEV(1)) (PC(20)) of 4 and 8 mg/mL. Mean (+/- SD) baseline FEV(1) was 87.8 +/- 12% of predicted. After BD administration the mean FEV(1) increased by 4.3 +/- 3.9%. The prevalence of BHR was 17.7% and 25.8% for PC(20) for PC(20) of 4 mg/mL and 8 mg/mL, respectively. The post-BD FEV(1) increment for subjects with positive and negative MCT tests was 3.9% +/- 3.3% versus 4.4% +/- 4.1%, respectively; p = 0.89, using cutoff of 4 mg/mL. The corresponding figures for cutoff of 8 mg/ml were 4.3% +/- 3.1% vs. 4.3% +/- 4.2%, respectively; p = 0.8465. There was no correlation between post-BD FEV(1) increment and PC(20) values in patients with positive MCT test for the above-mentioned cutoff levels (correlation coefficient r = 0.1645, p = 0.6289; and r = 0.2417, p = 0.4051, respectively). | To determine the origin of the neoplastic cell in central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL) and its role in tumor formation and distribution, we characterized and differentiated neoplastic cells from hemangioblastomas removed from VHL patients. A total of 31 CNS hemangioblastomas from 25 VHL patients were resected and analyzed. Tumor cells from the hemangioblastomas were characterized, grown, and differentiated into multiple lineages. Resected hemangioblastomas were located in the cerebellum (11 tumors), brainstem (five tumors), and spinal cord (15 tumors). Consistent with an embryologically derived hemangioblast, the neoplastic cells demonstrated coexpression of the mesodermal markers brachyury, Flk-1 (vascular endothelial growth factor-2), and stem cell leukemia (Scl). The neoplastic cells also expressed hematopoietic stem cell antigens and receptors including CD133, CD34, c-kit, Scl, erythropoietin, and erythropoietin receptor. Under specific microenvironments, neoplastic cells (hemangioblasts) were expanded and differentiated into erythrocytic, granulocytic, and endothelial progenitors. Deletion of the wild-type VHL allele in the hematopoietic and endothelial progeny confirmed their neoplastic origin. |
Is loss to follow-up of cervical smears without endocervical columnar cells disturbing? | To investigate the six-month recommended follow-up after mass screening of Pap smears because of the absence of endocervical columnar cells (ECC-) or ECC+ smears with atypical squamous or glandular cells of undetermined origin (ASCUS/AGUS) or low-grade squamous or glandular intraepithelial lesions (LSIL/LGIL) in a Dutch mass screening cervical cancer programme. Data were extracted from computerised medical records of national representative Dutch general practices. We have studied the attendance at and the outcome of the subsequent Pap smears after a 6-month recommendation. The six-month follow-up was linked to 8.7% of the Pap smears (n = 1,002); 77.6% were without endocervical columnar cells (ECC-). Clear differences were found between the follow-up of ECC+ and ECC- smears; after 36 weeks of follow-up of 43.5% the women had an ECC- smear and 66.9% had other conditions. For initial ECC- Pap smears, 84.1% had no abnormalities in the subsequent Pap smear; for initial ECC+ Pap smears, in about 64% of the cases no abnormalities were found (p < 0.0001). | Determination of the anabolic response to exercise and nutrition is important for individuals who may benefit from increased muscle mass. Intake of free amino acids after resistance exercise stimulates net muscle protein synthesis. The response of muscle protein balance to intact protein ingestion after exercise has not been studied. This study was designed to examine the acute response of muscle protein balance to ingestion of two different intact proteins after resistance exercise. Healthy volunteers were randomly assigned to one of three groups. Each group consumed one of three drinks: placebo (PL; N = 7), 20 g of casein (CS; N = 7), or whey proteins (WH; N = 9). Volunteers consumed the drink 1 h after the conclusion of a leg extension exercise bout. Leucine and phenylalanine concentrations were measured in femoral arteriovenous samples to determine balance across the leg. Arterial amino acid concentrations were elevated by protein ingestion, but the pattern of appearance was different for CS and WH. Net amino acid balance switched from negative to positive after ingestion of both proteins. Peak leucine net balance over time was greater for WH (347 +/- 50 nmol.min(-1).100 mL(-1) leg) than CS (133 +/- 45 nmol.min(-1).100 mL(-1) leg), but peak phenylalanine balance was similar for CS and WH. Ingestion of both CS and WH stimulated a significantly larger net phenylalanine uptake after resistance exercise, compared with the PL (PL -5 +/- 15 mg, CS 84 +/- 10 mg, WH 62 +/- 18 mg). Amino acid uptake relative to amount ingested was similar for both CS and WH (approximately 10-15%). |
Does cXCR3 antagonist VUF10085 bound to an intrahelical site distinct from that of the broad spectrum antagonist TAK-779? | The chemokine receptor CXCR3 is implicated in a variety of clinically important diseases, notably rheumatoid arthritis and atherosclerosis. Consequently, antagonists of CXCR3 are of therapeutic interest. In this study, we set out to characterize binding sites of the specific low MW CXCR3 antagonist VUF10085 and the broad spectrum antagonist TAK-779 which blocks CXCR3 along with CCR2 and CCR5. Molecular modelling of CXCR3, followed by virtual ligand docking, highlighted several CXCR3 residues likely to contact either antagonist, notably a conserved aspartate in helix 2 (Asp-112(2:63) ), which was postulated to interact with the quaternary nitrogen of TAK-779. Validation of modelling was carried out by site-directed mutagenesis of CXCR3, followed by assays of cell surface expression, ligand binding and receptor activation. Mutation of Asn-132(3.33) , Phe-207 and Tyr-271(6.51) within CXCR3 severely impaired both ligand binding and chemotactic responses, suggesting that these residues are critical for maintenance of a functional CXCR3 conformation. Contrary to our hypothesis, mutation of Asp-112(2:63) had no observable effects on TAK-779 activity, but clearly decreased the antagonist potency of VUF 10085. Likewise, mutations of Phe-131(3.32) , Ile-279(6.59) and Tyr-308(7.43) were well tolerated and were critical for the antagonist activity of VUF 10085 but not for that of TAK-779. | The purpose of this qualitative study was to explore the meaning of the phrase "image of the nurse" in the context of the desired brand experience of assurance. A brand is a promise that lives in the minds of consumers. Nurses play a key role in delivering on the brand promise of a hospital. Using focus groups, the authors applied a deductive approach to generate data. Discussion transcripts were analyzed by establishing codes and identifying themes. The most frequent comment from participants was that for nurses to communicate assurance, they must 1st be clean, well groomed, and understated in overall appearance. Nurse behaviors that reassure patients include being present with patients, helping patients know what to expect, and demonstrating a consistent team approach. |
Is long noncoding RNA PCA3 gene promoter region related to the risk of prostate cancer on Chinese males? | Long noncoding RNA prostate cancer gene antigen 3 (PCA3) is one of the most prostate cancer-specific genes at present. Consequently, the prostate-specific expression and the sharp up-regulation of PCA3 RNA in prostate cancer suggest a unique transcriptional regulation, which possibly can be attributed to promoter polymorphism. In this study, we investigated a short tandem repeat (STR) polymorphism of TAAA in the promoter region of PCA3 gene found in our previous study in prostate cancer (PCa) patients and benign prostatic hypertrophy (BPH) patients, aiming to evaluate the association between the STR and increased risk for PCa. 120 PCa cases and 120 benign prostatic hypertrophy (BPH) cases were identified among participants. The region encompassing the TAAA repeat was amplified with a specific primer set we designed and screened by PCR-based cloning and sequencing in paired peripheral blood leukocytes and prostate tissues. Genotype-specific risks were estimated as odds ratios (ORs) associated with 95% confidence intervals (CIs) and adjusted for age by means of unconditional logistic regression. 5 PCA3 TAAA STR polymorphisms and 8 genotypes were found in both peripheral blood leukocytes and prostate tissues, the carriers with more TAAA repeats were associated with increased risk for PCa than individuals having less TAAA repeats. Interestingly, 18 (15.0%) of 120 PCa patients had more (TAAA)n repeats in prostate tissues than that in peripheral blood leukocytes, and 3 (2.5%) of 120 had less (TAAA)n repeats in prostate tissues. | Photorealistic simulations may provide efficient transfer of certain skills to the real system, but by being opaque may fail to encourage deeper learning of the structure and function of the system. Schematic simulations that are more abstract, with less visual fidelity but make system structure and function transparent, may enhance deeper learning and optimize retention and transfer of learning. We compared learning effectiveness of these 2 modes of externalizing the output of a common simulation engine (the Virtual Anesthesia Machine, VAM) that models machine function and dynamics and responds in real time to user interventions such as changes in gas flow or ventilation. Undergraduate students (n = 39) and medical students (n = 35) were given a single, 1-hour guided learning session with either a Transparent or an Opaque version of the VAM simulation. The following day, the learners' knowledge of machine components, function, and dynamics was tested. The Transparent-VAM groups scored higher than the Opaque-VAM groups on a set of multiple-choice questions concerning conceptual knowledge about anesthesia machines (P = 0.009), provided better and more complete explanations of component function (P = 0.003), and were more accurate in remembering and inferring cause-and-effect dynamics of the machine and relations among components (P = 0.003). Although the medical students outperformed undergraduates on all measures, a similar pattern of benefits for the Transparent VAM was observed for these 2 groups. |
Does tegaserod ( HTF 919 ) stimulate gut motility in normal horses? | It has been shown that the selective 5-HT4 receptor agonist tegaserod induces an increase in frequency and amplitude of contractions in isolated muscle preparations of equine ileum and pelvic flexure. To investigate the effects of tegaserod on gut motility and transit of spheres in normal horses. Six mature Freiberger horses were kept under standardised conditions. Effects of tegaserod (0.02 mg/kg bwt i.v. b.i.d. for 2 days) or vehicle on intestinal transit of barium-filled spheres, defaecation and gut sounds were studied in a cross-over design. Spheres were given via stomach tube prior to the first dosing of tegaserod or vehicle. Faeces were collected every 3 h and spheres eliminated were identified radiologically in the faeces. Tegaserod significantly accelerated the gastrointestinal (GI) transit time of spheres and increased the frequency of defaecation and scores of gut sounds compared to vehicle. The compound was well tolerated; no effects on behaviour, body temperature, heart rate, respiratory rate and clinical laboratory data were observed. | Angiogenesis is essential for tumour growth and metastasis. There are conflicting reports as to whether microvessel density (MVD) using the endothelial marker CD105 (cluster of differentiation molecule 105) in clear-cell renal cell carcinomas (ccRCC) is associated with prognosis. Recently, CD105 has been described as a RCC cancer stem cell marker. A total of 102 ccRCC were analysed. Representative tumour sections were stained for CD105. Vascularity (endothelial CD105) was quantified by MVD. The immunohistochemistry analysis detected positive (if present) or negative (if absent) CD105 tumoral staining. This retrospective population-based study was evaluated using Kaplan-Meier method, t-test and Cox proportional hazard model. We found that the expression of endothelial CD105 (MVD) negatively correlated with nuclear grade (P<0.001), tumour stage (P<0.001) and Leibovitch score (P<0.001), whereas the expression of tumoral CD105 positively correlated with these three clinicopathological factors (P<0.001). In multivariate analysis, tumoral CD105 was found to be an independent predictor of poor overall survival (P=0.002). |
Does network analysis of differentially expressed genes reveal key genes in small cell lung cancer? | A combination of comparative analysis of gene expression profiles between normal tissue samples and small cell lung cancer (SCLC) samples and network analysis was performed to identify key genes in SCLC. Microarray data set GSE43346 was downloaded from Gene Expression Omnibus (GEO), including 43 normal tissue samples and 23 clinical SCLC samples. Differentially expressed genes (DEGs) were screened out with t-test. Coexpression network and gene regulatory network were then constructed for the DEGs. GO enrichment analysis as well as KEGG pathway were performed with DAVID online tools to reveal over-represented biological processes. A total of 457 DEGs were obtained in SCLC, 259 up-regulated and 198 down-regulated. Some of them exhibited enzyme inhibitor activity and chemokine activity. A coexpression network including 457 nodes was constructed, from which a functional module was extracted. Genes in the modules were closely related with cell cycle. Top 10 nodes in the regulatory network were acquired and their sub-networks were extracted from the whole network. Genes in these sub-networks were related to cell cycle, apoptosis and transcription. A network comprising 43 microRNAs (miRNAs) and their target genes (also DEGs) were also constructed. Regulation of cell proliferation, cell cycle and regulation of programmed cell death were over-represented in these genes. | Non-alcoholic fatty liver disease (NAFLD) and viral hepatitis are associated with hepatic oxidative stress, which is partially dependent on the amount of hepatic fat. To determine whether the circulating lipid and oxidative stress parameters could be non-invasive markers of hepatic steatosis. Sixty-four patients with NAFLD or viral hepatitis were tested for lipid peroxidation products and antioxidant defence systems, lipid parameters and liver function tests. Hepatic steatosis was correlated with lipids, gamma-glutamyltranspeptidase, thiobarbituric acid-reactive substances, superoxide dismutase and superoxide dismutase/erythrocyte glutathione peroxidase ratio. gamma-Glutamyltranspeptidase, triglycerides and low-density lipoprotein cholesterol were significantly higher in the presence of steatosis. No difference in blood oxidative stress markers was observed according to the presence or absence of steatosis except for the superoxide dismutase/erythrocyte glutathione peroxidase ratio. Total cholesterol, triglycerides and low-density lipoprotein cholesterol were significantly higher in the NAFLD group (n = 17, 60% mean steatosis grade) than in the viral hepatitis group (n = 20, 13% mean steatosis grade). Only superoxide dismutase was lower and vitamin E higher in NAFLD than in viral hepatitis patients. |
Does very urgent carotid endarterectomy increase the procedural risk? | The timing of CEA for symptomatic internal carotid artery (ICA) stenosis remains a matter of controversy. Recent registry data showed a significantly increased risk, especially in the very early days after the onset of symptoms. In this study the outcome of CEA in the hyperacute phase has been investigated. The outcome of CEA for symptomatic ICA stenosis between January 2004 and December 2013 has been retrospectively analyzed. Patients were divided into four timing groups: surgery within 0 and 2 days, between 3 and 7 days, 8 and 14 days, and thereafter. The post-operative 30 day stroke and death rates were assessed. A total of 761 symptomatic patients (40.1% with transient ischemic attack [TIA], 21.3% with amaurosis fugax, and 38.6% with ischemic stroke) were included, with an overall peri-operative stroke and death rate of 3.3%. A stroke and death rate of 4.4% (9/206) for surgery within 0 and 2 days, 1.8% (4/219) between 3 and 7 days, 4.4% (6/136) between 8 and 14 days, and 2.5% (5/200) in the period thereafter (p = .25 for the difference between the groups) was observed. The timing of surgery did not influence the peri-operative outcome in a multivariate regression analysis (OR 0.93 [0.63-1.36], p = .71). | Formation of a bipolar mitotic spindle in somatic cells requires the cooperation of two assembly pathways, one based on kinetochore capture by centrosomal microtubules, the other on RanGTP-mediated microtubule organization in the vicinity of chromosomes. How RanGTP regulates kinetochore-microtubule (K-fiber) formation is not presently understood. Here we identify the mitotic spindle protein HURP as a novel target of RanGTP. We show that HURP is a direct cargo of importin beta and that in interphase cells, it shuttles between cytoplasm and nucleus. During mitosis, HURP localizes predominantly to kinetochore microtubules in the vicinity of chromosomes. Overexpression of importin beta or RanT24N (resulting in low RanGTP) negatively regulates its spindle localization, whereas overexpression of RanQ69L (mimicking high RanGTP) enhances HURP association with the spindle. Thus, RanGTP levels control HURP localization to the mitotic spindle in vivo, a conclusion supported by the analysis of tsBN2 cells (mutant in RCC1). Upon depletion of HURP, K-fiber stabilization is impaired and chromosome congression is delayed. Nevertheless, cells eventually align their chromosomes, progress into anaphase, and exit mitosis. HURP is able to bundle microtubules and, in vitro, this function is abolished upon complex formation with importin beta and regulated by Ran. These data indicate that HURP stabilizes K-fibers by virtue of its ability to bind and bundle microtubules. |
Does [ Prophylactic administration of Yunnan Baiyao capsule reduce intra-operative blood loss in orthognathic surgery ]? | To evaluate the haemostatic efficacy and safety of prophylactic oral administration of Yunan Baiyao capsules on reduction of blood loss in bimaxillary orthognathic surgery. Eighty-seven patients scheduled for Le Fort I osteotomy and bilateral sagittal split ramus osteotomy (BSSRO) were enrolled in the prospective, randomized, double-blind, placebo-controlled clinical study. Forty-three patients took prophylactic oral administration of Yunnan Baiyao capsules 3 days before operation, and 44 patients without Yunnan Baiyao administration served as control. The intraoperative blood loss during Le Fort I osteotomy and bilateral sagittal split ramus osteotomy was estimated and the safety of Yunnan Baiyao capsules was evaluated. The total blood loss in the Yunnan Baiyao group (330.5 +/- 134.4) ml was significantly lower than that of the control group (420.3 +/- 175.9) ml. The blood loss of Le Fort I osteotomy in the Yunnan Baiyao group (154.9 +/- 84.3) ml was also significantly lower than that of the control group (203.8 +/- 98.1) ml. The mean blood loss of BSSRO in the Yunnan Baiyao group was also lower than that of the control group, but the differences was not significant. The post-operative fibrinolysis was in the same level in both groups. Thromboemblic events or other side effects were not observed in this clinical trial. | Intact surface active agent (surfactant) composed of surfactant-associated proteins (SPs) and lipids is necessary for respiration and prevents alveoli from collapsing. CD26, a transmembrane glycoprotein exerting dipeptidyl peptidase activity (DPP4), highly expressed in lung parenchyma, is involved in inflammatory processes. A pharmacological inhibition of DPP4 influenced not only the inflammation but also elevated the SPs. Thus, DPP4 inhibitors may be a novel drug for treatment of diseases with surfactant deficiency. Therefore, we tested firstly the hypothesis that DPP4 inhibitors increase the expression of SPs in healthy rats. SP mRNA and protein expression were determined different times after nebulization of aerosolized DPP4 inhibitors [L-isoleucine-thiazolidide (L-Ile-Thia), L-valine-pyrrolidide (L-Val-Pyrr)], budesonide, saline or stereoisomers. Compared with negative controls (1) L-Ile-Thia as well as budesonide led to a significant higher and L-Val-Pyrr had the tendency to a significant higher expression of SP-A mRNA 6 h after nebulization, (2) the expression of SP-D mRNA increased significantly 6 h after nebulization with L-Ile-Thia and 3 and 6 h after nebulization with Val-pyrr, (3) SP-B mRNA levels showed significantly higher values 3 and 6 h after nebulization with L-Val-Pyrr, (4) protein levels of SP-A, SP-B and SP-C were elevated significantly 6 h after nebulization with L-Val-Pyrr as well as with budesonide, and (5) phospholipids were also increased in response to DPP4 inhibition; the minimal surface tension was comparable. |
Does chronic-leptin attenuate Cisplatin cytotoxicity in MCF-7 breast cancer cell line? | Large-scale epidemiological studies support a correlation between obesity and breast cancer in postmenopausal women. Circulating leptin levels are increased in obese and it has been suggested to play a significant role in mammary tumor formation and progression. Moreover, regulation of oxidative stress is another important factor in both tumor development and responses to anticancer therapies. The aim of this study was to examine the relationship between oxidative stress and chronic leptin exposure. We treated MCF-7 breast cancer cells with 100 ng/mL leptin for 10 days and analyzed cell growth, ROS production and oxidative damage, as well as, some of the main antioxidant systems. Furthermore, since the hyperleptinemia has been associated with a worse pathology prognosis, we decided to test the influence of leptin in response to cisplatin anticancer treatment. Leptin signalling increased cell proliferation but reduced ROS production, as well as, oxidative damage. We observed an upregulation of SIRT1 after leptin exposure, a key regulator of stress response and metabolism. Additionally, leptin counteracted cisplatin-induced cytotoxicity in tumor cells, showing a decrease in cell death. | This study investigated if feG-COOH would decrease allergen-induced airway inflammation. Seven adult cats sensitised to Bermuda grass allergen (BGA) to induce an asthmatic phenotype. Cats were randomized to receive either feG-COOH (1 mg/kg, PO) or placebo (saline 1 ml, PO) immediately prior to BGA aerosol challenge in a cross-over design. Bronchoalveolar lavage fluid (BALF) was collected and airway inflammatory response assessed via inflammatory cell number and type; IL-4, IFN-gamma and nitric oxide metabolite concentrations. A paired t test was used to compare parameters with a P < 0.05 considered significant. The BALF eosinophil percentage was significantly lower in asthmatic cats treated with feG compared with placebo (placebo, 35.3 +/- 12.2%; feG, 22.4 +/- 8.6%; P = 0.002). Treatment with feG did not result in a significant change in any other parameter measured. |
Does oral administration of tetrahydrobiopterin slow the progression of atherosclerosis in apolipoprotein E-knockout mice? | Although it has been reported that oral administration of tetrahydrobiopterin (BH4) prevents endothelial dysfunction and vascular oxidative stress in various rat models, the effect of treatment with BH4 on atherogenesis remains unclear. In this study, we investigated whether oral BH4 treatment might slow the progression of atherosclerosis using hypercholesterolemic apolipoprotein E-knockout mice. We report that ingesting BH4 in drinking water is sufficient to inhibit atherogenesis in mice. Furthermore, we report that BH4 treatment improves endothelial dysfunction and attenuates increased mRNA expression of NADPH oxidase components, as well as a number of inflammatory factors, such as LOX-1 and MCP-1, in the aortas of apolipoprotein E- knockout mice. | The aim of the study was to evaluate the prognostic value of the ratio of metastatic to examined lymph nodes (LNR) in patients with rectal cancer. Lymph nodes ratio (LNR) has been shown to have prognostic value in patients with colon cancer. The impact of LNR on disease-free and overall survival in patients with rectal cancer is unknown. From 1998 to 2004, 307 patients underwent rectal resection for adenocarcinoma. The relationships between overall and disease-free survival at 3 years and 15 variables, including the presence or absence of metastatic lymph nodes, the total number of lymph nodes examined, and LNR, were analyzed by multivariate analysis. Patients were then assigned to 4 groups based on LNR: LNR = 0 (N0 patients), LNR = 0.01 to 0.07, LNR >0.07 to 0.2, LNR >0.2. The mean number of lymph nodes examined was 22 +/- 12. In the multivariate analysis, LNR was a significant prognostic factor for both disease-free (P = 0.006) and overall survival (P = 0.0003), whereas the presence or absence of metastatic lymph nodes was not. LNR remained a significant prognostic factor in the 59 patients in whom fewer than 12 lymph nodes were examined (P = 0.0058). According to LNR values, disease-free and overall survival decreased significantly with increasing LNR (P < 0.001). |
Is detection of micrometastatic prostate cancer cells in the lymph nodes by reverse transcriptase polymerase chain reaction predictive of biochemical recurrence in pathological stage T2 prostate cancer? | We evaluated whether detecting prostate cancer cells by the nested reverse transcriptase-polymerase chain reaction (RT-PCR) in lymph nodes has predictive value for serum prostate specific antigen (PSA) recurrence in patients undergoing radical prostatectomy. We assessed the presence of prostate cancer cells by RT-PCR for prostate specific membrane antigen and PSA assay in lymph nodes dissected from 38 patients with localized prostate cancer treated with radical prostatectomy. The results of nested RT-PCR assay were compared with biochemical recurrence. Nested RT-PCR was positive in the lymph nodes of 2 of 18 patients (11%) with stage pT2a and 5 of 20 (25%) with stage pT2b disease. All 7 patients had biochemical recurrence. We noted a significant difference in the Kaplan-Meier recurrence-free actuarial probability curve in those with positive and negative nested RT-PCR results for prostate specific membrane antigen, PSA and prostate specific membrane antigen-PSA in the lymph nodes (p = 3.02x10(-7), 2.23x10(-7) and 3.02x10(-7), respectively). Multivariate analysis of serum PSA, Gleason score and preoperative RT-PCR assay in peripheral blood showed that nested RT-PCR for prostate specific membrane antigen, PSA and prostate specific membrane antigen-PSA in the lymph nodes were independent predictors of recurrence (p = 0.0089, 0.0075 and 0.0089, respectively). | 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. |
Do proteomic and genomic analyses suggest the association of apolipoprotein C1 with abdominal aortic aneurysm? | Abdominal aortic aneurysm (AAA) is an important cause of mortality in the elderly. Mouse models are widely used to investigate AAA pathogenesis but their suitability for biomarker discovery is unexplored. We conducted a three-phase study. Phase 1: Aortas from angiotensin-II-infused apolipoprotein E deficient (ApoE(-/-) ) mice with and without AAA were assessed via iTRAQ and analyzed in silico to identify potential circulating markers. Microarray data from ApoE(-/-) mice and human patients were analyzed in parallel. Phase 2: Putative markers were compared between datasets to shortlist common candidates. Phase 3: The relationship of two shortlisted markers and AAA presence was assessed. iTRAQ identified eight proteins with biomarker potential. Microarray data identified 72 and 96 potential biomarkers from ApoE(-/-) mice and human patients, respectively. All three datasets suggested apolipoprotein C1 (ApoC1) as a marker for AAA; microarray data identified matrix metalloproteinase 9 (MMP9) as a second potential marker. Plasma ApoC1 and MMP9 concentrations positively correlated with AAA diameter in ApoE(-/-) mice. | The efficacy of fractional photothermolysis and topical use of calcineurin inhibitors as treatments of idiopathic guttate hypomelanosis (IGH) have been reported. Data on combination treatments are lacking. To evaluate the efficacy and safety of 1550-nm ytterbium/erbium fiber laser combined with 0.1% tacrolimus ointment as a treatment of IGH. In each patient with IGH, two lesions were assigned as a treatment group, whilst two lesions on another side were chosen as control. Four treatments by fractional 1550-nm ytterbium/erbium fiber laser were delivered every four weeks combined with a twice daily topical application of 0.1% tacrolimus ointment. Lesional skin color was measured by colorimeter. Digital and dermoscopic digital photographs were taken and evaluated by three dermatologists. A total of 120 lesions were treated. Combination treatment normalized the relative lightness index of IGH which reached statistical significant compared with the control at week 12, after three sessions of laser treatment (p = 0.026). Physicians' assessment score revealed that 91.67% of the lesions on treatment side showed an improvement. Swelling and redness were the most common side effects which spontaneously resolved. |
Does single-chamber ventricular pacing increase markers of left ventricular dysfunction compared with dual-chamber pacing? | Large randomized trials comparing DDD with VVI pacing have shown no differences in mortality, but conflicting evidence exists in regard to heart failure endpoints. Here we evaluated the effect of pacing mode on serum levels of brain natriuretic peptide (BNP) and amino-terminal-proBNP (NT-proBNP). Methods Forty-one patients (age 73 +/- 10 years) with dual-chamber pacemakers were included in a prospective, single-blind, randomized crossover study evaluating the impact of DDD(R)/VDD versus VVI(R) mode on objective and functional parameters. Data were collected after a 2-week run-in phase and after 2 weeks each of VVI(R) and DDD(R)/VDD pacing or vice versa. Results BNP and NT-proBNP levels during DDD(R)/VDD stimulation (151 +/- 131 and 547 +/- 598 pg/mL) showed no change compared with baseline (154 +/- 130 and 565 +/- 555 pg/mL), but a significant 2.4-fold increase was observed during VVI(R) mode [360 +/- 221 and 1298 +/- 1032 pg/mL; P < 0.001 compared with DDD(R)/VDD]. The assessment of functional class, the presence of pacemaker syndrome [49% in VVI(R) mode] and the patients' preferred pacing mode showed significant differences in favour of DDD(R)/VDD pacing. | In HLA-B27-transgenic rats, the development of a disorder that mimics spondyloarthritis (SpA) is highly correlated with dendritic cell (DC) dysfunction. The present study was undertaken to analyze the underlying mechanisms of this via transcriptome analysis. Transcriptome analysis of ex vivo-purified splenic CD103+CD4+ DCs from B27-transgenic rats and control rats was performed. Transcriptional changes in selected genes were confirmed by quantitative reverse transcriptase-polymerase chain reaction. A meta-analysis of our rat data and published data on gene expression in macrophages from ankylosing spondylitis (AS) patients was further performed. Interferon (IFN) signaling was the most significantly affected pathway in DCs from B27-transgenic rats; the majority of genes connected to IFN were underexpressed in B27-transgenic rats as compared to controls. This pattern was already present at disease onset, persisted over time, and was conserved in 2 disease-prone B27-transgenic rat lines. In DCs from B27-transgenic rats, we further found an up-regulation of suppressor of cytokine signaling 3 (which may account for reverse IFN signaling) and a down-regulation of interleukin-27 (a cytokine that opposes Th17 differentiation and promotes Treg cells). The meta-analysis of data on conventional DCs from rats and data on monocyte-derived macrophages from humans revealed 7 IFN-regulated genes that were negatively regulated in both human and rat SpA (i.e., IRF1, STAT1, CXCL9, CXCL10, IFIT3, DDX60, and EPSTI1). |
Does oxidative stress impair vasorelaxation induced by the soluble guanylyl cyclase activator BAY 41-2272 in spontaneously hypertensive rats? | BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine) relaxes mesenteric arteries (MA) in a synergistic fashion with nitric oxide (NO). We hypothesized that the relaxation to BAY 41-2272 is decreased in spontaneously hypertensive rats (SHR) because of the reduced NO bioavailability in this strain and that relaxation would be improved by inhibiting the oxidative stress. We aimed to evaluate the influence of oxidative stress in BAY 41-2272-induced vasorelaxation in isolated MA from SHR. MA function was evaluated by concentration-response curves to BAY 41-2272. We measured protein expression of endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC) and human-antigen R (HuR) (sGC mRNA-stabilizing protein), sGC activity and plasma levels of superoxide dismutase (SOD), and total antioxidant status (TAS). Cyclic guanosine monophosphate (cGMP)-dependent and -independent relaxation induced by BAY 41-2272 (0.0001-1 micromol/l) was impaired in SHR compared with Wistar-Kyoto (WKY). We observed reduced expression of eNOS, sGC and HuR, and decreased sGC activity in SHR. Plasma levels of SOD and TAS were also diminished in SHR. Incubation with SOD or indomethacin increased relaxation to BAY 41-2272 in SHR. Furthermore, acetylcholine (ACh)-induced relaxation was increased in the presence of BAY 41-2272 or SOD, apocynin, or indomethacin. | Hepatitis B s antigen (HBsAg) seroclearance is regarded as the optimal virological end-point. To investigate the dynamic changes in serum cytokine levels around the time of HBsAg seroclearance. This was a case-control study. Consecutive patients with chronic hepatitis B (CHB) who lost HBsAg were matched with those remained positive for HBsAg with same age, gender, HBeAg status and presence of cirrhosis in 1:2 ratio. Relevant serum cytokines [interleukin (IL)-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IL-15, IL-21 interferon-γ, tumour necrosis factor-α (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF) and interferon-inducible protein 10 (IP-10)] were assayed at the time (Year 0) and 3 years before (Year -3) HBsAg seroclearance. Seventy-one and 142 CHB patients who did and did not achieve HBsAg seroclearance were included. Mean age was 48 ± 11 years; 76% were male, 20% had positive HBeAg, 99 (46%) patients received anti-viral therapy, and mean baseline HBV DNA was 3.78 ± 2.28 log IU/mL vs. 4.36 ± 2.13 log IU/mL respectively (P = 0.05). In those who achieved HBsAg seroclearance, serum IL-15 and GM-CSF levels decreased significantly from Year -3 to Year 0 (P = 0.017 and 0.05 respectively). When compared to controls, only serum IP-10 level was significantly lower at Year 0 than at Year -3 in patients with HBsAg seroclearance. Lower serum IP-10 level at Year 0 was the only factor associated with HBsAg seroclearance. There was no correlation between serum IP-10 and HBsAg levels around the time of HBsAg seroclearance. |
Is follicular blood flow a better predictor of the outcome of in vitro fertilization-embryo transfer than follicular fluid vascular endothelial growth factor and nitric oxide concentrations? | To investigate the relationship between follicular blood flow and the follicular fluid vascular endothelial growth factor (VEGF) and nitric oxide (NO) concentrations and to determine which factor might be a better predictor of the outcome of IVF-ET. Prospective study. Academic research laboratory. Forty-seven cycles of IVF (tubal factor, 25 cycles; male factor, 22 cycles) at the infertility clinic of Pusan National University Hospital from February 2002 to June 2002. Follicular blood flow was estimated on the day of hCG administration. Each follicular fluid sample was collected at oocyte retrieval, and follicular fluid VEGF and NO concentrations were assessed. Follicular blood flow and follicular fluid VEGF and NO concentrations according to the age of patients, the cause of infertility, and pregnancy rate. Of 47 cycles, 18 (38.3%) cycles resulted in a pregnancy. Follicular blood flow was significantly higher in the pregnant group compared with the nonpregnant group, but there was no statistically significant difference in age and infertility cause. Follicular fluid concentrations of VEGF and NO did not show statistically significant differences in age, infertility cause, or pregnancy outcome. As the follicle size increases, the follicular blood flow and follicular fluid VEGF concentrations increased significantly but the follicular fluid NO concentrations decreased. There was no correlation between VEGF and NO concentrations in the follicular fluid by linear regression analysis. | Cognitive dysfunction is very common in multiple sclerosis (MS) and it severely impairs patients' quality of life. Thus, we explored whether memantine might improve cognitive performance in patients with MS. We conducted a pilot trial with memantine (30 mg/day) in patients with MS with cognitive impairment. The trial was designed as a 1-year, randomized, double-blind, crossover study comparing memantine against a placebo in 60 patients with MS and cognitive impairment. Cognitive impairment was defined as the performance 1.5 standard deviations below the normative data in at least two tests of two cognitive domains in the Brief Repeatable Battery-Neuropsychology. The primary endpoint was improvement of verbal memory and the secondary endpoints were safety and improvements in the other cognitive domains, disability and quality of life. The trial was registered at www.clinicaltrials.org: NCT00638833. Although 19 patients had been included, the trial was halted after nine patients reported a worsening of their neurologic symptoms that deteriorated their quality of life. Seven of the nine patients in the memantine arm had blurred vision, fatigue, severe headache, increased muscle weakness, walking difficulties, or unstable gait. Only two patients in the placebo group reported neurologic symptoms and in both cases they were related with changes in their disease-modifying therapy. The adverse events only occurred on reaching the maximum dose (30 mg/day). After stopping medication, the patients reverted to their baseline disability within a few days. |
Does chemotherapy affect the pattern of failure after shear loading of the proximal tibial growth plate? | Tibial bones are shorter and less resistant to shear forces after treatment with doxorubicin, methotrexate, or cisplatin. We investigated the pattern of failure after shear loading of the proximal tibial growth plate in rats treated with these chemotherapeutic agents. Male Wistar rats from the age of 4 weeks were given doxorubicin intravenously at 15 mg/m2 body surface area (BSA), methotrexate 60 mg/m2 BSA, or cisplatin 7.5 mg/m2 BSA. There was one nontreated control group fed ad libitum an d a diet control group for each drug-treated group. At the age of 13 weeks the tibial bones were dissected. The proximal growth plate was shear loaded to failure in the posteroanterior direction. The pattern of failure through the growth plate was examined. In rats fed ad libitum the failure pattern ran mainly through the transitional zone between proliferating and hypertrophic chondrocytes, but the pattern of failure showed considerable variability. The pattern in rats treated with methotrexate or cisplatin and that in their diet controls were comparable. In rats treated with doxorubicin the fracture ran mainly through the trabecular zone. | Sleep apnoea, which constitutes a major social problem because of its high prevalence and its emerging association with cardiovascular morbidity and mortality, is known to affect autonomic nervous system activity. We assessed the hypothesis that treatment of sleep apnoea patients with continuous positive airway pressure (CPAP) alters the indices of heart rate variability (HRV) that reflect sympathetic and parasympathetic autonomic nervous system activity. We studied 26 patients (18 men, aged 49.2 +/- 7.6 years) with obstructive sleep apnoea-hypopnoea syndrome. In all patients, a 24-hour Holter recording was obtained one week before initiation of CPAP treatment and another one two months later. From these recordings we assessed the time domain indices of HRV (pNN50, rMSSD, SDNN, SDANN, SD) during the day (08:00-23:00) and during the night hours (23:00-08:00) as well as their post-treatment changes. The same HRV indices were also assessed in a group of 19 age and sex matched controls, without sleep apnoea. No significant differences in the HRV indices were observed during the daytime hours, while during the night both pNN50 and rMSSD were significantly higher in patients compared to controls (19.5 +/- 12.5 vs. 13.8 +/- 9.7, p=0.001, for pNN50 and 54.7 +/- 23.1 vs. 44.0 +/- 15.9, p=0.001, for rMSSD, for patients and controls respectively). No such differences were observed in any of the monitored indices following CPAP treatment. |
Is among inflammation and coagulation markers , PAI-1 a true component of the metabolic syndrome? | To investigate whether leukocyte count, fibrinogen, von Willebrand factor (vWF) and plasminogen activator inhibitor-1 activity (PAI-1) are increased in subjects with the metabolic syndrome as defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and the World Health Organisation (WHO). Cross-sectional study. A total of 520 overweight and obese subjects: 379 women and 141 men, visiting the weight management clinic of a University Hospital. Waist circumference, triglycerides, HDL cholesterol, blood pressure and fasting glucose were determined, and the presence or absence of the metabolic syndrome according to the NCEP-ATPIII criteria was assessed. In 349 subjects, data on the waist-to-hip ratio (WHR) and albumin excretion rate were available and the WHO criteria were applied. Insulin resistance was defined using the HOMA-IR index. Subjects with the metabolic syndrome according to the NCEP-ATPIII criteria had significantly higher levels of leukocyte count (P < 0.001) and PAI-1 (P < 0.001), while no significant differences were found for fibrinogen or vWF (P > 0.05). Using the WHO criteria, similar results were found except for vWF, where higher levels were found in subjects with the metabolic syndrome. When subjects were classified according to the number of components of the metabolic syndrome, levels of leukocyte count, vWF and PAI-1 activity were significantly different (P < 0.05). In logistic regression analysis PAI-1, gender and leukocyte count were independent determinants of the metabolic syndrome (P < 0.001). | Accumulating evidence suggests that dysregulated snoRNA may play a role in the development of malignancy. In the present study, we investigated the role of SNORD78 in the tumorigenesis of non-small cell lung cancer (NSCLC). We determined the expression level of SNORD78 in NSCLC tissues with quantitative real-time PCR and then studied its clinical significance. We explored the biological significance of SNORD78 with gain-and-loss-of-function analyses both in vitro and in vivo. A great upregulation of SNORD78 was observed in cancer tissues compared to their adjacent normal tissues. Meanwhile, patients with high SNORD78 expression have significantly poorer prognosis than those with low expression. Inhibition of SNORD78 suppressed the proliferation of NSCLC cells via inducing G0/G1 cell cycle arrest and apoptosis while SNORD78 overexpression promoted the cell proliferation. SNORD78 promoted invasion of NSCLC cells via inducing epithelial-mesenchymal-transition (EMT). SNORD78 was also obviously upregulated in cancer stem-like cells and is required for the self-renewal of NSCLC. The oncogenic activity of SNORD78 was also confirmed with in vivo data. |
Is spontaneous Preterm Delivery , Particularly with Reduced Fetal Growth , Associated with DNA Hypomethylation of Tumor Related Genes? | Preterm delivery and sub-optimal fetal growth are associated with each other and affect both mother and infant. Our aim was to determine (i) whether there are detectable differences in DNA methylation between early and late gestation and (ii) whether changes in DNA methylation from entry are associated with spontaneous preterm delivery with and without reduced fetal growth. We conducted a case-control study nested within a large prospective cohort. Gene specific methylation was measured by Methyl-Profiler PCR Array in a Human Breast Cancer Signature Panel of 24 genes from maternal peripheral leukocytes genomic DNA at entry and 3 There was significantly decrease in DNA methylation in 15 of 24 genes during the 3 | THE AIM OF THE STUDY WAS: Is primary Arterio-venous fistula the vascular access of choice for adequate dialysis and better patient outcome in end stage renal disease. The present study was done in the department of cardiovascular and thoracic surgery at Sher-i-Kashmir institute of medical sciences, Soura, Srinagar Kashmir. Native Arterio-Venous (AV) fistulas were made in the patients with end stage renal disease for performing hemodialysis. They were followed for patency and adequacy of blood flow during hemodialysis. All the patients were operated under local anesthesia. The results showed that 77% of the AV fistulas based on radial artery with side-to-side anastomosis and 80% of those with end-to-side anastomosis were functionally patent after one year. After two years, the patency rate in side-to-side and end-to-side anastomosis was 50% and 55%, respectively. In addition, the patency rate was 90% in brachial artery based AV fistula with end-to-side anastomosis, whether done primarily or secondarily, at the end of one year. However, a rapid decline was observed in the patency rate during the third year in both radial artery based and brachial artery based AV fistulas. |
Does optic nerve crush induce spatial and temporal gene expression patterns in retina and optic nerve of BALB/cJ mice? | Central nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and optic nerve (ON) gene expression, (b) identify neurodegenerative pathogenic pathways and (c) discover potential new therapeutic targets. Only 54% of total neurons survived in the ganglion cell layer (GCL) 28 days post crush. Using Bayesian Estimation of Temporal Regulation (BETR) gene expression analysis, we identified significantly altered expression of 1,723 and 2,110 genes in the retina and ON, respectively. Meta-analysis of altered gene expression (≥1.5, ≤-1.5, p < 0.05) using Partek and DAVID demonstrated 28 up and 20 down-regulated retinal gene clusters and 57 up and 41 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters were quantitatively and qualitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR. | This study examines the relationship between the existence of chest wall tenderness evoked by palpation and the absence of ischemic heart disease defined by myocardial perfusion imaging in patients with known or suspected stable angina pectoris. Two hundred seventy-five patients were recruited. Myocardial perfusion imaging was performed on 273 of the subjects. Chest pain was classified according to type by criteria given by the Danish Society of Cardiology and severity by the Canadian Cardiovascular Society. Pectoralis major and pectoralis minor were palpated for tenderness using a standardized procedure. The association between tenderness and myocardial perfusion imaging (normal vs abnormal) produced an odds ratio (OR) of 2.24 (confidence interval, 1.26-3.99; P = .009). The OR was the same magnitude and significance when stratified by sex, age, type of pain, or class. When adjusting simultaneously for sex, age, type of pain, and class, the association between tenderness and myocardial perfusion imaging (normal vs abnormal) was still present (OR = 2.57; confidence interval, 1.342-4.902; P = .004). |
Does invasive aortic pulse wave velocity as a marker for arterial stiffness predict outcome of renal sympathetic denervation? | A recurrent finding of trials on renal sympathetic denervation is a certain percentage of non-responders. The aim of this study was to examine the influence of arterial stiffness to predict response. Eighty-eight patients were included in the study. Arterial stiffness was measured by invasive pulse wave velocity. Antihypertensive medication had to be unchanged during follow-up. Ambulatory blood pressure measurement (ABPM) was used to record blood pressure before and six months after denervation. Fifty-eight patients without changes in medication were included in the final analysis. Responders (n=37; blood pressure reduction -12.8±6.4 mmHg) had a significantly lower pulse wave velocity (14.4±4.4 m/s versus 17.7±4.5 m/s; p=0.009) compared to non-responders (n=21; blood pressure reduction +3.0±4.5 mmHg; p<0.001 for comparison with responders). In multivariate analysis, invasive pulse wave velocity was the only significant predictor of blood pressure reduction after denervation (odds ratio 1.15, 95% confidence interval [CI] 1.014-1.327; p=0.03). Patients with increased stiffness were older (p=0.001), had a higher prevalence of diabetes (p=0.008), more often had isolated systolic hypertension (p=0.007), and had a higher invasive pulse pressure (p<0.001). | The recently sequenced genome of Lactobacillus helveticus DPC4571 revealed a dairy organism with significant homology (75% of genes are homologous) to a probiotic bacteria Lb. acidophilus NCFM. This led us to hypothesise that a group of genes could be determined which could define an organism's niche. Taking 11 fully sequenced lactic acid bacteria (LAB) as our target, (3 dairy LAB, 5 gut LAB and 3 multi-niche LAB), we demonstrated that the presence or absence of certain genes involved in sugar metabolism, the proteolytic system, and restriction modification enzymes were pivotal in suggesting the niche of a strain. We identified 9 niche specific genes, of which 6 are dairy specific and 3 are gut specific. The dairy specific genes identified in Lactobacillus helveticus DPC4571 were lhv_1161 and lhv_1171, encoding components of the proteolytic system, lhv_1031 lhv_1152, lhv_1978 and lhv_0028 encoding restriction endonuclease genes, while bile salt hydrolase genes lba_0892 and lba_1078, and the sugar metabolism gene lba_1689 from Lb. acidophilus NCFM were identified as gut specific genes. |
Does arg-gly-asp-mannose-6-phosphate inhibit activation and proliferation of hepatic stellate cells in vitro? | To investigate the effect of arg-gly-asp-mannose-6 phosphate (RGD-M6P) on the activation and proliferation of primary hepatic stellate cells in vitro. Hepatic stellate cells (HSCs) were isolated from rats by in situ collagenase perfusion of liver and 18% Nycodenz gradient centrifugation and cultured on uncoated plastic plates for 24 h with DMEM containing 10% fetal bovine serum (FBS/DMEM) before the culture medium was substituted with 2% FBS/DMEM for another 24 h. Then, HSCs were cultured in 2% FBS/DMEM with transforming growth factor beta1, M6P, RGD, or RGD-M6P, respectively. Cell morphology was observed under inverted microscope, smooth muscle alpha-actin (alpha-SMA) was detected by immunocytochemistry, type III procollagen (PC III) in supernatant was determined by radioimmunoassay, and the proliferation rate of HSCs was assessed by flow cytometry. RGD-M6P significantly inhibited the morphological transformation and the alpha-SMA and PC III expressions of HSCs in vitro and also dramatically prevented the proliferation of HSCs in vitro. Such effects were remarkably different from those of RGD or M6P. | It is well known that animals show a stress response when confronted with a novel environment. The aim of the this study was to investigate whether humans show a similar response by studying the reaction to a travel-related transitory change of residence. Forty-eight individuals (32 women, 16 men, age 40-83 years) traveling to a health resort approximately 120 km from their home town participated in the study. Individuals monitored their blood pressure (BP) twice a day 3 weeks before (baseline) and during the stay and filled out a diary stating their mood and sleep. The change of the variables relative to baseline on the day before departure, the travel day, and the day after arrival as well as 5 days after arrival were determined. Systolic and diastolic BPs were increased on the day before travel and diastolic BP remained increased on the travel day and the day after arrival. Sleep was poorer during the first night at the new residence. All three variables had returned to baseline level 5 days into the stay. Mood was not affected by the change of residence. |
Is number of positive preoperative biopsy cores a predictor of positive surgical margins ( PSM ) in small prostates after robot-assisted radical prostatectomy ( RARP )? | To determine the impact of prostate size on positive surgical margin (PSM) rates after robot-assisted radical prostatectomy (RARP) and the preoperative factors associated with PSM. In all, 1229 men underwent RARP by a single surgeon, from 2005 to August of 2013. Excluded were patients who had transurethral resection of the prostate, neoadjuvant therapy, clinically advanced cancer, and the first 200 performed cases (to reduce the effect of learning curve). Included were 815 patients who were then divided into three prostate size groups: <31 g (group 1), 31-45 g (group 2), >45 g (group 3). Multivariate analysis determined predictors of PSM and biochemical recurrence (BCR). Console time and blood loss increased with increasing prostate size. There were more high-grade tumours in group 1 (group 1 vs group 2 and group 3, 33.9% vs 25.1% and 25.6%, P = 0.003 and P = 0.005). PSM rates were higher in prostates of <45 g with preoperative PSA levels of >20 ng/dL, Gleason score ≥7, T3 tumour, and ≥3 positive biopsy cores. In group 1, preoperative stage T3 [odds ratio (OR) 3.94, P = 0.020] and ≥3 positive biopsy cores (OR 2.52, P = 0.043) were predictive of PSM, while a PSA level of >20 ng/dL predicted the occurrence of BCR (OR 5.34, P = 0.021). No preoperative factors predicted PSM or BCR for groups 2 and 3. | Lactate dehydrogenase-elevating virus (LDV) is a natural infectious agent of mice. Like several other viruses, LDV causes widespread and very rapid but transient activation of both B cells and T cells in lymphoid tissues and the blood. The mechanism of this activation has not been fully described and is the focus of the current studies. A known inducer of early lymphocyte activation is IFNalpha, a cytokine strongly induced by LDV infection. Neutralization of IFNalpha in the plasma from infected mice ablated its ability to activate lymphocytes in vitro. Since the primary source of virus-induced IFNalpha in vivo is often plasmacytoid dendritic cells (pDC's), we depleted these cells prior to LDV infection and tested for lymphocyte activation. Depletion of pDC's in vivo eradicated both the LDV-induced IFNalpha response and lymphocyte activation. A primary receptor in pDC's for single stranded RNA viruses such as LDV is the toll-like receptor 7 (TLR7) pattern recognition receptor. Infection of TLR7-knockout mice revealed that both the IFNalpha response and lymphocyte activation were dependent on TLR7 signaling in vivo. Interestingly, virus levels in both TLR7 knockout mice and pDC-depleted mice were indistinguishable from controls indicating that LDV is largely resistant to the systemic IFNalpha response. |
Do evaluation of triple antibiotic paste removal by different irrigation procedures? | Regenerative endodontics aims to re-establish a functional pulp-dentin complex. First, the root canal system is disinfected primarily by irrigants and medicaments. Triple antibiotic paste (TAP), a commonly used intracanal medicament, has been shown to be directly toxic to stem cells at concentrations greater than 0.1 g/mL. Thus, its complete removal is a crucial step in regenerative endodontic procedures. We hypothesized that currently used irrigation techniques do not completely remove TAP from root canal system. TAP was radiolabeled by the incorporation of I(125), and calcium hydroxide (Ultracal; Ultradent, South Jordan, UT) was radiolabeled with Ca(45). The intracanal medicaments were placed into standardized human root segments and incubated for 28 days at 37°C. Then, canals were irrigated with EndoActivator (Dentsply, Tulsa, OK), passive ultrasonic irrigation, EndoVac (SybronEndo, Coppell, TX), or a syringe/Max-i-Probe needle (Dentsply Rinn, Elgin, IL) using a standardized irrigation protocol in a closed system. Radioactivity levels (counts per minute values) were measured for each tooth before and after the irrigation protocols. Furthermore, the canals were sequentially enlarged and dentin samples collected and evaluated for radioactivity. Data were analyzed with analysis of variance and Bonferroni post hoc testing (P < .05). Approximately 88% of the TAP was retained in the root canal system regardless of the irrigation technique used (no difference among groups). Furthermore, approximately 50% of the radiolabeled TAP was present circumferentially up to 350 μm within the dentin. Conversely, up to 98% of the radiolabeled intracanal calcium hydroxide was removed, and most residual medicament was found present in the initial 50 μm of dentin. | To investigate the antithrombin (AT) activity (AT: A) and AT antigen (AT: Ag) level in a Chinese family with type I antithrombin (AT) deficiency, and to explore the molecular mechanism of AT deficiency. Immuno-nephelometry and chromogenic assay were used to detect the plasma level of AT: A and AT: Ag, respectively. Genomic DNA was isolated from the peripheral blood, and all the seven exons and exon-intron boundaries of AT gene were amplified by PCR and direct sequencing. The plasma levels of AT: A and AT: Ag of the proband were 45% and 97 mg/L, respectively, which led to a type I AT deficiency. A heterozygous T to A mutation was found at nucleotide 9833 in exon 5 resulting in a Tyr363Stop nonsense mutation. The sequencing results from the pedigree indicated that four other members also had this mutation. |
Does the Natural Time Course of Membrane Alterations During Peritoneal Dialysis be Partly Altered by Peritonitis? | ♦ The quality of the peritoneal membrane can deteriorate over time. Exposure to glucose-based dialysis solutions is the most likely culprit. Because peritonitis is a common complication of peritoneal dialysis (PD), distinguishing between the effect of glucose exposure and a possible additive effect of peritonitis is difficult. The aim of the present study was to compare the time-course of peritoneal transport characteristics in patients without a single episode of peritonitis-representing the natural course-and in patients who experienced 1 or more episodes of peritonitis during long-term follow-up. ♦ This prospective, single-center cohort study enrolled incident adult PD patients who started PD during 1990-2010. A standard peritoneal permeability analysis was performed in the first year of PD treatment and was repeated every year. The results in patients without a single episode of peritonitis ("no-peritonitis group") were compared with the results obtained in patients who experienced 1 or more peritonitis episodes ("peritonitis group") during a follow-up of 4 years. ♦ The 124 patients analyzed included 54 in the no-peritonitis group and 70 in the peritonitis group. The time-course of small-solute transport was different in the groups, with the peritonitis group showing an earlier and more pronounced increase in the mass transfer area coefficient for creatinine (p = 0.07) and in glucose absorption (p = 0.048). In the no-peritonitis group, the net ultrafiltration rate (NUFR) and the transcapillary ultrafiltration rate (TCUFR) both showed a steep increase from the 1st to the 2nd year of PD that was absent in the peritonitis group. Both groups showed a decrease in the NUFR after year 3. A decrease in the TCUFR occurred only in the peritonitis group. That decrease was already present after the year 1 in patients with severe peritonitis. The time-course of free water transport showed a continuous increase in the patients without peritonitis, but a decrease in the patients who experienced peritonitis (p < 0.01). No difference was observed in the time-course of the effective lymphatic absorption rate. The time-courses of immunoglobulin G and α2-macroglobulin clearances showed a decrease in both patient groups, with a concomitant increase of the restriction coefficient. Those changes were not evidently influenced by peritonitis. The two groups showed a similar decrease in the mesothelial cell mass marker cancer antigen 125 during follow-up. ♦ | Prolonged re-exposure to a fear-eliciting cue in the absence of an aversive event extinguishes the fear response to the cue, and has been clinically used as an exposure therapy. Arc (also known as Arg3.1) is implicated in synaptic and experience-dependent plasticity. Arc is regulated by the transcription factor cAMP response element binding protein, which is upregulated with and necessary for fear extinction. Because Arc expression is also activated with fear extinction, we hypothesized that Arc expression is required for fear extinction. Extinction training increased the proportion of Arc-labeled cells in the basolateral amygdala (BLA). Arc was transcribed during latter part of extinction training, which is possibly associated with fear extinction, as well as former part of extinction training. Intra-BLA infusions of Arc antisense oligodeoxynucleotide (ODN) before extinction training impaired long-term but not short-term extinction memory. Intra-BLA infusions of Arc antisense ODN 3 h after extinction training had no effect on fear extinction. |
Does carotid Arterial Hemodynamic in Ischemic Levkoaraiosis suggest Hypoperfusion Mechanism? | Leukoaraiosis (ILA) is believed to be ischaemic in origin due to its similar location as that of lacunar infarctions and its association with cerebrovascular risk factors. However, its pathophysiology is not well understood. The ischaemic injuries may be a result of increased pulsatility or cerebral hypo-perfusion. We used carotid duplex ultrasound to prove that the underlying mechanism is hypo-perfusion. We compared 55 ILA patients to 44 risk factor-matched controls with normal magnetic resonance imaging (MRI) of the head. ILA diagnosis was based on MRI and was further categorised according to the Fazekas scale. We measured carotid artery blood flow velocity and diameter and calculated carotid blood flow and resistance indexes. Blood flow velocities and blood flows were significantly lower in the ILA group, including diastolic, systolic and mean pressures (p ≤ 0.05). The resistance indices were higher in the ILA group, but the differences were not statistically significant. All the velocities and blood flows showed a decreasing trend with higher Fazekas score, whereas resistance indexes showed an increasing trend. | Notch signaling plays a critical role in maintaining the balance between cell proliferation, differentiation, and apoptosis, and thereby may contribute to the development of pancreatic cancer. Therefore, the down-regulation of Notch signaling may be a novel approach for pancreatic cancer therapy. It has been reported that curcumin down-regulates many genes that are known to promote survival and also up-regulates genes that are known promoters of apoptosis in pancreatic cancer cells in vitro. It also has been reported that there is cross-talk between Notch-1 and another major cell growth and apoptotic regulatory pathway, the nuclear factor kappaB (NF-kappaB) pathway, which is down-regulated by both curcumin and reduction of Notch-1 levels. However, to the authors' knowledge to date, no studies have determined whether the down-regulation of Notch-1 signaling, resulting in the inactivation of NF-kappaB activity, contributes to curcumin-induced cell growth inhibition and apoptosis in pancreatic cancer cells. The authors used multiple molecular approaches, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, an apoptosis assay, gene transfection, real-time reverse transcriptase-polymerase chain reaction analysis, Western blot analysis, and an electrophoretic mobility shift assay to measure the DNA binding activity of NF-kappaB. Curcumin inhibited cell growth and induced apoptosis in pancreatic cancer cells. Notch-1, Hes-1, and Bcl-XL expression levels concomitantly were down-regulated by curcumin treatment. These results correlated with the inactivation of NF-kappaB activity and increased apoptosis induced by curcumin. The down-regulation of Notch-1 by small-interfering RNA prior to curcumin treatment resulted in enhanced cell growth inhibition and apoptosis. |
Do hot flushes and night sweats differ in associations with cardiovascular markers in healthy early postmenopausal women? | The aim of this study was to evaluate the associations between vasomotor symptoms ([VMS] hot flushes or flashes and night sweats) and markers of cardiovascular risk. Healthy postmenopausal women in a randomized controlled trial of progesterone for VMS recorded VMS frequency in the Daily Menopause Diary for 28 days at baseline. Accepted risks for cardiovascular disease were measured: body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), blood pressure (BP), endothelial function by venous occlusion plethysmography, fasting lipids, glucose, high-sensitivity C-reactive protein, albumin, and D-dimer. Relationships between risk variables and VMS frequency (24 h, day and night) were assessed by univariate and multivariate robust regressions with adjustment for age and WHtR. Data were available for 145 healthy, nonsmoking women without heart disease, hypertension, or diabetes who were 1 to 11 years past their final menstruation and were aged 43 to 65 years, with a mean (SD) BMI of 25.0 (2.9) kg/m and WC of 79.1 (7.1) cm. Anthropometric variables (BMI, WC, and WHtR) were significantly negatively associated with total (24-h day) VMS frequency and with day VMS but not with night VMS frequency. Systolic BP decreased with greater 24-hour VMS frequency, and both systolic and diastolic BPs were inversely related to day but not night VMS frequency. Albumin was positively associated with night VMS frequency but not with day or 24-hour VMS frequency. Other variables showed little association with VMS frequency. | The phenotypic characteristics that allow some tumor cells to metastasize have not been fully identified. The production and/or response of tumor cells to various growth factors have been shown to distinguish cells of differing metastatic potentials. To determine (1) whether rat hepatocellular carcinoma cell lines produce interleukin-6 (IL-6) and (2) whether production of IL-6 correlates with either metastatic potential or tumorigenicity. The clonal cell lines 1682.C.2.9.L0 (poorly metastatic) and 1682.C.2.9.L10 (highly metastatic) were selected from a parental hepatocellular carcinoma induced in ACI rats by feeding an ethionine-containing diet and adapted to growth in vitro. Both cell lines resulted in primary tumors with equal frequency and developed a 40-mm nodule in a similar period time, when an inoculum of 5 X 10(6) cells was injected subcutaneously; however, only L10 cells metastasized to the lung. These cell lines did not demonstrate differential expression of several antigens noted to correlate with metastatic potential, including CD44 variant glycoprotein, p53, transferrin receptor, and E-cadherin. In contrast, L0 cells produced less than 10 U of IL-6 per milliliter in culture (as determined by bioassay using 7TD1 cells), whereas L10 cells released more than 95 U of this cytokine per milliliter under identical culture conditions (P<.01, Student's t test). In addition, serum concentrations of IL-6 were elevated in animals bearing L10-induced primary tumors but not in those with L0-induced tumors of comparable mass. Exogenous addition of IL-6 to both tumor cell lines had no effect on the rate of growth in vitro, supporting the similar the tumorigenic potentials observed in vivo. |
Is online information for women and their families regarding reduced fetal movements of variable quality , readability and accountability? | reduced fetal movements (RFM) are experienced by 46-50% of women prior to the diagnosis of stillbirth. Empowering women with evidenced-based information regarding RFM may allow for prompt contact with a health care provider and access to appropriate management. Use of the Internet is growing in popularity as a source of pregnancy information to aid mothers׳ decision-making. This study aimed to identify and examine the available online information for pregnant women regarding RFM. a systematic search was performed using Google, Yahoo and Bing to identify the most popular websites giving information about RFM. The websites were assessed for readability, accountability and content using the Flesh-Kincaid ease of readability score; the Silberg criteria; and by comparison to evidence-based guidelines respectively. Chat forums were assessed using a qualitative thematic analysis. 70 information articles and 63 chat forums were analysed from 77 unique websites. The mean readability score was 65.7 (suitable for the average 13-15 year old) and therefore above the recommended level set for health materials; only 15 (21.4%) websites met all accountability criteria; and 43 (70%) websites contained information that was not in accordance with evidence-based recommendations. Typical questions on forums were 'Is this normal? What should I do?' and responses were 'Better safe than sorry', 'There is no harm in calling'. | Inflammatory processes are an integral component of the initiation, progression, and destabilization of atherosclerotic lesions. Tumor necrosis factor-alpha (TNF-alpha) is considered a primary mediator of inflammatory processes. The role of TNF-alpha in plaque progression and plaque destabilization was investigated in the innominate arteries of older TNF-alpha receptor p55 deficient mice that were generated on a hyperlipidemic apolipoprotein E deficient background (p55-/- apoE-/-). There were no significant differences in levels of circulating cytokines, plaque progression, plaque composition or features of plaque destabilization in p55-/- apoE-/- compared to wild type (p55+/+ apoE-/-) mice. |
Do both host and graft vessels contribute to revascularization of xenografted human ovarian tissue in a murine model? | To characterize the human ovarian xenograft revascularization process. Prospective experimental study. Gynecology research unit in a university hospital. Ovarian biopsies were obtained from 12 women aged 22-35 years. Frozen-thawed human ovarian fragments were intraperitoneally grafted into nude mice. Graft perfusion was evaluated by Hoechst 33342 uptake. Murine and human vascularization was analyzed by CD31 and von Willebrand factor double immunostaining. On day 3, some murine neovessels and perfused areas were located at the periphery of the fragments. Nonperfused native human vessels were present in the fragments. From day 5, perfused areas and murine endothelial areas progressively increased. Host angiogenesis initiated ovarian graft reperfusion: murine neovessels penetrated from the periphery and were colocalized with perfused areas. By day 10, the increase in perfusion and murine vascularization was significant. The center of the fragments was perfused and a significant increase was observed in human vasculature. | To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men. Prospective cohort study. A Department of Veterans Affairs primary care clinic. Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension. The outcomes were measured using the Hopkins Verbal Recall Test (HVRT) for short-term memory and the instrumental activity of daily living (IADL) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants' primary care visit records and quantified as total anticholinergic burden using a clinician-rated anticholinergic score. Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point (95% confidence interval (CI)= 0.05-0.58) and 0.10-point (95% CI=0.04-0.17) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory (0.29, 95% CI=0.01-0.56) and executive function (0.08, 95% CI=0.02-0.15) after further adjustment for concomitant non-anticholinergic medications. |
Is routine pathology evaluation of hydrocele and spermatocele specimens associated with significant costs and no identifiable benefit? | Hydrocelectomy and spermatocelectomy are routine scrotal surgeries. A significant number of the surgical specimens are sent for pathology analysis. However, to our knowledge no study has been done to examine outcomes and necessity, which results in significant potentially unnecessary costs to the patient and the health care system. We evaluated outcomes and surgical pathology analysis of hydroceles and spermatoceles. We performed a retrospective, single institution chart review of all patients who underwent initial surgery for hydrocele or spermatocele between January 2000 and August 2013. We determined the number of cases in which a surgical specimen was sent for pathology examination. The cost for each specimen was estimated at the department of pathology. A total of 264 routine scrotal cases were performed during the 14-year period. Surgical specimens were sent for pathology analysis in 102 hydrocelectomy cases (51%) and in 57 spermatocelectomy cases (90%). No pathology specimen showed any indication of malignancy. The estimated direct total cost of pathology analysis was $49,449 in this cohort. | Thiazolidinediones (TZDs) are synthetic agonists for the peroxisome proliferator-activating receptor-gamma receptor and are currently in use as oral glucose-lowering drugs. TZDs have immune-modulating effects in vitro and in vivo. Because patients with type 2 diabetes have an increased risk for pneumonia, we evaluated the influence of ciglitazone, a TZD, on markers of inflammation and outcome during pneumonia caused by Streptococcus pneumoniae. In vivo animal study and in vitro study. University research laboratory. Female C57Bl/6 mice and murine alveolar macrophage-like MH-S cells. C57Bl/6 mice were inoculated with 10 colony-forming units of S. pneumoniae intranasally. The following interventions were studied: 1) vehicle at t = 0; 2) ciglitazone 5 mg/kg intraperitoneally at t = 0; and 3) ciglitazone 5 mg/kg intraperitoneally at t = 0 and 24 hours. Mice were killed at either 24 or 48 hours after infection. Additionally, phagocytosis and killing of S. pneumoniae by MH-S cells were assessed in vitro. Single treatment with ciglitazone reduced bacterial loads at 24 hours but not at 48 hours, whereas repeated ciglitazone treatment did diminish bacterial loads at 48 hours. After 24 hours, cytokine levels in lung homogenate were lower in single-dose ciglitazone-treated mice; however, after 48 hours, there was no difference in lung cytokines between any of the experimental groups. Repeated ciglitazone treatment was associated with less pulmonary inflammation, as judged by histologic examination. On both time points, there was no difference in plasma cytokine levels or lung myeloperoxidase levels between experimental groups. In an additional experiment, ciglitazone treatment (given once daily) tended to reduce mortality. Ciglitazone did not influence phagocytosis or killing of S. pneumoniae by murine alveolar macrophages. |
Does assessment of procedural skills using virtual simulation remain a challenge? | The LAP Mentor is a procedural simulator that provides a stepwise training for laparoscopic cholecystectomy. This study addresses its "construct" validity that is present when a simulator is able to discriminate between persons with known differences in performance level on the laparoscopic cholecystectomy in real life. Three groups with different skill levels performed 2 trials of 4 distinct parts of the cholecystectomy procedure (cholecystectomy exercises) and 1 full procedure on the LAP Mentor. Assessment parameters concerning the quantity and the quality of performance were compared between groups using the Kruskal-Wallis and Mann-Whitney U tests. The entire research was performed in the Center for Surgical Technologies, Leuven, Belgium. For study purposes, 5 expert abdominal laparoscopists (>100 laparoscopic cholecystectomies performed), 11 surgical residents (10-30 cholecystectomies performed), and 10 novices (minimal laparoscopic experience) were recruited. With regard to the quantity of performance (time needed and number of movements), the experts showed significantly better results compared with the novices in the cholecystectomy exercises. Only in the full procedure, the results of all the parameters (except speed) were significantly different between the 3 groups, with the best results observed for the experts and worst for the novices. With respect to quality of performance, only the parameter "accuracy rate of dissection" in exercise 3 showed significantly better performance by the experts. | To characterize phenotypes of T cells that accumulated in multiple sclerosis (MS) lesions, to compare the lesional T-cell receptor (TCR) repertoire of T-cell subsets to peripheral blood, and to identify paired α and β chains from single CD8(+) T cells from an index patient who we followed for 18 years. We combined immunohistochemistry, laser microdissection, and single-cell multiplex PCR to characterize T-cell subtypes and identify paired TCRα and TCRβ chains from individual brain-infiltrating T cells in frozen brain sections. The lesional and peripheral TCR repertoires were analyzed by pyrosequencing. We found that a TCR Vβ1(+) T-cell population that was strikingly expanded in active brain lesions at clinical onset comprises several subclones expressing distinct yet closely related Vα7.2(+) α chains, including a canonical Vα7.2-Jα33 chain of mucosal-associated invariant T (MAIT) cells. Three other α chains bear striking similarities in their antigen-recognizing, hypervariable complementarity determining region 3. Longitudinal repertoire studies revealed that the TCR chains that were massively expanded in brain at onset persisted for several years in blood or CSF but subsequently disappeared except for the canonical Vα7.2(+) MAIT cell and a few other TCR sequences that were still detectable in blood after 18 years. |
Is lorazepam an independent risk factor for transitioning to delirium in intensive care unit patients? | Delirium has recently been shown as a predictor of death, increased cost, and longer duration of stay in ventilated patients. Sedative and analgesic medications relieve anxiety and pain but may contribute to patients' transitioning into delirium. In this cohort study, the authors designed a priori an investigation to determine whether sedative and analgesic medications independently increased the probability of daily transition to delirium. Markov regression modeling (adjusting for 11 covariates) was used in the evaluation of 198 mechanically ventilated patients to determine the probability of daily transition to delirium as a function of sedative and analgesic dose administration during the previous 24 h. Lorazepam was an independent risk factor for daily transition to delirium (odds ratio, 1.2 [95% confidence interval, 1.1-1.4]; P = 0.003), whereas fentanyl, morphine, and propofol were associated with higher but not statistically significant odds ratios. Increasing age and Acute Physiology and Chronic Health Evaluation II scores were also independent predictors of transitioning to delirium (multivariable P values < 0.05). | The effect of in vitro expansion of human adipose-derived stem cells (ASCs) on stem cell properties is controversial. We examined serial subcultivation with expansion on the ability of ASCs to grow and differentiate into osteoblastic lineages. Flow cytometric analysis, growth kinetics, cell population doubling time, light microscopy and confocal analysis, and osteogenesis induction were performed to assess growth and osteogenic potential of subcultivated ASCs at passages 2 (P2), P4 and P6. Flow cytometric analysis revealed that ASCs at P2 express classical mesenchymal stem cell markers including CD44, CD73, and CD105, but not CD14, CD19, CD34, CD45, or HLA-DR. Calcium deposition and alkaline phosphatase activity were the highest at P2 but completely abrogated at P4. Increased passage number impaired cell growth; P2 cultures exhibited exponential growth, while cells at P4 and P6 showed near linear growth with cell population doubling times increased from 3.2 at P2 to 4.8 d at P6. Morphologically, cells in various subcultivation stages showed flattened shape at low density but spindle-like structures at confluency as judged by phalloidin staining. |
Does post-repolarization refractoriness increase vulnerability to block and initiation of reentrant impulses in heterogeneous infarcted myocardium? | Myocardial infarction causes remodeling of the tissue structure and the density and kinetics of several ion channels in the cell membrane. Heterogeneities in refractory period (ERP) have been shown to occur in the infarct border zone and have been proposed to lead to initiation of arrhythmias. The purpose of this study is to quantify the window of vulnerability (WV) to block and initiation of reentrant impulses in myocardium with ERP heterogeneities using computer simulations. We found that ERP transitions at the border between normal ventricular cells (NZ) with different ERPs are smooth, whereas ERP transitions between NZ and infarct border zone cells (IZ) are abrupt. The profile of the ERP transitions is a combination of electrotonic interaction between NZ and IZ cells and the characteristic post-repolarization refractoriness (PRR) of IZ cells. ERP heterogeneities between NZ and IZ cells are more vulnerable to block and initiation of reentrant impulses than ERP heterogeneities between NZ cells. The relationship between coupling intervals of premature impulses (V1V2) and coupling intervals between premature and first reentrant impulses (V2T1) at NZ/NZ and NZ/IZ borders is inverse (i.e. the longer the coupling intervals of premature impulses the shorter the coupling interval between the premature and first reentrant impulses); this is in contrast with the reported V1V2/V2T1 relationship measured during initiation of reentrant impulses in canine infarcted hearts which is direct. | Probiotics can prevent pathological bacterial translocation in cirrhosis by modulating intestinal microbiota and improving gut barrier and immune disturbances. To evaluate the effect of probiotic VSL#3 on bacterial translocation, intestinal microbiota, gut barrier and inflammatory response in rats with experimental cirrhosis. Forty-six Sprague-Dawley rats with CCl4 -induced cirrhosis were randomized into two groups: VSL#3 group (n = 22) that received VSL#3 in drinking water, and water group (n = 24) that received water only. Treatment began at week 6 of cirrhosis induction and continued until laparotomy, performed 1 week after development of ascites or at week 20. A control group included 11 healthy rats. At this study end, we evaluated bacterial translocation, intestinal flora, intestinal barrier (ileal claudin-2 and 4, β-defensin-1, occludin and malondialdehyde as index of oxidative damage) and serum cytokines. Mortality during this study was similar in the VSL#3 group (10/22, 45%) and the water group (10/24, 42%) (P = 1). The incidence of bacterial translocation was 1/12 (8%) in the VSL#3 group, 7/14 (50%) in the water group (P = 0.03 vs. VSL#3 group) and 0/11 in the control group (P = 0.008 vs. water group). The concentration of ileal and caecal enterobacteria and enterococci was similar in the two groups of cirrhotic rats. The ileal occludin concentration was higher and ileal malondialdehyde and serum levels of TNF-α were lower in the VSL#3 group than in the water group (P < 0.05). |
Does serum Thyroglobulin Concentration be a Weak Marker of Iodine Status in a Pregnant Population with Iodine Deficiency? | To assess the reliability of thyroglobulin (Tg) as a marker of iodine status during pregnancy. 299 women aged 30.5 ± 4.8 years (mean ± SD) were studied. In every subject, we measured urinary iodine concentration (UIC), serum thyrotropin (TSH), Tg, free thyroxine (fT4), Tg autoantibodies (TgAbs) and human chorionic gonadotropin (hCG) levels. We excluded samples with increased TgAbs from the analysis. According to WHO criteria, the study population was iodine deficient in every trimester. Serum Tg levels did not differ during the three trimesters of pregnancy. Serum hCG levels fell significantly as pregnancies advanced. A weak, significantly negative correlation (limited to the 3rd trimester) was found between Tg and UIC (ρ = -0.187, p = 0.039). Serum fT4 decreased as pregnancies advanced and TSH increased. Serum fT4 was negatively correlated with TSH (ρ = -0.161, p = 0.006) and positively with hCG (ρ = +0.165, p = 0.005). The multiple regression equation of Tg based on hCG, TSH, UIC and trimester of pregnancy was significant but weak (F = 4.057, p = 0.003; R(2) = 0.055), with hCG as a significant predictor Tg (p for log hCG = 0.041). | Wnts are secreted glycoproteins that regulate diverse aspects of development, including cell proliferation, cell fate specification and differentiation. More recently, Wnts have been shown to direct axon guidance in vertebrates, flies and worms. However, little is known about the intracellular signaling pathways downstream of Wnts in axon guidance. Here we show that the posterior C. elegans Wnt protein LIN-44 repels the axons of the adjacent D-type motor neurons by activating its receptor LIN-17/Frizzled on the neurons. Moreover, mutations in mig-5/Disheveled, gsk-3, pry-1/Axin, bar-1/beta-catenin and pop-1/TCF, also cause disrupted D-type axon pathfinding. Reduced BAR-1/beta-catenin activity in D-type axons leads to undergrowth of axons, while stabilization of BAR-1/beta-catenin in a lin-23/SCF(beta-TrCP) mutant results in an overextension phenotype. |
Does polo-like Kinase Inhibitor Volasertib exhibit Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies? | Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies. Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib. Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide. | To determine whether obese patients undergoing laparoscopic surgery within an enhanced recovery program had worse short-term outcomes. A prospective study of consecutive patients undergoing laparoscopic colorectal resection was carried out between 2008 and 2011 in a single institution. Patients were divided in groups based on body mass index (BMI). Short-term outcomes including operative data, length of stay, complications and readmission rates were recorded and compared between the groups. Continuous data were analysed using t-test or one-way Analysis of Variance. χ(2) test was used to compare categorical data. Two hundred and fifty four patients were included over the study period. The majority of individuals (41.7%) recruited were of a healthy weight (BMI < 25), whilst 50 patients were classified as obese (19.6%). Patients were matched in terms of the presence of co-morbidities and previous abdominal surgery. Obese patients were found to have a statistically significant difference in The American Society of Anesthesiologists grade. Length of surgery and intra-operative blood loss were no different according to BMI. |
Does the ubiquitin proteasome system acutely regulate presynaptic protein turnover and synaptic efficacy? | The ubiquitin proteasome system (UPS) mediates regulated protein degradation and provides a mechanism for closely controlling protein abundance in spatially restricted domains within cells. We hypothesized that the UPS may acutely determine the local concentration of key regulatory proteins at neuronal synapses as a means for locally modulating synaptic efficacy and the strength of neurotransmission communication. We investigated this hypothesis at the Drosophila neuromuscular synapse by using an array of genetic and pharmacological tools. This study demonstrates that UPS components are present in presynaptic boutons and that the UPS functions locally in the presynaptic compartment to rapidly eliminate a conditional transgenic reporter of proteasome activity. We assayed a panel of synaptic proteins to determine whether the UPS acutely regulates the local abundance of native synaptic targets. Both acute pharmacological inhibition of the proteasome (<1 hr) and targeted genetic perturbation of proteasome function in the presynaptic neuron cause the specific accumulation of the essential synaptic vesicle-priming protein DUNC-13. Most importantly, acute pharmacological inhibition of the proteasome (<1 hr) causes a rapid strengthening of neurotransmission (an approximately 50% increase in evoked amplitude) because of increased presynaptic efficacy. The proteasome-dependent regulation of presynaptic protein abundance, both of the exogenous reporter and native DUNC-13, and the modulation of presynaptic neurotransmitter release occur on an intermediate, rapid (tens of minutes) timescale. | This study was done to assess the relationship between prevalent cardiovascular disease and arterial wall thickness in middle-aged US adults. The association of preexisting coronary heart disease, cerebrovascular disease, and peripheral vascular disease with carotid and popliteal intimal-medial thickness (IMT) (measured by B-mode ultrasound) was assessed in 13,870 black and white men and women, aged 45 to 64, during the Atherosclerosis Risk in Communities (ARIC) Study baseline examination (1987 through 1989). Prevalent disease was determined according to both participant self-report and measurements at the baseline examination (including electrocardiogram, fasting blood glucose, and medication use). Across four race and gender strata, mean carotid far wall IMT was consistently greater in participants with prevalent clinical cardiovascular disease than in disease-free subjects. Similarly, the prevalence of cardiovascular disease was consistently greater in participants with progressively thicker IMT. The greatest differences in carotid IMT associated with prevalent disease were observed for reported symptomatic peripheral vascular disease (0.09 to 0.22 mm greater IMT in the four race-gender groups). |
Do alcohol cues increase cognitive impulsivity in individuals with alcoholism? | Individuals with alcoholism are characterized by both attentional bias for alcohol cues and prepotent response inhibition deficit. We tested the hypothesis that alcoholics exhibit greater cognitive disinhibition when the response to be suppressed is associated with alcohol-related information. Forty recently detoxified individuals with alcoholism were compared with 40 healthy non-substance abusers on the "Alcohol-Shifting Task", a variant of the go/no-go paradigm requiring a motor response to targets and no response to distracters. The aim was to test the ability of alcoholics to discriminate between alcohol-related and neutral words. Sometimes, the alcohol-related words were the targets for the "go" response, with neutral words as distracters, sometimes the reverse. Several shifts in target type occurred during the task. Alcoholics made significantly more commission errors (i.e., press a key when a distracter displayed) and more omission errors (i.e., not press a key when a target displayed) than controls. Moreover, the number of commission errors was greater in alcoholics when alcohol-related stimuli had to be detected. | Previous studies have demonstrated deregulation of the expression and changes in the intracellular distribution of TGF-beta pathway components in human endometrial cancer (EC). The aim of this study was to assess the relationship between the expression of TGF-beta cascade components, including TGF-beta receptor type I (TGF beta RI) and type II (TGF beta RII), SMAD2, SMAD3, SMAD4, and clinicopathological features--tumor grade, FIGO classification, and depth of myometrial invasion--of type I (endometrioid-type) ECs to give some insight into the role of TGF-beta cascade components in endometrial tumorigenesis. The expression of TGF beta RI, TGF beta RII, SMAD2, SMAD3, and SMAD4 was evaluated both at the mRNA and protein level using reverse transcription polymerase chain reaction (RT-PCR) and ELISA, respectively. Infiltrating endometrial carcinomas (less and more than half of the myometrial wall thickness) express significantly higher TGF beta RII protein level compared with non-infiltrating tumors (P = 0.04 and P = 0.01, respectively). Decreased level of SMAD2 and SMAD4 mRNAs was observed in the uterine tumors infiltrating less and more than half of the myometrial wall (P = 0.03 and P = 0.02, respectively) compared with noninfiltrating ECs. Significantly higher SMAD4 protein level in the cytoplasmic fraction of ECs was found when tumor grade and depth of myometrial invasion were considered (P < 0.05). Generally, tumor progression was associated with a decreased number of cases characterized by the presence of SMADs in the nuclear fraction only. |
Is empiric use of ampicillin and cefotaxime , compared with ampicillin and gentamicin , for neonates at risk for sepsis associated with an increased risk of neonatal death? | We reported previously that the use of cephalosporin among premature neonates increased the risk of subsequent fungal sepsis. As a result, we recommended that ampicillin and gentamicin be used as empiric coverage for early-onset neonatal sepsis while culture results are awaited. To describe antibiotic use during the first 3 days after birth for neonates admitted to the NICU and to evaluate the outcomes for neonates treated with 2 different antibiotic regimens. We assembled a cohort of inborn neonates, from our deidentified administrative database, who had documented exposure to ampicillin during the first 3 days after birth. Infants treated concurrently with cefotaxime or gentamicin were evaluated, to identify the factors that were associated independently with death before discharge, with both univariate and multivariate analyses. There were 128,914 neonates selected as the study cohort; 24,111 were treated concurrently with ampicillin and cefotaxime and 104,803 were treated concurrently with ampicillin and gentamicin. Logistic modeling showed that neonates treated with ampicillin/cefotaxime were more likely to die (adjusted odds ratio: 1.5; 95% confidence interval: 1.4-1.7) and were less likely to be discharged to home or foster care than were neonates treated with ampicillin/gentamicin. This observation was true across all estimated gestational ages. Other factors that were associated independently with death included immature gestational age, need for assisted ventilation on the day of admission to the NICU, indications of perinatal asphyxia or major congenital anomaly, and reported use of ampicillin/cefotaxime. | The aim of this study was to investigate the blood pressure (BP) response to exercise in normotensive patients with type II diabetes mellitus (DM). A cross-sectional study was carried out on 75 normotensive subjects with type 2 DM (group 1), and 70 age-gender matched normotensive healthy volunteers (group 2). Treadmill exercise test, 24-h ambulatory BP monitoring (ABPM) were performed for each patients and healthy volunteers. There were 67 patients (mean age 52 ± 9 years and 42% male) in group 1 and 68 healthy volunteers (mean age 51 ± 7 years and 43% male) in group 2. Eight patients from group 1 and 2 subjects from group 2 were excluded because of high BP on ABPM. Groups were similar for systolic BP (SBP) and diastolic BP (DBP) on office measurements and on ABPM. Groups were similar for rest SBP, DBP, heart rate, exercise duration on exercise test. Peak SBP was significantly higher in group 1 than in group 2, but peak DBP was not (196.9 ± 18 vs 165.9 ± 18.6 mmHg, p<0.001; 88.1 ± 11.6 vs 86.2 ± 8.7 mmHg, p = 0.283, respectively). Hypertensive response to exercise (HRE) was more frequent in group 1 than in group 2 [39 (58%) vs 6 (9%), p<0.001]. Independent predictors of peak SBP were DM, office SBP and male gender, while independent predictors of HRE were DM, office SBP and age in multivariate analysis. |
Is vasoactive-inotropic score associated with outcome after infant cardiac surgery : an analysis from the Pediatric Cardiac Critical Care Consortium and Virtual PICU System Registries? | To empirically derive the optimal measure of pharmacologic cardiovascular support in infants undergoing cardiac surgery with bypass and to assess the association between this score and clinical outcomes in a multi-institutional cohort. Prospective, multi-institutional cohort study. Cardiac ICUs at four academic children's hospitals participating in the Pediatric Cardiac Critical Care Consortium during the study period. Children younger than 1 year at the time of surgery treated postoperatively in the cardiac ICU. None. Three hundred ninety-one infants undergoing surgery with bypass were enrolled consecutively from November 2011 to April 2012. Hourly doses of all vasoactive agents were recorded for the first 48 hours after cardiac ICU admission. Multiple derivations of an inotropic score were tested, and maximum vasoactive-inotropic score in the first 24 hours was further analyzed for association with clinical outcomes. The primary composite "poor outcome" variable included at least one of mortality, mechanical circulatory support, cardiac arrest, renal replacement therapy, or neurologic injury. High vasoactive-inotropic score was empirically defined as more than or equal to 20. Multivariable logistic regression was performed controlling for center and patient characteristics. Patients with high vasoactive-inotropic score had significantly greater odds of a poor outcome (odds ratio, 6.5; 95% CI, 2.9-14.6), mortality (odds ratio, 13.2; 95% CI, 3.7-47.6), and prolonged time to first extubation and cardiac ICU length of stay compared with patients with low vasoactive-inotropic score. Stratified analyses by age (neonate vs infant) and surgical complexity (low vs high) showed similar associations with increased morbidity and mortality for patients with high vasoactive-inotropic score. | Cerebral deposition of phospho-tau in Alzheimer's disease (AD) occurs with varying patterns within hippocampus. Lamina-specific tau changes in AD may reflect trans-synaptic propagation of phospho-tau along neuroanatomical pathways. To study patterns of tau deposition within inner (IML) and outer (OML) molecular layers of dentate gyrus and their clinical and neuropathological correlates. 98 consecutive autopsied brains from the Columbia University Brain Bank were stained for phospho-tau using AT-8. Staining density was rated as High versus Low within IML and OML. Four patterns were observed among the 98 brains: High IML&OML, n = 44; High OML Only (n = 35); High IML Only (n = 5); and Low IML&OML (n = 14). Demographic, clinical, and neuropathological characteristics of these four groups were compared. High IML&OML subjects, versus High OML Only, were more likely to fulfill CERAD criteria for Definite AD (93% versus 66%, p < 0.01) and to have higher median Braak stage (6 versus 5, p < 0.01) and earlier mean age of onset (65.9 versus 73.7 y, p = 0.02), with similar symptom duration. Using logistic regression, the association between High IML&OML and AD remained significant after adjustment for demographics but not symptom duration. In the 70 subjects with Definite AD, High IML&OML was associated with younger age of onset (mean difference 3.7 years, 95%CI -6.7 to -0.7, p < 0.01), after adjustment for demographics and symptom duration. |
Does vitamin C protect against lysophosphatidylcholine-induced expression of monocyte chemoattractant protein-1 in cultured human umbilical vein endothelial cells? | It is well documented that oxidized low-density lipoproteins (LDLs) can stimulate human vascular endothelial cells to produce monocyte chemoattractant protein-1 (MCP-1). Vitamin C is known to be an important antioxidant for vasodilatation. The purpose of this study was to determine whether pretreatment with vitamin C could protect against oxidized-LDL-induced expression of MCP-1 in cultured human umbilical vein endothelial cells (HUVECs). Cultured HUVECs were used for desired experiments before passage 4. Lysophosphatidylcholine (lysoPC), an oxidized component of LDL, was designated as the stimulator for MCP-1 synthesis from cultured HUVECs. MCP-1 concentrations in the cultured media were determined by enzyme-linked immunosorbent assay. MCP-1 RNA was evaluated by a semi-quantitative reverse transcriptase-polymerase chain reaction. HUVECs secreted MCP-1 within 30 minutes after exposure to 50 microM lysoPC. Compared with samples treated with lysoPC alone, pretreatment with vitamin C in concentrations of 50, 100, 150, and 200 microM, reduced levels of MCP-1 in the culture medium by 44%, 51%, 60%, and 67%, respectively, while levels of MCP-1 mRNA decreased by 15%, 18%, 80%, and 82%, respectively. | Determine the effect that increased medical surgical (med/surg) bed occupancy has on the time interval from admission order to arrival in the bed for the patients admitted from the emergency department (ED). This retrospective observational study compares the total hospital bed occupancy rate and the medical surgical inpatient bed occupancy rate to daily averages for the time interval from admission order (patient posting for admission) to the patient's arrival in the inpatient bed. Medical surgical inpatient bed occupancy of 92% was chosen because beyond that rate we observed more frequent extended daily transfer times. The data is from a single large tertiary care institute with 590 beds and an annual ED census of 80,000. Group 1 includes 38 days with (med/surg) inpatient bed occupancy rate of less than 92%, with an average ED daily wait of 2.5 hrs (95% confidence interval 2.23-2.96) for transfer from the ED to the appropriate hospital bed. Group 2 includes 68 days with med/surg census greater than 92% with an average ED daily wait of 4.1 hours (95% confidence interval 3.7-4.5). Minimum daily average for the two groups was 1.2 hrs and 1.3 hrs, respectively. The maximum average was 5.6 hrs for group 1 and 8.6 hrs for group 2. Comparison of group 1 to 2 for wait time to hospital bed yielded p <0.01. Total reported hospital occupied capacity shows a correlation coefficient of 0.16 to transfer time interval, which indicates a weak relationship between total occupancy and transfer time into the hospital. Med/surg occupancy, the beds typically used by ED patients, has a 0.62 correlation coefficient for a moderately strong relationship. |
Do augmentative therapies potentiate the antidepressant-like effects of deep brain stimulation in rats? | Clinical trials have shown promising results with the use of subcallosal cingulate gyrus deep brain stimulation (DBS) for treatment-resistant depression. However, strategies to manage patients who do not respond to this therapy have not been explored in detail. In rats, DBS in the ventromedial prefrontal cortex (vmPFC) induces a significant antidepressant-like response in the forced swim test (FST). We have used this test to investigate potential interactions between DBS and clinically used augmentative regimens. Rats undergoing the FST were treated with vmPFC DBS along with different augmentative drugs, namely buspirone, risperidone and pindolol. Locomotor activity was tested in an open field. DBS induced a significant reduction in immobility scores as compared to saline treated controls. These antidepressant-like effects, however, were not potentiated by the co-administration of buspirone, risperidone or pindolol. | Multiple myeloma is a heterogeneous entity with variable course. Plasma cells found in bone marrow smears are characterised by extremely high diversity of morphology. We have attempted to determine whether the morphological characteristics of myeloma cells vary with the natural course of the disease. We investigated the incidence of selected morphological features and planimetric parameters of myeloma cells present in bone marrow smears. Material collected from 103 patients was evaluated at diagnosis and then during relapse. It was found that in the same patients, plasma cell morphology changes in the course of the disease: cell surface, nucleus surface, tumour cell anisocytosis and nuclear-cytoplasmic ratio increase significantly. The results suggest that some morphological features are more common in clinically advanced disease. These include the number of nucleoli, the number of myeloma cells with irregular nuclei, and larger nuclei. Using the classification systems according to Greipp and Goasguen, we have noted changes in morphological pattern of myeloma cells in some patients with progressive multiple myeloma. This was associated with the appearance of a cell clone characterised by a set of traits indicating a low degree of maturity. |
Does blood-injury phobia with and without a history of fainting : disgust sensitivity explain the fainting response? | Individuals diagnosed with blood-injury phobia respond to venipuncture with strong psychophysiological responses. We investigated whether disgust sensitivity contributes to the fainting response and is associated with parasympathetic activation, as suggested by previous research. Twenty individuals diagnosed with blood-injury phobia (9 with a history of fainting to the sight of blood, 11 without such a fainting history) and 20 healthy controls were compared. Psychophysiological responses and self-report measures of anxiety, disgust, and embarrassment were monitored during rest, a paced breathing task, and venipuncture. In addition, trait disgust sensitivity and blood-injury fears were assessed. Blood-injury phobics reported enhanced anxiety, disgust, and embarrassment during venipuncture. They also experienced heightened arousal, as indicated by heart rate, respiration rate, and minute ventilation. Blood-injury phobics without a fainting history tended toward higher anxiety and disgust scores. There was no evidence for increased parasympathetic activation in either blood-injury phobic subgroup or of an association of disgust and parasympathetic activation. | We have previously identified in articular cartilage an abundant pool of the heparin-binding growth factor, fibroblast growth factor 2 (FGF-2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF-2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF-2 suppresses interleukin-1-driven aggrecanase activity in human cartilage explants, suggesting a chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF-2 in murine cartilage. Basal characteristics of the articular cartilage of Fgf2(-/-) and Fgf2(+/+) mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase-polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2(-/-) and Fgf2(+/+) mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF-2 on OA progression was assessed in Fgf2(-/-) mice. Fgf2(-/-) mice were morphologically indistinguishable from wild-type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2(-/-) mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2(-/-) mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2(-/-) mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase. |
Does casticin inhibit COX-2 and iNOS expression via suppression of NF-κB and MAPK signaling in lipopolysaccharide-stimulated mouse macrophages? | The fruits of Vitex rotundifolia L. are widely used to treat inflammation of the airway in Traditional Chinese medicine. Previous studies found that casticin, isolated from Vitex rotundifolia, could induce apoptosis of tumor cells. In this study, we evaluated the anti-inflammatory effects of casticin and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated macrophages. RAW264.7 cells were pretreated with various concentrations of casticin (0.3-10μM), and then treated with LPS to induce inflammation. We assayed the levels of proinflammatory cytokines and prostaglandin E2 (PGE2) using ELISA, and examined the protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and heme oxygenase (HO)-1 by Western blot. We also investigated the anti-inflammatory molecular mechanism by analyzing inflammatory-associated signaling pathways, including the nuclear transcription factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. We found casticin inhibited the levels of nitric oxide and PGE2, and decreased the production of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α). In addition, iNOS and COX-2 expression levels were suppressed and casticin increased HO-1 and Nrf2 production in a concentration-dependent manner. Furthermore, casticin significantly inhibited NF-κB subunit p65 proteins in the nucleus and decreased Akt and MAPK activation. | This study examined the impact of a low-cost contingency management (CM) delivered by program clinicians on treatment attendance and utilization for patients enrolled in outpatient psychosocial substance abuse treatment. The study used a pre-posttest design to compare substance abuse patients who received Reinforcement-Based Treatment (RBT) plus low cost CM (n=130; RBT+CM) to patients who received RBT only (n=132, RBT). RBT+CM participants received a $10 incentive for returning to treatment the day following intake assessment (day one), and a $15 incentive for attending treatment on day five following admission. RBT clients received standard care intervention without the addition of the CM procedures. Groups were compared on proportion of participants who returned to treatment on day one, mean days of treatment attendance, individual sessions attended, and treatment utilization during the first week and the first month following treatment admission. Both the RBT+CM and RBT group participants returned to the clinic on day one at high rates (95% versus 89%, respectively). However, the RBT group participants were more likely to attend the intake assessment only (i.e., never return to treatment) compared to the RBT+CM participants. Additionally, the RBT+CM participants attended significantly more treatment days, attended more individual counseling sessions, and had higher rates of overall treatment utilization compared to the RBT participants during the one week and one month following treatment admission. |
Does bilobalide modulate serotonin-controlled behaviors in the nematode Caenorhabditis elegans? | Dysfunctions in the serotonergic system have been implicated in several neurological disorders such as depression. Elderly individuals who have been diagnosed with clinical depression show elevated cases of neurodegenerative diseases. This has led to suggestions that modulating the serotonin (5-HT) system could provide an alternative method to current therapies for alleviating these pathologies. The neuroprotective effects of bilobalide in vitro have been documented. We aim to determine whether bilobalide affects the 5-HT system in the nematode C. elegans. The wild type worms, as well as well-characterized 5-HT mutants, were fed with bilobalide in a range of concentrations, and several 5-HT controlled behaviors were tested. We observed that bilobalide significantly inhibited 5-HT-controlled egg-laying behavior in a dose-dependent manner, which was blocked in the 5-HT receptor mutants (ser-4, mod-1), but not in the 5-HT transporter (mod-5) or synthesis (tph-1) mutants. Bilobalide also potentiated a 5-HT-controlled, experience-dependent locomotory behavior, termed the enhanced slowing response in the wild type animals. However, this effect was fully blocked in 5-HT receptor mod-1 and dopamine defective cat-2 mutants, but only partially blocked in ser-4 mutants. We also demonstrated that acetylcholine transmission was inhibited in a transgenic C. elegans strain that constitutively expresses Abeta, and bilobalide did not significantly affect this inhibition. | Septic hip revisions are associated with greater complications and higher costs than aseptic revisions. It is unclear whether blood loss and transfusion requirements are different in septic and aseptic revisions. We hypothesized that the blood loss and transfusion are dependent on the complexity of the revision surgery and patient's general health rather than the presence of infection. We retrospectively reviewed 626 revision total hip arthroplasties in 547 patients between 2009 and 2013. All the procedures were classified as septic (n = 120) or aseptic (n = 506) based on the Musculoskeletal Infection Society criteria for periprosthetic joint infection. Independent risk factors for transfusion and blood loss were analyzed using a multiple regression analysis. The transfusion rate was higher in septic revisions (septic = 108/120 [90%], aseptic = 370/506 [73%]; P < .001), so was the average amount of blood loss (septic = 2533 ± 161 mL, aseptic = 1974 ± 68 mL; P < .001). After adjusting for potential confounders, infection was not an independent risk factor for transfusion (P = .176) or blood loss (P = .437). Increasing age (P = .004), higher American Society of Anesthesiologists score (P = .047), lower preoperative hemoglobin (P < .001), cell saver use (P < .001), and complex revision surgery (P < .001) were independently associated with greater risk of transfusion. |
Are elevations of plasma methylarginines in obesity and ageing related to insulin sensitivity and rates of protein turnover? | Increased circulating methylarginines (MA) have been linked to the metabolic syndrome to explain endothelial dysfunction and cardiovascular disease risk. Proteins that contain MA are regulatory and release them during catabolism. We hypothesised that increased protein turnover in insulin-resistant states contributes to an increase in circulating MA. MATWERIALS AND METHODS: We performed hyperinsulinaemic, euglycaemic, and isoaminoacidaemic experiments on 49 lean, obese and elderly subjects, with measurements of the kinetics of glucose and protein metabolism. Plasma MA, i.e. asymmetrical dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA), and N -monomethyl-L-arginine (NMMA), lipids and body composition were measured. Insulin resistance of glucose and protein metabolism occurred in obese and elderly subjects. ADMA concentrations were 29 to 120% higher in obese and 34% higher in elderly than in lean subjects. SDMA were 34 and 20% higher in obese than in lean and than in elderly subjects, respectively. NMMA were 32% higher in obese than in lean subjects. ADMA differed by sex, being higher in men, namely by 1.75x in obese men and by 1.27x in elderly men. Postabsorptive ADMA (r=0.71), SDMA (r=0.46), and NMMA (r=0.31) correlated (all p<0.05) with rates of protein flux. All three MA correlated negatively with clamp glucose infusion rates and uptake (p<0.001). ADMA and SDMA correlated negatively with net protein synthesis and clamp amino acid infusion rates (p<0.05). All MA also correlated with adiposity indices and fasting insulin and triglycerides (p<0.05). | Interprofessional collaboration is the process in which different professional groups work together to positively impact health care. We aimed to explore physicians' attitudes toward interprofessional collaboration in the context of chronic pain management with the implication that if attitudes are not positive, appropriate interventions could be developed. A quantitative attitudes study. The ethical committee approved the study. A web-based survey about interprofessional treatment of chronic pain was administered to physicians. Outcome measures were as follows: physicians' demographic and workplace information, previous experience of working within an interprofessional team, and attitudes towards interprofessional collaboration in chronic pain management. There were 90 physicians who responded to the survey. Physicians had positive attitudes towards team work in the context of chronic pain, but they were undecided about sharing their role within an interprofessional team. The family physician was singled out as the most important as well as the most common collaborator in chronic pain treatment. Interprofessional educational seminars and workshops were suggested as methods for improving interprofessional collaboration. |
Are [ Serum osteoprotegrin and serum bone gamma-carboxyglutamine acid-containing protein correlated with bone mineral density in normal women ]? | To study the relationships of serum osteoprotegrin (sOPG), serum bone gamma-carboxyglutamine acid-containing protein (sBGP), and urine deoxypyridinoline (uDPD)/creatinine (Cr) with age and bone mineral density (BMD) in women. ELISA was used to examine the sOPG, sBGP, and uDPD/Cr of 672 female volunteers aged 20-80. The BMD (QDR4500A) value of the anteroposterior lumbar spine and femoral neck were measured by DXA. (1) The levels of sOPG, sBGP, and uDPD/Cr in the age group of 30-39 were 2.8 pmol/L +/- 1.4 pmol/L, 5 microg/L +/- 3 microg/L, and 4.9 nmol/mmol +/- 2.5 nmol/mmol respectively, all significantly lower than those in the age groups 40-49, 50-59, and 60-69 (all P < 0.05). (2) In the age group 40-49, the values of sOPG, sBGP, and uDPD in menopausal subjects were significantly higher than those of the non-menopausal subjects (5.7 pmol/L +/- 3.1 pmol/L vs 3.4 pmol/L +/- 2.0 pmol/L, 11 microg/L +/- 5 microg/L vs 6 microg/L +/- 3 microg/L, and 6.9 nmol/mmol +/- 3.3 nmol/mmol vs 5.2 nmol/mmol +/- 3.9 nmol/mmol, all P < 0.001). (3) Age was positively correlated with sOPG, sBGP, uDPD/Cr, and BMD of anteroposterior lumbar spine and femoral neck (r = 0.130, 0.355, 0.106, -0.600, -0.545; P < 0.01). sOPG and sBGP were negatively correlated to anteroposterior lumbar spine BMD (r = -0.183, -0.108, P < 0.01; and r = -0.541, -0.441, P < 0.001). sOPG was positively correlated with sBGP and uDPD/Cr (r = 0.216 and 0.083; both P < 0.05). | Neosquamous epithelium (NSE) can arise within Barrett's esophagus as a consequence of medical or surgical acid reduction therapy, as well as after endoscopic ablation. Morphologic studies have suggested that NSE can develop from adjacent squamous epithelium, submucosal gland ducts, or multipotent progenitor cell(s) that can give rise to either squamous or Barrett's epithelium, depending on the luminal environment. The cells responsible for Barrett's epithelium self-renewal are frequently mutated during neoplastic progression. If NSE arises from the same cells that self-renew the Barrett's epithelium, the two tissues should be clonally related and share genetic alterations; if NSE does not originate in the self-renewing Barrett's, NSE and Barrett's esophagus should be genetically independent. We isolated islands of NSE and the surrounding Barrett's epithelium from 20 patients by microdissection and evaluated each tissue for genetic alterations in exon 2 of CDKN2A or exons 5 to 9 of the TP53 gene. Nine patients had p16 mutations and 11 had TP53 mutations within the Barrett's epithelium. In 1 of 20 patients, a focus of NSE had a 146 bp deletion in p16 identical to that found in surrounding Barrett's epithelium. The NSE in the remaining 19 patients was wild-type for p16 or TP53. |
Does cholinergic stimulation improve autonomic and hemodynamic profile during dynamic exercise in patients with heart failure? | Parasympathetic dysfunction is an independent risk factor for mortality in heart failure for which there is no specific pharmacologic treatment. This article aims to determine the effect of pyridostigmine, an anticholinesterase agent, on the integrated physiologic responses to dynamic exercise in heart failure. Patients with chronic heart failure (n = 23; 9 female; age = 48 +/- 12 years) were submitted to 3 maximal cardiopulmonary exercise tests on treadmill in different days. The first test was used for adaptation and to determine exercise tolerance. The other tests were performed after oral administration of pyridostigmine (45 mg, 3 times/day, for 24 hours) or placebo, in random order. All patients were taking their usual medication. Pyridostigmine reduced cholinesterase activity by 30%, inhibited the chronotropic response throughout exercise, up to 60% of maximal effort (pyridostigmine = 108 +/- 3 beats/min vs. placebo = 113 +/- 3 beats/min; P = .040), and improved heart rate reserve (pyridostigmine = 73 +/- 5 beats/min vs. placebo = 69 +/- 5 beats/min; P = 0.035) and heart rate recovery in the first minute after exercise (pyridostigmine = 25 +/- 2 beats/min vs. placebo = 22 +/- 2 beats/min; P = .005), whereas peak heart rate was similar to placebo. Oxygen pulse, an indirect indicator of stroke volume, was higher under pyridostigmine during submaximal exercise. | To clarify the effect of human umbilical cord-derived mesenchymal stem cell (hUC-MSCs) treatment on colitis and to explore the role of CD5(+) B cells in MSC therapy. The trinitrobenzenesulfonic acid (TNBS)-induced colitis mouse model was used. HUC-MSCs were transferred peritoneally. Survival rates, colitis symptoms, and macroscopic and histologic scores were evaluated. CD4(+) T helper (Th) cell subgroups and CD5(+) regulatory B cell (Bregs) in lymphocytes were quantitated by flow cytometry. Cytokine levels were detected by ELISA and Bio-plex. CD5(+) B cells were isolated for in vitro co-culture and adaptive transfer. HUC-MSC treatment alleviated TNBS-induced colitis by increasing survival rates, relieving symptoms, and improving macroscopic and histologic scores. Labeled hUC-MSCs were located in the inflamed areas of colitis mice. Increases in regulatory T cells (Tregs) and CD5(+) B cells and decreases in Th1 cells, Th17 cells, and several pro-inflammatory cytokines were observed with hUC-MSC treatment. After adaptive transfer, CD5(+) B cells, which were located mainly in the peritoneal lavage fluid, improved TNBS-induced colitis by correcting Treg/Th1/Th17 imbalances. CD5(+) B cells also inhibited T-cell proliferation and produced interleukin (IL)-10. |
Does population-based study reveal new risk-stratification biomarker panel for Barrett 's esophagus? | The risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is low and difficult to calculate. Accurate tools to determine risk are needed to optimize surveillance and intervention. We assessed the ability of candidate biomarkers to predict which cases of BE will progress to EAC or high-grade dysplasia and identified those that can be measured in formalin-fixed tissues. We analyzed data from a nested case-control study performed using the population-based Northern Ireland BE Register (1993-2005). Cases who progressed to EAC (n = 89) or high-grade dysplasia ≥ 6 months after diagnosis with BE were matched to controls (nonprogressors, n = 291), for age, sex, and year of BE diagnosis. Established biomarkers (abnormal DNA content, p53, and cyclin A expression) and new biomarkers (levels of sialyl Lewis(a), Lewis(x), and Aspergillus oryzae lectin [AOL] and binding of wheat germ agglutinin) were assessed in paraffin-embedded tissue samples from patients with a first diagnosis of BE. Conditional logistic regression analysis was applied to assess odds of progression for patients with dysplastic and nondysplastic BE, based on biomarker status. Low-grade dysplasia and all biomarkers tested, other than Lewis(x), were associated with risk of EAC or high-grade dysplasia. In backward selection, a panel comprising low-grade dysplasia, abnormal DNA ploidy, and AOL most accurately identified progressors and nonprogressors. The adjusted odds ratio for progression of patients with BE with low-grade dysplasia was 3.74 (95% confidence interval, 2.43-5.79) for each additional biomarker and the risk increased by 2.99 for each additional factor (95% confidence interval, 1.72-5.20) in patients without dysplasia. | Shilajit has been used as a rejuvenator for ages in Indian ancient traditional medicine and has been validated for a number of pharmacological activities. The effect of processed shilajit which was standardized to dibenzo-α-pyrones (DBPs;0.43% w/w), DBP-chromoproteins (DCPs; 20.45% w/w) and fulvic acids (56.75% w/w) was evaluated in a rat model of chronic fatigue syndrome (CFS). The mitochondrial bioenergetics and the activity of hypothalamus-pituitary-adrenal (HPA) axis were evaluated for the plausible mechanism of action of shilajit. CFS was induced by forcing the rats to swim for 15mins for 21 consecutive days. The rats were treated with shilajit (25, 50 and 100mg/kg) for 21 days before exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility and the climbing period. The post-CFS anxiety level was assessed by elevated plus maze (EPM) test. Plasma corticosterone and adrenal gland weight were estimated as indices of HPA axis activity. Analysis of mitochondrial complex chain enzymes (Complex I, II, IV and V) and mitochondrial membrane potential (MMP) in prefrontal cortex (PFC) were performed to evaluate the mitochondrial bioenergetics and integrity respectively. Shilajit reversed the CFS-induced increase in immobility period and decrease in climbing behavior as well as attenuated anxiety in the EPM test. Shilajit reversed CFS-induced decrease in plasma corticosterone level and loss of adrenal gland weight indicating modulation of HPA axis. Shilajit prevented CFS-induced mitochondrial dysfunction by stabilizing the complex enzyme activities and the loss of MMP. Shilajit reversed CFS-induced mitochondrial oxidative stress in terms of NO concentration and, LPO, SOD and catalase activities. |
Is reactivity to alpha agonists heightened in immature porcine pulmonary arteries? | Pulmonary hypertension after cardiopulmonary bypass is a common problem in pediatric cardiac operations. This study tested the hypothesis that there is a difference between adult and immature pulmonary artery constrictor and dilator responses. Reactivity of pulmonary artery ring segments from 22 mature (15 to 19 weeks) and 15 immature pigs (4 to 5 weeks) was tested in a vessel myograph. Potassium as a receptor-independent vasoconstrictor and phenylephrine as an alpha-receptor-mediated vasoconstrictor were used to assess smooth-muscle vasoconstriction. To assess endothelial cell function (nitric oxide production and secretion), we used increasing concentrations of bradykinin or acetylcholine. Sodium nitroprusside was used to produce maximum smooth-muscle relaxation at the end of each experiment. The data demonstrated maturation-independent endothelium and smooth-muscle-mediated vasodilation. Pulmonary artery ring segments from immature pigs had significantly less KCl constriction compared with mature pigs (p < 0.05). In contrast, pulmonary ring segments from immature pigs demonstrated enhanced alpha-receptor-mediated constriction compared with mature pigs. | Systemic lupus erythematosus (SLE) is characterised by the presence of antibodies to double stranded DNA (dsDNA), which are involved in the pathogenesis of SLE. Previous studies showed that at least two thirds of patients develop a clinical relapse within six months after a significant rise in the anti-dsDNA level, and most relapses were prevented by the administration of corticosteroids at the time of the rise. To determine whether mofetil mycophenolate (MMF) can prevent a clinical relapse without the side effects associated with corticosteroids. 36 patients with SLE were examined monthly to determine whether a rise in anti-dsDNA level had occurred. A rise was defined as an increase of 25% of the level of the previous sample of at least 15 IU/ml within a four month period. After a rise patients were treated with MMF 2000 mg daily for six months. Patients were monitored monthly for the occurrence of a clinical relapse and to assess the serological activity and state of activation of CD4+, CD8+, and CD19+ lymphocyte subsets. Anti-dsDNA rose in 10 patients. Treatment with MMF was started in all these patients, and after six months no clinical relapse had occurred. Side effects were minimal. Antibodies to dsDNA decreased during the treatment (p<0.001), associated with a decrease in the state of activation of CD19+ lymphocytes. No changes were found in the state of activation of CD4+ or CD8+ lymphocyte subsets. |
Are socioeconomic inequalities still a barrier to full child vaccine coverage in the Brazilian Amazon : a cross-sectional study in Assis Brasil , Acre , Brazil? | Vaccines are very important to reduce morbidity and mortality by preventable infectious diseases, especially during childhood. Optimal coverage is not always achieved, for several reasons. Here we assessed vaccine coverage for the first 12 months of age in children between 12 and 59 months old, residing in the urban area of a small Amazonian city, and factors associated with incomplete vaccination. A census was performed in the urban area of Assis Brasil, in the Brazilian Amazon, in January 2010, with mothers of 282 children aged 12 to 59 months old, using structured interviews and data from vaccination cards. Mixed logistic regression was used to determine factors associated with incomplete vaccination schemes. Only 82.6% of all children had a completed the basic vaccine scheme for the first year of life. Vaccine coverage ranged from 52.7% coverage (oral rotavirus vaccine) to 99.7% coverage (for Bacille Calmette-Guérin). The major deficiencies occurred in doses administered after the first six months of life. Incomplete vaccination was associated with not having enough income to buy a house (aOR = 2.12, 95% CI 1.06-4.21), low maternal schooling (aOR = 2.60, 95% CI 1.28 - 5.29) , and time of residence of the child in the urban area of the city (aOR = 0.73, 95% CI 0.55 - 0.95). | 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. |
Are joystick interfaces suitable for robotized endoscope applied to NOTES? | NOTES has changed the working environment of endoscopy, leading to new difficulties. The limitations of conventional endoscopes call for the development of new platforms. Robotics may be the answer. The authors compared human to robotized manipulation of a flexible endoscope into the abdominal cavity, in an animal model. Thirty-two participants were enrolled. Results were analyzed according to the clinical background of the participants: experienced endoscopists, experienced laparoscopists, and medical students. Two single-channel gastroscopes were used. Whereas one was not modified, the other had the handling wheels replaced by motors controlled through a computer and a joystick. A NOTES transgastric approach was used to access the peritoneal cavity. The time to touch previously positioned intra-abdominal numbered plastic targets was recorded 3 times with each endoscope. Mean time to complete the tasks was significantly shorter using the conventional endoscope (2.71 vs 6.96 minutes, P < .001). When the robotized endoscope was used, the mean times of endoscopists (7.42 minutes), laparoscopists (6.84 minutes), and students (6.77 minutes) were statistically identical. No differences were found between laparoscopists and students in both techniques. | Cerebral white matter hyperintensities on magnetic resonance imaging (MRI) scans have been associated with vascular disease and late-life depression, both in the general population and in psychiatric patients. Therefore, a cerebrovascular etiology for late-onset depression has been hypothesized. However, longitudinal studies on the causal role of white matter hyperintensities in the development of depressive symptoms in elderly adults are lacking. To investigate the relation between white matter hyperintensities and depressive symptoms in elderly subjects at risk of cardiovascular disease. In the Dutch sample of the PROSPER (PROspective Study of Pravastatine in the Elderly at Risk of cardiovascular disease) cohort, 527 non-demented elderly, all aged 70 years or older, received a cranial MRI scan and the 15-item Geriatric Depression Scale, at baseline and 33 months (SD 1.6) later. Presence of white matter hyperintensities at baseline was not related to baseline depressive symptoms nor to the development of depressive symptoms during follow-up. Moreover, no association was found between progression of white matter lesion volume and progression of depressive symptoms. |
Are overexpression of p53 protein and DNA content important biologic prognostic factors for thyroid cancer? | Many factors gave been reported to be of prognostic importance for thyroid cancer. Biologic aggressiveness may influence postoperative recurrences and the prognosis of thyroid cancer. Immunohistochemical staining for the p53 protein and DNA content are novel factors that suggest biologic aggressiveness. Retrospective study of the survival rate after operation of differentiated thyroid cancer was undertaken at Osaka Police Hospital. Age, gender operative method, extent of lymph node dissection, use of radioiodine, primary or recurrent tumor, tumor size and invasion, lymph node involvement, presence of distant metastases, DNA ploidy, percentage of S phase and G2M phase fractions, positive staining for the p53 protein, and histologic type and subtype were evaluated as possible prognostic factors by univariate and multivariate analyses of survival. Positive staining for the p53 protein was related to postoperative local recurrence, and DNA ploidy was related to distant metastatic recurrence. Univariate analysis suggested that age, tumor size and invasion, lymph node involvement, presence of distant metastases, percentage of S phase fraction, histologic subtype, DNA ploidy, and positive staining for the p53 protein were significant prognostic factors. Multivariate analysis suggested that positive staining of the protein and DNA ploidy were independent prognostic factors for overall survival. | N-acetylcysteine (NAC) has a protective effect against vascular dysfunction by decreasing the level of reactive oxygen species (ROS) in experimental and human hypertension. This study was designed to examine whether NAC would relax vascular rings in vitro via nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, extracellular Ca2+ and/or K+ channels. Rat aortic arteries were mounted in an organ bath, contracted with 0.1, 0.5 or 1 micromol/L phenylephrine to plateau, and the vasodilatory effect of NAC was examined in the absence or presence of ROS scavengers, inhibitors of NO-cGMP pathway or K+ channels. Vascular smooth muscle cells (VSMCs) were loaded with a calcium sensitive fluorescent dye fluo-3 AM, and [Ca2+](i) was determined with laser-scanning confocal microscopy. NAC (0.1-4 mmol/L) dose-dependently relaxed rat aorta pre-contracted with phenylephrine. Endothelium removal, endothelial nitric oxide synthase inhibitor N(omega)-Nitro-l-arginine (L-NNA) (100 micromol/L) or soluble guanylyl cyclase (sGC) inhibitor (ODQ) (10 micromol/L) did not affect NAC-induced vasodilation. In contrast, NAC-induced vasodilation was blunted after extracellular calcium was removed and calcium imaging showed that 4 mmol/L NAC quickly decreased [Ca2+](i) in fluo-3 AM loaded VSMCs. NAC-induced vasodilation was significantly reduced in the presence of voltage-gated K+ channels (Kv) inhibitor 4-aminopyridine (4-AP). |
Do natural triterpenic diols promote apoptosis in astrocytoma cells through ROS-mediated mitochondrial depolarization and JNK activation? | Triterpene alcohols and acids are multifunctional compounds widely distributed throughout the plant kingdom that exhibit a variety of beneficial health properties, being synthetic analogs of oleanolic acid under clinical evaluation as anti-tumoral therapeutic agents. However, the antineoplastic activity of two natural occurring triterpenoid alcohols extracted from olive oil, erythrodiol (an intermediate from oleanolic acid), and its isomer, uvaol, has barely been reported, particularly on brain cancer cells. Astrocytomas are among the most common and aggressive type of primary malignant tumors in the neurological system lacking effective treatments, and in this study, we addressed the effect of these two triterpenic diols on the human 1321N1 astrocytoma cell line. Erythrodiol and uvaol effectively affected cell proliferation, as well as cell cycle phases and induced 1321N1 cell death. Both triterpenes successfully modulated the apoptotic response, promoting nuclear condensation and fragmentation. They caused retraction and rounding of cultured cells, which lost adherence from their supports, while F-actin and vimentin filaments disappeared as an organized cytoplasmic network. At molecular level, changes in the expression of surface proteins associated with adhesion or death processes were also observed. Moreover, triterpene exposure resulted in the production of reactive oxygen species (ROS) with loss of mitochondrial transmembrane potential, and correlated with the activation of c-Jun N-terminal kinases (JNK). The presence of catalase reversed the triterpenic diols-induced mitochondrial depolarization, JNK activation, and apoptotic death, indicating the critical role of ROS in the action of these compounds. | To assess how different imputation methods used to account for missing variance data in primary studies influence tests of heterogeneity and pooled results from a meta-analysis with continuous outcomes. Point and variance estimates for changes in serum creatinine, glomerular filtration rate, systolic blood pressure, and diastolic blood pressure were variably reported among 48 primary longitudinal studies of living kidney donors (71%-78% of point estimates were reported, 8%-13% of variance data were reported). We compared the results of meta-analysis, which either were restricted to available data or used four methods to impute missing variance data. These methods used reported P-values, reported nonparametric summaries, results from other similar studies using multiple imputation, or results from estimated correlation coefficients. Significant heterogeneity was present in all four outcomes regardless of the imputation methods applied. The random effects point estimates and 95% confidence intervals varied little across imputation methods, and the differences were not clinically significant. |
Does lipoic acid decrease peritoneal adhesion formation in a rat uterine scar model? | To investigate the effects of lipoic acid in the prevention of postoperative pelvic adhesions by a visual scoring system and immunohistochemistry in a rat uterine horn model with full thickness injury. Twenty-eight female Wistar albino rats were randomised into four groups: uterine trauma control, 15 days and 30 days, and uterine trauma + lipoic acid, 15 days and 30 days. A full thickness defect was established by incising a segment of approximately 1.0 cm in length from each uterine horn, leaving the mesometrium intact. Extension and severity of the adhesions in each group were scored by a visual scoring system and evaluated immunohistochemically. Adhesion scores were 2.00±0.81, 2.14±0.69 0.71±0.75, and 0.85±0.69 for extent and 2.28±0.48, 2.14±0.69, 0.85±0.69, and 1.14±0.69 for severity in Groups 1, 2, 3 and 4, respectively. Adhesion extent and severity were significantly less for groups treated by lipoic acid but no difference was observed between long and short administration. Both Vitronectin and u-PAR staining were significantly increased in treatment groups when compared to the control group. | Pulmonary hypertension (PH) is prognosti- cally important in chronic obstructive pulmonary disease (COPD). Since PH only weakly correlates with hypoxemia, other factors must play a role. To investigate whether polymorphisms of the serotonin transporter (5HTT), serotonin-2a receptor (5HTR2a) and endothelial nitric oxide synthetase (eNOS) are related to PH in COPD. In 59 COPD patients who underwent right heart catheterization, 6-min walking distance, NYHA functional class, pulmonary function tests, blood gases and 5HTT, 5HTR2a and eNOS (4ab and T298C) polymorphisms were determined. Forty-nine COPD patients in NYHA functional class III-IV were included. Ten were excluded due to comorbid causes of PH (mainly chronic thromboembolic). PH (mPAP > or =25 mm Hg) was present in 55% and usually mild, but out of proportion (mPAP > or =40 mm Hg) in 12%. Patients with PH had significantly higher frequencies of the 5HTT-L-allele (52%) compared to individuals without PH (36%), and LL homozygote patients had more severe PH. In patients with out-of-proportion PH, the L-allelic frequency was even 75%. We found no association of 5HTR2a and eNOS polymorphism with PH in COPD. |
Do low-energy gamma-emitting stents inhibit intimal hyperplasia with minimal `` edge effects '' in a pig coronary artery model? | The objective of this study was to determine the effects of different doses of gamma-emitting radioactive stents on intimal hyperplasia in a porcine coronary stent model at 28 days. Sixty-four bare stents and those coated with palladium-103 [activities of 0 (control), 0.5, 1.0, 2.0, and 4.0 mCi] were implanted in the coronary arteries of 32 pigs. Stented segments were evaluated by histomorphometry at 28 days. There was significantly more intima in the 0.5- and 1-mCi stents than in controls (4.27+/-0.52 and 4.71+/-1.13 vs. 1.71+/-0.61 mm(2); P<.0001). Neointimal formation in 2-mCi stents was similar to that in controls, while that in 4-mCi stents was reduced compared to that in controls (2.34+/-1.61 and 0.82+/-0.25 vs. 1.71+/-0.61 mm(2); P=NS and P<.05, respectively). Stent margin neointimal response was representative of that within the stent body, with nonsignficant modest increases in intimal area at adjacent nonstented segments in radioactive stent groups. There was a dose-dependent increase in inflammation scores. Radioactive stents had lower intimal smooth muscle and higher fibrin scores. There was an increase in adventitial fibrosis in 1- and 2-mCi stents versus controls (1.26+/-0.99, and 2.25+/-1.27 vs. 0.21+/-0.31; P<.001). | Altered cerebrospinal fluid (CSF) levels of lactate have been described in neurodegenerative diseases and related to mitochondrial dysfunction and neuronal degeneration. We investigated the relationship between CSF lactate levels, disease severity, and biomarkers associated with neuroaxonal damage in patients with multiple sclerosis (MS). One-hundred eighteen subjects with relapsing-remitting multiple sclerosis (RRMS) were included, along with one-hundred fifty seven matched controls. CSF levels of lactate, tau protein, and neurofilament light were detected at the time of diagnosis. Patients were followed-up for a mean of 5 years. Progression index (PI), multiple sclerosis severity scale (MSSS), and Bayesian risk estimate for multiple sclerosis (BREMS) were assessed as clinical measures of disease severity and progression. Differences between groups and correlation between CSF lactate, disease severity and CSF biomarkers of neuronal damage were explored. CSF lactate was higher in RRMS patients compared to controls. A negative correlation was found between lactate levels and disease duration. Patients with higher CSF lactate concentration had significantly higher PI, MSSS, and BREMS scores at long-term follow-up. Furthermore, CSF lactate correlated positively and significantly with CSF levels of both tau protein and neurofilament light protein. |
Is hHV-8 ( KSHV ) associated with bacillary angiomatosis? | Bacillary angiomatosis is a rare pseudoneoplastic angioproliferative lesion occurring in patients with AIDS. This condition has been associated with Bartonella henselae and Bartonella quintana infections. Human herpesvirus 8 (HHV-8) is thought to be the causative agent of Kaposi's sarcoma, a vasoproliferative neoplasm, also commonly found in patients with AIDS. The presence of HHV-8 in a cohort of patients with bacillary angiomatosis was investigated. Eight cutaneous cases of biopsy confirmed bacillary angiomatosis were assessed for HHV-8 using standard solution phase polymerase chain reaction (PCR). No case of bacillary angiomatosis harboured HHV-8 DNA. | Zinc concentrates at excitatory synapses, both at the postsynaptic density and in a subset of glutamatergic boutons. Zinc can modulate synaptic plasticity, memory formation and nociception by regulating transmitter receptors and signal transduction pathways. Also, intracellular zinc accumulation is a hallmark of degenerating neurons in several neurological disorders. To date, no single zinc extrusion mechanism has been directly localized to synapses. Based on the presence of a canonical PDZ I motif in the Zinc Transporter-1 protein (ZnT1), we hypothesized that ZnT1 may be targeted to synaptic compartments for local control of cytosolic zinc. Using our previously developed protocol for the co-localization of reactive zinc and synaptic proteins, we further asked if ZnT1 expression correlates with presynaptic zinc content in individual synapses. Here we demonstrate that ZnT1 is a plasma membrane protein that is enriched in dendritic spines and in biochemically isolated synaptic membranes. Hippocampal CA1 synapses labelled by postembedding immunogold showed over a 5-fold increase in ZnT1 concentration at synaptic junctions compared with extrasynaptic membranes. Subsynaptic analysis revealed a peak ZnT1 density on the postsynaptic side of the synapse, < 10 nm away from the postsynaptic membrane. ZnT1 was found in the vast majority of excitatory synapses regardless of the presence of vesicular zinc in presynaptic boutons. |
Does cytokeratin 7 staining of hepatocytes predict progression to more severe fibrosis in alcohol-fed baboons? | Not all alcoholic patients develop severe liver disease with fibrosis progressing to cirrhosis. It is of practical importance to determine whether some markers can predict progression of liver fibrosis. We used a baboon model that mimics human alcoholic liver disease. Cytokeratin 7 and 19 expression and fat deposition were investigated in serial liver biopsies of 18 animals undergoing prolonged alcohol administration (range 2-17 years) and in four controls. Fibrosis was graded histologically and was also assessed quantitatively by image analysis. Ten animals did not show a progression of liver disease even after 17 years of alcohol administration, but eight animals fed alcohol exhibited a progression of liver disease from no fibrosis or perivenular fibrosis to septal fibrosis or cirrhosis within 7 years. In normal liver, cytokeratin 7 and cytokeratin 19 immunostaining is restricted to bile duct cells. Hepatocellular cytokeratin 7 was observed only in those animals which progressed to more severe stages of fibrosis and it anticipated this progression by 4.2 years on average. | To identify the indications and outcomes of total thyroidectomy for Graves' disease in a North American cohort. Prospective database of 297 patients undergoing total thyroidectomy in a tertiary care center identified 49 patients with Graves'. There were 37 women and 12 men (mean age, 37.9 years). Common indications for surgery were: refusal of radioactive iodine (20%), thyroid storm (18%), a thyroid nodule (16%), failure of I131(14%), and ophthalmopathy (14%). Complications included: symptomatic hypocalcemia (14%), permanent hypoparathyroidism (0%), and symptoms of recurrent laryngeal nerve injury (0%). Graves' patients had more bleeding (117 mL versus 48 mL, P<0.05). Clinical nodules were malignant in 38%. Papillary thyroid carcinoma occurred in 10% of patients, with 60% multifocal, and 60% lymph node metastases. |
Does alteration of inflammatory response by shock wave therapy lead to reduced calcification of decellularized aortic xenografts in mice†? | Tissue-engineered xenografts represent a promising treatment option in heart valve disease. However, inflammatory response leading to graft failure and incomplete in vitro repopulation with recipient cells remain challenging. Shock waves (SWs) were shown to modulate inflammation and to enhance re-epithelialization. We therefore aimed to investigate whether SWs could serve as a feasible adjunct to tissue engineering. Porcine aortic pieces were decellularized using sodium deoxycholate and sodium dodecylsulphate and implanted subcutaneously into C57BL/6 mice (n = 6 per group). The treatment (shock wave therapy, SWT) group received SWs (0.1 mJ/mm(2), 500 impulses, 5 Hz) for modulation of inflammatory response directly after implantation; control animals remained untreated (CTR). Grafts were harvested 72 h and 3 weeks after implantation and analysed for inflammatory cytokines, macrophage infiltration and polarization, osteoclastic activity and calcification. Transmission electron microscopy (TEM) was performed. Endothelial cells (ECs) were treated with SWs and analysed for macrophage regulatory cytokines. In an ex vivo experimental set-up, decellularized porcine aortic valve conduits were reseeded with ECs with and without SWT (0.1 mJ/mm(2), 300 impulses, 3 Hz), fibroblasts as well as peripheral blood mononuclear cells (all human) and tested in a pulsatile flow perfusion system for cell coverage. Treated ECs showed an increase of macrophage migration inhibitory factor and macrophage inflammatory protein 1β, whereas CD40 ligand and complement component C5/C5a were decreased. Subcutaneously implanted grafts showed increased mRNA levels of tumour necrosis factor α and interleukin 6 in the treatment group. Enhanced repopulation with recipient cells could be observed after SWT. Augmented macrophage infiltration and increased polarization towards M2 macrophages was observed in treated animals. Enhanced recruitment of osteoclastic cells in proximity to calcified tissue was found after SWT. Consequently, SWT resulted in decreased areas of calcification in treated animals. The reseeding experiment revealed that fibroblasts showed the best coverage compared with other cell types. Moreover, SW-treated ECs exhibited enhanced repopulation compared with untreated controls. | Fatigue is likely to be an important limiting factor in adolescents with spastic cerebral palsy (CP). To determine the effects of walking-induced fatigue on postural control adjustments in adolescents with unilateral CP and their typically developing (TD) peers. Ten adolescents with CP (14.2 ± 1.7 yr) and 10 age-, weight- and height-matched TD adolescents (14.1 ± 1.9 yr) walked for 15 min on a treadmill at their preferred walking speed. Before and after this task, voluntary strength capacity of knee extensors (MVC) and postural control were evaluated in 3 conditions: eyes open (EO), eyes closed (EC) and with dual cognitive task (EODT). After walking, MVC decreased significantly in CP (-11%, P<0.05) but not in TD. The CoP area was only significantly increased in CP (90%, 34% and 60% for EO, EC and EODT conditions, respectively). The CoP length was significantly increased in the EO condition in CP and TD (20% and 21%) and was significantly increased in the EODT condition by 18% in CP only. |
Does the dual S1PR1/S1PR5 drug BAF312 ( Siponimod ) attenuate demyelination in organotypic slice cultures? | BAF312 (Siponimod) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. This drug is currently undergoing clinical trials for the treatment of secondary progressive multiple sclerosis (MS). Here, we investigated the effects of BAF312 on isolated astrocyte and microglia cultures as well as in slice culture models of demyelination. Mouse and human astrocytes were treated with S1PR modulators and changes in the levels of pERK, pAkt, and calcium signalling as well as S1PR1 internalization and cytokine levels was investigated using Western blotting, immunochemistry, ELISA and confocal microscopy. Organotypic slice cultures were prepared from the cerebellum of 10-day-old mice and treated with lysophosphatidylcholine (LPC), psychosine and/or S1PR modulators, and changes in myelination states were measured by fluorescence of myelin basic protein and neurofilament H. BAF312 treatment of human and mouse astrocytes activated pERK, pAKT and Ca(2+) signalling as well as inducing S1PR1 internalization. Notably, activation of S1PR1 increased pERK and pAKT in mouse astrocytes while both S1PR1 and S1PR3 equally increased pERK and pAKT in human astrocytes, suggesting that the coupling of S1PR1 and S1PR3 to pERK and pAKT differ in mouse and human astrocytes. We also observed that BAF312 moderately attenuated lipopolysaccharide (LPS)- or TNFα/IL17-induced levels of IL6 in both astrocyte and microglia cell cultures. In organotypic slice cultures, BAF312 reduced LPC-induced levels of IL6 and attenuated LPC-mediated demyelination. We have shown previously that the toxic lipid metabolite psychosine induces demyelination in organotypic slice cultures, without altering the levels of cytokines, such as IL6. Importantly, psychosine-induced demyelination was also attenuated by BAF312. | To investigate a putative increased risk of rectal cancer subsequent to prostatic radiotherapy. In an analysis of the Surveillance, Epidemiology, and End Results registry, we compared men who had radiotherapy for prostatic carcinoma with those treated surgically and those treated with neither modality. Kaplan-Meier analyses for the time to failure from rectal cancer were performed between age-matched subgroups of the three cohorts. Cox proportional hazards analyses were performed to ascertain what influences might affect the incidence of subsequent rectal cancer. In all, 33,831 men were irradiated, 167,607 were treated surgically, and 36,335 received neither modality. Rectal cancers developed in 243 (0.7%) of those irradiated (mean age, 70.7 years), 578 (0.3%) of those treated surgically (68.7 years), and 227 (0.8%) of those treated with neither modality (74.2 years). When age effects and the differences between the surgical and untreated cohorts were controlled for, we were unable to demonstrate any significant increased incidence of rectal cancer in men irradiated for prostatic cancer. |
Does human umbilical cord mesenchymal stem cells transplantation promote cutaneous wound healing of severe burned rats? | Severe burns are a common and highly lethal trauma. The key step for severe burn therapy is to promote the wound healing as early as possible, and reports indicate that mesenchymal stem cell (MSC) therapy contributes to facilitate wound healing. In this study, we investigated effect of human umbilical cord MSCs (hUC-MSCs) could on wound healing in a rat model of severe burn and its potential mechanism. Adult male Wistar rats were randomly divided into sham, burn, and burn transplanted hUC-MSCs. GFP labeled hUC-MSCs or PBS was intravenous injected into respective groups. The rate of wound closure was evaluated by Image Pro Plus. GFP-labeled hUC-MSCs were tracked by in vivo bioluminescence imaging (BLI), and human-specific DNA expression in wounds was detected by PCR. Inflammatory cells, neutrophils, macrophages, capillaries and collagen types I/III in wounds were evaluated by histochemical staining. Wound blood flow was evaluated by laser Doppler blood flow meter. The levels of proinflammatory and anti-inflammatory factors, VEGF, collagen types I/III in wounds were analyzed using an ELISA. We found that wound healing was significantly accelerated in the hUC-MSC therapy group. The hUC-MSCs migrated into wound and remarkably decreased the quantity of infiltrated inflammatory cells and levels of IL-1, IL-6, TNF-α and increased levels of IL-10 and TSG-6 in wounds. Additionally, the neovascularization and levels of VEGF in wounds in the hUC-MSC therapy group were markedly higher than those in other control groups. The ratio of collagen types I and III in the hUC-MSC therapy group were markedly higher than that in the burn group at indicated time after transplantation. | Metformin treatment may induce a decrease/suppression in serum TSH levels, mimicking sub-clinical hyperthyroidism (SHT). The aim of the present study was to retrospectively evaluate changes in several electrocardiographic indices in euthyroid subjects with diabetes who, after starting metformin treatment, developed a low serum TSH as compared to patients with SHT resulting from an underlying thyroid disease or TSH suppressive treatment with L-thyroxine. Heart rate, P wave duration, P wave dispersion, QTmax, QTmin and QT-dispersion were assessed in 23 patients with diabetes treated with metformin before and after 6 months of TSH-suppression and in 31 control patients with SHT. No significant changes in electrocardiographic parameters were observed from baseline to the TSH-suppression measurement. A significant difference in P wave duration (102.9 ± 7.4 vs. 92.1 ± 5.8 ms, p<0.001), P wave dispersion (13.1 ± 3.4 vs. 7.1 ± 3.5 ms, p<0.001), QTmax (399 ± 18 vs. 388 ± 16 ms, p=0.024), QTmin (341 ± 14 vs. 350 ± 17 ms, p=0.038) and QT dispersion (49.9 ± 9.6 vs. 30.9 ± 9.2 ms, p<0.001) were observed between the control group with SHT and the group of diabetic patients with low serum levels of TSH. |
Does tissue-type plasminogen activator predict endocrine responsiveness of human pancreatic carcinoma cells? | Estrogen receptor (ER) has been found in human pancreatic carcinoma, but the potential benefit of endocrine therapy never has been assessed adequately. The aim of this study was to determine whether the presence of ER can be used as an indicator of hormone responsiveness, and whether modulation of tissue-type plasminogen activator (t-PA) by ER can identify hormone-responsive pancreatic carcinomas. The authors investigated ER status and hormonal regulation of t-PA in nine human pancreatic carcinoma cell lines, AsPC-1, BxPC-3, Capan-1, Capan-2, Hs-700T, Hs-766T, MiaPaCa-2, PANC-1, and SUIT-2. Furthermore, to examine whether estrogen dependency of t-PA production in pancreatic carcinoma cells correlated with responsiveness to endocrine therapy, the in vivo effects of various endocrine agents on the growth of the nine pancreatic cell lines transplanted into nude mice were examined. In a 17 beta-estradiol (E2)-binding assay, three of the nine pancreatic carcinoma cell lines (BxPC-3, Capan-2, and MiaPaCa-2) contained measurable levels of estradiol binding sites in vitro and in vivo using tumors transplanted into nude mice. Although t-PA was present in the culture medium in eight of the nine pancreatic carcinoma cell lines (not in Hs-700T), t-PA production was regulated by estrogen via an ER system in vitro only in the Capan-2 cell line. E2 injection into tumor-bearing mice showed acceleration of tumor growth only in Capan-2 tumors. Administration of a competitive ER antagonist, toremifene, and a luteinizing hormone-releasing hormone analogue, leuprorelin acetate (LEU), to Capan-2-bearing mice significantly reduced the rate of tumor growth, although there was no actual shrinkage of tumor mass. These agents failed to exert any antitumor effect on the other eight pancreatic cell lines. Although aromatase inhibitors, CGS 20267 and vorozole did not modify the in vivo growth of the nine pancreatic carcinoma cell lines significantly, the combined use of aromatase inhibitors with LEU exhibited a synergistic antitumor effect on Capan-2-bearing mice. Medroxyprogesterone acetate treatment significantly reduced the tumor volume of Capan-2 and also caused delayed growth in two other cell lines, AsPC-1 and MiaPaCa-2. | Recently, there has been increasing concern about adverse health effects of exposure to desert dust events. However, the association between dust and the incidence of ischemic heart diseases is unknown. The aim of the present study was to elucidate whether Asian dust (AD), a windblown sand dust originating from mineral soil in China and Mongolia, is associated with the incidence of acute myocardial infarction (AMI). We investigated the data regarding hospitalization because of AMI among 3068 consecutive patients from 4 AMI centers in Fukuoka, Japan, and data for AD from April 2003 to December 2010. We applied a time-stratified case-crossover design to examine the association between AD and the incidence of AMI. Using a conditional logistic regression analysis, we estimated the odds ratios of AMI associated with AD after controlling for ambient temperature and relative humidity. The occurrence of AD events 0 to 4 days before the day of admission was significantly associated with the incidence of AMI. In particular, the occurrence of AD 4 days before admission was significantly associated with the onset of AMI. |
Does incidence and correlate of tardive dyskinesia in first episode of schizophrenia? | There is controversy over whether tardive dyskinesia (TD) is solely a consequence of antipsychotic drug treatment or in part may reflect an intrinsic aspect of the disease process. Pathophysiologic factors could, independently or in concert with drug effects, lead to the development of dyskinetic signs. We studied prospectively 118 patients in their first episode of psychosis who were treatment-naive or had less than 12 weeks of antipsychotic drug exposure at study entry. Patients received standardized antipsychotic drug treatment and were evaluated for up to 8 1/2 years with regular assessments of psychopathologic signs and symptoms and side effects. The cumulative incidence of presumptive TD was 6.3% after 1 year of follow-up, 11.5% after 2 years, 13.7% after 3 years, and 17.5% after 4 years. Persistent TD had a cumulative incidence of 4.8% after 1 year, 7.2% after 2 years, and 15.6% after 4 years. Taken individually, both antipsychotic drug dose, entered as a time-dependent covariate, and poor response to treatment of the first psychotic episode were significant predicters of time to TD. When antipsychotic drug dose and treatment response were examined together, treatment responders had significantly lower hazards for presumptive TD than nonresponders (hazard ratio, 0.29; 95% confidence interval, 0.09 to 0.97). Dose was a trend-level predicter, with each 100-mg chlorpromazine equivalent unit increase in dose associated with a 5% increase in the hazard of presumptive TD (hazard ratio, 1.05; 95% confidence interval, 0.99 to 1.11). | Our previous in-vivo and in-vitro studies demonstrated that inflammation accelerated the progression of atherosclerosis via the dysregulation of the low-density lipoprotein receptor (LDLr) pathway. The current study aimed to investigate the effects and their underlying mechanisms of inflammation on lipid accumulation in the radial arteries of endstage renal disease (ESRD) patients with arteriovenostomy. 30 ESRD patients with arteriovenostomy were included. The patients were divided into two groups based on their plasma levels of C-reactive protein: a control (n = 16) and an inflamed group (n = 14). The expression of tumor necrosis factor-alpha (TNF-alpha) and monocyte chemotactic protein-1 of the radial arteries were increased in the inflamed group. Foam cell formation and lipid droplet accumulation were examined by hematoxylin and eosin (H & E) and Oil Red O staining. Intracellular cholesterol trafficking-related proteins were examined by immunohistochemistry and immunofluorescent staining. There was significant lipid accumulation in the radial arteries of the inflamed group compared with the control. Further analysis demonstrated that this accumulation was correlated with the increased protein expression of LDLr, sterol regulatory element-binding protein-2 (SREBP-2), and SREBP cleavageactivating protein (SCAP). Confocal microscopy showed that inflammation enhanced the translocation of SCAP escorting SREBP-2 from the endoplasmic reticulum to the Golgi, thereby activating LDLr gene transcription. Interestingly, upregulated LDLr expression was positively associated with the increased protein expression of mammalian target of rapamycin (mTOR), which had enhanced coexpression with SREBP-2. This finding suggests that the activation of mTOR may be involved in LDLr pathway disruption through the upregulation of SREBP-2 expression. |
Does increased nucleated red blood cells count in prolonged rupture of membranes is not erythropoietin driven? | The aim of this study is to examine the hypothesis that prolonged rupture of membranes (PROM) is associated with increased cord blood erythropoietin (EPO) concentrations, proportional to the duration of ruptured membranes. This study is a prospective, cross-sectional, observational (noninterventional) cohort study of mother-infant pairs. Criteria for inclusion were as follows: active labor with or without ruptured membranes and vaginally delivered neonates. Excluded were infants with major factors known to be associated with a potential increase in fetal erythropoiesis. A total of 40 mother-infant pairs were recruited. EPO was not influenced by duration of ruptured membranes and significantly correlated only with maternal body mass index. | To deal with processing-time in the nervous system, visuomotor control requires anticipation. An index for such anticipation is provided by the 'flash-lag illusion' in which moving objects are perceived ahead of static objects while actually being in the same place. We investigated the neurophysiological relation between visuomotor anticipation and motor velocity in Parkinson's disease (PD) and controls. Motor velocity was assessed by the number of keystrokes in 30s ('kinesia score') and visuomotor anticipation in a behavioural flash-lag paradigm while electroencephalography data was obtained. PD patients (n = 24) were divided in a 'PDslow' and a 'PDfast' group based on kinesia score. The PDslow group had a lower kinesia score than controls (resp. 40.3 ± 1.7 and 64.9 ± 4.6, p < 0.001). The flash-lag illusion was weaker in the PDslow group than in controls (resp. fractions 0.32 ± 0.04 and 0.50 ± 0.09 of the responses indicating perceived lagging, p = 0.03). Furthermore, the magnitude of the flash-lag illusion correlated with the kinesia score (cc = 0.45, p = 0.02). Finally, electroencephalography background frequency was lower in the PDslow group than in controls (resp 8.24 ± 0.24 and 9.1 ± 0.32 Hz, p = 0.01) and background frequency correlated with the kinesia score (cc = 0.58, p = 0.001). |
Do circulating microparticles generate and transport monomeric C-reactive protein in patients with myocardial infarction? | Elevated serum C-reactive protein (CRP) following myocardial infarction (MI) is associated with poor outcomes. Although animal studies have indicated a direct pathogenic role of CRP, the mechanism underlying this remains elusive. Dissociation of pentameric CRP (pCRP) into pro-inflammatory monomers (mCRP) may directly link CRP to inflammation. We investigated whether cellular microparticles (MPs) can convert pCRP to mCRP and transport mCRP following MI. MPs enriched in lysophosphatidylcholine were obtained from cell cultures and patient whole-blood samples collected following acute MI and control groups. Samples were analysed by native western blotting and flow cytometry. MPs were loaded with mCRP in vitro and incubated with endothelial cells prior to staining with monoclonal antibodies. In vitro experiments demonstrated that MPs were capable of converting pCRP to mCRP which could be inhibited by the anti-CRP compound 1,6 bis-phosphocholine. Significantly more mCRP was detected on MPs from patients following MI compared with control groups by western blotting and flow cytometry (P = 0.0005 for association). MPs containing mCRP were able to bind to the surface of endothelial cells and generate pro-inflammatory signals in vitro, suggesting a possible role of MPs in transport and delivery of pro-inflammatory mCRP in vascular disease. | Tobacco smoking is a public health issue and has been implicated in adverse reproductive outcomes including semen quality. Available data however provides conflicting findings. The objective of this study was to evaluate the effect of tobacco smoking on semen quality among men in Ghana. In this study, a total of 140 subjects were recruited, comprising 95 smokers and 45 non-smokers. Smokers were further categorized into mild, moderate and heavy smokers. Semen parameters such as sperm concentration, motility, viability and normal morphology were measured according to the World Health Organisation criteria. The study showed that smokers had significantly lower semen volume, sperm concentration, sperm motility, total sperm count, sperm morphology, free testosterone and follicle stimulating hormone (p <0.05 respectively), compared with non-smokers. Smokers were at a higher risk of developing oligospermia, asthenozoospermia and teratozoospermia (OR = 3.1, 4.2 and, 4.7; p <0.05) than non-smokers. |
Is vitamin D deficiency associated with inflammation in older Irish adults? | Inadequate vitamin D status is common within elderly populations and may be implicated in the etiology of autoimmune disease and inflammation. Few studies have investigated the relationship between vitamin D status and age-related immune dysfunction in humans. The aim of this study was to investigate the association between vitamin D status and immune markers of inflammation in a large sample of older adults. An observational investigation of 957 Irish adults (>60 years of age) recruited in Northern Ireland (55°N latitude) as part of the Trinity Ulster Department of Agriculture aging cohort study. We measured serum 25-hydroxyvitamin D (25(OH)D) by liquid chromatography tandem mass spectrometry and serum cytokines IL-6, TNF-α, IL-10, and C-reactive protein (CRP) by ELISA. Concentrations of IL-6, CRP, and the ratios of IL-6 to IL-10 and CRP to IL-10 were significantly higher in individuals with deficient (<25 nmol/L) serum 25(OH)D compared with those with sufficient (>75 nmol/L) status after adjustment for age, sex, and body mass index (P < .05). Vitamin D status was a significant predictor of the IL-6 to IL-10 cytokine ratio, and those participants defined as deficient were significantly more likely to have an IL-6 to IL-10 ratio >2:1 compared with those defined as sufficient. | Epinephrine commonly is added to epidural opioids and local anesthetics, however, little is known about the fate of epidurally administered epinephrine. Studies have identified the epinephrine metabolizing enzyme, catechol-O-methyl transferase (COMT), in the cranial meninges of several species. The purpose of this study was to determine whether the spinal meninges also contain COMT and are capable of metabolizing epinephrine. If so, then the spinal meninges may have an important impact in limiting the bioavailability of epinephrine in both the spinal cord and epidural space. Spinal meningeal specimens measuring 4 cm2 were obtained from monkeys (M. nemestrina) and farm-bred pigs and were incubated in bicarbonate-buffered mock cerebrospinal fluid. Epinephrine (200 micrograms base) was added at t = 0, and 200 min later, the mock cerebrospinal fluid was collected for metanephrine analysis. In separate experiments, pig meningeal specimens were separated into dura mater, pia-arachnoid mater, and pia mater, and the experiments were repeated to determine which meninx had the greatest COMT activity. Metanephrine was produced by monkey meninges at the rate of 0.47 ng.min-1.cm-2 and by pig meninges at the rate of 0.23 ng.min-1.cm-2 (P > 0.05). The pia-arachnoid meninx produced metanephrine at a greater rate (4.48 +/- 0.46 ng.min-1.mg-1 tissue) than did the pia mater (1.3 +/- 0.15 ng.min-1.mg-1 tissue) or dura mater alone (1.82 +/- 0.23 ng.min-1.mg-1 tissue). |
Is proteasome activation by hepatitis C core protein reversed by ethanol-induced oxidative stress? | The proteasome is a major cellular proteinase. Its activity is modulated by cellular oxidants. Hepatitis C core protein and ethanol exposure both cause enhanced oxidant generation. The aim was to investigate whether core protein, by its ability to generate oxidants, alters proteasome activity and whether these alterations are further affected by ethanol exposure. These interactions were examined in Huh-7 cell lines that expressed inducible HCV core protein and/or constitutive cytochrome P450 2E1 (CYP2E1) and as purified components in a cell-free system. Chymotrypsin-like proteasome activity was measured fluorometrically. Proteasome activity in core-positive 191-20 cells was 20% higher than that in core-negative cells and was enhanced 3-fold in CYP2E1-expressing L14 cells. Exposure of core-positive cells to glutathione ethyl ester, catalase, or the CYP2E1 inhibitor diallyl sulfide partially reversed the elevation of proteasome activity in core-positive cells, whereas ethanol exposure suppressed proteasome activity. The results indicate that proteasome activity was up-regulated by low levels of core-induced oxidative stress but down-regulated by high levels of ethanol-elicited stress. These findings were partially mimicked in a cell-free system. Addition of core protein enhanced the peptidase activity of purified 20S proteasome containing the proteasome activator PA28 and was further potentiated by addition of liver mitochondrial and/or microsome fractions. However, proteasome activation was significantly attenuated when fractions were obtained from ethanol-fed animals. | To determine whether patients with a rapid rate of joint space narrowing (JSN) in the hip have higher initial bone mineral density (BMD) in the proximal femur and/or lumbar spine than corresponding patients with a slow rate of JSN. Twenty-eight patients undergoing unilateral total hip replacement (THR) for osteoarthritis (OA), but whose contralateral hips were asymptomatic and had minimal or no radiographic OA, were evaluated. The contralateral proximal femur (i.e., non-operated hip) and lumbar spine were scanned by dual energy x-ray absorptiometry at baseline (prior to THR) and at 2 years. The rate of JSN was determined by serial longitudinal quantification of the joint spaces over the 2 year period following THR from conventional radiographs, and the patients were divided into a group with a slow rate of JSN (< or = 0.2 mm/yr, n = 20) and a group with a rapid rate of JSN (> 0.2 mm/yr, n = 8). The baseline BMD z and t scores at the femoral neck, Ward's triangle, and lumbar spine of the patients with subsequent rapid rates of JSN were significantly higher than those of patients with slower rates (p < 0.05). There was no difference between the rapid and slow narrowers at the greater trochanter (p > 0.2). Age, sex, weight, height, body mass index, Kellgren- Lawrence scores, and initial joint space width were not significantly different between the 2 groups. |
Is evidence-based care for alcohol use disorders affordable? | Despite efficacious treatment, alcohol use disorders contribute significantly to the disability burden. Although wider dissemination of evidence-based health care may impact on the population burden, the affordability of this strategy is unknown. This article compares the cost-effectiveness of current treatment for alcohol use disorders with the cost-effectiveness of optimal treatment, a hypothetical treatment scenario that has been informed by evidence-based practice to determine the affordability of such an approach. This study calculated the cost-effectiveness in the Australian population of evidence-based health care for alcohol harmful use and alcohol dependence, as defined by the International Classification of Diseases, Injuries, and Causes of Death, 10th Revision. Outcome was calculated as years lived with disability (YLD) averted. Data from the Australian National Survey of Mental Health and Wellbeing, in conjunction with published meta-analyses and expert reviews, were used to estimate 1-year costs (1997-98 Australian dollars) and YLD averted by current health care services as well as costs and outcomes for an optimal strategy of evidence-based health care. Of those currently seeking treatment, approximately 45% of those with alcohol harmful use and 58% of those with alcohol dependence receive an evidence-based intervention. The cost of this care was estimated at 73 million dollars, resulting in a cost per YLD averted of 96,813 dollars for harmful use of alcohol and 98,095 dollars for alcohol dependence. Under optimal care for harmful use, costs declined and health gains doubled, substantially reducing the cost per YLD averted to 8861 dollars. For dependence, costs doubled, but optimal treatment resulted in increased health gains, reducing the cost per YLD to 57,542 dollars. | Soluble trophoblast extracts (HME) from some human hydatidiform mole pregnancies suppress IL-2-dependent T-cell proliferation, while others express no immunosuppressive bioactivity. This study was designed to determine if suppression by HME was correlated with gestational age, uterine size, or hCG secretion. Soluble extracts were prepared from nine hydatidiform mole trophoblast samples and screened for immunosuppressive activity using a murine cytotoxic T-cell proliferation assay (CTLL-2). Gestational ages were determined from last menstrual cycle and uterine size was estimated at the time of surgery. Serum samples were collected prior to uterine evacuation and were assayed for human chorionic gonadotropin (hCG). Four of nine HME samples significantly (P < 0.05) suppressed CTLL2 proliferation, while five exhibited no suppressive activity. A strong positive correlation (r = 0.639) was noted for the relationship between gestational age of the molar pregnancies and interleukin-2 (IL-2)-stimulated CTLL2 proliferation (expressed as % of control) in the presence of HME (500 micrograms/mL). This indicates that HME suppression of CTLL2 proliferation is highest in early gestation and then declines with increasing gestational age. A similar correlation was observed between estimated uterine size at surgery and CTLL2 proliferation with added HME, although the association was not as strong (r = 0.359). No association was noted between hCG levels and CTLL2 proliferative responses (r = -0.091). |
Do presence of antigen-specific somatic allelic mutations and splice variants predict for immunological response to genetic vaccination? | Antigen-specific anti-tumor vaccines have demonstrated clinical efficacy, but immunological and clinical responses appear to be patient-dependent. We hypothesized that naturally-occurring differences in amino acid sequence of a host's target antigen might predict for immunological outcome from genetic vaccination by presentation of epitopes different from the vaccine. Using peripheral blood cells from 33 patients who had been treated with a DNA vaccine encoding prostatic acid phosphatase (PAP), we sequenced the exons encoding PAP and PSA genes from somatic DNA to identify single nucleotide polymorphisms. In addition, mRNA was collected to detect alternative splice variants of PAP. We detected four synonymous coding mutations of PAP among 33 patients; non-synonymous coding mutations were not identified. Alternative splice variants of PAP were detected in 22/27 patients tested. The presence of detectable splice variants was not predictive of immunological outcome from vaccination. Immune responses to peptides encoded by these splice variants were common (16/27) prior to immunization, but not associated with immune responses elicited with vaccination. | Previous studies of biomechanical efficiency (external work/energy input--Watt/O(2) consumed) in heart failure (HF) using cardiopulmonary exercise testing (CPET) and magnetic resonance spectroscopy (MRS) have had discordant results with increased efficiency by CPET and decreased efficiency by MRS. Compare biomechanical efficiency of HF subjects and normal controls during steady state (SS=35 W for 6 min) and ramp cycle ergometer exercise. The hypothesis was that HF subjects would have impaired biomechanical efficiency that correlated with HF symptoms. Biomechanical efficiency used the actual Vo(2) during exercise and recovery. Gross (Vo(2) above zero), Net (Vo(2) above the resting Vo(2)) and Work (Vo(2) above the unloaded pedaling Vo(2)) efficiencies were calculated. HF subjects had an 18% higher Vo(2) during SS exercise (P=0.029). Biomechanical efficiency was reduced during SS exercise (gross -15%, P=0.019, net -15%, P=0.062, and work -35%, P=0.002). Gross Efficiency during SS exercise had the strongest correlation with HF symptoms (r=0.55). During ramp exercise gross (-26%), net (-10%) and work (-8%) biomechanical efficiency were all reduced (all P<0.05). The slope of the Vo(2)/Watt relationship during ramp exercise had the best correlation with HF symptoms (r=0.46). |
Does new model for end stage liver disease improve prognostic capability after transjugular intrahepatic portosystemic shunt? | Cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites or recurrent variceal bleeding are at risk for decompensation and death. This study examined whether a new model for end stage liver disease (MELD), which incorporates serum sodium (MELDNa), is a better predictor of death or transplant after TIPS than the original MELD. One hundred forty-eight consecutive patients undergoing nonemergent TIPS for refractory ascites or recurrent variceal bleeding from 1997 to 2006 at a single center were evaluated retrospectively. Cox model analysis was performed with death or transplant within 6 months as the end point. The models were compared using the Harrell's C index. Recursive partitioning determined the optimal MELDNa cutoff to maximize the risk:benefit ratio of TIPS. The predictive ability of MELDNa was superior to MELD, particularly in patients with low MELD scores. The C indices (95% confidence interval [CI]) for MELDNa and MELD were 0.65 (95% CI, 0.55-0.71) and 0.58 (95% CI, 0.51-0.67) using a cut-off score of 18, and 0.72 (95% CI, 0.60-0.85) and 0.62 (95% CI, 0.49-0.74) using a cut-off score of 15. Using a MELDNa >15, 22% of patients were reclassified to a higher risk with an event rate of 44% compared with 10% when the score was <or=15. | To investigate specific neuropathologic correlates of agitation and physical aggression in Alzheimer disease (AD). Neuronal counts in the nucleus basalis, locus ceruleus, and substantia nigra were compared in the brains of patients with pathologically definite AD with or without histories of agitation or interpersonal violence. Alzheimer disease center of a university department of neurology. Neuron densities in the nucleus basalis and absolute neuron counts in the locus ceruleus and substantia nigra pars compacta. The patients with AD who had histories of unequivocal interpersonal violence had significantly greater neuron counts in the substantia nigra pars compacta than did the nonviolent patients with AD. This finding remained significant after multiple clinical and neuropathologic variables were adjusted for. Neuropathologic findings in the nucleus basalis and locus ceruleus were not different between violent and nonviolent patients. |
Do smad3-deficient mice have reduced esophageal fibrosis and angiogenesis in a model of egg-induced eosinophilic esophagitis? | Eosinophilic esophagitis (EoE) is a food-triggered disease associated with esophageal fibrosis and stricture formation in a subset of patients. In the present study we used a murine model of egg (ovalbumin [OVA])-induced EoE to determine whether inhibiting transforming growth factor-β1 (TGF-β1) signaling through the Smad3 pathway would inhibit features of esophageal remodeling including fibrosis, angiogenesis, and basal zone hyperplasia. Wild-type (WT) and Smad3-deficient (KO [knockout]) mice were sensitized intraperitoneally and then challenged chronically with intraesophageal OVA for 1 month. Levels of esophageal eosinophils, esophageal TGF-β1+ and vascular endothelial growth factor (VEGF)+ cells, and features of esophageal remodeling (fibrosis, angiogenesis, basal zone hyperplasia) were quantitated by immunohistochemistry and image analysis. OVA challenge induced a similar increase in the levels of esophageal major basic protein (MBP)+ eosinophils and esophageal TGF-β1+ cells in WT and Smad3 KO mice. Smad3 KO mice challenged with OVA had significantly less esophageal fibrosis and esophageal angiogenesis compared with OVA-challenged WT mice. The reduced esophageal angiogenesis in Smad3 KO mice was associated with reduced numbers of VEGF+ cells in the esophagus. There was a trend toward OVA-challenged Smad3 KO to have reduced basal zone hyperplasia, but this was not statistically significant. | Protocols call for the start of hormonal therapy with levothyroxine after the declaration of brain death. As the hormonal perturbations occur during the process of brain death, the role of the early initiation of levothyroxine therapy (LT) to salvage organs is not well defined. The aim of this study was to evaluate the impact of early LT (before the declaration of brain death) on the number of solid organs procured per donor. We performed an 8-year retrospective analysis of all trauma patients who progressed to brain death. Patients who consented for organ donation, received LT, and donated solid organs were included. Patients were dichotomized into two groups: early LT group, patients who received LT before the declaration of brain death, and late LT group, those who received LT after brain death. The two groups were compared for differences in demographics, clinical characteristics, need for vasopressor, and number of solid organ donation. A total of 100 solid organ donors were identified of which, 41% (n=77) donors who received LT therapy were included. LT before the declaration of brain death was initiated in 37 patients compared with 40 patients who had it started after the declaration of brain death. There was no difference in demographics between the two groups except that patients in the early LT group were more likely to be hypotensive on presentation (54% vs. 25%, p = 0.001). Early LT therapy was associated with an increase in solid organ procurement rate (odds ratio, 1.9; 95% confidence interval, 1.4-2.7; p = 0.01). Sixty-seven patients donated a total of 291 solid organs. |
Does [ Problem/case-based learning compared to lecture for acquiring knowledge of air embolism in continuing medical education ]? | The efficacy of continuing medical education in anesthesiology has been examined very little. This study compared the efficacy of a lecture on air embolism to that of a class that used a problem/case-based learning approach. Prospective, randomized study enrolling 52 experienced anesthesiologists participating in a professional development course. Twenty-six anesthesiologists attended a lecture on air embolism in anesthesia and 25 attended a problem-based class. The objectives were the same for both groups and had been defined previously. The participants' knowledge was evaluated before and after the instruction with tests based on 2 cases dealing with the same knowledge areas: risk factors and symptoms, diagnosis, monitoring, and treatment. No significant between-group differences were found for any of the knowledge areas before or after the classes. After instruction, participants who listened to the lecture improved their scores for knowledge of monitoring (P = .03) and treatment (P = .001). Participants in the problem-based learning group also improved their scores for knowledge of treatment (P = .003). | Psoriasis is a common benign skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. The transcription factor activator protein 1 (AP-1) is known to play an important role in cell proliferation and differentiation. To investigate AP-1 DNA binding activity in psoriatic skin. Keratome biopsies were taken from patients with plaque-type psoriasis. Electrophoretic mobility shift assays were used to determine the AP-1 DNA binding activity, whereas Western and Northern blotting was used to determine Jun and Fos protein and mRNA expression. We found that AP-1 DNA binding activity was almost completely abolished in lesional psoriatic skin compared with nonlesional psoriatic skin. Furthermore, experiments revealed that the protein and mRNA expression of the AP-1 subunits c-Fos, Fra-1 and c-Jun was reduced in lesional psoriatic skin compared with nonlesional psoriatic skin, whereas the protein and mRNA expression of the subunit JunB was increased. Topical application of the vitamin D analogue calcipotriol under occlusion to involved psoriatic skin for 4 days resulted in an increase in AP-1 DNA binding activity, and an increase in the protein and mRNA expression of c-Fos, Fra-1 and c-Jun, together with a decrease in JunB protein and mRNA expression. |
Does specific locations of linear furrow in patients with esophageal eosinophilia? | Linear furrows are the most frequently found endoscopic abnormality in patients with esophageal eosinophilia (EE); however, the precise endoscopic features remain to be fully elucidated. Here, we aimed to clarify the endoscopic features of EE, essential for the diagnosis of eosinophilic esophagitis (EoE), by focusing on the specific locations of linear furrows in a Japanese population. We enrolled 70 cases with EE (≥15 eosinophils/high-power field) who were diagnosed at our hospital and related facilities. Information regarding endoscopic findings and clinical parameters was retrospectively reviewed. Next, the position of linear furrows in relation to esophageal longitudinal folds (ridge or valley) was evaluated in each case and compared with the position of mucosal breaks in patients with reflux esophagitis. Finally, the relationship between linear furrows and eosinophilic infiltration was evaluated. Of the 70 EE patients, 63 (90%) had linear furrows. Those occurred in a radial pattern and were widespread throughout the lower to upper esophagus, and exclusively found in esophageal longitudinal mucosal fold valleys, not on ridges, which was different from the position of mucosal breaks in patients with reflux esophagitis. Increased eosinophilic infiltration was significantly more frequent in linear furrows in the valleys (93%) as compared to mucosa on adjacent ridges (60%) (P < 0.05). | Oral anticoagulation (OAC) with vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) is an effective strategy that is used for stroke prevention in patients with atrial fibrillation (AF). However, OAC is underused particularly in elderly patients, who are often physically disabled or cognitively impaired. We aimed at evaluating the effect of cognitive status and disability on OAC adherence 1 year after stroke or TIA. In this prospective, single-center, observational study patients with ischemic stroke or TIA were consecutively included between 3/2011 and 9/2012. The detailed medical history, basic demographic variables, cardiovascular risk factors, stroke severity according to the National Institutes of Health Stroke Scale (NIHSS), medication including OAC were all recorded. Cognitive performance was measured using the Montreal Cognitive Assessment (MoCA) score at baseline. The functional status was assessed by recording activities and instrumental activities of daily living, respectively (ADL, IADL). After 12 months, patients had a follow-up visit to reassess the cognitive and functional status (MoCA, ADL and IADL) and to document the current use of OAC. In total, 12 months after the ischemic stroke or TIA AF had been diagnosed in 160/586 (27.3%). Of these, 151 patients (94.4%) were treated with OAC. OAC was performed using VKA in 79/151 (52.3%) and DOACs in 72/151 (47.7%). Cognitive impairment at 12 months follow-up was not associated with the absence of OAC treatment. However, regression analysis revealed that patients with AF with physical (ADL) and functional disability (IADL) were less likely to be treated with OAC (p = 0.08 and p = 0.04, respectively) 12 months after a stroke. None of these two factors, however, was independently associated with nonadherence to OAC 12 months after stroke. Although cognitive performance was similar in patients receiving VKA and direct anticoagulants (DOAC), adherence to VKA tended to be lower (82.6 vs. 94.6%, p = 0.12). |
Is reductions in behavioral deficits and neuropathology in the R6/2 mouse model of Huntington 's disease following transplantation of bone-marrow-derived mesenchymal stem cells dependent on passage number? | Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat (greater than 38) on the short arm of chromosome 4, resulting in loss and dysfunction of neurons in the neostriatum and cortex, leading to cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. Although an effective treatment for HD has remained elusive, current studies using transplants of bone-marrow-derived mesenchymal stem cells provides considerable promise. This study further investigates the efficacy of these transplants with a focus on comparing how passage number of these cells may affect subsequent efficacy following transplantation. In this study, mesenchymal stem cells isolated from the bone-marrow of mice (BM MSCs), were labeled with Hoechst after low (3 to 8) or high (40 to 50) numbers of passages and then transplanted intrastriatally into 5-week-old R6/2 mice, which carries the N-terminal fragment of the human HD gene (145 to 155 repeats) and rapidly develops symptoms analogous to the human form of the disease. It was observed that the transplanted cells survived and the R6/2 mice displayed significant behavioral and morphological sparing compared to untreated R6/2 mice, with R6/2 mice receiving high passage BM MSCs displaying fewer deficits than those receiving low-passage BM MSCs. These beneficial effects are likely due to trophic support, as an increase in brain derived neurotrophic factor mRNA expression was observed in the striatum following transplantation of BM MSCs. | Acute appendicitis (AA) is a common indication for urgent abdominal surgery. CA-125 glycoprotein antigen is a non-specific marker for epithelial ovarian cancer; CA-125 serum levels also increased in the conditions of peritoneal inflammation. The aim of this study was to examine the correlation between serum CA-125 levels and AA. All emergency department (ED) patients with suspected AA were prospectively enrolled in the study. The serum level of CA-125 was checked in every patient on arrival to the ED in addition to the routine clinical and laboratory evaluation. Data regarding demographic, clinical, radiological, operative and pathological features were analysed. One hundred consecutive patients (48 males) were enrolled in the study. We found a statistically significant correlation between CA-125 levels in males and the severity of appendicitis as described in the operative and pathology reports (P = 0.008 and P = 0.02, respectively). In addition, we observed a trend towards higher levels of CA-125 in males with AA compared with males without AA (9.9 ± 4.7 versus 7.8 ± 3.2 U/mL, respectively; P = 0.09). |
Does pharmacological preconditioning using intraportal infusion of L-arginine protect against hepatic ischemia reperfusion injury? | The present study examined the effects of intraportal infusion of L-arginine on ischemia/reperfusion injury (I/RI) in pig livers, by observing changes in the liver function, liver cell morphology, and changes in the mitochondrial ultrastructure. The involvement of the nitric oxide (NO) pathway in the reperfusion-ischemic phenomenon is complex and not fully understood. Likewise, little is known about the possible benefit of intraportal infusion of L-arginine (substrate for the NO synthesis) on liver I/RI. A pig model consisting of 90 min of hepatic ischemia and 180 min of reperfusion was employed. Eighteen female hybrid pigs were randomly divided into three groups: sham-operated, non-preconditioned, and pharmacologically preconditioned group (intraportal infusion of L-arginine 400 mg/kg) 10 min before being subjected to ischemia and reperfusion. Serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), thiobarbituric acid reactive substances (TBARS), and the bile flow were measured. Liver biopsies were taken 180 min after reperfusion for histology, caspase-3 immunohistochemistry, and ultrastructural examination of mitochondria. In the pharmacologically preconditioned group, we observed increased bile flow (P < 0.01) and improved serum AST levels (P < 0.01) relative to the non-preconditioned group. Serum concentrations of TBARS did not differ between the groups. Sinusoidal congestion (P = 0.02) was more evident in the non-preconditioned group than in the sham operated group. Infiltrating PMNs (P = 0.01) were more evident in the non-preconditioned group than in the sham and pharmacologically preconditioned group. The pharmacologically preconditioned group showed an approximately 2.5-fold decrease in caspase-3 activity relative to the non-preconditioned group (P < 0.01). Notably, damage to the mitochondrial ultrastructure in the pharmacologically preconditioned group was reduced relative to the other groups (P < 0.01). | We examined the association between cognitive domains and research consent capacity in PD. Our hypothesis was that research consent capacity is best predicted by executive function. A cohort of 90 PD patients and 30 healthy older adults were administered the MacArthur Competence Assessment Tool for Clinical Research, Dementia Rating Scale-2, and the MoCA. Experts classified patients as either "capable" or "not capable" of providing informed consent to participate in two clinical trials. MacArthur Competence Assessment Tool for Clinical Research Reasoning scores for both clinical trial types were most associated with executive functions and delayed recall. As scores on these domains improved, the odds of an expert rating of "capable of consent" increased. |
Does fluid consumption and taste novelty determine transcription temporal dynamics in the gustatory cortex? | Novel taste memories, critical for animal survival, are consolidated to form long term memories which are dependent on translation regulation in the gustatory cortex (GC) hours following acquisition. However, the role of transcription regulation in the process is unknown. Here, we report that transcription in the GC is necessary for taste learning in rats, and that drinking and its consequences, as well as the novel taste experience, affect transcription in the GC during taste memory consolidation. We show differential effects of learning on temporal dynamics in set of genes in the GC, including Arc/Arg3.1, known to regulate the homeostasis of excitatory synapses. | The prognostic importance of red cell distribution width (RDW) and neutrophil/lymphocyte ratio (NLR) in cardiovascular diseases has been shown. Ascending aortic dilatation (AAD) is a common cardiovascular disease and is associated with aortic wall inflammation and cystic degeneration. In this study, we aimed to investigate the relationship between serum levels of RDW, NLR and the presence of AAD. Two-hundred consecutive patients with AAD diagnosed by transthoracic echocardiography were prospectively recruited and were compared to 170 age-gender- matched subjects with normal aortic diameters. Complete blood counts (CBCs) were analyzed for hemoglobin, RDW and NLR counts, as well as mean corpuscular volume (MCV). If possible, results of CBC tests within the previous two years were also included and the averages were used. RDW [median 13.9, interquartile range (IQR) 1.40 vs. median 13.3, IQR 1.05%, p=0.01], NLR (median 2.04, IQR 1.09 vs. median 1.78, IQR 0.90, p=0.01) and high-sensitive C-reactive protein (hs-CRP) (median 0.60, IQR 0.80 vs. median 0.44, IQR 0.68 mg/L, p=0.01) levels were significantly higher in the AAD group compared to the control group. In univariate correlation analysis, ascending aortic diameters were correlated with RDW levels (r=0.31, p=0.01), NLR levels (r=0.15, p=0.01) and hs-CRP levels (r=0.12, p=0.03). In multivariate logistic regression analysis, increased levels of RDW and hs-CRP remained as the independent correlates of AAD in the study population. Receiver operating characteristic (ROC) curve analysis revealed that a RDW measurement higher than >13.8% predicted AAD with a sensitivity of 49.5% and a specificity of 82.8% (area under the curve [AUC] 0.681, p=0.01). |
Does doxazosin modify Bcl-2 and Bax protein expression in the left ventricle of spontaneously hypertensive rats? | Increased apoptosis has recently been reported in the heart of spontaneously hypertensive rats (SHRs). To investigate the molecular basis of apoptosis in the left ventricle of SHRs in terms of the expression of Bcl-2 protein (which protects from apoptosis) and Bax protein (which acts as an apoptotic promoter). In addition, we analysed the involvement of alpha -adrenergic receptors in the left ventricular apoptosis of SHRs. The study was performed in untreated SHRs (n=16) and SHRs that were orally treated with doxazosin (10 mg/kg body weight per day, for 15 days), a selective alpha1-receptor blocker (n=16). A group of Wistar-Kyoto (WKY) rats (n=16) was used as the control. The left ventricles of untreated SHRs showed a significant increase in Bcl-2 protein expression and a reduced presence of Bax protein. The ratio of Bcl-2:Bax in SHRs was higher than in WKY rats, suggesting an anti-apoptotic state. Paradoxically, both the number of apoptotic cardiac cells and the cleavage of an 85-kDa fragment of the poly (ADP-ribose) polymerase (PARP), a marker of caspase-3 activity, were higher in the left ventricle of SHRs than in WKY rats, suggesting an apoptotic situation. Bax promotes cell apoptosis when it is bound to Bcl-2. We then determined the abundance of Bax-Bcl-2 complexes in the left ventricle of the two groups of animals. Bax-Bcl-2 complexes were more abundant in SHRs than WKY rats. In a second set of experiments, we analysed the role of alpha1-adrenergic blockade by doxazosin in the above-described mechanisms. Doxazosin treatment reduced the formation of Bax-Bcl-2 complexes in the left ventricle of SHRs, and this was accompanied by a decrease in the levels of 85kDa PARP and a reduction in apoptotic left ventricular cells. | Indication for rotating hinge (RH) total knee arthroplasty (TKA) includes primary and revision cases, with contradictory results. The aim of this study was to report prospective early results of a new modular rotating hinge TKA (EnduRo). For this implant several new design features and a new bearing material (carbon-fiber reinforced poly-ether-ether-ketone) have been developed. Furthermore, we tried to establish a new classification of failure modes for revision TKA. 152 EnduRo rotating-hinge prostheses were implanted in two centers. In 90 patients a primary implantation has been performed and 62 patients were revision cases. Knee Society Score (KSS), Western Ontario and McMaster Osteoarthritis Index (WOMAC), Oxford Knee Score (OKS), and Range of motion (ROM) were assessed before surgery, 3 months postoperatively, 12 months postoperatively, and annually thereafter. We defined 3 types of complications: Type 1, infection; type 2, periprosthetic complications; type 3, implant failures. KSS, WOMAC, OKS, and ROM revealed significant improvements between the preoperative and the follow-up investigations. There were 14 complications (9.2%) leading to revision surgery, predominantly type 2. |
Is fibromyalgia associated with coronary heart disease : a population-based cohort study? | We examined whether patients with a diagnosis of fibromyalgia have an increased risk of coronary heart disease (CHD), compared with age- and sex-matched control patients. We hypothesized that patients diagnosed with fibromyalgia are at increased risk of adverse coronary events. Using a matched-cohort study design, we analyzed data retrieved from the Longitudinal Health Insurance Database 2000 released by the National Health Research Institute, Taiwan. The Longitudinal Health Insurance Database 2000 includes medical claims data and registration files for 1 million enrollees randomly selected from the 2000 Registry for Beneficiaries (n = 23.72 million) of the National Health Insurance program. Patients treated for fibromyalgia at least once a month for 3 consecutive months following their initial diagnosis were enrolled in our study. The primary end point was the composite of CHD events, including percutaneous coronary interventions and coronary artery bypass grafting procedures. A propensity score was estimated by a logistic regression method, in which the fibromyalgia status was regressed on baseline prognostic factors. The hazard ratios and the 95% confidence intervals were estimated using multivariate Cox proportional-hazards regression models while adjusting for the propensity score. After adjusting for the propensity score, the patients with fibromyalgia showed a significantly higher subsequent risk of a CHD event (hazard ratio, 2.11; 95% confidence interval, 1.46-3.05; P < 0.001) than the patients without fibromyalgia. | Recently, several reports have described the ability of recombinant baculoviruses to transduce a variety of mammalian cells. Yet, mechanisms involved in baculovirus entry in those cells remain largely unexplored, particularly at the primary binding step of the virions to the cell membrane. This report focused on the primary virus-cell interactions that lead to in vitro transduction of human 293 cells using a polyhedrin-deleted baculovirus harboring a CMV-driven beta-galactosidase gene (BacLacZ). Infection rate monitored for 8 h and transduction rate with a multiplicity of infection of up to 800 were, both, non-saturable. Temperatures from 37 degrees C to 4 degrees C dramatically impaired BacLacZ but not adenovirus cell attachment. Competitive infections performed with an excess of a non LacZ-expressing baculovirus hardly competed at a 1/1 ratio. Consistent with an adsorptive binding process onto the cell surface, interactions through electrostatic charges between both viral and cell membranes appeared to be critical for BacLacZ transduction. The addition of polybrene to the cells prior to or during the infection prevented both virus binding and LacZ gene transfer, suggesting the involvement of negatively charged epitopes exposed at the cell surface. The simultaneous presence of the highly charged heparin abrogated BacLacZ binding to the cell surface and subsequent gene transfer. Lastly, direct in vitro binding of BacLacZ to heparin but not BSA columns could be demonstrated after elution of infectious BacLacZ virus in high salt molarity. |
Is a New Radiographic Classification System for Developmental Hip Dysplasia Reliable and Predictive of Successful Closed Reduction and Late Pelvic Osteotomy? | The Tonnis radiographic classification of developmental dysplasia of the hip (DDH) has been used as a prognostic indicator for patients with walking-age DDH. The International Hip Dysplasia Institute (IHDI) classification, a new radiographic classification system, has been proposed to be more reliable by its creators. We sought to validate its reliability using independent observers, to compare it to the Tonnis method, and to assess its prognostic significance in a large cohort of patients. A consecutive series of walking-age DDH patients were examined radiographically and classified by the Tonnis and IHDI schemes by 3 independent observers. Interobserver agreement was determined using the Kappa method. Clinical data were collected on patients with regard to success of closed reduction, need for later pelvic osteotomy, and presence of subsequent radiographic avascular necrosis (AVN). The prognostic value of the Tonnis and IHDI classifications to predict these clinical outcomes was determined. A total of 287 hips were available for analysis of the classification schemes. In total, 235 hips underwent attempted closed reduction and were eligible for analysis of successful closed reduction, and 131 hips had >4-year follow-up and were utilized for analysis of late pelvic osteotomy and AVN. Both classifications showed excellent interobserver reliability and in general, there was nonstatistically significant better reliability for the IHDI versus the Tonnis classification. In multivariate analysis, both IHDI and Tonnis classifications were found to be predictive of successful closed reduction and need for late pelvic osteotomy. Both methods showed trends toward being predictive of AVN rate, without statistical significance. | Licorice has been used to treat many ailments including cardiovascular disorders in China for long time. Recent studies have shown that the cardiac actions of licorice have been attributed to its active component, glycyrretinic acid (GA). However, its mechanism remains poorly understood. The effects of GA on the cardiac sodium currents (I(Na)), L-type calcium currents (I(Ca,L)) and hyperpolarization-activated inward currents (I(f)) were investigated. Human isoforms of wild-type and DeltaKPQ-mutant type sodium channels were expressed in Xenopus oocytes, and the resulting currents (peak and late I(Na)) were recorded using a two-microelectrode voltage-clamp technique. A perforated patch clamp technique was employed to record I(Ca,L) and I(f) from isolated rabbit sinoatrial node pacemaker cells. GA inhibited peak I(Na) (33% at 90 microM) and late I(Na) (72% at 90 microM), but caused no significant effects on I(Ca,L) and I(f). |
Do wall shear stress and strain modulate experimental aneurysm cellularity? | Clinical evidence indicates that hemodynamic conditions influence abdominal aortic aneurysm (AAA) disease. We modified blood flow to evaluate the effects of wall shear stress (WSS) and relative wall strain (RWS) on aneurysm structure and cellularity. Rodent AAAs were created with porcine pancreatic elastase infusion. In group 1 AAA WSS was increased with left femoral arteriovenous fistula creation, whereas in group 2 AAA WSS was decreased with left iliac artery ligation. Aortic flow, wall motion, and blood pressure were recorded in both groups. AAA diameter, endothelial and smooth muscle cellularity (CD31 and alpha-smooth muscle actin immunostaining), markers for cell proliferation (5-bromodeoxyuridine), endothelial and smooth muscle cell growth factor production (vascular endothelial growth factor-D and platelet-derived growth factor-beta, respectively), and apoptosis (deoxyuridine triphosphate nick end-labeled [TUNEL] stain) were compared between groups when the animals were killed. Arteriovenous fistula creation increased WSS (high-flow AAA) by 300% and RWS by 150%. Iliac ligation reduced WSS (low-flow AAA) by 60%. Neither procedure significantly altered systolic, diastolic, or mean aortic pressure. When the animals were killed 7 days after elastase infusion, low-flow AAAs were significantly larger than high-flow AAAs. High-flow AAAs also contained more endothelial cells and smooth muscle cells, and evidence of increased growth factor production, cell proliferation, and decreased apoptosis. No difference in type or severity of AAA inflammatory cell infiltrate was noted between groups. | Most antidepressant and neuroleptic agents are metabolized by the polymorphic cytochrome P450 enzyme CYP2D6. This study evaluates the importance of the CYP2D6 genotype for the disposition of the neuroleptic agents perphenazine and zuclopenthixol. Patients treated with neuroleptic agents (n = 36) were studied prospectively with regard to CYP2D6 genotype and neuroleptic plasma concentration during oral treatment. Because no patient provided enough samples for individual kinetic modeling, a bayesian approach was used for determination of the clearance. Population kinetic parameters for this procedure were collected from retrospective therapeutic drug monitoring data (n = 113) by use of a nonparametric approach. The CYP2D6 genotype significantly predicted the oral clearance of perphenazine and zuclopenthixol (p < 0.01 by multiple regression). The difference in clearance between homozygous extensive metabolizers and poor metabolizers was threefold for perphenazine and twofold for zuclopenthixol. |
Do early and intermediate-term complications of self-expanding stents limit its potential application in children with congenital heart disease? | We report on the early and intermediate-term follow-up results of self-expanding Wallstent (Schneider, Switzerland) implanted in children with congenital heart disease. The inherent shortcomings of balloon-expandable stents prompted the trial of an alternative stent. Twenty patients underwent 22 implantations of 25 self-expanding Wallstents between December 1993 and June 1997 in two institutions. The mean age and weight were 10.8+/-4.5 years and 30.5+/-14.2 kg, respectively. The patients were divided into two groups: 1) Group I comprised 17 patients with pulmonary arterial stenoses, 2) Group II comprised four patients with venous stenoses (one belonged to both groups). Sixteen patients underwent recatheterization at a median of 5.8 months (range 0.5 to 31, mean 8.1 months) after stenting. Hemodynamic and angiographic changes after the interventional procedures and complications were documented. All the stents were successfully deployed in the intended position. In Group I, the narrowest diameter of the stented vessel increased from 4.1+/-1.5 to 8+/-2 mm (95% increase, p < 0.0001) while the systolic pressure gradient across decreased from 24.6+/-15.8 to 12.1+/-11.4 mm Hg (51% decrease, p = 0.001). In Group II, the dimensional changes of the narrowest segment increased from 4.3+/-0.5 to 7.5+/-0.4 mm (75% increase, p = 0.003), and the pressure gradient reduced from 5.0+/-2.9 to 0.9+/-1.0 mm Hg (82% decrease, p = 0.04) across the stented venous channel. Distal migration of two optimally positioned stents occurred within 24 h of implantation. At recatheterization, significant neointimal ingrowth (>30% of the expanded diameter) was noted in 7 (28%) of the 25 implanted stents. This responded poorly to balloon dilation. Predisposing factors for the neointimal ingrowth included stents of smaller diameter (<9 mm) and longer period after implantation. | Cocaine and alcohol are frequently used simultaneously and this combination is associated with enhanced toxicity. We recently showed that active cocaine abusers have a markedly enhanced sensitivity to benzodiazepines. Because both benzodiazepines and alcohol facilitate GABAergic neurotransmission we questioned whether cocaine abusers would also have an enhanced sensitivity to alcohol that could contribute to the toxicity. In this study we compared the effects of alcohol (0.75 g/kg) on regional brain glucose metabolism between cocaine abusers (n = 9) and controls (n = 10) using PET and FDG. Alcohol significantly decreased whole brain metabolism and this effect was greater in controls (26+/-6%) than in abusers (17+/-10%) even though they had equivalent levels of alcohol in plasma. Analysis of the regional measures showed that cocaine abusers had a blunted response to alcohol in limbic regions, cingulate gyrus, medial frontal and orbitofrontal cortices. |
Is congenital cytomegalovirus infection associated with high maternal socio-economic status and corresponding low maternal cytomegalovirus seropositivity? | Human cytomegalovirus (CMV) is the leading infectious cause of congenital infection in developed countries. Globally, CMV seropositivity has been associated with low socio-economic status (SES); however, Australian data are lacking. Therefore, we examined the association between SES and CMV seroprevalence in children and pregnant women. Three groups were examined: 1, a prospective cohort of Australian children aged 0-15 years (n = 220); 2, a clinic-based sample of pregnant women (n = 778); and 3, a case series of infants and children (n = 219) with symptomatic congenital CMV infection. SES was determined using a postcode-based score from the Australian Bureau of Statistics.Group 1 was recruited from endocrinology clinics and follow-up at Prince of Wales Hospital and Children's Hospital at Westmead. Group 2 was recruited at the Royal Hospital for Women. Congenitally infected infants were identified through the Australian Paediatric Surveillance Unit. CMV seroprevalence among all children was 20% (95% confidence interval (CI) 15-25%), and there was no association with SES (P = 0.58). Seroprevalence among pregnant women was 57% (53-60%), and higher rates of CMV seropositivity were associated with lower SES (P < 0.001). More congenital CMV cases were reported in the highest socio-economic groups (55%) than the lowest (9%) (P < 0.001). | Pirfenidone (5 methyl-1-phenyl-2(1H)-pyridone) is a novel anti-fibrotic agent, which has been shown to decrease collagen deposition in a variety of animal models in vivo, and recently in hepatic fibrosis also. At cellular level, we have recently demonstrated that pirfenidone is able to inhibit proliferation of hepatic stellate cells induced by platelet-derived growth factor, as well as collagen type I accumulation and alpha1(I) procollagen mRNA expression. To evaluate if pirfenidone maintains its anti-fibrotic properties also when administered after the induction of hepatic damage and to further investigate the molecular mechanisms leading to the anti-fibrotic effect of pirfenidone. Rats treated with dimethylnitrosamine (10 mg/kg) for 5 weeks received a liquid diet containing 0.5% pirfenidone starting from the third week. Pirfenidone treatment reduced the degree of liver injury, as determined by alanine aminotransferase values and necro-inflammatory score, which was associated with reduced hepatic stellate cells proliferation and collagen deposition. Treatment with dimethylnitrosamine increased transcripts levels for transforming growth factorbeta1, procollagen alpha1(I), tissue inhibitors of metalloproteinase-1 and matrix metalloproteinase-2 by 7-, 7-, 4- and 15-fold, respectively. Pirfenidone administration downregulated elevated levels of those transcripts by 50-60%, and this was associated with a 70% reduction in collagen deposition. |
Does l-Glutamine enhance Tight Junction Integrity by Activating CaMK Kinase 2-AMP-Activated Protein Kinase Signaling in Intestinal Porcine Epithelial Cells? | The tight junctions (TJs) are essential for maintenance of the intestinal mucosal barrier integrity. Results of our recent work show that dietary l-glutamine (Gln) supplementation enhances the protein abundance of TJ proteins in the small intestine of piglets. However, the underlying mechanisms remain largely unknown. This study was conducted to test the hypothesis that Gln regulates TJ integrity through calcium/calmodulin-dependent kinase 2 (CaMKK2)-AMP-activated protein kinase (AMPK) signaling which, in turn, contributes to improved intestinal mucosal barrier function. Jejunal enterocytes isolated from a newborn pig were cultured in the presence of 0-2.0 mmol Gln/L for indicated time points. Cell proliferation, monolayer transepithelial electrical resistance (TEER), paracellular permeability, expression and distribution of TJ proteins, and phosphorylated AMPK were determined. Compared with 0 mmol Gln/L, 2.0 mmol Gln/L enhanced (P < 0.05) cell growth (by 31.9% at 48 h and 11.1% at 60 h). Cells treated with 2 mmol Gln/L increased TEER by 32.2% at 60 h, and decreased (P < 0.05) TJ permeability by 20.3-40.0% at 36-60 h. In addition, 2.0 mmol Gln/L increased (P < 0.05) the abundance of transmembrane proteins, such as occludin, claudin-4, junction adhesion molecule (JAM)-A, and the plaque proteins zonula occludens (ZO)-1, ZO-2, and ZO-3 by 1.8-6 times. In contrast, 0.5 mmol Gln/L had a moderate effect on TJ protein abundance (20.2-70.5%; P < 0.05) of occludin, claudin-3, claudin-4, JAM-A, and ZO-1. 2.0 mmol Gln/L treatment led to a greater distribution of claudin-1, claudin-4, and ZO-1 at plasma membranes compared with 0 mmol Gln/L. This effect of Gln was mediated by the activation of CaMKK2-AMPK signaling, because either depletion of calcium from the medium or the presence of an inhibitor of CaMKK2 abrogated the effect of Gln on epithelial integrity. | Prostate biopsy positivity after radiotherapy (RT) is a significant determinant of eventual biochemical failure. We mapped pre- and post-treatment tumor locations to determine if residual disease is location-dependent. There were 303 patients treated on a randomized hypofractionation trial. Of these, 125 underwent prostate biopsy 2-years post-RT. Biopsy cores were mapped to a sextant template, and 86 patients with both pre-/post-treatment systematic sextant biopsies were analyzed. The pretreatment distribution of positive biopsy cores was not significantly related to prostate region (base, mid, apex; p=0.723). Whereas all regions post-RT had reduced positive biopsies, the base was reduced to the greatest degree and the apex the least (p=0.045). In 38 patients who had a positive post-treatment biopsy, there was change in the rate of apical positivity before and after treatment (76 vs. 71%; p=0.774), while significant reductions were seen in the mid and base. |
Does core needle biopsy of breast cancer tumors increase distant metastases in a mouse model? | Incisional biopsies, including the diagnostic core needle biopsy (CNB), routinely performed before surgical excision of breast cancer tumors are hypothesized to increase the risk of metastatic disease. In this study, we experimentally determined whether CNB of breast cancer tumors results in increased distant metastases and examine important resultant changes in the primary tumor and tumor microenvironment associated with this outcome. To evaluate the effect of CNB on metastasis development, we implanted murine mammary 4T1 tumor cells in BALB/c mice and performed CNB on palpable tumors in half the mice. Subsequently, emulating the human scenario, all mice underwent complete tumor excision and were allowed to recover, with attendant metastasis development. Tumor growth, lung metastasis, circulating tumor cell (CTC) levels, variation in gene expression, composition of the tumor microenvironment, and changes in immunologic markers were compared in biopsied and non-biopsied mice. Mice with biopsied tumors developed significantly more lung metastases compared to non-biopsied mice. Tumors from biopsied mice contained a higher frequency of myeloid-derived suppressor cells (MDSCs) accompanied by reduced CD4 + T cells, CD8 + T cells, and macrophages, suggesting biopsy-mediated development of an increasingly immunosuppressive tumor microenvironment. We also observed a CNB-dependent up-regulation in the expression of SOX4, Ezh2, and other key epithelial-mesenchymal transition (EMT) genes, as well as increased CTC levels among the biopsy group. | Attentional and executive dysfunctions are associated with falls in community-dwelling elderly individuals and patients with PD. Frontal cognitive dysfunction and falls are frequent symptoms of PSP. We studied to identify the cognitive domains associated with recurrent falls in patients with PSP. We performed a battery of neuropsychological tests in 59 individuals with probable PSP. We categorized patients into infrequent fall (≤one fall during the last 12 months, n=29) or recurrent fall (≥two falls during the last 12 months, n=30) groups. UPDRS subscores for axial deficits were significantly higher in the recurrent fall group than the infrequent fall group, but there were no significant differences in UPDRS total motor scores or subscores for bradykinesia, rigidity, and tremor. There was no difference between groups in MMSE scores. ANCOVA with adjustment for confounding factors showed that, recurrent falls were associated with abnormalities in alternating hand movement, alternating square and triangle, RCFT copying task, and ideomotor apraxia. Group difference of abnormalities in Stroop test was marginal (p=0.054). However, there were no group differences in the frequency of abnormalities in forward or backward digit span, motor impersistence, fist-edge-palm, contrast programming, go-no-go, Luria loop drawing, or Controlled Oral Word Association Tests. Recurrent falls were not associated with memory or language dysfunction. |
Are sleep spindles related to schizotypal personality traits and thalamic glutamine/glutamate in healthy subjects? | Schizophrenia is a severe mental disorder affecting approximately 1% of the worldwide population. Yet, schizophrenia-like experiences (schizotypy) are very common in the healthy population, indicating a continuum between normal mental functioning and the psychosis found in schizophrenic patients. A continuum between schizotypy and schizophrenia would be supported if they share the same neurobiological origin. Two such neurobiological markers of schizophrenia are: (1) a reduction of sleep spindles (12-15 Hz oscillations during nonrapid eye movement sleep), likely reflecting deficits in thalamo-cortical circuits and (2) increased glutamine and glutamate (Glx) levels in the thalamus. Thus, this study aimed to investigate whether sleep spindles and Glx levels are related to schizotypal personality traits in healthy subjects. Twenty young male subjects underwent 2 all-night sleep electroencephalography recordings (128 electrodes). Sleep spindles were detected automatically. After those 2 nights, thalamic Glx levels were measured by magnetic resonance spectroscopy. Subjects completed a magical ideation scale to assess schizotypy. Sleep spindle density was negatively correlated with magical ideation (r = -.64, P < .01) and thalamic Glx levels (r = -.70, P < .005). No correlation was found between Glx levels in the thalamus and magical ideation (r = .12, P > .1). | This study aimed to analyze adjuvant therapy among patients with extrahepatic cholangiocarcinoma (EHC) at a national level. The American College of Surgeons National Cancer Data Base was used to identify patients with resected EHC (pathologic stages 1-3) between 1998 and 2006 (n = 8741). Three groups were compared: surgery only (S, n = 5766), surgery plus adjuvant chemotherapy (AC, n = 450), and surgery plus adjuvant chemotherapy and radiation therapy (ACR, n = 1918). The study investigated how patient demographics, provider characteristics, and tumor-specific variables were associated with receipt of adjuvant therapy and overall survival. Patients who received adjuvant treatment were more likely to be younger (median age S, 70 years; AC, 65 years; ACR, 63 years), in the highest income quartile (>$46,000: S, 38.3 %; AC, 43.4 %; ACR, 44.7 %), and treated at a community cancer center (S, 43.0 %; AC, 50.7 %; ACR, 52.9 %) (all p < 0.001). These patients also were more likely to have positive lymph nodes (S, 34.7 %; AC, 69.6 %; ACR, 63.3 %), positive surgical margins (S, 5.9 %; AC, 7.1 %; ACR, 10.7 %), and stage 3 disease (S, 21.4 %; AC, 37.8 %; ACR, 37.9 %) (all p < 0.001). Multivariate analysis of the entire cohort showed improved survival with ACR (hazard ratio [HR] 0.82; 95 % confidence interval [CI] 0.75-0.91). The survival benefit was independent of margin status (R0: HR 0.88; 95 % CI 0.79-0.97; R1: HR 0.49; 95 % CI 0.38-0.62). |
Does [ Private umbilical cord blood banking reduce the number of samples for scientific stem cell research ]? | Private umbilical cord blood (UCB) banking after delivery has increased over the last decade. For adult/somatic stem cell research UCB is an essential source of stem cells and researchers question if the number of UCB samples for research might be reduced by private banking. A survey among seven private blood banks in Germany and analysis and comparison of the number of UCB samples donated for research within the STEMMAT project with private blood banking were performed from 03/2003 to 06/2005 at the Frauenklinik (OB/GYN), Technical University Munich, Germany. Within 27.5 months 1,551 UCB samples were collected for research purposes; the effective recruitment rate was higher than expectations at an effective 66.2 %. Private UCB banking [n = 24] was distributed among three cord blood banks [n = 16, 6 and 4]. The rate of private blood banking was 0.99 % for all deliveries, thus reducing the effective rate for research purpose by only 1.5 %. | Corticosteroid treatment affects muscle protein and glutamine metabolism. In the present study we aimed to clarify to what extent anorexia, weight loss and corticosteroids determine protein and glutamine metabolism in muscle. The study was performed in Wistar rats (300-350 g, n = 40) given triamcinolone (0.25 mg/kg/day i.m.) treatment (CS group) for 14 days, sham treated free fed (FF group), sham treated pair fed (PF group) and sham treated pair weight (PW group). In vivo protein and glutamine turnover were measured using L-[2,6-3H]phenylalanine and L-[3,4-3H]glurtamine as tracer in a three compartment model across the hindquarter. Corticosteroid treatment decreased total body weight to a greater extent than can be explained by decreased food intake only, justifying the need for pair weight controls. Muscle weight loss was relatively greater in the corticosteroid treated rats than in the pair weight controls indicating specific corticosteroid induced changes in muscle protein metabolism. Pair weight rats increased muscle net protein breakdown rates from -5 +/- 3 nmol x 100 g body weight(-1) x min(-1) to -15 +/- 3 nmol x 100 g body weight(-1) x min(-1) (P < 0.05 vs FF). In the corticosteroid treated rats net protein breakdown rates increased to -22 +/- 4 nmol x 100 g body weight(-1) x min(-1) (P < 0.01 CS vs FF/PF) Net protein breakdown in corticosteroid treated rats was accompanied by increased glutamine efflux from the hindquarter (P < 0.05, CS vs FF/PF/PW). The latter could predominantly be explained by de novo synthesis. Furthermore, corticosteroid treatment induced a loss of plasma to free muscle glutamine gradient indicating down regulation of glutamine membrane transport rates into muscle. This effect was, however, similar in the pair weight control group and can thus be fully accounted for by the muscle weight loss. |
Does pEG-IFN alpha but not ribavirin alter NK cell phenotype and function in patients with chronic hepatitis C? | Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown. Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells. Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load. | International registries for acute type A aortic dissection (TAAD) demonstrate stagnant operative mortality rates in excess of 20% and stroke rates of 9% to 25%, with little global emphasis on stroke reduction or carotid involvement. Cerebral malperfusion with TAAD has been linked to poorer outcome. We hypothesize that concomitant carotid dissection or complex dissection flaps in the arch play a major role in stroke development and that aggressive reconstruction of the arch and carotid arteries can improve neurologic outcomes in TAAD. A standardized protocol focused on expedient care, neurocerebral protection, and common carotid and total arch reconstruction was developed for 264 consecutive TAADs. Arch and complete carotid replacement was based on arch dissection anatomy, carotid involvement, or an intraarch tear. Neurocerebral monitoring with continuous electroencephalogram/somatosensory evoked potentials was used in all cases. The postoperative stroke and hospital mortality rates were 3.4% and 9.1%, and stroke rates by extent of arch replacement were 4%, 3%, and 0% for hemiarch, total arch, and total arch with complete carotid replacement, respectively. An intraoperative change in the electroencephalogram/somatosensory evoked potentials was strongly predictive of stroke and had a negative predictive value of 98.2%. |
Does interaction of acetylcholinesterase with neurexin-1β regulate glutamatergic synaptic stability in hippocampal neurons? | Excess expression of acetylcholinesterase (AChE) in the cortex and hippocampus causes a decrease in the number of glutamatergic synapses and alters the expression of neurexin and neuroligin, trans-synaptic proteins that control synaptic stability. The molecular sequence and three-dimensional structure of AChE are homologous to the corresponding aspects of the ectodomain of neuroligin. This study investigated whether excess AChE interacts physically with neurexin to destabilize glutamatergic synapses. The results showed that AChE clusters colocalized with neurexin assemblies in the neurites of hippocampal neurons and that AChE co-immunoprecipitated with neurexin from the lysate of these neurons. Moreover, when expressed in human embryonic kidney 293 cells, N-glycosylated AChE co-immunoprecipitated with non-O-glycosylated neurexin-1β, with N-glycosylation of the AChE being required for this co-precipitation to occur. Increasing extracellular AChE decreased the association of neurexin with neuroligin and inhibited neuroligin-induced synaptogenesis. The number and activity of excitatory synapses in cultured hippocampal neurons were reduced by extracellular catalytically inactive AChE. | It has been shown that increased red blood cell distribution width (RDW) predicts adverse outcomes in cardiovascular disease and in patients undergoing a percutaneous coronary intervention. The aim of the present study was to assess the predictive value of preinterventional RDW on the development of in-stent restenosis (ISR) in patients undergoing stent implantation. In this retrospective study, we compared 131 patients with ISR and 138 patients without ISR who had undergone bare metal stent implantation. Preprocedural RDW was significantly higher in patients with ISR than those without restenosis (14.6±3.2 vs. 13.4±1.6%, P<0.001). Stent length was significantly longer in patients with than those without restenosis (17.9±5.6 vs. 16.2±5.2 mm, respectively, P=0.03). Compared with patients with restenosis, patients without restenosis had a lower rate of diabetes (28 vs. 61 patients, P=0.001), a significantly short period between two coronary angiographies (9.8±9.3 vs. 12.9±11.6 months, respectively, P=0.02), and lower triglyceride levels (133±53 vs. 198±121 mg/dl, respectively, P=0.05). In multivariate logistic regression analysis, diabetes mellitus, stent length, preprocedural RDW, and current smoking independently predicted ISR. |
Is strain echocardiography related to fibrosis and ventricular arrhythmias in hypertrophic cardiomyopathy? | Hypertrophic cardiomyopathy (HCM) patients are at risk of ventricular arrhythmias (VAs). We aimed to explore whether systolic function by strain echocardiography is related to VAs and to the extent of fibrosis by cardiac magnetic resonance imaging (CMR). We included 150 HCM patients and 50 healthy individuals. VAs were defined as non-sustained and sustained ventricular tachycardia and aborted cardiac arrest. Left ventricular function was assessed by ejection fraction (EF) and by global longitudinal strain (GLS) assessed by speckle tracking echocardiography. Mechanical dispersion was calculated as standard deviation (SD) of time from Q/R on ECG to peak longitudinal strain in 16 left ventricular segments. Late gadolinium enhancement (LGE) was assessed by CMR. HCM patients had similar EF (61 ± 5% vs. 61 ± 8%, P = 0.77), but worse GLS (-15.7 ± 3.6% vs. -21.1 ± 1.9%, P < 0.001) and more pronounced mechanical dispersion (64 ± 22 vs. 36 ± 13 ms, P < 0.001) compared with healthy individuals. VAs were documented in 37 (25%) HCM patients. Patients with VAs had worse GLS (-14.1 ± 3.6% vs. -16.3 ± 3.4%, P < 0.01), more pronounced mechanical dispersion (79 ± 27 vs. 59 ± 16 ms, P < 0.001), and higher %LGE (6.1 ± 7.8% vs. 0.5 ± 1.4%, P < 0.001) than patients without VAs. Mechanical dispersion correlated with %LGE (R = 0.52, P < 0.001) and was independently associated with VAs (OR 1.6, 95% CI 1.1-2.3, P = 0.02) and improved risk stratification for VAs. | Phototherapy may be effective in atopic dermatitis (AD). Medium-dose (MD) ultraviolet (UV) A1 was introduced for the treatment of AD. Few immunohistochemical data are available pertaining to phototherapy in AD. Regulatory T cells may play a role in clearing AD. We sought to compare the clinical and immunohistochemical effects of narrowband (NB) UVB and MD UVA1 treatment in patients with AD. Thirteen adult patients with AD were included in this randomized investigator-blinded half-sided comparison study between NB UVB and MD UVA1. Disease activity was measured using the Leicester sign score. Skin biopsy specimens were taken before and after phototherapy. Regulatory T cells were stained with the forkhead box protein P3 (FoxP3). NB UVB and MD UVA1 both significantly decreased AD severity (P < .01) and the dermal cellular infiltrate. The percentage of FoxP3(+)CD3(+) T cells did not change after NB UVB or MD UVA1 treatment. |
Is it all in the factors : effects of cognitive remediation on symptom dimensions? | Cognitive remediation (CR) aims primarily to improve cognition and functional outcomes. However, a limited number of studies reported a positive effect on symptoms. This limited effect may be because the symptom clusters considered are too broad and heterogeneous. This study explores, for the first time, the effect of CR on five empirically defined symptom dimensions of schizophrenia. Participants were patients with schizophrenia taking part in a randomised controlled trial comparing CR plus treatment as usual (CR, N=43) to treatment as usual (TAU, N=42). All participants were assessed at baseline and 14-weeks (i.e. at the conclusion of treatment for the CR group) with the Positive and Negative Symptoms Scale (PANSS). Five symptom dimensions were derived from the PANSS scores: Positive (POS), Negative (NEG), Disorganised (DIS), Excited (EXC) and Emotional Distressed (EMD). After CR, the therapy group had a significant reduction in DIS and NEG symptom dimensions compared to the TAU group. The traditional PANSS factors showed no effect of CR on symptoms. | Compressive mechanical stress produced during growth in a confining matrix limits the size of tumor spheroids, but little is known about the dynamics of stress accumulation, how the stress affects cancer cell phenotype, or the molecular pathways involved. We co-embedded single cancer cells with fluorescent micro-beads in agarose gels and, using confocal microscopy, recorded the 3D distribution of micro-beads surrounding growing spheroids. The change in micro-bead density was then converted to strain in the gel, from which we estimated the spatial distribution of compressive stress around the spheroids. We found a strong correlation between the peri-spheroid solid stress distribution and spheroid shape, a result of the suppression of cell proliferation and induction of apoptotic cell death in regions of high mechanical stress. By compressing spheroids consisting of cancer cells overexpressing anti-apoptotic genes, we demonstrate that mechanical stress-induced apoptosis occurs via the mitochondrial pathway. |
Is combined Use of Bivalirudin and Radial Access in Acute Coronary Syndromes Superior to the Use of Either One Separately : Meta-Analysis of Randomized Controlled Trials? | The aim of this meta-analysis was to study the relation between access site and bivalirudin use on outcomes in patients with acute coronary syndrome (ACS). Bivalirudin and radial access use are 2 strategies that are increasingly used to lower major bleeding in patients with ACS undergoing invasive approaches. The interaction between these 2 strategies and the benefit of using them in combination are unclear. This analysis included randomized controlled trials that compared bivalirudin to heparin with or without glycoprotein IIb/IIIa inhibitors in patients with ACS and reported outcomes stratified by arterial access site. Meta-analyses of outcome data were performed on the basis of access site and anticoagulation regimen. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from event rates using random-effects models. Eight trials with a total of 27,491 patients were included. Bivalirudin reduced major bleeding risk in patients with femoral access (OR: 0.51; 95% CI: 0.46 to 0.6; p < 0.001) but not in patients with radial access (OR: 0.75; 95% CI: 0.45 to 1.26; p = 0.28). Moreover, radial access reduced major bleeding risk in patients treated with heparin (OR: 0.57; 95% CI: 0.43 to 0.77; p < 0.001) but not in patients treated with bivalirudin (OR: 0.96; 95% CI: 0.65 to 1.41; p = 0.83). There were no differences in major adverse cardiovascular events or all-cause mortality between bivalirudin and heparin, regardless of access site. | To determine whether repeated seizures contribute to hippocampal sclerosis, we investigated whether cell loss in the (para) hippocampal region was related to the severity of chronic seizure activity in a rat model for temporal lobe epilepsy (TLE). Chronic epilepsy developed after status epilepticus (SE) that was electrically induced 3-5 months before. The presence of neuronal damage was assessed by using Fluoro-Jade and dUTP nick end-labeling (TUNEL) of brain sections counterstained with Nissl. We found a negative correlation between the numbers of surviving hilar cells and the duration of the SE (r = -0.66; p < 0.01). In the chronic phase, we could discriminate between rats with occasional seizures (0.15 +/- 0.05 seizures per day) without progression and rats with progressive seizure activity (8.9 +/- 2.8 seizures/day). In both groups, the number of TUNEL-positive cells in parahippocampal regions was similar and higher than in controls. In the hippocampal formation, this was not significantly different from controls. Fluoro-Jade staining showed essentially the same pattern at 1 week and no positive neurons in chronic epileptic rats. |
Does autophagy Inhibitor 3-MA weaken Neuroprotective Effects of Posttraumatic Brain Injury Moderate Hypothermia? | The role of autophagy in moderate hypothermia in posttraumatic brain injury (post-TBI) remains elusive. In this study, we evaluated the protective role of autophagy in post-TBI moderate hypothermia. Adult male Sprague-Dawley rats were randomly divided into 3 groups (n = 36/group): TBI with hypothermia group (sham), TBI with hypothermia and a single intracerebroventricular injection of saline (saline, 5 μL), and TBI with hypothermia and a single intracerebroventricular injection of 3-methyladenine (600 nmol, diluted in 0.9% saline to a final volume of 5 μL). All rats, except those in the behavioral tests, were killed at 24 hours after fluid percussion TBI. Immunohistochemistry staining, western blot, and transmission electron microscopy were performed to assess changes in apoptosis and autophagy after injection of 3-methyladenine. Motor function (beam-walk test) and spatial learning/memory (Morris water maze) were assessed on postoperative days 1-5 and 11-15, respectively. Our results showed downregulation of the expression level of microtubule-associated protein 1 light chain 3 and Beclin-1, aggravation of behavioral outcome, and increase of apoptosis. | The objective of our study was to determine the degree to which Framingham risk estimates and the National Cholesterol Education Program (NCEP) Adult Treatment Panel III core risk categories correlate with total coronary atherosclerotic plaque burden (calcified and noncalcified) as estimated on coronary CT angiograms. Coronary CT angiography was performed in 1,653 patients (1,089 men, 564 women) without a history of coronary heart disease (mean age+/-SD: men, 51.6+/-9.7 years; women, 56.9+/-10.5 years). The most common reasons for the examination were hypercholesterolemia, family history, hypertension, smoking, and atypical chest pain. The coronary tree was divided into 16 segments; four different methods were used to quantify the amount of atherosclerotic plaque or the degree of stenosis in each segment, and segment scores were combined to give total scores. Framingham risk estimates and NCEP risk categories were calculated for each patient. Correlation of plaque scores with the Framingham 10-year risk estimates were modest: Spearman's rho was 0.49-0.55. For all comparisons of NCEP risk categories to plaque score categories, the proportion of raw agreement, p(0), was less than 0.50. Cohen's kappa ranged from 0.18 to 0.20. Overall, 21% of the patients would have their perceived need for statins changed by using the coronary CTA plaque estimates in place of the NCEP core risk categories; 26% of the patients on statins had no detectable plaque. |
Is serum carbonic anhydrase 9 level associated with postoperative recurrence of conventional renal cell cancer? | We explored the clinical usefulness of serum carbonic anhydrase 9 as a potential biomarker for conventional renal cell cancer. This study included 91 patients with conventional renal cell cancer and 32 healthy individuals. Enzyme linked immunosorbent assay was used to measure the carbonic anhydrase 9 level. A followup (median 38 months) was performed to track early recurrence after surgery for patients with localized disease. Recurrence-free survival curves were calculated by the Kaplan-Meier method and compared using the log rank test. The mean serum carbonic anhydrase 9 level in patients with metastatic conventional renal cell cancer (216.68 +/- 67.02 pg/ml) or localized conventional renal cell cancer (91.65 +/- 13.29 pg/ml) was significantly higher than in healthy individuals (14.59 +/- 6.22 pg/ml, p <0.001 and p = 0.001, respectively). The mean serum carbonic anhydrase 9 level in patients with metastatic conventional renal cell cancer was significantly higher than in those with localized disease (p = 0.004). Of patients with localized disease those with recurrence had a significantly higher serum carbonic anhydrase 9 than those without recurrence (p = 0.001). On univariate analysis serum carbonic anhydrase 9, tumor stage, tumor grade and tumor size were associated with recurrence. The recurrence-free survival curve indicates that patients with a high serum carbonic anhydrase 9 level had a significantly higher recurrence rate than those with a low serum carbonic anhydrase 9 (p = 0.001). | This study examined the influence of the menstrual cycle on pain and emotion in women with fibromyalgia (FM) as compared with women with rheumatoid arthritis (RA) and to healthy controls. One hundred and twenty-five premenopausal women (21-45 years old) participated in this study (57 with FM, 20 with RA, and 48 controls). Pain and emotion assessments were conducted during the follicular and the luteal phases of the menstrual cycle. Women with FM experienced more pain, menstrual symptoms, and negative affect than did women with RA and the controls. All women reported less positive affect during the luteal phase, although this pattern was more pronounced in women with FM and RA than in controls. |
Does lithium ameliorate LPS-Induced Astrocytes Activation Partly via Inhibition of Toll-Like Receptor 4 Expression? | Astrocytes are critical for the development of postoperative cognitive dysfunction (POCD). In addition, astrocytes express toll-like receptors 4 (TLR4) and build up responses to innate immune triggers by releasing pro-inflammatory molecules. The pathogenesis of neurological disorders often involves the activation of astrocytes and associated inflammatory processes. Lithium, a primary drug for the treatment of bipolar disorder, has recently been suggested to have a role in neuroprotection during neurodegenerative diseases. In this study, we aimed to investigate whether lithium can ameliorate LPS-induced astrocytes activation via inhibition of TLR4 expression. Primary astrocytes cells were pretreated with lithium and stimulated with lipopolysaccharide (LPS). Cellular activation, cytokine production, and TLR4 expression, were assessed. Lithium significantly inhibited LPS-induced astrocytes activation and pro-inflammatory cytokine production, as well as LPS-induced TLR4 expression. | We previously showed that fibromuscular dysplasia (FMD) of the renal artery may be familial. Case reports have associated alpha1-antitrypsin deficiency and FMD. The aim of this study was to test the implication of the alpha1-antitrypsin (AAT) gene in a large cohort of patients with renal FMD. A case-control study comparing the genotype frequencies in 161 consecutive patients with angiographically proven renal FMD with those observed in three sets of controls (353 hypertensive patients, 288 normotensive patients, 444 normotensive women) was conducted. High-resolution echotracking of the carotid and radial arteries was performed in a subset of 77 FMD patients. Three functional polymorphisms of the AAT gene (PiM1, PiZ, PiS) were investigated. Clinical (age 44.3 +/- 13.8 years, 85.1% women) and radiological (77.1% of multifocal lesions) characteristics of the FMD population were consistent with those previously published. No differences were found in AAT genotype frequencies in the FMD subjects compared with the 1085 controls. We found no correlation between the AAT genotypes and the clinical and angiographical characteristics of the FMD patients. Echotracking results confirmed our previously published results in FMD patients with a specific pattern and a mean arterial phenotypic score greater than 3. However, no difference in the arterial score was observed across the genotypes. |
Are concomitant symptoms itemized in the Reflux Disease Questionnaire associated with attenuated heartburn response to acid suppression? | The Reflux Disease Questionnaire (RDQ) contains six symptom items for diagnosing and gauging gastroesophageal reflux disease (GERD) severity. However, clinical trials have generally focused only on the "substernal burning" item and limited data exist on the effect of concomitant items on the treatment response of "substernal burning". Data from two large randomized trials of AZD0865 25-75 mg/day vs. esomeprazole 20 or 40 mg/day in patients with GERD defined by moderate to severe (≥ 4 days per week) "substernal burning" (non-erosive reflux disease (NERD), N = 1,460; reflux esophagitis (RE), N = 1,514) were re-analyzed. As no differences were found between drugs or doses in treatment response of "substernal burning", pooled data were used to determine the impact of additional RDQ items on the response of "substernal burning" to acid suppression. At baseline, patients reported an average of four RDQ items. "Substernal burning" was the most responsive to therapy in the 3.3% of individuals with this as their only baseline RDQ symptom. The report of any other RDQ item was associated with a reduction in the responsiveness of "substernal burning" to acid suppression (e.g., RE patients with high severity "dyspepsia-pain" had an odds ratio of 0.20 for an improvement in "substernal burning" to treatment). | Recently the authors have shown that neuron-glial antigen 2 (NG2) is expressed by perivascular cells along arterioles and capillaries, but not along venules in quiescent rat mesenteric microvascular networks. To investigate how the spatial distribution of this proteoglycan changes during microvascular remodeling, the objective of this study was to characterize the expression of NG2 in adult rat mesenteric microvascular networks undergoing active remodeling. The distribution of NG2 expression was evaluated in adult rat mesenteric microvascular networks. Tissues were harvested from 250 g, female, Sprague-Dawley rats at 1, 3, and 5 days poststimulation and double immunolabeled for NG2 and CD31 (endothelial cell marker). After 1 day, NG2 expression was observed along 27 +/- 11% of network draining venules (14-55 microm) and after 3 days, 59 +/- 10% of draining venules (13-59 microm) stained positive for the proteoglycan. By 5 days poststimulation, the percentage of network draining venules (18-59 microm) staining positive for NG2 returned to 18 +/- 7%, indicating a downregulation of the proteoglycan toward quiescent levels along larger-sized venules. |
Does prenatal high-dose vitamin D3 supplementation have balanced effects on cord blood Th1 and Th2 responses? | Antenatal vitamin D3 (vitD3) supplementation significantly increases maternal and neonatal 25-hydroxyvitamin D3 (25(OH)D3) concentration, yet the effect of an improvement in maternal-fetal vitamin D status on the neonatal immune response is unclear. To assess the effect of prenatal vitD3 supplementation on cord blood T cell function, healthy pregnant Bangladeshi women (n = 160) were randomized to receive either oral 35,000 IU/week vitD3 or placebo from 26 to 29 weeks of gestation to delivery. In a subset of participants (n = 80), cord blood mononuclear cells (CBMC) were cultured, non-adherent lymphocytes were isolated to assess T cell cytokine responses to phytohemagglutinin (PHA) and anti-CD3/anti-CD28 (iCD3/iCD28), measured by multiplex assay. In 12 participants, lymphocyte gene expression profiles were analyzed by PCR array. In supplemented group, increased concentrations of IL-10 (P < 0.000) and TNF-α (P = 0.05) with iCD3/iCD28 stimulation and IFN-γ (p = 0.05) with PHA stimulation were obtained compared to placebo group. No differences in the gene expression profile were noted between the two groups. However, PHA stimulation significantly induced the expression of genes encoding Th1 and Th2 cytokines and down-regulated a number of genes involved in T-cell development, proliferation and differentiation of B cells, signal transduction pathway, transcriptional regulation and pattern recognition receptors (PRRs) in the vitamin D group (vitD group). | Although results of the randomized International Subarachnoid Aneurysm Trial suggested that coil embolization was superior to surgical clipping 1 year after treatment, a paucity of data on long-term outcomes has been a major concern. In an ambidirectional cohort study, 9 institutions with expertise in intracranial aneurysm treatment identified all ruptured saccular aneurysms treated 1996 to 1998. After an initial medical record review, all patients meeting entry criteria were contacted by postal questionnaire or telephone. Possible reruptures were adjudicated independently by a neurologist, a neurosurgeon, and a neurointerventional radiologist. Rates of delayed (>1 year) and early rerupture and retreatment were evaluated using Kaplan-Meier survival analysis and the log-rank test. A total of 1010 patients (711 surgically clipped, 299 treated with coil embolization) were included. Patients treated with coil embolization were older, more likely to have smaller aneurysms arising from the posterior circulation, and less likely to have middle cerebral artery aneurysms. Rerupture of the index aneurysm after 1 year occurred in 1 patient treated with coil embolization during 904 person-years of follow-up (annual rate 0.11%) and in no patients treated with surgical clipping during 2666 person-years (P=0.11). Aneurysm retreatment after 1 year was more frequent in patients treated with coil embolization (P<0.0001), but major complications were rare during retreatment. |
Is [ X-chromosomal inactivation skewing in blood cells associated with early development of lung ]? | To observe the relationship between skewed X-chromosomal inactivation (SXCI) and development of lung cancer in females. DNA was isolated from peripheral blood cells from patients with primary lung cancer (n = 148) and control subjects (n =289). Exon 1 of androgen receptor ( AR) gene was amplified, with its products from different alleles resolved on denaturing polyacrylamide gels and visualized by silver staining. The corrected ratio (CR) between products from different AR alleles before and after Hpa II pretreatment was calculated. All statistical tests were two-sided. With CR> or = 10 adopted as the criterion, SXCI was found more frequently in the younger patients ( C50 years; 7. 9%) than in the controls of the same age group (1. 2% ; P = 0. 046). The SXCI frequency, however, were not significantly different between the old patients ( > 50 years; 4. 5% ) and the controls of the same age group (5. 4% ; P =0. 488). Whether taking CR> or =3 or CR> or =10 as the criteria, the average ages of the patients with SXCI were more than 10 years younger than those without SXCI (P < 0. 05). | The basis of the treatment of painful diabetic neuropathy is the use of drugs that block the transmission of pain (antineuritics) and a good metabolic control of underlying disease. To describe the outcomes of 17 type-2 diabetics with painful neuropathy, treated between 1988 and 2005 with symptomatic therapy plus intensified insulin. Review of medical records of 17 type-2 diabetic patients, aged 63+/-11 years and a duration of diabetes of 15+/-8 years. All patients received intensified insulin therapy with 0.35 units/kg of NPH insulin (2/3 before breakfast and 1/3 evening meal), plus capillary glucose measurements and regular insulin (with sliding-scale centered in approximately 0.1 units/kg) before the 3 main meals. All patients were also treated with gabapentin, nortriptyline or clomipramine. Pain was assessed using a visual analog score of 10 points. After 1 year, glycosilated hemoglobin decreased from 10.0+/-1.4% to 7.7+/-1.2% (p approximately =0.003). Pain decreased from 10 to 5.1+/-3.3 at one month, 2.3+/-3.2 at six months, and 3.1+/-3.6 at 1 year (p <0.01). There was a direct statistical correlation between the reduction of HbA1C and pain decline (r =0.736; p =0.037). Pain scores were lower than those reported elsewhere for Pregabalin (n =76; p =0.05), Lamotrigine (n =27; p <0.0005), Topiramate (n =208; p <0.005), and Gabapentin (n =84; p <0.025). The lack of difference to Sodium Valproate (n =21; p =0.07) had borderline significance. |
Does limited evidence suggest standard fluoride toothpaste reduces caries potential in preschool children? | CENTRAL, Medline, Embase, Web of Science, LILACS and BBO databases, the Brazilian database of thesis and dissertations (Banco de Teses CAPES), a Brazilian register of ethically approved projects involving human beings (SISNEP) and two registers of ongoing trials (Current Controlled Trials and Clinical-Trials.gov). Reference lists were also scanned for relevant papers. Study authors were contacted for additional information. Individual or cluster-randomised or quasi-randomised controlled trials conducted in children under seven were included. Study selection and data abstraction were conducted by two reviewers independently. Risk of bias assessment was undertaken using the Cochrane Collaboration tool. Meta-analyses of prevented fractions (PF) were performed to assess the effect of fluoride toothpaste on the dmft and dmfs. Meta-analyses were also performed to obtain a pooled relative risk (RR) to assess the effect of fluoride toothpastes on the proportion of children developing caries. Eight studies were included. When standard F toothpastes were compared to placebo or no intervention, significant caries reduction at surface (PF = 31%; 95% CI 18-43; 2644 participants in five studies), tooth (PF = 16%; 95% CI 8-25; 2555 participants in one study) and individual (RR = 0.86; 95% CI 0.81-0.93; 2806 participants in two studies) level were observed. Low F toothpastes were effective only at surface level (PF = 40%; 95% CI 5-75; 561 participants in two studies). | Endothelin-1 levels are raised in chronic thromboembolic pulmonary hypertension. Our aim in this study was to identify the presence of endothelin receptors in patients with CTEPH by analysing tissue removed at pulmonary endarterectomy. Pulmonary endarterectomy tissue cross-sections were analysed using autoradiography with [(125)I]-ET-1 using ligands selective for ETA or ETB to determine sub-type distribution. The precise cellular localisation of ETA and ETB receptors was determined using selective antisera to both sub-types and compared with haematoxylin and eosin, Elastic Van Gieson and smooth muscle actin labelled sections. Two patterns of ET-1 binding were found. In sections with frequent recanalised channels, ET-1 bound to the smooth muscle cells surrounding the channels. In sections where there was less organised thrombus with no obvious re-canalisation, minimal ET-1 binding was observed. Some contractile type smooth muscle cells not associated with recanalised channels and diffusely spread throughout the PEA material were associated with ET receptor antibody binding on immunohistochemistry. There was a greater expression of the ETA receptor type in the specimens. |
Does peroxisome proliferator activated receptor gamma in colonic epithelial cells protect against experimental inflammatory bowel disease? | Peroxisome proliferator activated receptor gamma (PPARgamma) is expressed in epithelial cells, macrophage, and T and B lymphocytes. Ligand induced activation of PPARgamma was reported to attenuate colitis activity but it is not clear whether this protection is mediated by epithelial or leucocyte PPARgamma. Mice with targeted disruption of the PPARgamma gene in intestinal epithelial cells, generated using a villin-Cre transgene and floxed PPARgamma allele and designated PPARgamma(DeltaIEpC), were compared with littermate mice having only the PPARgamma floxed allele with no Cre transgene that expressed PPARgamma in the gut, designated PPARgamma(F/F). Colitis was induced by administering dextran sodium sulphate (DSS) and the two mouse lines compared for typical symptoms of disease and expression of inflammatory cytokines. PPARgamma(DeltaIEpC) mice displayed reduced expression of the PPARgamma target genes ADRP and FABP in the gut but were otherwise normal. Increased susceptibility to DSS induced colitis, as defined by body weight loss, colon length, diarrhoea, bleeding score, and altered histology, was found in PPARgamma(DeltaIEpC) mice in comparison with PPARgamma(F/F) mice. Interleukin (IL)-6, IL-1beta, and tumour necrosis factor alpha mRNA levels in colons of PPARgamma(DeltaIEpC) mice treated with DSS were higher than in similarly treated PPARgamma(F/F) mice. The PPARgamma ligand rosiglitazone decreased the severity of DSS induced colitis and suppressed cytokine production in both PPARgamma(F/F) and PPARgamma(DeltaIEpC) mice. | The objective of this study was to investigate the effect of changes in expiratory intrathoracic pressure on stroke volume (SV) at rest and during moderate exercise in patients with heart failure versus healthy individuals. SV was obtained by echocardiography during spontaneous breathing and during expiratory loads of 5 and 10 cm H2O produced by a ventilator in 11 patients with heart failure (61 ± yr, ejection fraction: 32 ± 4%, New York Heart Association, 32% ± 4%; NYHA class I-II) and 11 age-matched healthy individuals at rest and during exercise at 60% of aerobic capacity on a semirecumbent cycle ergometer. At rest, expiratory loading did not change HR, SV index (SVI), or cardiac index (CI) in either group. During moderate exercise, expiratory loading increased SVI and CI in patients with heart failure but decreased SVI and CI in healthy individuals. There was a negative correlation between changes in gastric pressure and SVI (r = -0.51, P < 0.05) in healthy individuals, whereas there was a positive correlation between changes in gastric pressure accompanying expiratory loading and CI (r = 0.83, P < 0.01) in patients with heart failure. |
Does a whole blood-based perfusate provide superior preservation of myocardial function during ex vivo heart perfusion? | Ex vivo heart perfusion (EVHP) provides the opportunity to resuscitate unused donor organs and facilitates assessments of myocardial function that are required to demonstrate organ viability before transplantation. We sought to evaluate the effect of different oxygen carriers on the preservation of myocardial function during EVHP. Twenty-seven pig hearts were perfused ex vivo in a normothermic beating state for 6 hours and transitioned into working mode for assessments after 1 (T1), 3 (T3), and 5 (T5) hours. Hearts were allocated to 4 groups according to the perfusate composition. Red blood cell concentrate (RBC, n = 6), whole blood (RBC+Plasma, n = 6), an acellular hemoglobin-based oxygen carrier (HBOC, n = 8), or HBOC plus plasma (HBOC+Plasma, n = 7) were added to STEEN Solution (XVIVO Perfusion, Goteborg, Sweden) to achieve a perfusate hemoglobin concentration of 40 g/liter. The perfusate composition affected the preservation of systolic (T5 dP/dtmax: RBC+Plasma = 903 ± 99, RBC = 771 ± 77, HBOC+Plasma = 691 ± 82, HBOC = 563 ± 52 mm Hg/sec; p = 0.047) and diastolic (T5 dP/dtmin: RBC+Plasma = -574 ± 48, RBC = -492 ± 63, HBOC+Plasma = -326 ± 32, HBOC = -268 ± 22 mm Hg/sec; p < 0.001) function, and the development of myocardial edema (weight gain: RBC+Plasma = 6.6 ± 0.9, RBC = 6.6 ± 1.2, HBOC+Plasma = 9.8 ± 1.7, HBOC = 16.3 ± 1.9 g/hour; p < 0.001) during EVHP. RBC+Plasma hearts exhibited less histologic evidence of myocyte damage (injury score: RBC+Plasma = 0.0 ± 0.0, RBC = 0.8 ± 0.3, HBOC+Plasma = 2.6 ± 0.2, HBOC = 1.75 ± 0.4; p < 0.001) and less troponin-I release (troponin-I fold-change T1-T5: RBC+Plasma = 7.0 ± 1.7, RBC = 13.1 ± 1.6, HBOC+Plasma = 20.5 ± 1.1, HBOC = 16.7 ± 5.8; p < 0.001). Oxidative stress was minimized by the addition of plasma to RBC and HBOC hearts (oxidized phosphatidylcholine compound fold-change T1-T5: RBC+Plasma = 1.83 ± 0.20 vs RBC = 2.31 ± 0.20, p < 0.001; HBOC+Plasma = 1.23 ± 0.17 vs HBOC = 2.80 ± 0.28, p < 0.001). | Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders. A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development. Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults. |
Does increasing angulation decrease measured aortic stent graft pullout forces? | Experimentally measured pullout forces for stent grafts (SGs) are used in clinical discussions and as reference values in bench studies and computer simulations. Previous values of these forces are available from studies in which the SG was pulled out in the straight caudal direction. However, clinical and numerical studies have suggested that displacement forces acting on SGs are directed more anteriorly. The objective of this study was to measure pullout forces as a function of angulation and to test the hypothesis that pullout forces decrease with increasing angulation. Six different SGs (Bolton Treovance, Cook Zenith Flex, Cook Zenith LP, Medtronic Endurant, Medtronic Talent, and Vascutek Anaconda) were deployed in fresh bovine aortas, then pulled out by an electronic motor at 1 mm/s, while tension force was measured continuously with a digital load cell. The SG off-axis angulation was changed from 0 to 90 degrees in increments of 10 degrees. The test system was submerged in a custom-built temperature-controlled saline bath at 37°C. At least three tests were performed for each device at each angle (with the exception of the Cook Zenith Flex, which experienced plastic deformation of its barbs after a single test per device). Each aortic specimen was used only once and then discarded. Hand-sutured graft anastomoses were also tested at 0 degrees to provide a reference value. A total of 374 pullout tests were performed for the SGs and anastomoses. Sixty-four tests were excluded because of failure of the aorta or apparatus before device pullout. The remaining 310 tests showed pullout forces that demonstrated a decrease in the average pullout force for all six devices from 0 to 90 degrees (Bolton Treovance from 39.3 N to 23.9 N; Cook Zenith Flex from 59.8 N to 48.9 N; Cook Zenith LP from 50.3 N to 41.8 N; Medtronic Endurant from 29.9 N to 25.8 N; Medtronic Talent from 6.0 N to 5.5 N; and Vascutek Anaconda from 37.0 N to 30.3 N). For reference, the mean pullout force for the hand-sutured anastomoses was 63 N. | Mitochondrial DNA (mtDNA) with pathogenic mutations has been found in patients with cognitive disorders. However, little is known about whether pathogenic mtDNA mutations and the resultant mitochondrial respiration deficiencies contribute to the expression of cognitive alterations, such as impairments of learning and memory. To address this point, we used two groups of trans-mitochondrial mice (mito-mice) with heteroplasmy for wild-type and pathogenically deleted (Δ) mtDNA; the "low" group carried 50% or less ΔmtDNA, and the "high" group carried more than 50% ΔmtDNA. Both groups had normal phenotypes for not only spatial learning, but also memory at short retention delays, indicating that ΔmtDNA load did not affect learning and temporal memory. The high group, however, showed severe impairment of memory at long retention delays. In the visual cortex and dentate gyrus of these mice, we observed mitochondrial respiration deficiencies, and reduced Ca²(+)/calmodulin-dependent kinase II-α (α-CaMKII), a protein important for the establishment of spatial remote memory. |
Do viscoelasticity and temperature variations decrease tension and stiffness of hamstring tendon grafts following anterior cruciate ligament reconstruction? | Hamstring tendon grafts used for anterior cruciate ligament reconstruction are typically harvested early in the surgical procedure and are preconditioned prior to reimplantation. Postoperatively, the grafts undergo stress relaxation and warm from the temperature of the operating room to body temperature. The hypothesis of this study was that the tension within semitendinosus and gracilis tendon grafts and the stiffness of the grafts significantly decrease postoperatively because of both stress relaxation and an increase in temperature. Double-strand grafts were created from six semitendinosus tendons and six gracilis tendons harvested from cadaver specimens. The grafts were loaded to 65 N while at operating-room temperature (20 degrees C). After fifteen minutes of stress relaxation, graft tension was measured and the grafts were stretched by 0.1 mm to determine stiffness. The tension and stiffness measurements represented graft properties immediately following reconstruction. Additional tension and stiffness measurements were made following three hours of stress relaxation and after increasing the temperature to the body temperature at the knee (34 degrees C). Both types of graft were examined for differences in stiffness and tension due to stress relaxation and the temperature increase. For both types of graft, the tension and stiffness decreased following stress relaxation to approximately 50% and 80%, respectively, of the value immediately after reconstruction. Increasing the temperature decreased the tension and stiffness further to approximately 40% and 70%, respectively, of the value after reconstruction for both types of graft. All changes in tension and stiffness were significant (p < 0.01). | We have previously demonstrated that celecoxib, a selective COX-2 inhibitor, reaches the retina following repeated oral administrations and inhibits diabetes-induced vascular endothelial growth factor (VEGF) mRNA expression and vascular leakage in a rat model. The aim of this study was to quantify the relative retinal bioavailability of celecoxib from the subconjunctival route compared to a systemic route. The plasma and ocular tissue distribution of celecoxib was determined in male Sprague-Dawley rats following subconjunctival and intraperitoneal administrations of drug suspension at a dose of 3 mg/rat. The animals were sacrificed at 0.5, 1, 2, 3, 4, 8, and 12 h post-dosing, the blood was collected, and the eyes were enucleated and frozen. The plasma, sclera, retina, vitreous, lens, and the cornea were isolated and celecoxib levels were determined using an HPLC method. The tissue exposure of the drug was measured as the area under the curve (AUC(0-infinity)) of the concentration vs. time profiles. The relative bioavailability was estimated as the AUC(0-infinity) ratio between subconjunctival and intraperitoneal groups. For the subconjunctivally dosed (ipsilateral) eye, the AUC(0-infinity) ratios between subconjunctival and intraperitoneal groups were 0.8 +/- 0.1, 53 +/- 4, 54 +/- 8, 145 +/- 21, 61 +/- 16, and 52 +/- 6 for plasma, sclera, retina, vitreous, lens, and cornea, respectively. For the contralateral ocular tissues, the AUC0-infinity ratios were 1.2 +/- 03, 11 +/- 0.3, 1.1 +/- 0.4, 1.0 +/- 0.3, and 1.2 +/- 0.3 in the sclera, retina, vitreous, lens, and the cornea, respectively, between the subconjunctival and the intraperitoneal groups. Assuming that the drug AUCs in contralateral eye were equal to the systemic pathway contribution to AUCs in the ipsilateral eye, the percent contribution of local pathways as opposed to systemic circulation for celecoxib delivery to the ipsilateral eye tissues was estimated to be 98% or greater. |
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