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Is prevalence of Foxp3 positive T regulatory cells increased during progression of cutaneous squamous tumors? | Forkhead box p3 (Foxp3) positive T regulatory cells (Tregs) have a functionally immunosuppressive property that prevents effector cells from acting against self in autoimmune diseases or a tumor. It is known that Tregs may be highly relevant in cancer progression. Dendritic cells (DCs) induce cutaneous immune response, however several studies have suggested that DCs are involved in immunosuppression. The aim of this study is to evaluate the prevalence of Tregs and DCs infiltration in cutaneous premalignant and malignant squamous lesions. We evaluated Tregs and DCs in skin tissue samples obtained from 83 patients with actinic keratosis, Bowen's disease or squamous cell carcinoma by immunohistochemistry. The prevalence of Tregs and DCs was significantly higher in squamous cell carcinoma and Bowen's disease than in actinic keratosis. In addition, the number of DCs was closely correlated with the prevalence of Tregs, and DCs were also located in direct proximity to Tregs. | This study was undertaken to investigate the antihypertensive and antihyperlipedimic potential of morin against deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Hypertension was induced in uninephrectomized rats (UNX) by weekly twice subcutaneous injection of DOCA (25 mg/kg) and 1% NaCl in the drinking water for six consecutive weeks. Morin (50 mg/kg) was administered to DOCA-salt rats orally using an intragastric tube daily for a period of 6 weeks. The DOCA-salt hypertensive rats showed significant elevation in mean arterial pressure (MAP), heart rate (HR) and reduction in body weight. A significant increase in the concentrations of plasma and tissue (liver, kidney, heart, and aorta) lipids such as total cholesterol, triglycerides, free fatty acids, phospholipids, plasma low-density and very low-density lipoproteins cholesterol, and a decrease in the concentration of high-density lipoprotein cholesterol were noticed in DOCA-salt hypertensive rats. Also, the levels of urinary protein and the activity of 3-hydroxy 3-methylglutaryl coenzyme A reductase in the plasma and tissues were increased, and lecithin cholesterol acyl transferase activity in the plasma was decreased in DOCA-salt rats. Morin supplementation (50 mg/kg) throughout the experimental period restored all the above parameters significantly. |
Are adherence measurement and patient recruitment methods poor in intervention trials to improve patient adherence? | To develop a scale and survey the measurement of patient adherence and patient recruitment, and to explore how these methods impact the results in randomized controlled trials of interventions to improve patient adherence to medications. Analytic survey of a purposively selected sample of patient adherence intervention trials from a systematic review, assessing the quality of adherence measurement and patient recruitment methods. We identified 44 different measures of adherence, with qualities ranging from valid and objective to unreliable and subjective. The median overall quality of measures of adherence was 5 (interquartile range [IQR], 3; range, 0-9, 9 is high quality). The quality of the measures was associated with variation in the estimate of adherence (Spearman r = 0.66; 95% confidence interval: 0.39, 0.83). The median overall quality of patient recruitment methods was 2 (IQR, 1; maximum score 6, higher is better). There was no significant correlation between the power of the trial to detect an effect and the quality of the patient recruitment methods. | Cells detect and adapt to hypoxic and nutritional stress through immediate transcriptional, translational and metabolic responses. The environmental effects of ischemia on chromatin nanostructure were investigated using single molecule localization microscopy of DNA binding dyes and of acetylated histones, by the sensitivity of chromatin to digestion with DNAseI, and by fluorescence recovery after photobleaching (FRAP) of core and linker histones. Short-term oxygen and nutrient deprivation of the cardiomyocyte cell line HL-1 induces a previously undescribed chromatin architecture, consisting of large, chromatin-sparse voids interspersed between DNA-dense hollow helicoid structures 40-700 nm in dimension. The chromatin compaction is reversible, and upon restitution of normoxia and nutrients, chromatin transiently adopts a more open structure than in untreated cells. The compacted state of chromatin reduces transcription, while the open chromatin structure induced upon recovery provokes a transitory increase in transcription. Digestion of chromatin with DNAseI confirms that oxygen and nutrient deprivation induces compaction of chromatin. Chromatin compaction is associated with depletion of ATP and redistribution of the polyamine pool into the nucleus. FRAP demonstrates that core histones are not displaced from compacted chromatin; however, the mobility of linker histone H1 is considerably reduced, to an extent that far exceeds the difference in histone H1 mobility between heterochromatin and euchromatin. |
Does underutilization of radiation therapy in early-stage marginal zone lymphoma negatively impact overall survival? | Multiple population-based studies have suggested increasing omission of radiation therapy in favor of alternative treatment strategies in lymphomas, with an associated negative impact on survival. Radiation therapy has long been considered the standard management for many mucosa-associated lymphoid tissue lymphomas. Thus, we aimed to evaluate patterns of treatment utilization and survival. A retrospective analysis based on the National Cancer Database was performed on 22,378 patients with splenic, nodal, or extranodal stage I-II marginal zone lymphoma diagnosed between 1998 and 2012. A logistic regression model was used to assess the association between sociodemographic, tumor, and treatment characteristics and the utilization of radiation therapy. Multivariate propensity score-adjusted Cox proportional hazards models were performed to identify factors independently associated with overall survival (OS). Of 22,378 patients, 82% had stage I disease, 77% had extranodal mucosa-associated lymphoid tissue lymphoma, 5% had splenic marginal zone lymphoma, and 64% were older than 60 years. Radiation therapy utilization decreased from a peak of 39% in 2007 to 33% in 2011 (P < .001), with a corresponding significant increase in systemic therapy utilization. Radiation therapy was associated with a 5- and 10-year OS of 86.7% and 68.8% compared with 78.3% and 54.3% for no radiation therapy (P < .001). On multivariate propensity score-adjusted survival analysis, radiation therapy remained independently associated with improved OS (hazard of death, 0.75; 95% confidence interval, 0.65-0.85; P < .001). | Heart failure (HF) electrophysiological remodeling (HF-ER) often includes the effect of chronically increased intraventricular pressures (IVPs) and promotes ventricular tachycardia/ventricular fibrillation (VT/VF). In addition, acutely increased IVPs have been associated with a higher rate of VT/VF episodes in chronic HF. We hypothesized that increased IVPs and/or an ionic-imbalanced (acidified), catecholamine-rich (adrenergic) milieu (AA milieu) may contribute as much as HF-ER to the substrate for reentry in HF. We used a porcine model of tachycardiomyopathy and evaluated the individual/combined contributions of (1) increased IVPs, (2) HF-ER, and (3) an AA milieu. HF-ER was induced in 7 pigs by rapid pacing. Seven pigs were used as controls. Hearts were isolated and Langendorff perfused. Programmed ventricular stimulation was conducted under low or increased IVP and normal/AA milieu (4 combinations). Epicardial optical mapping was used to quantify conduction velocity (CV), action potential duration (APD), and dispersion of repolarization (DoR). HF-ER decreased CV (-34%; P = .002) and increased APD (11%; P = .024) and DoR (21%; P = .007). Increased IVP amplified DoR (36%; P < .001) and decreased CV (-17%; P = .001) and APD (-8%; P < .001). The AA milieu consistently modified only APD (-9%; P < .001) and led to amplified inter-/intra-subject heterogeneity. Increased IVP similarly raised the odds of inducing sustained VT/VF as the presence of HF-ER (>6-fold). |
Does receptor Interacting Protein 2 ( RIP2 ) be Dispensable for OVA-Induced Airway Inflammation in Mice? | Asthma is a pulmonary chronic inflammatory disease characterized by airway obstruction and hyperresponsiveness. Pattern recognition receptors are known to play a key role in the development of allergic diseases as well as host defenses against microbial infection. Receptor interacting protein 2 (RIP2), a serine/threonine kinase, is an adaptor molecule of NOD1 and NOD2, and genetic variation in this receptor is known to be associated with the severity of allergic asthma in children. In this study, we examined the role of RIP2 in the development of allergic airway inflammation in a mouse model. Airway inflammation was induced in mice through intranasal administration of ovalbumin (OVA) after 2 intraperitoneal immunizations with OVA. Lung inflammation and mucus hypersecretion were examined histologically and total cell infiltration in bronchoalveolar (BAL) fluids was determined. Levels of the Th2-related cytokines, IL-5 and IL-13, in lung extracts were measured by ELISA. Serum antigen-specific IgE and IgG1 levels were also assessed. OVA-induced lung inflammation and mucus hypersecretion were not different between WT and RIP2-deficient mice. The IL-5 and IL-13 levels in the bronchoalveolar (BAL) fluids were also not impaired in RIP2-deficient mice compared to WT mice. Moreover, RIP2 deficiency did not affect serum OVA-specific IgG1 and IgE levels. | Malnutrition is a common, hence frequently underdiagnosed condition in patients with liver cirrhosis as well as in patients with cancer and has been shown to have a negative impact on survival in these patients. Frequently applied screening tools including anthropometric measurements or laboratory parameters to screen for malnutrition are not suitable for patients with liver cirrhosis with additional pathophysiological mechanisms leading to hypoalbuminemia and edema. Prospective data on the prevalence and prognostic impact of malnutrition in patients with HCC are scarce. Fifty-one consecutive patients with hepatocellular carcinoma were prospectively enrolled into this study and screened for malnutrition by anthropometric measurements, the MNA score, the NRS score, laboratory work-up, and BIA measurement. The results of the different screening tools were compared to each other and with the BIA assessment and correlated with the outcome of patients. The calculation of a body mass index (BMI) was not suitable to identify malnourished patients with HCC. The MNA identified 19, the NRS score 17 patients at a risk for malnutrition. BIA revealed a reduction in relative body cell mass in 12 patients. Univariate Cox regression analyses identified tumor stage, MNA score, and phase angle obtained by BIA as significant factors with influence on survival. Multivariate analyses confirmed the phase angle at a cut-off of 4.8 to be an independent factor. |
Does platelet-rich plasma have no effect on increasing free fat graft survival in the nude mouse? | Free fat grafts have an unpredictable survival rate, which may be dependent on host bed vascularity. Therefore, the authors hypothesized that the presence of growth factors in platelet-rich plasma (PRP), may enhance free fat graft survival. Free fat grafts and autologous PRP were harvested from a healthy female and processed using the Coleman technique and the Medtronic Magellan system respectively. The experiment comprised two groups of 12 nude mice each with injection of free fat grafts into the scalp. The experimental group comprised the combination of 0.8 ml of free fat graft and 0.2 ml of PRP. The control group comprised the combination of 0.8 ml of free fat graft and 0.2 ml of normal saline. The mice were euthanized after 16 weeks and the fat grafts explanted and measured for weight and volume. Histology was performed with Oil Red O stain. Statistical analysis of the weight and volume in between groups was performed using the independent samples T-test (SPSS v11). The Mann-Whitney test was used to compare the ranking of six histological parameters between the two groups. The mean weight and volume for the experimental arm were 0.503 g and 0.545 ml respectively. The mean weight and volume for the control arm were 0.500 g and 0.541 ml respectively. The weight, volume and histological parameters between the two groups were not statistically significant. A mouse from each group died of unknown causes. | We sought to determine the association between low caregiver health literacy and child emergency department (ED) use, both the number and urgency of ED visits. This year long cross-sectional study utilized the Newest Vital Sign questionnaire to measure the health literacy of caregivers accompanying children to a pediatric ED. Prior ED visits were extracted from a regional database. ED visit urgency was classified by resources utilized during the index ED visit. Regression analyses were used to model 2 outcomes-prior ED visits and ED visit urgency-stratified by chronic illness. Analyses were weighted by triage level. Overall, 503 caregivers completed the study; 55% demonstrated low health literacy. Children of caregivers with low health literacy had more prior ED visits (adjusted incidence rate ratio 1.5; 95% confidence interval 1.2, 1.8) and increased odds of a nonurgent index ED visit (adjusted odds ratio 2.4; 95% confidence interval 1.3, 4.4). Among children without chronic illness, low caregiver health literacy was associated with an increased proportion of nonurgent index ED visits (48% vs. 22%; adjusted odds ratio 3.2; 1.8, 5.7). |
Does coronary blood flow become uncoupled from myocardial work during obstructive sleep apnea in the presence of endothelial dysfunction? | Patients with obstructive sleep apnea (OSA) and coronary artery disease have a poor long-term prognosis. It is unknown whether the coronary blood flow (CBF) response to OSA is appropriate for myocardial metabolic requirements. Therefore, CBF was assessed during OSA, before and after the development of coronary artery endothelial dysfunction. University Hospital Animal Laboratory. Newborn lambs. Lambs were surgically instrumented for invasive hemodynamic monitoring and sleep-wake EEG recordings. A tracheostomy was inserted to control the upper airway and model OSA during sleep. Coronary artery endothelial dysfunction was created using infusions of lipopolysaccharide (LPS). The CBF response during OSA was assessed and compared to changes in myocardial work (rate-pressure product [RPP]), O2 saturation, and cortical arousal, before and after the LPS infusions. During OSA, CBF increased by 8.6% +/- 2.4% above baseline in the pre-LPS condition and 8.8% +/- 1.9% post-LPS, peaking following termination of the respiratory event. Pre-LPS, change in CBF post-apnea was independently correlated with change in RPP (R2 = 0.50), minimum SpO2 (R2 = 0.11) and the presence of cortical arousal (R2 = 0.04) (P < 0.01, forward stepwise regression analysis). Following LPS, the only predictor of CBF was degree of O2 desaturation (R2 = 0.14, P < 0.05). | The purpose of this study was to identify comprehensive hand injury patterns in different pediatric age groups and to assess their risk factors. This retrospective study was conducted among patients younger than 16-year-old who presented to the emergency room of a general hospital located in Gyeonggi-do, Republic of Korea, and were treated for an injury of the finger or hand from January 2010 to December 2014. The authors analyzed the medical records of 344 patients. Age was categorized according to five groups. A total of 391 injury sites of 344 patients were evaluated for this study. Overall and in each group, male patients were in the majority. With regard to dominant or non-dominant hand involvement, there were no significant differences. Door-related injuries were the most common cause in the age groups of 0 to 3, 4 to 6, and 7 to 9 years. Sport/recreational activities or physical conflict injuries were the most common cause in those aged 10 to 12 and 13 to 15. Amputation and crushing injury was the most common type in those aged 0 to 3 and 4 to 6 years. However, in those aged 10 to 12 and 13 to 15, deep laceration and closed fracture was the most common type. With increasing age, closed injuries tended to increase more sharply than open injuries, extensor tendon rupture more than flexor injuries, and the level of injury moved proximally. |
Does circulating atrial natriuretic peptide genetic association study identify a novel gene cluster associated with stroke in whites? | The goal of this study was to identify genetic determinants of plasma N-terminal proatrial natriuretic peptide (NT-proANP) in the general community by performing a large-scale genetic association study and to assess its functional significance in in vitro cell studies and on disease susceptibility. Genotyping was performed across 16 000 genes in 893 randomly selected individuals, with replication in 891 subjects from the community. Plasma NT-proANP1-98 concentrations were determined using a radioimmunoassay. Thirty-three genome-wide significant single-nucleotide polymorphisms were identified in the MTHFR-CLCN6-NPPA-NPPB locus and were all replicated. To assess the significance, in vitro functional genomic studies and clinical outcomes for carriers of a single-nucleotide polymorphism rs5063 (V32M) located in NPPA that represented the most significant variation in this genetic locus were assessed. The rs5063 variant allozyme in transfected HEK293 cells was decreased to 55±8% of wild-type protein (P=0.01) as assessed by quantitative western blots. Carriers of rs5063 had lower NT-proANP levels (1427 versus 2291 pmol/L; P<0.001) and higher diastolic blood pressures (75 versus 73 mm Hg; P=0.009) and were at an increased risk of stroke when compared with wild-type subjects independent of age, sex, diabetes mellitus, hypertension, atrial fibrillation, and cholesterol levels (hazard ratio, 1.6; P=0.004). | This study evaluated two surgical procedures, total splenectomy and spleen-preserving surgery, for the treatment of spleen cystic echinococcosis (CE). A total of 21 patients who underwent surgery for removal of spleen CE were evaluated retrospectively. Patients were divided into two groups, those who received a total splenectomy (n=7) and those who underwent spleen-preserving surgery (n=14). Total splenectomy surgery took 127.1±11.1min and spleen-preserving surgery took 104.3±25.3min (p<0.05). The length of hospital stay was the same for both patient groups (10.6 days on average). No patient suffered from recurrence during follow-up and all of the patients made a good recovery. No patient developed post-splenectomy sepsis or serious infectious complications. No patient suffered recurrence. |
Are tissue factor expression and activity increased in peripheral monocytes isolated from uncomplicated hypertensive patients? | Systemic hypertension is one of the main risk factors for atherothrombosis. Tissue factor (TF) is found in the adventitia of blood vessels and in the lipid core of atherosclerotic plaques, and is specifically expressed on monocyte or macrophage cell membrane surfaces. TF plays a pivotal role in blood clotting physiology and is involved in pro-inflammatory action and atherosclerotic plaque destabilization. In this study we investigated whether there is any relationship between TF messenger RNA expression and activity in blood monocytes isolated from hypertensive patients with clinical signs of atherosclerosis, uncomplicated hypertensive individuals and normotensive control subjects. Eighty subjects (41 men and 39 women, mean age 41 +/- 12 years) with untreated essential hypertension and 41 control subjects matched for sex and age were enrolled in the study. Patients were classified according to whether they had a normal (</= 1 mm, 41 patients) or abnormal (> 1 mm, 39 patients) intima-media thickness (IMT). TF mRNA expression and activity in hypertensive individuals with no carotid atherosclerosis were no different from control subjects in unstimulated and stimulated monocytes. Abnormal IMT patients showed a higher TF mRNA expression compared with normal IMT hypertensive subjects (P < 0.001). | Endoscopic submucosal dissection (ESD) may be very time consuming, and depending on the anesthesia, the contents of the stomach may reflux to the esophagus and cause the patient to aspirate. To prevent these situations, many practitioners suggest using an overtube, but no study has been done to evaluate the effect of the use of an overtube while performing the ESD procedure. Our aim was to investigate the effects of performing an upper gastrointestinal ESD with and without overtube. Records of patients who underwent ESD were evaluated for histopathological results, complications, speed of dissection, dosages of anesthetic medications, and number of suctions performed during the procedure. The patients were classified into two depending on whether an overtube was used or not. There were a total of 58 patients on which 63 upper gastrointestinal ESD procedures were performed. Regarding age, gender, localization of the lesions, duration of the procedures, dosage of propofol, histopathological results, rate of complete resection, and rate of en-bloc resection, there was no difference between the two groups (p > 0,05). But the size of the lesions, the size of the resected specimen, and the speed of dissection were statistically different in two groups (p = 0.018, p < 0.001, p < 0.001, respectively).The need for suction during the procedure was much lower in the overtube group than those with no overtube (p < 0.001). |
Do polymorphisms in the regulatory region of the Cyclophilin A gene influence the susceptibility for HIV-1 infection? | Previous studies have demonstrated an association between polymorphisms in the regulatory regions of Cyclophilin A (CypA) and susceptibility to both HIV-1 infection and disease progression. Here we studied whether these polymorphisms are associated with susceptibility to HIV-1 infection and disease progression in the Amsterdam Cohort on HIV-1 infection and AIDS (ACS) in a group of men having sex with men (MSM) and drug users (DU). We screened participants of the ACS for the C1604G and A1650G polymorphisms in the regulatory regions of CypA. The prevalence of the 1650G allele was significantly higher in high risk seronegative MSM than in HIV-1 infected MSM. However, C1604G or A1650G were not associated with the clinical course of infection in MSM of the ACS. Interestingly, participants of the ACS-DU who carried the 1604G allele showed a significantly accelerated progression when viral RNA load above 10(4.5) copies per ml plasma was used as an endpoint in survival analysis. | Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is one of the major causes of heart failure. The aim of present study was to investigate the therapeutic effect of hydrogen molecule on streptozotocin-induced diabetic cardiomyopathy in mice. Diabetes was induced in adult male mice by consecutive peritoneal injection of streptozotocin (50 mg/kg/day) for 5 days. Then, they were treated with hydrogen water (1.3±0.2 mg/l) for 8 weeks (four groups, n=83-88 in each group). Although treatment of diabetic mice with hydrogen water did not significantly affect blood glucose level, it significantly attenuated cardiac hypertrophy and reduced expression of atrial natriuretic factor and β-myosin heavy chain; it alleviated cardiac fibrosis and reduced expression of collagen I and III, transforming growth factor beta, alpha-smooth muscle actin, and osteopontin; it reduced cardiac caspase-3 activity and ratio of bax/bcl-2. Importantly, hydrogen water treatment improved cardiac function in streptozotocin-diabetic mice. Furthermore, it was found that hydrogen water treatment abated oxidative stress, suppressed inflammation, and attenuated endoplasmic reticulum stress in the hearts of streptozotocin-diabetic mice. In addition, hydrogen water treatment suppressed activation of Jun NH2-terminal kinase and p38 mitogen activated protein kinase signaling and nuclear factor κB signaling in the hearts of streptozotocin-diabetic mice. |
Do performance of genomic prediction within and across generations in maritime pine? | Genomic selection (GS) is a promising approach for decreasing breeding cycle length in forest trees. Assessment of progeny performance and of the prediction accuracy of GS models over generations is therefore a key issue. A reference population of maritime pine (Pinus pinaster) with an estimated effective inbreeding population size (status number) of 25 was first selected with simulated data. This reference population (n = 818) covered three generations (G0, G1 and G2) and was genotyped with 4436 single-nucleotide polymorphism (SNP) markers. We evaluated the effects on prediction accuracy of both the relatedness between the calibration and validation sets and validation on the basis of progeny performance. Pedigree-based (best linear unbiased prediction, ABLUP) and marker-based (genomic BLUP and Bayesian LASSO) models were used to predict breeding values for three different traits: circumference, height and stem straightness. On average, the ABLUP model outperformed genomic prediction models, with a maximum difference in prediction accuracies of 0.12, depending on the trait and the validation method. A mean difference in prediction accuracy of 0.17 was found between validation methods differing in terms of relatedness. Including the progenitors in the calibration set reduced this difference in prediction accuracy to 0.03. When only genotypes from the G0 and G1 generations were used in the calibration set and genotypes from G2 were used in the validation set (progeny validation), prediction accuracies ranged from 0.70 to 0.85. | Calcium ions are highly versatile spacial and temporal intracellular signals of non-excitable cells and have an important impact on nearly every aspect of cellular life controlling cell growth, metabolism, fluid secretion, information processing, transcription, apoptosis, and motility. Neurons and glia respond to stimuli, including neurotransmitters, neuromodulators, and hormones, which increase the intracellular calcium concentration. The function of intracellular calcium in gliomas is unknown. Lots of daily used drugs may act via receptors that can be linked to the intracellular calcium system and therefore could influence glioma biology. Glioma cells were loaded with the calcium ion sensitive dye Fura 2-AM. Subsequently, cells were stimulated with 25 different medical drugs for 30 s. The increase of free intracellular calcium ions was measured and calculated by a microscope-camera-computer-unit. Except for the buffer solution HEPES that served as negative control and for the cortisol derivative dexamethasone, all other 24 tested drugs induced a rise of intracellular calcium ions. The cellular calcium responses were classified into seven functional groups. The tested substances activated several types of calcium channels and receptors. |
Does a combination of assays reveal biomass differences in biofilms formed by Escherichia coli mutants? | The aim of this study was to develop an assay system that can quantify the amount of biomass in biofilms formed by different isogenic mutants of an Escherichia coli K-12 strain. The reported assay, which is based on the BacTiter-Glo assay from Promega, uses bioluminescence to detect the intracellular concentration of ATP, which correlates with viable bacterial cell numbers. The quantitative data obtained with this ATP assay were compared to those obtained with the conventional crystal violet assay. As a qualitative control, scanning electron microscopy was performed. | Recent evidence suggests that the exposure of children to their parents' smoking adversely effects endothelial function in adulthood. We investigated whether the association was also present with carotid intima-media thickness (IMT) up to 25 years later. The study comprised participants from the Cardiovascular Risk in Young Finns Study (YFS, n = 2401) and the Childhood Determinants of Adult Health (CDAH, n = 1375) study. Exposure to parental smoking (none, one, or both) was assessed at baseline by questionnaire. B-mode ultrasound of the carotid artery determined IMT in adulthood. Linear regression on a pooled dataset accounting for the hierarchical data and potential confounders including age, sex, parental education, participant smoking, education, and adult cardiovascular risk factors was conducted. Carotid IMT in adulthood was greater in those exposed to both parents smoking than in those whose parents did not smoke [adjusted marginal means: 0.647 mm ± 0.022 (mean ± SE) vs. 0.632 mm ± 0.021, P = 0.004]. Having both parents smoke was associated with vascular age 3.3 years greater at follow-up than having neither parent smoke. The effect was independent of participant smoking at baseline and follow-up and other confounders and was uniform across categories of age, sex, adult smoking status, and cohort. |
Do aversive stimuli drive drug seeking in a state of low dopamine tone? | Stressors negatively impact emotional state and drive drug seeking, in part, by modulating the activity of the mesolimbic dopamine system. Unfortunately, the rapid regulation of dopamine signaling by the aversive stimuli that cause drug seeking is not well characterized. In a series of experiments, we scrutinized the subsecond regulation of dopamine signaling by the aversive stimulus, quinine, and tested its ability to cause cocaine seeking. Additionally, we examined the midbrain regulation of both dopamine signaling and cocaine seeking by the stress-sensitive peptide, corticotropin releasing factor (CRF). Combining fast-scan cyclic voltammetry with behavioral pharmacology, we examined the effect of intraoral quinine administration on nucleus accumbens dopamine signaling and hedonic expression in 21 male Sprague-Dawley rats. We tested the role of CRF in modulating aversion-induced changes in dopamine concentration and cocaine seeking by bilaterally infusing the CRF antagonist, CP-376395, into the ventral tegmental area (VTA). We found that quinine rapidly reduced dopamine signaling on two distinct time scales. We determined that CRF acted in the VTA to mediate this reduction on only one of these time scales. Further, we found that the reduction of dopamine tone and quinine-induced cocaine seeking were eliminated by blocking the actions of CRF in the VTA during the experience of the aversive stimulus. | 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. |
Does the ALK/ROS1 Inhibitor PF-06463922 overcome Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma? | Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants and inhibits ALK more effectively than crizotinib in vitro. Most importantly, PF-06463922 induces complete tumor regression in both crizotinib-resistant and crizotinib-sensitive xenograft mouse models of neuroblastoma, as well as in patient-derived xenografts harboring the crizotinib-resistant F1174L or F1245C mutations. These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK-mutated xenograft tumors, while also inducing responses in an R1275Q xenograft model. Taken together, these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK-mutated neuroblastoma. | Deep wound infections pose an increasing problem in cardiac surgery patients. Prospective infection monitoring is thus a means of identifying possible risk factors. Within a period of 5 months, a total of 376 adult patients, 260 men and 116 women, with a mean age of 62.6 years (range 18-88), underwent coronary bypass grafting (n=281) or other cardiac surgery procedures (n=95). Nasal cultures were taken preoperatively from every patient, as well as cultures of the wound during surgery and when dressings were changed thereafter. In addition, nasal cultures were taken from all the medical and nursing staff. To differentiate endogenous and exogenous infection pathways, DNA fingerprint analysis was performed. A total of 38 patients (10.1%) developed a wound infection, in 14 patients this happened to be a deep wound infection, in 24 patients a superficial one. Five sternal wound infections were associated with mediastinitis (1.3%). The occurrence of a wound infection overall resulted in prolonged hospitalization (29.4+/-24 vs. 11.9+/-6.9 days, P=0.001), but not in increased hospital mortality (4.4% vs. 3.9%). Obesity, diabetes mellitus and nasal carriage of Staphylococcus aureus proved to be independent risk factors with an odds ratio of 2.07, 2.26 and 2.28, respectively. In all but one of the sternal colonizations with S. aureus, DNA fingerprint analysis demonstrated an identical pattern of S. aureus from the patient's nose and sternum, indicating an endogenous infection pathway. |
Does maraviroc concentrate in the cervicovaginal fluid and vaginal tissue of HIV-negative women? | To compare single- and multiple-dose maraviroc exposures in cervicovaginal fluid (CVF) and vaginal tissue (VT) with blood plasma (BP) and quantify maraviroc protein binding in CVF. Open-label pharmacokinetic study. In 12 HIV-negative women, 7 paired CVF and BP samples were collected over 12 hours after 1 maraviroc dose. Subjects then received maraviroc twice daily for 7 days. After the last dose, subjects underwent CVF and BP sampling as on day 1, with additional sampling during terminal elimination. VT biopsies were obtained at steady state. Day 1 and day 7 median maraviroc CVF AUCtau were 1.9- and 2.7-fold higher, respectively, than BP. On day 1, 6 of 12 subjects had detectable maraviroc CVF concentrations within 1 hour; 12 of 12 were detectable within 2 hours, and all exceeded the protein-free IC90. On day 7, maraviroc CVF protein binding was 7.6% and the VT AUCtau was 1.9-fold higher than BP. Maraviroc CVF concentrations 72 hours after dose and BP concentrations 12 hours after dose were similar. | The regulation of strong emotions has important implications for health, particularly among individuals with chronic illness. We focus this brief review on effective psychosocial interventions that emphasize and teach skills to improve emotion regulation in the context of health-related outcomes. Recent work in the area of emotion-regulation interventions has tested the effects of emotion-regulation family therapy, group-based emotion-regulation psychotherapy, expressive writing, and school-based prevention programs. Emotion-regulation psychotherapy for families shows some benefits for both patients and their family members. Group emotion-regulation interventions and expressive writing result in physical and psychosocial improvement for patients with medical or psychiatric illness. School-based programs show improved emotion knowledge, emotion regulation, and emotional competence, relative to standard academic curricula and existing prevention programs. |
Are cDKN2A ( p16 ) and HRAS frequently mutated in vulvar squamous cell carcinoma? | Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs). A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry. Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53=58, CDKN2A(p16)=14, HRAS=10, PIK3CA=7, PPP2R1A=3, KRAS=1, PTEN=1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P=.035), with a large effect from patients carrying HRAS-mutations. | Recent findings suggest that higher levels of intermuscular adipose tissue (IMAT) are associated with glucose dysregulation, lower levels of muscle strength, and a heightened risk of disability. Although several studies have described adaptations in muscle after reduced physical activity, the change in IMAT in healthy young adults is unknown. The objective was to determine whether reduced lower limb activity alters IMAT in healthy young adults and to assess whether this change affects muscle strength loss. The subjects (6 men and 12 women aged 19-28 y) underwent a 4-wk control period, which was followed by 4 wk of unilateral lower limb suspension. Volumes of whole muscle, subcutaneous adipose tissue, and IMAT were assessed by using magnetic resonance imaging in the thigh and calf. Muscle strength was assessed during maximal voluntary isometric contractions. No changes were observed in the control period. Reduced physical activity decreased thigh and calf muscle volumes by 7.4% and 7.9% (P < 0.001), respectively; no significant change in subcutaneous adipose tissue was observed. Additionally, IMAT increased in both regions; the increase was larger in the calf (20%) than in the thigh (14.5%) (P <or= 0.005) and was partially explained by the loss in muscle (R(2) = 26%). The loss in strength was greater in the thigh (20.4%) than in the calf (15%). Strength loss was associated with increases in IMAT (P = 0.039) after adjustment for the loss in muscle, initial strength, initial IMAT, and initial muscle volume. |
Is low postoperative platelet count associated with negative outcome after liver resection for hepatocellular carcinoma? | Hepatocellular carcinoma is one of the most common malignancies worldwide. The only curative treatment is surgery. As hepatocellular carcinoma is often associated with liver cirrhosis, patients are at risk for postoperative liver failure. In the recent years, platelets are thought to play an important role in liver regeneration.The aim of this study was to discover the relevance of postoperative platelet counts after liver resection for hepatocellular carcinoma. Data of 68 patients who underwent liver resection for hepatocellular carcinoma between July 2007 and July 2012 in a single centre were analysed. Postoperative morbidity and mortality were evaluated in regard to postoperative platelet counts. Comparative analysis between patients with platelet counts ≤100 2x109/ l and >100 x109/ l at d1 was performed in regard to postoperative outcome. Within this cohort, 43 patients (63%) suffered from histologically proven liver cirrhosis. Postoperative mortality was statistically significant associated with postoperative reduced platelet counts. Comparative analysis showed significantly elevated postoperative bilirubin levels and lower prothrombin time in patients with platelet counts ≤ 100 1x109/ l at d1. | Congenital myasthenic syndromes are rare inherited disorders characterized by fatigable weakness caused by malfunction of the neuromuscular junction. We performed whole exome sequencing to unravel the genetic aetiology in an English sib pair with clinical features suggestive of congenital myasthenia. We used homozygosity mapping and whole exome sequencing to identify the candidate gene variants. Mutant protein expression and function were assessed We identified a novel homozygous missense mutation in the |
Does interleukin-1 stimulate human uterine prostaglandin production through induction of cyclooxygenase-2 expression? | Uterine infection occurs in as much as 20% of preterm labor and results in increased decidual cytokines. The objective of this study was to examine the effect of interleukin-1 (IL-1) and the cyclooxygenase-2 (COX-2) inhibitor, NS-398, on myometrial prostaglandin (PG) production and COX-2 expression. Human uterine myocytes were stimulated with IL-1 (0-50 ng/mL) over 24 hr. PGE2, PGF2alpha, and 6-keto F1alpha were measured by enzyme-linked immunosorbent assay. Both COX-1 and COX-2 proteins and mRNA were measured by western and northern blot, respectively. IL-1 increased PG production beginning at 6 hr, COX-2 protein increased beginning at 4 hr and continued to increase at 24 hr. COX-2 mRNA increased at 2 hr and peaked at 4 hr. NS-398 blocked PG production but had no effect on COX-2 protein or mRNA. | To examine whether alcohol-related attentional bias (AB) can be reduced by training heavy drinkers to attend to soft drinks as an alternative to alcohol. Diminishing AB is important because AB has been suggested to be a significant factor in the development, maintenance and relapse of addictive behaviours. AB was trained in a clinically relevant design, and we studied the generalization of this training. DESIGN, PARTICIPANTS AND INTERVENTION: We assigned randomly 106 heavy drinking male college and university students to the attentional re-training (AR; modified visual-probe task) or control condition (standard visual-probe task). Laboratory at Maastricht University. We measured the effects of AR on the visual-probe task with stimuli that were presented in the AR and with new stimuli, and on an alternative measure of AB, the flicker paradigm. We further measured effects on craving and preference for either an alcohol beverage or a soft drink. After AR, participants had learned to avoid alcohol stimuli and had developed an AB for soft drinks. This effect was restricted to stimuli used in the AR. The flicker task, where AB for alcohol was found in both the AR and control groups, was not affected by the AR. No effect was found on craving and the preference task. |
Does bisphenol A increase atherosclerosis in pregnane X receptor-humanized ApoE deficient mice? | Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA has recently been associated with increased risk of cardiovascular disease (CVD) in multiple large-scale human population studies, but the underlying mechanisms remain elusive. We previously reported that BPA activates the pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism and has pro-atherogenic effects in animal models upon activation. Interestingly, BPA is a potent agonist of human PXR but does not activate mouse or rat PXR signaling, which confounds the use of rodent models to evaluate mechanisms of BPA-mediated CVD risk. This study aimed to investigate the atherogenic mechanism of BPA using a PXR-humanized mouse model. A PXR-humanized ApoE deficient (huPXR•ApoE(-/-)) mouse line was generated that respond to human PXR ligands and feeding studies were performed to determine the effects of BPA exposure on atherosclerosis development. Exposure to BPA significantly increased atherosclerotic lesion area in the aortic root and brachiocephalic artery of huPXR•ApoE(-/-) mice by 104% (P<0.001) and 120% (P<0.05), respectively. By contrast, BPA did not affect atherosclerosis development in the control littermates without human PXR. BPA exposure did not affect plasma lipid levels but increased CD36 expression and lipid accumulation in macrophages of huPXR•ApoE(-/-) mice. | The aim of this study was to describe clinical and virological outcomes in therapy-naive HIV-1-positive patients treated in a routine ART programme in rural Cameroon. In a prospective cohort, 300 consecutive patients starting first-line ART were enrolled and followed for 12 months. Among 238 patients with available viral load data at Month 12, logistic regression was used to analyse risk factors for virological failure (≥1000 HIV RNA copies/mL) including clinical, immunological and virological parameters, as well as data on drug adherence. Population sequencing was performed to detect the presence of drug-resistance mutations in patients with virological failure at Month 12; minority drug-resistance mutations at baseline were analysed using next-generation sequencing in these patients and matched controls. At Month 12, 38/238 (16%) patients experienced virological failure (≥1000 HIV RNA copies/mL). Patients with virological failure were younger, had lower CD4 cell counts and were more often WHO stage 3 or 4 at baseline. Sixty-three percent of patients with virological failure developed at least one drug-resistance mutation. The M184V (n = 18) and K103N (n = 10) mutations were most common. At baseline, 6/30 patients (20%) experiencing virological failure and 6/35 (17%) matched controls had evidence of minority drug-resistance mutations using next-generation sequencing (P = 0.77). Lower CD4 count at baseline (OR per 100 cells/mm(3) lower 1.41, 95% CI 1.02-1.96, P = 0.04) and poorer adherence (OR per 1% lower 1.05, 95% CI 1.02-1.08, P < 0.001) were associated with a higher risk of virological failure. Unavailability of ART at the treatment centre was the single most common cause for incomplete adherence. |
Do rabbit nucleus pulposus cells facilitate differentiation of adipose-derived stem cells into nucleus pulposus-like cells? | To investigate the feasibility of inducing adipose-derived stem cells (ADSCs) to nucleus pulposus cells (NPCs). ADSCs were isolated from rabbit while NPCs were isolated from an allogeneic rabbit. NPCs were co-cultured with the 3rd generation ADSCs in co-cultured system. Only NPCs were cultured in single culturing group. Through the collagen type II collagen immunohistochemistry, we observed NPCs and then identify NPC. Proteoglycan messenger RNA (mRNA) and collagen type II mRNA level were measured by real-time polymerase chain reaction. In two group cells, collagen type II collagen were detected by immunohistochemistry. The amount of proteoglycan mRNA and collagen type II mRNA was both significantly higher in co-cultured group than in single cultured group. | Antibiotic exposure in early childhood is a possible contributor to the increasing asthma prevalence in industrialized countries. Although a number of published studies have tested this hypothesis, the results have been conflicting. To explore the association between antibiotic exposure before 1 year of age and development of childhood asthma. Using administrative data, birth cohorts from 1997 to 2003 were evaluated (N = 251817). Antibiotic exposure was determined for the first year of life. After the first 24 months of life, the incidence of asthma was determined in both those exposed and not exposed to antibiotics in the first 12 months of life. Cox proportional hazards models were used to adjust for potential confounders and determine the hazard ratios associated with antibiotic exposure for the development of asthma. Antibiotic exposure in the first year of life was associated with a small risk of developing asthma in early childhood after adjusting for gender, socioeconomic status at birth, urban or rural address at birth, birth weight, gestational age, delivery method, frequency of physician visits, hospital visit involving surgery, visits to an allergist, respirologist, or immunologist, congenital anomalies, and presence of otitis media, acute, or chronic bronchitis, and upper and lower respiratory tract infections during the first year of life. As the number of courses of antibiotics increased, this was associated with increased asthma risk, with the highest risk being in children who received >4 courses. All antibiotics were associated with an increased risk of developing asthma, with the exception of sulfonamides. |
Does d-Serine in the nucleus accumbens region modulate behavioral sensitization and extinction of conditioned place preference? | D-serine, the endogenous co-agonist of N-methyl-D-aspartate receptors (NMDARs), is considered to be essential for learning and memory. The aim of the current investigation was to systematically evaluate the role of D-serine on addiction behaviors considered to be mediated by the nucleus accumbens (NAc). D-Serine concentration in the NAc was measured by high-performance liquid chromatography (HPLC). Cocaine-induced behavioral sensitization and conditioned place preference (CPP) models were used to evaluate the relation between changes in serine in the nucleus accumbens and cocaine-induced behavioral effects. The expression of serine racemase (SR), D-amino acid oxidase (DAAO), the cAMP response element-binding protein (CREB) and upstream kinases, and N-methyl-D-aspartate (NMDA) receptors subunits were analyzed by western blot. Long-term depression (LTD) in the NAc was investigated by electrophysiological methods. The NAc slices obtained from the behavioral sensitization rats presented significantly reduced D-serine concentrations, increased expression of DAAO, and down-regulated expression of SR in a dose-dependent manner. Furthermore, D-serine injections into the nucleus accumbens blocked the development of behavioral sensitization and caused extinction of CPP. The ERK-CREB-Fos pathway and the NMDA receptor NR2B subunits in the NAc were involved in the cocaine-induced behavioral sensitization. We also found that D-serine was essential for NMDAR-dependent LTD and D-serine-regulated LTD in a bell-shaped concentration-dependent manner. The disrupted NMDAR-dependent LTD in the NAc of cocaine-treated rats was reversed by D-serine. | Endothelial dysfunction has been found to be present in subjects with both small and medium-size blood vessel vasculitides. We assess whether endothelial dysfunction was also present in patients with biopsy-proven giant cell arteritis (GCA) and whether it might be improved following steroid treatment. Endothelial function was determined in cross-sectional and longitudinal studies of 6 patients with biopsy-proven GCA diagnosed between January and May 2002 by measuring flow-mediated endothelial-dependent and independent vasodilatation (EDV and EIV) by brachial ultrasonography. Patients were assessed for endothelial function within 48 hours after the onset of steroid therapy, 4 weeks after the onset of steroid therapy, and 2 years after the disease diagnosis. EDV was significantly impaired in patients with GCA compared with 12 matched controls [mean 2.9%, median 2.45% (range 2.1% to 4.7%) vs mean 6.5%, median 6.6% (range 3.9% to 9.3%) in matched controls; p = 0.002]. However, no significant difference existed between patients and controls in EIV. Significant improvement of EDV after the suppression of inflammation was achieved. At Week 4 after the onset of steroid therapy all 6 patients showed enhanced responses (p = 0.028). This improvement of EDV was still present when steroid treatment was ended, 2 years after diagnosis. |
Does long-term treadmill exercise attenuate tau pathology in P301S tau transgenic mice? | Recent epidemiological evidence suggests that modifying lifestyle by increasing physical activity could be a non-pharmacological approach to improving symptoms and slowing disease progression in Alzheimer's disease and other tauopathies. Previous studies have shown that exercise reduces tau hyperphosphorylation, however, it is not known whether exercise reduces the accumulation of soluble or insoluble tau aggregates and neurofibrillary tangles, which are both neuropathological hallmarks of neurodegenerative tauopathy. In this study, 7-month old P301S tau transgenic mice were subjected to 12-weeks of forced treadmill exercise and evaluated for effects on motor function and tau pathology at 10 months of age. Exercise improved general locomotor and exploratory activity and resulted in significant reductions in full-length and hyperphosphorylated tau in the spinal cord and hippocampus as well as a reduction in sarkosyl-insoluble AT8-tau in the spinal cord. Exercise did not attenuate significant neuron loss in the hippocampus or cortex. Key proteins involved in autophagy-microtubule-associated protein 1A/1B light chain 3 and p62/sequestosome 1 -were also measured to assess whether autophagy is implicated in the exercised-induced reduction of aggregated tau protein. There were no significant effects of forced treadmill exercise on autophagy protein levels in P301S mice. | Advanced hepatobiliary-pancreatic malignancy occasionally involves major vasculatures, such as the portal vein or the inferior vena cava, and complete removal of the tumor is required for longterm survival. We used a left renal vein graft to reconstruct resected vessels in some patients. In this study, we evaluated early and late renal complications of this procedure. We identified 14 patients undergoing vascular reconstruction with use of a left renal vein graft in hepatobiliary-pancreatic surgery. Renal function and graft patency were assessed by observing serum creatinine levels and radiologic findings during perioperative and followup periods. Of these 14 patients, 7 were men and 7 were women. Diseases included hilar cholangiocarcinoma in two, gallbladder carcinoma in two, intrahepatic cholangiocarcinoma in one, pancreas carcinoma in five, hepatic metastasis in three, and mass-forming pancreatitis in one. No significant postoperative renal dysfunction was recognized, and the mean value of the maximal serum creatinine was 1.0 mg/dL during the perioperative period. Renal scintigraphy was performed in six patients postoperatively, and there was no significant left renal dysfunction. Mean followup time was 18 months after operation, and no severe renal dysfunction was found. Graft patency, which was assessed with enhanced abdominal CT, was well maintained after operation. |
Is syndecan-1 expression upregulated in degenerating articular cartilage in a transgenic mouse model for osteoarthritis? | Mice heterozygous for the Del1 transgene locus with a short deletion mutation in the type II collagen gene develop early-onset degenerative changes in the knee joints that progress to end-stage osteoarthritis by the age of 12-15 months. This study focuses on the expression and distribution of syndecan-1, a cell-surface heparan sulfate proteoglycan, during the development of osteoarthritic cartilage degeneration, to better understand its role in this disease. Northern analyses of total RNA extracted from knee joints of transgenic Del1 mice and their nontransgenic controls were used to monitor changes in syndecan-1 mRNA levels during development, growth, ageing, and cartilage degeneration. Immunohistochemistry was used to study the distribution of syndecan-1 in the knee joints at different stages of cartilage degeneration. Syndecan-1 mRNA was present in knee joints throughout life, with the highest mRNA levels in ageing knee joints. In Del1 mice, a transient upregulation of syndecan-1 mRNA synthesis was observed at the age of 6 months coinciding with early stages of cartilage degeneration and a period of attempted repair. Immunostaining for syndecan-1 was most intense in chondrocytes of superficial and intermediate zones of articular cartilage adjacent to defect areas. Chondrocyte clusters also stained strongly for syndecan-1. | To investigate the therapeutic potential of reverse gastric pacing (RGP) for obesity by studying the effects of RGP on food intake and symptoms in dogs. The study was performed in 9 dogs in 3 sessions (control, strong RGP and moderate RGP). Gastric myoelectrical activity and food intake were measured in each session. RGP was performed using serosal electrodes implanted in the distal stomach at the physiological frequency of the intrinsic gastric myoelectrical activity with a pulse width of 550-950 ms. The amplitude of the stimulus was set at a level maximally tolerable by the animals in the strong RGP session and 50% of the maximum level in the moderate session. 1) Compared with the control, strong RGP (p<0.001) and moderate RGP (p<0.01) significantly reduced the amount of food intake by 62.9% and 31.7%, respectively (p<0.05, ANOVA). 2) Whereas strong RGP induced significant symptoms, moderate RGP did not induce any significant symptoms in comparison with the control session. 3) The regularity and coupling of gastric myoelectrical activity were significantly impaired with both strong RGP and moderate RGP in the fasting state. |
Does epidemiology and correlate of daily smoking and nicotine dependence among young adults in the United States? | We describe the epidemiology of smoking behaviors in a national young adult sample and identify common and unique demographic, social, and psychological correlates of daily smoking and lifetime and current nicotine dependence by race/ethnicity. Data are from the National Longitudinal Survey of Adolescent Health, wave III. Dependence was measured by the Revised Fagerström Test for Nicotine Dependence. Logistic regressions were estimated. Hispanic ethnicity, low education, parental and peer smoking, novelty seeking, early age of smoking onset, and pleasurable initial smoking experiences are significantly correlated with daily smoking and lifetime nicotine dependence. Depressive symptoms are uniquely associated with lifetime and current dependence. Few factors are highly associated with current dependence. Initial sensitivity to smoking has a significantly greater impact on daily smoking than on dependence. Correlates of smoking behaviors are mostly common across racial/ethnic groups, although parental and peer smoking are significant for Whites and Hispanics but not for African Americans. | Acute kidney injury is a common and serious problem after cardiac surgery. Postoperative acute kidney injury is independently associated with in-hospital mortality and long-term morbidity, even after adjustment for comorbid diseases. Chronic kidney disease has been recognized as a strong risk factor of acute kidney injury after cardiac surgery. The association between proteinuria and postcardiotomy acute kidney injury in patients with preserved glomerular filtration rate remains uncertain. Patients with an estimated glomerular filtration rate greater than 60 mL/min/1.73 m(2) who underwent cardiac surgery between January 2003 and December 2007 in a tertiary medical center were retrospectively analyzed. Dipstick urinalysis was performed before surgery. Proteinuria was categorized into negative, trace, 1+, 2+, or 3+. Postoperative acute kidney injury was defined by the Acute Kidney Injury Network criteria. Multinomial logistic regression was used to clarify whether proteinuria is an independent risk factor of postoperative acute kidney injury. A total of 1246 patients were included in this study, with a mean estimated glomerular filtration rate of 80 ± 13 mL/min/1.73 m(2). Proteinuria was present in 290 patients (23.4%). Postoperative acute kidney injury developed in 434 patients (34.8%), and 36 patients (2.9%) required renal replacement therapy. Proteinuria was independently associated with all stages of postcardiotomy acute kidney injury and dialysis-requiring acute kidney injury. The crude risk of acute kidney injury was greater in patients with a higher grade of proteinuria. In subgroup analysis for gender, diabetes, and surgical type, preoperative proteinuria remains a strong risk factor of acute kidney injury after cardiac surgery. |
Does oxidative stress contribute to soluble fms-like tyrosine kinase-1 induced vascular dysfunction in pregnant rats? | Recent evidence indicates that both increased oxidative stress and an altered balance between pro- and anti-angiogenic factors such as vascular-endothelial growth factor (VEGF) and the soluble VEGF receptor (sFlt-1) contribute to endothelial dysfunction in preeclampsia. We hypothesized that chronic infusion of sFlt-1 to mimic the increase observed in preeclamptic patients would reduce plasma VEGF concentrations, increase blood pressure (BP) and vascular superoxide levels, and cause endothelial dysfunction in the pregnant rat. Recombinant sFlt-1 was infused (500 ng/h) during days 13-18 of pregnancy. BP, fetal and placental weight, oxidative stress and vessel vasorelaxation were determined on day 18 of pregnancy. Plasma sFlt-1 concentrations (299 +/- 33 vs. 100 +/- 16 pg/ml; P < 0.01) and BP (117 +/- 6 vs. 98 +/- 4 mm Hg; P < 0.01) were increased, while plasma-free VEGF concentrations (570 +/- 77 vs. 780 +/- 48 pg/ml; P < 0.01) were decreased when compared to vehicle infused dams. sFlt-1 rats had smaller fetuses (1.3 +/- 0.03 vs. 1.5 +/- 0.04 g, P < 0.01) and placentas (0.41 +/- 0.01 vs. 0.47 +/- 0.02 g; P < 0.05). Placental (180 +/- 66 vs. 24 +/- 2.3 RLU/min/mg; P < 0.05) and vascular (34 +/- 8 vs. 12 +/- 5 RLU/min/mg; P < 0.05) superoxide production was increased in the sFlt-1 compared to vehicle infused rats. Vasorelaxation to acetylecholine (ACh) and sodium nitroprusside (SNP) were both decreased (P < 0.05) in the sFlt-1 infusion group compared to the vehicle and this decrease was attenuated (P < 0.05) by the superoxide scavenger Tiron. | Endurance exercise demonstrates beneficial effects in polymyositis/dermatomyositis (PM/DM); however, the molecular effects of exercise on skeletal muscle are incompletely understood. We undertook this controlled pilot study to investigate the effects of a 12-week endurance exercise training program on the molecular profile of skeletal muscle in patients with established PM/DM compared to a nonexercised control group of patients with established PM/DM. Fifteen patients (7 in the exercise group and 8 in the control group) with paired baseline and 12-week follow-up muscle biopsy samples were included. Messenger RNA expression profiling, mass spectrometry-based quantitative proteomics, and immunohistochemical analyses were performed on muscle biopsy samples to determine molecular adaptations associated with changes in clinical measurements induced by endurance exercise. Compared to the control group, the exercise group improved in minutes of cycling time (P < 0.01) and Vo2 max (P < 0.05). The exercise group also had reduced disease activity (P < 0.05) and reduced lactate levels at exhaustion (P < 0.05). Genes related to capillary growth, mitochondrial biogenesis, protein synthesis, cytoskeletal remodeling, and muscle hypertrophy were up-regulated in the exercise group, while genes related to inflammation/immune response and endoplasmic reticulum stress were down-regulated. Mitochondrial pathways including the oxidative phosphorylation metabolic pathway were most affected by the endurance exercise, as demonstrated by proteomics analysis. The exercise group also showed a higher number of capillaries per mm(2) in follow-up biopsy samples (P < 0.05). |
Does laboratory and dialysis characteristics in hemodialysis patients suffering from chronic itch -- result from a representative cross-sectional study? | A representative cross-sectional study showed that chronic itch (lasting for a minimum of 6 weeks) affects 25.2 % (point prevalence) of hemodialysis (HD) patients. Pathophysiology and etiology of chronic itch (CI) in HD are still unclear. We investigated 860 HD patients from a representative randomly selected cluster-sample considering the regional distributions of dialysis units in Germany. The current analyses report comorbidities, laboratory values and dialysis characteristics of HD patients in relation to CI. Diabetes was the only comorbidity that was associated with the occurrence of itch but interestingly with less CI. Except for creatinine, phosphorus, and parathormone, there were no significant associations between the occurrence and characteristics of CI and any laboratory value. Kt/V was not associated with the presence of CI. Patients dialyzed with polyarylethersulfone-membrane showed significantly more CI in all prevalence estimates and those dialyzed with polysulfone-membrane were significantly less affected by CI. | Our previous data demonstrated that targeting non-homologous end-joining repair (NHEJR) yields a higher radiosensitivity than targeting homologous recombination repair (HRR) to heavy ions using DNA repair gene knockouts (KO) in mouse embryonic fibroblast (MEF). In this study, we determined if combining the use of an NHEJR inhibitor with carbon (C) ion irradiation was more efficient in killing human cancer cells compared with only targeting a HRR inhibitor. The TP53-null human non-small cell lung cancer cell line H1299 was used for testing the radiosensitizing effect of NHEJR-related DNA-dependent protein kinase (DNA-PK) inhibitor NU7026, HRR-related Rad51 inhibitor B02, or both to C ion irradiation using colony forming assays. The mechanism underlying the inhibitor radiosensitization was determined by flow cytometry after H2AX phosphorylation staining. HRR-related Rad54-KO, NHEJR-related Lig4-KO, and wild-type TP53-KO MEF were also included to confirm the suppressing effect specificity of these inhibitors. NU7026 showed significant sensitizing effect to C ion irradiation in a concentration-dependent manner. In contrast, B02 showed a slight sensitizing effect to C ion irradiation. The addition of NU7026 significantly increased H2AX phosphorylation after C ion and x-ray irradiations in H1299 cells, but not B02. NU7026 had no effect on radiosensitivity to Lig4-KO MEF and B02 had no effect on radiosensitivity to Rad54-KO MEF in both irradiations. |
Does method of presenting oncology treatment outcomes influence patient treatment decision-making in metastatic colorectal cancer? | The methods used to communicate relevant outcomes in oncology to patients will likely influence treatment decisions. The purpose of this study was to examine the influence of three different methods of describing the efficacy of therapy on treatment decisions regarding management of metastatic colorectal cancer. Participants reviewed a clinical scenario and randomly received one of three ways of describing efficacy of chemotherapy in metastatic colorectal cancer: (1) relative risk reduction, (2) tumor response rate, and (3) median overall survival. They received the same clinical scenario but were presented four treatment options: (1) observation and supportive care, (2) chemotherapy, (3) surgery, and (4) surgery and chemotherapy and the accompanying median overall survival estimate. Participants included 102 preclinical medical students. In the first scenario, 85% chose chemotherapy in the relative risk reduction group, as did 88% of the tumor response rate group, but significantly fewer participants did so in the median overall survival group (35%; P < .001). In the second scenario, there was a significant difference in treatment preferences, with 4% of participants choosing observation/supportive care. None chose chemotherapy only, 19% chose surgery only, and 77% chose surgery plus chemotherapy (P < .001). | IL-1β plays a vital role in the terminal processes of human labour and delivery. Inflammasome activation is required to process pro IL-1β to an active, secreted molecule. Recent studies have shown that autophagy regulates IL-1β via the inflammasome. The aims were to determine the effect of (i) human spontaneous term and preterm labour on the expression of autophagy proteins in fetal membranes; and (ii) autophagy inhibition on IL-1β release. Fetal membranes, from term and preterm, were obtained from non-labouring and labouring women. Tissue explants were used to determine the effect of inhibition of autophagy on IL-1β secretion. Expression of the autophagy proteins Beclin-1, Atg3, Atg5, Atg7, Atg12, Atg16L1 were lower after spontaneous term labour. Beclin-1 and Atg7 expression were lower after spontaneous preterm labour. Beclin-1, Atg3, and Atg7 expression were lower after preterm pre-labour rupture of membranes (PPROM) compared to preterm with intact membranes. LC3B-I expression was higher after spontaneous term and preterm labour and with PPROM; there was no difference in LC3B-II expression between the two groups. The autophagy inhibitor LY290042 increased IL-1β secretion in the presence of bacterial endotoxin LPS; IL-1β secretion was ameliorated in the presence inflammasome inhibitors. |
Is pretreatment T3-4 stage an adverse prognostic factor in patients with esophageal squamous cell carcinoma who achieve pathological complete response following preoperative chemoradiotherapy? | Preoperative chemoradiotherapy (CRT) followed by esophagectomy is becoming one of the standard treatment strategies for esophageal cancer. Pathologic complete response (pCR) after CRT is the best predictor of survival in squamous cell carcinoma (SCC) of the esophagus. Although no adjuvant treatment is recommended for individuals who achieve pCR, approximately 30% of these patients develop recurrence. Herein we sought to retrospectively investigate the independent predictors of tumor recurrence in this patient group. Between 1995 and 2004, we investigated seventy patients (69 males and 1 female; mean age: 56.1 years) with esophageal SCC who achieved pCR following preoperative chemoradiotherapy. Study end points included tumor recurrence, disease-specific survival (DSS), and disease-free survival (DFS). Univariate and multivariate analyses were used to identify risk factors for the study end points. Mean follow-up time for patients who survived was 65.8 months. At the time of analysis, 18 patients (25.7%) died of the disease and 22 patients (31.4%) developed recurrence. Multivariate analysis showed that pretherapy T3-4 disease was the most important adverse factor for tumor recurrence (P = 0.007), DFS (P = 0.005), and DSS (P = 0.026). The 5-year DFS was 45% for patients with clinical T3-4 disease and 85% for those with clinical T1-2 disease (P = 0.02). | In contrast to insulin-resistant individuals, insulin-sensitive athletes possess high intramyocellular lipid content (IMCL), good mitochondrial function and high perilipin 5 (PLIN5) levels, suggesting a role for PLIN5 in benign IMCL storage. We hypothesised a role for PLIN5 in modulating fasting-mediated insulin resistance. Twelve men were fasted for 60 h, before and after which muscle biopsies were taken and stained for lipid droplets (LDs), PLIN5 and laminin. Confocal microscopy images were analysed for LD size, number, PLIN5 association and subcellular distribution. Fasting elevated IMCL content 2.8-fold and reduced insulin sensitivity (by 55%). Individuals with the most prominent increase in IMCL showed the least reduction in insulin sensitivity (r = 0.657; p = 0.028) and mitochondrial function (r = 0.896; p = 0.006). During fasting, PLIN5 gene expression or PLIN5 protein content in muscle homogenates was unaffected, microscopy analyses revealed that the fraction of PLIN5 associated with LDs (PLIN5+) increased significantly (+26%) upon fasting, suggesting PLIN5 redistribution. The significant increase in LD number (+23%) and size (+23%) upon fasting was entirely accounted for by PLIN5+ LDs, not by LDs devoid of PLIN5. Also the association between IMCL storage capacity and insulin resistance and mitochondrial dysfunction was only apparent for PLIN5+ LDs. |
Is warfarin-associated intracerebral hemorrhage inadequately treated at community emergency departments? | The purpose of this study was to investigate time delays, adherence to guidelines, and their impact on outcomes in patients with warfarin-associated intracerebral hemorrhage transferred from community emergency departments to a comprehensive stroke center. We collected demographic, clinical, transfer time, treatment, and outcome data for patients transferred to our institution with warfarin-associated intracerebral hemorrhage from community emergency departments. Among 928 patients with intracerebral hemorrhage, 56 (6%) with warfarin-associated intracerebral hemorrhage (median international normalized ratio, 2.55) were transferred to the comprehensive stroke center. Twenty patients received no acute reversal therapy before transfer, only 4 of whom had international normalized ratios ≤1.4 in the community emergency department. Median time of emergency department stay was 3.66 hours and median time to initiation of acute reversal therapy was 4.48 hours. Those who received ≥3 U of fresh-frozen plasma or recombinant activated Factor VIIa (11 patients) before transfer had lower repeat international normalized ratios and better discharge dispositions than those treated less aggressively. | Considering the hypothesis that androgen-independent but growth factor dependent epithelial cell division may be important in the development and progression of prostate cancer and that protein tyrosine kinases and phosphotyrosine protein phosphatases are key enzymes modulating the levels of specific phosphotyrosylated proteins implicated in several growth factor regulated signal transduction pathways, our aim was to study the cellular distribution of phosphotyrosine proteins in normal and hyperplastic dog prostates as well as in those of castrated dogs supplemented with either androgens or estrogens in order to modify the relative proportion of basal versus secretory epithelial cells. Following the determination of optimal conditions to specifically detect phosphotyrosine proteins by a rabbit polyclonal antibody directed against phosphotyrosine, immunohistochemistry was performed on prostate tissue sections from these experimental animals. In addition to morphological criteria, an antibody to high molecular weight cytokeratins and antisera against arginine esterase were used to selectively identify basal and secretory cells. Since prostatic acid phosphatase may be involved in the local regulation of phosphotyrosine proteins, its distribution was also evaluated with a human prostatic acid phosphatase antiserum. In all prostatic tissues examined, basal epithelial cells were preferentially and specifically stained with antiphosphotyrosine. The staining intensity per basal cell was highest in the estrogen-supplemented dogs. In addition, basal cells were numerically increased and all were highly immunoreactive for high molecular weight cytokeratins. In prostates displaying a well-differentiated glandular epithelium, the number of positive basal cells and their staining intensity varied in the following order: normal < hyperplastic < androgen-supplemented dogs. At all times, the levels of phosphotyrosine proteins in prostatic acid phosphatase and arginine esterase positive cells (secretory) remained low. Fibroblasts and smooth muscle cells were unreactive to antiphosphotyrosine, even though estrogen supplementation increased the prostatic stromal volume. |
Do thermal injury-induced peroxynitrite production and pulmonary inducible nitric oxide synthase expression depend on JNK/AP-1 signaling? | To determine whether burn-induced peroxynitrite production and expression of lung inducible nitric oxide synthase (iNOS), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, CXCR2, macrophage inflammatory protein (MIP)-2, and neutrophil chemokine (KC) are mediated by the c-Jun NH2-terminal kinase (JNK). Prospective, experimental study. Research laboratory at a university hospital. Thermal injury models in the mice. In experiment 1, specific pathogen-free C57/BL6 mice were subjected to 30% total body surface area third-degree burn over shaved back. At 0 hr, 2 hrs, 4 hrs, and 6 hrs after burn, lung tissues of those mice were harvested for JNK activity assay, AP-1 DNA-binding activity, and pJNK immunohistochemistry. In experiment 2, a specific JNK inhibitor, SP600125, was given (30 mg/kg intraperitoneally) to mice immediately postburn to suppress the JNK activity. At 8 hrs after burn, blood was assayed for the peroxynitrite-mediated dihydrorhodamine (DHR) 123 oxidation. Lung tissues were harvested for myeloperoxidase (MPO) determination, ICAM-1, VCAM-1, CXCR2, KC, MIP-2, interleukin-1beta, and interleukin-6 messenger RNA expression; iNOS immunohistochemical staining; and histologic studies. Pulmonary microvascular dysfunction was quantified by measuring the extravasations of Evans blue dye. The JNK activity and AP-1 DNA-binding activity of lung tissue significantly increased to a peak at 2 hrs and 4 hrs, respectively, after thermal injury. Immunohistochemical study demonstrated that the increase of the pJNK was mostly from the bronchiole epithelial cells. This increase of MPO activity in lung, blood DHR 123 oxidation level, and lung permeability increased six-fold, nine-fold, and four-fold after burn. SP600125 administration obliterated the thermal injury-induced JNK activity, AP-1 DNA-binding activity, and iNOS expression in lung tissue. SP600125 treatment also significantly decreased MPO activity, blood DHR 123 oxidation, and lung permeability by 54%, 8%, and 47%, respectively, and markedly decreased the thermal injury-induced perivascular and interstitial inflammatory cell infiltration and septum edema. Furthermore, SP600125 abolished thermal injury-induced ICAM-1, VCAM-1, CXCR2, MIP-2, and KC but not interleukin-1beta and interleukin-6 messenger RNA levels of lung tissues. | Although highly controversial, directto-consumer (DTC) television advertising for prescription drugs is an established practice in the US health care industry. While the US Food and Drug Administration is currently reexamining its regulatory stance, little evidence exists regarding the impact of DTC advertising on patient health outcomes. The objective of this research was to study the relationship between heavy television promotion of 3 major hydroxymethylglutaryl coenzyme A reductase inhibitors ("statins") and the frequency with which patients are able to attain low-density lipoprotein cholesterol (LDL-C) blood-level goals after treatment with any statin. We used logistic regression to determine achievement of LDL-C goals at 6 months after statin treatment, using electronic medical record extract data from patients from geographically dispersed primary care practices in the United States. We identified LDL-C blood levels as being at or less than goal, as defined by risk-adjusted guidelines published by the National Heart, Lung, and Blood Institute from the Adult Treatment Panel III (ATP III) data. A total of 50,741 patients, identified from 88 practices, were diagnosed with hyperlipidemia and had begun therapy with any statin medication during the 1998-2004 time period. In addition, total dollars spent each month on television advertising at the national and local levels for atorvastatin, pravastatin, and simvastatin were obtained. DTC advertising data were merged by local media market where the physician practice was located and by the month in which the patient was first prescribed a statin. The models were run for all patients who initiated therapy, and also on a subsample of patients who continued to receive prescriptions for the drugs for at least 6 months. Logistic regressions were used to predict the likelihood that each patient attained the ATP III LDL-C blood-level goals as a function of DTC advertising and other factors. High levels of national DTC advertising when therapy was initiated were found to increase the likelihood that patients attained LDL-C goals at 6 months by 6% (P < 0.001)-although the effect was concentrated among patients with the least-restrictive ATP III LDL-C goals (<or=160 mg/dL). This result was found in both the entire set of patients as well as the restricted sample of patients who maintained therapy for at least 6 months. |
Does brazilian nut consumption by healthy volunteers improve inflammatory parameters? | The aim of this study was to investigate the effect of a single dose of Brazil nuts on the inflammatory markers of healthy individuals. A randomized crossover study was conducted with 10 healthy individuals (mean age 24.7 ± 3.4 y). Each individual was tested four times regarding intake of different portions of Brazil nuts: 0, 5, 20 and 50 g. At each testing period, peripheral blood was collected before and at 1, 3, 6, 9, 24, and 48 h after intake of nuts, as well as at 5 and 30 d after intake of various Brazil nut portions. Blood samples were tested for high-sensitivity to C-reactive protein, interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, aspartate and alanine aminotransferases, albumin, total protein, alkaline phosphatase, gamma-glutamyltransferase, urea, and creatinine. Consumption of nuts did not affect biochemical parameters for liver and kidney function, indicating absence of hepatic and renal toxicity. A single intake of Brazil nuts (20 or 50 g) caused a significant decrease in serum IL-1, IL-6, TNF-α, and IFN-γ levels (P < 0.05), whereas serum levels of IL-10 were significantly increased (P < 0.05). | To investigate the correlation between miR-221 and epithelial-mesenchymal transition (EMT) in drug-resistant glioma cells. The expression levels of miR-221, PTEN, p-Akt, E-cadherin, vimentin, and MRP1 were quantitatively analyzed in Z1 cells (primary drug-resistant cells), Z2 cells (drug-sensitive cells) and Z2-BCNU cells (drug-resistant cells) using fluorescent real-time PCR and Western blotting. The expression levels of PTEN were significantly increased in Z2 cells compared with Z1 and Z2-BCNU cells which overexpressed miR-221 and vimentin. The expression levels of vimentin, p-Akt and MRP1 were significantly decreased in Z2 cells overexpressing E-cadherin. |
Are adolescent Intermittent Alcohol Exposure : Dysregulation of Thrombospondins and Synapse Formation Associated with Decreased Neuronal Density in the Adult Hippocampus? | Adolescent intermittent alcohol exposure (AIE) has profound effects on neuronal function. We have previously shown that AIE causes aberrant hippocampal structure and function that persists into adulthood. However, the possible contributions of astrocytes and their signaling factors remain largely unexplored. We investigated the acute and enduring effects of AIE on astrocytic reactivity and signaling on synaptic expression in the hippocampus, including the impact of the thrombospondin (TSP) family of astrocyte-secreted synaptogenic factors and their neuronal receptor, alpha2delta-1 (α2δ-1). Our hypothesis is that some of the influences of AIE on neuronal function may be secondary to direct effects on astrocytes. We conducted Western blot analysis on TSPs 1 to 4 and α2δ-1 from whole hippocampal lysates 24 hours after the 4th and 10th doses of AIE, then 24 days after the last dose (in adulthood). We used immunohistochemistry to assess astrocyte reactivity (i.e., morphology) and synaptogenesis (i.e., colocalization of pre- and postsynaptic puncta). Adolescent AIE reduced α2δ-1 expression, and colocalized pre- and postsynaptic puncta after the fourth ethanol (EtOH) dose. By the 10th dose, increased TSP2 levels were accompanied by an increase in colocalized pre- and postsynaptic puncta, while α2δ-1 returned to control levels. Twenty-four days after the last EtOH dose (i.e., adulthood), TSP2, TSP4, and α2δ-1 expression were all elevated. Astrocyte reactivity, indicated by increased astrocytic volume and area, was also observed at that time. | Diastolic runoff in the abdominal aorta, with subsequent circulatory mesenteric insufficiency, has been postulated as a cause of necrotizing enterocolitis in term infants with congenital heart disease. With this study we sought to determine whether Doppler-flow characteristics in the abdominal aorta can predict which infants are at specific risk, independent of gestational age and type of congenital heart disease. We conducted a case-control study of term infants with congenital heart disease and proven necrotizing enterocolitis (n = 18) compared with gestational age-matched and diagnosis-matched control subjects (n = 20). Abdominal aortic Doppler velocities, time intervals, and reversals were analyzed. Groups were compared, and independent risk factors for necrotizing enterocolitis were determined. The groups were similar with regard to weight, pulse pressure, use of prostaglandins or inotropes, presence of a patent ductus arteriosus, and systolic function. However, 47% of the case subjects with necrotizing enterocolitis had persistent retrograde diastolic flow in the abdominal aorta compared with 15% of the control subjects. When adjusting for multiple risk factors, persistent diastolic flow reversal remained the only factor significantly associated with necrotizing enterocolitis. |
Are important technical parameters presented in reports of intraoral digital radiography in endodontic treatment : recommendations for future studies? | The aims of this study were to review the literature on intraoral digital radiography in endodontic treatment with focus on technical parameters and to propose recommendations for improving the quality of reports in future publications. Two electronic databases were searched. Titles and abstracts were selected according to preestablished criteria. Data were extracted using a model of image acquisition and interpretation. The literature search yielded 233 titles and abstracts; 61 reports were read in full text. Recent reports presented technical parameters more thoroughly than older reports. Most reported important parameters for the x-ray unit, but for image interpretation only about one-half of the publications cited resolution of the display system and fewer than one-half bit depth of the graphics card. | Circulating adrenomedullin (ADM), a potent vasorelaxing and natriuretic peptide involved in cardiovascular homeostasis, is increased after cardiac and renal transplantation. ADM is also implicated in hemodynamic abnormalities during liver cirrhosis, but whether ADM is increased late after liver transplantation is unknown. A total of 18 subjects--10 liver-transplant patients (Ltx) and 8 healthy subjects--were enrolled in the study. After a 15-min rest period in supine position, heart rate and systemic blood pressure were determined in all subjects. Then, venous blood samples were obtained in order to simultaneously determine the cyclosporine through levels, the biological (cyclosporine, renal and hepatic functions) and hormonal (ADM and atrial natriuretic peptide (ANP)) characteristics of the Ltx. ADM (27.2+/-4.1 vs. 53.8+/-6.9 pmol/l, P=0.02), and ANP (5.9+/-0.9 vs. 12.8+/-1.4 pmol/l, P=0.001) were significantly increased in late, stable Ltx (35.4+/-9.6 months after transplantation). Furthermore, increased ADM correlated positively with elevated creatinine (r=0.76, P=0.01) and ANP (r=0.64, P=0.04) after liver transplantation. |
Are association between vision loss and higher medical care costs in Medicare beneficiaries costs greater for those with progressive vision loss? | To identify the cost to the Medicare program for patients with either stable or progressive vision loss and to estimate the impact on eye-related and non-eye related care. Retrospective cohort study. The study population was Medicare beneficiaries included in the standard 5% analytic sample and continuously enrolled from 1999 to 2003, excluding Medicare managed-care enrollees. Vision loss was categorized as moderate loss, severe loss, and blindness, based on International Classification of Diseases 9, Clinical Modification codes. Average yearly cost of eye-related and non-eye related medical care during 1999 to 2003, in 2003 dollars. (1) depression, (2) injury, (3) skilled nursing facility (SNF) utilization, and (4) long-term care facility (LTC) admission. Compared with patients with normal vision, excess adjusted mean eye-related costs were 345 dollars, 407 dollars, and 237 dollars annually for those with moderate loss, severe loss, and blindness, respectively; annual excess non-eye related costs were 2193 dollars, 3301 dollars, and 4443 dollars, respectively. At each level of vision loss, those progressing from a presumably normal state at baseline incurred higher Medicare costs than those with that level of vision loss at baseline. Any degree of progressive vision loss was associated with an increased risk of depression, injury, SNF utilization, and LTC admission. Identifiable costs attributable to these complications explained 27% to 41% of the excess costs associated with vision loss. | Postnatal growth of the heart chiefly involves nonproliferative cardiomyocyte enlargement. Cardiac hypertrophy exists in a "physiological" form that is an adaptive response to long-term exercise training and as a "pathological" form that often is a maladaptive response to provocative stimuli such as hypertension and aortic valvular stenosis. A signaling cascade that includes the protein kinase Akt regulates the growth and survival of many cell types, but the precise role of Akt1 in either form of cardiac hypertrophy is unknown. To evaluate the role of Akt1 in physiological cardiac growth, akt1(-/-) adult murine cardiac myocytes (AMCMs) were treated with IGF-1, and akt1(-/-) mice were subjected to exercise training. akt1(-/-) AMCMs were resistant to insulin-like growth factor-1-stimulated protein synthesis. The akt1(-/-) mice were found to be resistant to swimming training-induced cardiac hypertrophy. To evaluate the role of Akt in pathological cardiac growth, akt1(-/-) AMCMs were treated with endothelin-1, and akt1(-/-) mice were subjected to pressure overload by transverse aortic constriction. Surprisingly, akt1(-/-) AMCMs were sensitized to endothelin-1-induced protein synthesis, and akt1(-/-) mice developed an exacerbated form of cardiac hypertrophy in response to transverse aortic constriction. |
Does anti-interleukin-6 antibody treatment improve survival during gut-derived sepsis in a time-dependent manner by enhancing host defense? | To determine the in vivo neutralizing activities of anti-interleukin-6 (IL-6) antibody on survival rate and host defense in a clinically relevant model of infection. Prospective, randomized, experimental animal study. University and Shriners Burns Institute research laboratories. Two hundred seventy-six adult, female Balb/c mice. Balb/c mice were treated with 10 micrograms of antimurine IL-6 antibody, nonspecific murine immunoglobulin G (IgG), or placebo at 2, 4, or 8 hrs after they underwent bacterial challenge by gavage of 10(10) Escherichia coli and thermal injury. The survival rate was determined. The number of viable translocated bacteria, the total amount of translocation, and the percentage of bacteria that survived were also studied in different tissues. Survival rate after burn and gavage was significantly improved in animals treated with antimurine IL-6 antibody at 2 and 4 hrs but not at 8 hrs after injury compared with control animals treated with nonspecific IgG or saline. The IL-6 serum concentration was significantly lower after burn and gavage in the animals treated 2 and 4 hrs after injury compared with nontreated animals. Better killing of translocated bacteria was observed in the tissues of animals treated with antimurine IL-6 antibody 2 hrs after injury. | Our purpose was to determine whether nuchal thickness measurement can identify the euploid fetuses in midtrimester pregnancies at increased risk for Down syndrome on the basis of maternal age and serum screening. Nuchal thickness was obtained prospectively in 651 consecutive fetuses at 14 to 21 weeks' gestation and at > or = 1:270 risk for Down syndrome on the basis of unconjugated estriol, alpha-fetoprotein, and human chorionic gonadotropin levels. The risk of Down syndrome with a normal nuchal thickness was determined. A receiver-operator characteristic curve was used to determine a serum-based risk threshold below which the risk for Down syndrome was low. The prevalence of Down syndrome in fetuses with both a normal nuchal thickness and a below-serum-risk threshold was compared with prevalence in either those above threshold risk or with an abnormal nuchal thickness. There were eight cases of trisomy 21 and one case each of 46,XX/47,XXX, 46,XY/47,XY, +7, and 46,XX, 11q-. The sensitivity of an abnormal nuchal thickness (> or = 6 mm) for detecting Down syndrome was four in eight (50%) (95%) confidence interval 15.3% to 84.6%). The risk of Down syndrome was significantly increased with an abnormal compared with a normal nuchal thickness, four in 13 (30.8%) versus four in 638 (0.6%), p < 0.0001. A risk threshold was defined at > or = 1:100 on the basis of the receiver-operator characteristic plot. Of 390 cases with a normal nuchal thickness and a serum risk estimate < 1:100, there were no cases of Down syndrome (0/390 vs 8/253, p = 0.002). |
Does weight loss reduce adipose tissue cathepsin S and its circulating levels in morbidly obese women? | Human adipose tissue produces several adipokines, including the newly identified protein cathepsin S (CTSS), a cysteine protease involved in the pathogenesis of atherosclerosis. Obesity is characterized by high levels of CTSS in the circulation and in sc white adipose tissue (scWAT). We investigated the effect of surgery-induced weight loss on circulating CTSS and its protein expression in scWAT. Fifty morbidly obese women before and 3 months after surgery and 10 healthy lean women were studied. We analyzed the relationships between circulating CTSS and clinical and biological parameters. Immunohistochemistry of the CTSS protein variations in scWAT was performed. Weight loss decreased by 42% (P < 0.0001) the circulating CTSS levels, which correlated with changes in body weight (P = 0.03). We observed a significant decrease in CTSS enzymatic activity by 25% after weight loss (P = 0.001). Adipose tissue CTSS content was reduced by 30% (P = 0.002) after surgery. The variations in CTSS expression in scWAT after surgery correlated with changes in circulating CTSS serum levels (P = 0.03). Most of the correlations between CTSS and clinical and biological parameters disappeared after adjustment for body mass index, emphasizing the strong link between CTSS and corpulence in humans. | The objective was to evaluate the association between grass pollen exposure, allergy symptoms and impact on measured treatment effect after grass sublingual immunotherapy (SLIT)-tablet treatment. The association between grass pollen counts and total combined rhinoconjunctivitis symptom and medication score (TCS) was based on a post hoc analysis of data collected over six trials and seven grass pollen seasons across North America and Europe, including 2363 subjects treated with grass SLIT-tablet or placebo. Daily pollen counts were obtained from centralized pollen databases. The effect of treatment on the relationship between the TCS and pollen counts was investigated, and the relative difference between grass SLIT-tablet and placebo as a function of average grass pollen counts was modelled by linear regression. The magnitude of treatment effect based on TCS was greater with higher pollen exposure (P < 0.001). The relative treatment effect in terms of TCS for each trial was correlated with the average grass pollen exposure during the first period of the season, with predicted reduction in TCS = 12% + 0.35% × pollen count (slope significantly different from 0, P = 0.003; R(2) = 0.66). Corresponding correlations to the entire grass pollen season and to the peak season were equally good, whereas there was a poor correlation between difference in measured efficacy and pollen exposure during the last part of the season. |
Do type 3 Muscarinic Receptors Contribute to Clearance of Citrobacter rodentium? | The role of muscarinic receptors in mucosal homeostasis, response to enteric pathogens, and modulation of immune cell function is undefined. The contribution of type 3 muscarinic receptors (M3R) to mucosal homeostasis within the colon and host defense against Citrobacter rodentium was determined in uninfected and C. rodentium-infected WT and M3R-deficient (Chrm3) mice. In addition, WT and Chrm3 bone marrow-derived macrophages were studied to determine the ability of M3R to modulate macrophage phenotype and function. In Chrm3 mice, clearance of C. rodentium was delayed despite an amplified TH1/TH17 response. Delayed clearance of C. rodentium from Chrm3 mice was associated with prolonged adherence of bacteria to colonic mucosa, decreased goblet cell number, and decreased mucin 2 gene expression. Treatment of bone marrow-derived macrophages with bethanechol, a muscarinic-selective agonist, induced a classically activated macrophage phenotype, which was dependent on M3R expression. Chrm3 bone marrow-derived macrophages retained their ability to attain a classically activated macrophage phenotype when treated with the TH1 cytokine IFN-γ. | To analyze the regulatory role of osteopontin on biomarkers associated with cell survival, invasiveness, and angiogenesis mechanisms in a clinical series and breast cancer cell lines. We analyzed by quantitative real-time polymerase chain reaction the messenger RNA (mRNA) expression of osteopontin, Bcl2, intercellular adhesion molecule 1 (ICAM-1), and vascular endothelial growth factor A (VEGFA) in several breast cancer cell lines and in 148 breast carcinomas classified into intrinsic subtypes. We found coexpression of osteopontin, Bcl2, ICAM-1, and VEGFA in triple-negative MDA-MB-468 and MDA-MB-231 cell lines. Furthermore, osteopontin silencing by small interfering RNA inhibited ICAM-1 and VEGFA expression and cell proliferation in MDA-MB-468 cells. In breast cancer specimens, we found a positive correlation between osteopontin, ICAM-1, and VEGFA mRNA expression, especially in triple-negative/basal-like tumors. Among patients with osteopontin-overexpressing tumors, VEGFA remained an independent prognostic indicator for recurrence (hazard ratio, 2.95; 95% confidence interval [CI], 1.48-5.87; P = .002) and death (hazard ratio, 3.25; 95% CI, 1.48-7.11; P = .003) (multivariate analysis, Cox regression). |
Does vitamin-D Deficiency be Associated with Gallbladder Stasis Among Pregnant Women? | Pregnant women are at increased risk of gallbladder (GB) stasis, an important risk factor for gallstones (GS). In non-pregnant women, Vitamin-D deficiency (VDD) is associated with GB stasis, which improves on supplementation. Relationship of VDD with GB stasis among pregnant women is not known. This is a prospective study in tertiary care centre. Consecutive healthy pregnant women (12-16 weeks gestation) were enrolled. Serum 25(OH) vitamin-D was estimated, and levels <20 ng ml(-1) were considered as VDD. Risk factors and clinical features of VDD were assessed. Gallbladder ejection fraction (GBEF) was assessed by ultrasound after a standard fatty meal, and <40 % was defined as stasis. Statistical analysis was performed to assess relationship of GB stasis and vitamin-D levels and identify factors associated with VDD. Median serum vitamin-D in 304 women was 7.9 ng ml(-1) (IQR 5.7, 12). VDD afflicted 92 % of them. Women with VDD more often had GB stasis (20 % vs 0 %; p = 0.015) and had lower GBEF [53.7 ± 17 % vs 59 ± 10 %; p = 0.026] compared to those with normal vitamin-D. GBEF showed positive correlation with vitamin-D levels (r = 0.117; p = 0.042). Risk factors for low vitamin-D levels were urban residence (p = 0.001), lower sun-exposure time (p = 0.005), limited skin exposure (p < 0.001), higher BMI (p = 0.05) and higher socioeconomic status (p = 0.02). Vitamin-D deficiency was associated with low serum calcium (ρ = 0.457; p < 0.001). | Different apoptosis pathways activate caspase-3. In a study involving 27 patients with traumatic brain injury (TBI), higher caspase-3 levels were found in contusion brain tissue resected from non-survivors than from survivors. The objective of this study was to determine whether there is an association in TBI patients between serum caspase-3 levels (thus using an easier, quicker, less expensive and less invasive procedure) and mortality, in a larger series of patients. We carried out a prospective, observational and multicenter study in six Spanish Hospital Intensive Care Units including 112 patients with severe TBI. All had Glasgow Coma Scale (GCS) scores lower than 9. Patients with an Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Blood samples were collected on day 1 of TBI to measure serum caspas-3 levels. The endpoint was 30-day mortality. We found that non-surviving patients (n = 31) showed higher (p = 0.003) serum caspase-3 levels compared to survivors (n = 81). Kaplan-Meier survival analysis showed a higher risk of death in TBI patients with serum caspase-3 levels >0.20 ng/mL than in patients with lower concentrations (Hazard Ratio = 3.15; 95% CI = 1.40 to 7.08; P < 0.001). Multiple logistic regression analysis showed that serum caspase-3 levels > 0.20 ng/mL were associated with mortality at 30 days in TBI patients controlling for Marshall CT classification, age and GCS (Odds ratio = 7.99; 95% CI = 2.116 to 36.744; P = 0.001). |
Does modulation of Lactobacillus plantarum gastrointestinal robustness by fermentation conditions enable identification of bacterial robustness markers? | Lactic acid bacteria (LAB) are applied worldwide in the production of a variety of fermented food products. Additionally, specific Lactobacillus species are nowadays recognized for their health-promoting effects on the consumer. To optimally exert such beneficial effects, it is considered of great importance that these probiotic bacteria reach their target sites in the gut alive. In the accompanying manuscript by Bron et al. the probiotic model organism Lactobacillus plantarum WCFS1 was cultured under different fermentation conditions, which was complemented by the determination of the corresponding molecular responses by full-genome transcriptome analyses. Here, the gastrointestinal (GI) survival of the cultures produced was assessed in an in vitro assay. Variations in fermentation conditions led to dramatic differences in GI-tract survival (up to 7-log) and high robustness could be associated with low salt and low pH during the fermentations. Moreover, random forest correlation analyses allowed the identification of specific transcripts associated with robustness. Subsequently, the corresponding genes were targeted by genetic engineering, aiming to enhance robustness, which could be achieved for 3 of the genes that negatively correlated with robustness and where deletion derivatives displayed enhanced survival compared to the parental strain. Specifically, a role in GI-tract survival could be confirmed for the lp_1669-encoded AraC-family transcription regulator, involved in capsular polysaccharide remodeling, the penicillin-binding protein Pbp2A involved in peptidoglycan biosynthesis, and the Na(+)/H(+) antiporter NapA3. Moreover, additional physiological analysis established a role for Pbp2A and NapA3 in bile salt and salt tolerance, respectively. | Nicotine causes ischemia and necrosis of skin flaps. Phosphodiesterase-5 (PDE-5) inhibition enhances blood flow and vasculogenesis. This study examines skin flap survival in rats exposed to nicotine that are treated with and without PDE-5 inhibition. Eighty six rats were divided into five groups. Group 1 received saline subcutaneous (SC) once per day. Group 2 received nicotine SC 2 mg/kg day. Group 3 received sildenafil intraperitoneal (IP) 10 mg/kg day. Group 4 received nicotine SC 2 mg/kg and sildenafil IP 10 mg/kg day. Group 5 received nicotine SC 2 mg/kg day and sildenafil IP 10 mg/kg two times daily. After 28 days of treatment, modified McFarlane flaps were created, silicone sheets were interposed, and flaps were sutured. Photographs were taken on postoperative days 1, 3, and 7 and fluorescence angiography was used on day 7, both to evaluate for skin flap necrosis. Rats were euthanized and flaps were harvested for Vascular Endothelial Growth Factor (VEGF) Western blot analysis. Images were analyzed by three blinded observers using ImageJ, and necrotic indices were calculated. The nicotine and PDE-5 inhibition twice-daily group showed a 46% reduction in flap necrosis when compared to saline only (P < 0.05) and a 54% reduction when compared to nicotine only (P < 0.01). Fluorescence angiographic image analysis revealed reductions in flap necrosis (P < 0.01). VEGF analysis trended toward increased VEGF for all sildenafil-treated groups (P > 0.05). |
Does pax6 influence expression patterns of genes involved in neuro- degeneration? | Pax6, a highly conserved multifunctional transcription factor, has been critical for neurogenesis and neuronal plasticity. It is presumed that if level of Pax6 approaches either low or null, critical genes responsible for maintaining functional status of neurons or glia would be modulated. Therefore, it has been intended to explore possibility of either direct or indirect influence of Pax6 in neurodegeneration. The cell lines having origin of murine embryonic fibroblast (Pax6-non expressing, NIH3T3-cell line), murine neuroblastoma (Pax6-expressing brain-derived, Neuro-2a-cell line), and human glioblastoma-astrocytoma (U87MG) were cultured and maintained in a CO2 incubator at 37°C and 5% CO2 in DMEM containing 10% fetal bovine serum. The knockdown of endogenous Pax6 in Neuro-2a cells was achieved through siRNA based gene knock-down approach. The efficiency and validation of knock-down was done by real time PCR. The knock-down of Pax6 was successfully achieved. The levels of expression of transcripts of some of the proposed putative markers of neurodegeneration like Pax6, S100β, GFAP, BDNF, NGN2, p73α, p73δ, LDH, SOD, and Catalase were analyzed in Pax6 knockdown condition for analysis of role of Pax6 in neurodegeneration. Since the Pax6 has been proposed to bind to promoter sequences of catalase, and catalase suppresses TGFβ, relative lower levels of catalase in Neuro-2a and U-87MG as compared to NIH-3T3 indicates a possible progressive dominant negative impact of Pax6. However, presence of SOD and LDH indicates alternative protective mechanism. | Most patients are admitted to the hospital through the emergency department (ED), and ED waiting times partly reflect the availability of inpatient beds. We test whether the balance between daily hospital admissions and discharges affects next-day ED length of stay. We conducted a cross-sectional study of hospitals in metropolitan Toronto, served by a single emergency medical services provider in a publicly funded system. During a 3-year period, we evaluated the daily ratio of admissions to discharges at each hospital and the next-day median ED length of stay in the same hospital by using linear regression. Across hospitals, the daily mean (SD) 50th percentile ED length of stay averaged 218 (51) minutes. As the inpatient admission-discharge ratio increased or decreased, next-day ED length of stay changed accordingly. Compared with ratios of 1.0, those less than 0.6 were associated with an 11-minute (95% confidence interval [CI] 5 to 16 minutes) shorter next-day median ED length of stay; at admission-discharge ratios of 1.3 to 1.4, ED length of stay was significantly prolonged by 5 minutes (95% CI 3 to 6 minutes). Admission-discharge ratios on weekends and among medical inpatients had a stronger influence on next-day ED length of stay; effects were also greater among higher-acuity and admitted ED patients. |
Do post-ERCP pancreatitis rates differ between needle-knife and pull-type pancreatic sphincterotomy techniques : a multiendoscopist 13-year experience? | Pancreatic sphincterotomy is one of several factors associated with an increased risk of post-ERCP pancreatitis (PEP). The needle-knife pancreatic sphincterotomy technique (NKS) is purported to result in less-frequent post-ERCP pancreatitis compared with a standard pull-type sphincterotomy (PTS). Our purpose was to analyze the experience with both endoscopic pancreatic sphincterotomy (EPS) techniques with respect to post-ERCP pancreatitis at a single tertiary-level referral center. Retrospective analysis. Tertiary-care medical center (Charleston, South Carolina). Patients without chronic pancreatitis and with normal retrograde pancreatogram who underwent EPS between 1994 and 2007 were identified. Patients were excluded for the following reasons: pancreatic stent not placed, both sphincterotomy techniques used, any balloon dilation of the ampullary orifice, precut or access papillotomy, pancreas divisum. A total of 481 patients were identified and underwent 510 ERCPs. Indications for ERCP were recurrent pancreatic-type pain (n = 353) or pancreatitis (n = 157). NKS was used for 395 of 510 (77.5%) cases versus 115 of 510 (22.5%) in which PTS was used. The incidence of post-ERCP pancreatitis was no different between NKS (25/395, 6.4%) and PTS (9/115, 7.8%). Most cases were mild pancreatitis; a single episode of severe PEP occurred in each group. | White matter lesions (WML) in brain aging are linked to dementia and depression. Ischemia contributes to their pathogenesis but other mechanisms may contribute. We used RNA microarray analysis with functional pathway grouping as an unbiased approach to investigate evidence for additional pathogenetic mechanisms. WML were identified by MRI and pathology in brains donated to the Medical Research Council Cognitive Function and Ageing Study Cognitive Function and Aging Study. RNA was extracted to compare WML with nonlesional white matter samples from cases with lesions (WM[L]), and from cases with no lesions (WM[C]) using RNA microarray and pathway analysis. Functional pathways were validated for selected genes by quantitative real-time polymerase chain reaction and immunocytochemistry. We identified 8 major pathways in which multiple genes showed altered RNA transcription (immune regulation, cell cycle, apoptosis, proteolysis, ion transport, cell structure, electron transport, metabolism) among 502 genes that were differentially expressed in WML compared to WM[C]. In WM[L], 409 genes were altered involving the same pathways. Genes selected to validate this microarray data all showed the expected changes in RNA levels and immunohistochemical expression of protein. |
Do human adenovirus Ad36 and its E4orf1 gene enhance cellular glucose uptake even in the presence of inflammatory cytokines? | Aging and obesity are associated with elevated pro-inflammatory cytokines such as monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)α, which are linked to insulin resistance. Anti-inflammatory agents have marginal effect in improving insulin resistance. Hence, agents are needed to improve glycemic control despite the inflammation. Ad36, a human adenovirus, increases TNFα and MCP1 mRNA in adipose tissue, yet improves glycemic control in mice. Ad36 via its E4orf1 gene, up-regulates AKT/glucose transporter (Glut)-4 signaling to enhance cellular glucose uptake. Directly test a role of Ad36, or E4orf1 in enhancing cellular glucose uptake in presence of inflammatory cytokines. Experiment 1: 3T3-L1 preadipocytes were treated with 0, 10 or 100 ng/mL lipopolysaccharides (LPS), and infected with 0 or 5 plaque forming units (PFU) of Ad36/cell. 3T3-L1 cells that stably and inducibly express E4orf1 or a null vector (pTRE-E4orf1 or pTRE-null cells), were similarly treated with LPS and then with doxycycline, to induce E4orf1. Experiment 2: 3T3L1 preadipocytes were treated with 25 nM MCP1 or 20 nM TNFα for 16 h, followed by infection with 0 or 5 PFU of Ad36/cell. Experiment 3: pTRE-E4orf1 or -null cells were similarly treated with MCP1 or TNFα followed by doxycycline to induce E4orf1. Cellular glucose uptake and cellular signaling were determined 72 h post-Ad36 infection or E4orf1-induction, in continued presence of MCP1 or TNFα. In 3T3-L1 preadipocytes, Ad36, but not E4orf1, increased MCP1 and TNFα mRNA, in presence of LPS stimulation. Ad36 or E4orf1 up-regulated AKT-phosphorylation and Glut4 and increased glucose uptake (P < 0.05) in the presence of MCP1 or TNFα. | Falls from heights are the most common traumatic event associated with emergency department visits in children. This study investigated the incidence and clinical course of cranial neuropathies caused by falls from heights in children. The computerized records of a tertiary pediatric medical center were searched for all patients admitted to the emergency department in 2004-2014 with a head injury caused by falling from a height. Those with cranial neuropathies involving optic and eye-motility disturbances were identified, and their clinical, imaging, and outcome data were evaluated. Of the estimated 61,968 patients who presented to the emergency department during the study period because of a fall, 18,758 (30.3 %) had head trauma. Only 12 (seven boys, five girls, average age 6.7 years) had a visual disturbance. Eight were diagnosed with traumatic optic neuropathy, one after a 6-month delay, including two with accompanying cranial nerve (CN) III injuries. Five patients had anisocoria or an abnormal pupillary response to light at presentation, one patient had CN VI paralysis and temporary vision loss, and one patient had an isolated CN III injury diagnosed on follow-up. Visual improvement varied among the patients. |
Does tumor vascular maturation and improved drug delivery induced by methylselenocysteine lead to therapeutic synergy with anticancer drugs? | Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and anticancer drugs could not be shown in vitro. Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug delivery in the observed therapeutic synergy in vivo. Mice bearing s.c. FaDu human head and neck squamous cell carcinoma xenografts were treated with MSC (0.2 mg/d x 14 days orally). Changes in microvessel density (CD31), vascular maturation (CD31/alpha-smooth muscle actin), perfusion (Hoechst 33342/DiOC7), and permeability (dynamic contrast-enhanced magnetic resonance imaging) were determined at the end of the 14-day treatment period. Additionally, the effect of MSC on drug delivery was investigated by determining intratumoral concentration of doxorubicin using high-performance liquid chromatography and fluorescence microscopy. Double immunostaining of tumor sections revealed a marked reduction ( approximately 40%) in microvessel density accompanying tumor growth inhibition following MSC treatment along with a concomitant increase in the vascular maturation index ( approximately 30% > control) indicative of increased pericyte coverage of microvessels. Hoechst 33342/DiOC7 staining showed improved vessel functionality, and dynamic contrast-enhanced magnetic resonance imaging using the intravascular contrast agent, albumin-GdDTPA, revealed a significant reduction in vascular permeability following MSC treatment. Consistent with these observations, a 4-fold increase in intratumoral doxorubicin levels was observed with MSC pretreatment compared with administration of doxorubicin alone. | Poor ventilation at day care centres (DCCs) was already reported, although its effects on attending children are not clear. This study aimed to evaluate the association between wheezing in children and indoor CO2 (a ventilation surrogate marker) in DCC and to identify behaviours and building characteristics potentially related to CO2. In phase I, 45 DCCs from Lisbon and Oporto (Portugal) were selected through a proportional stratified random sampling. In phase II, 3 months later, 19 DCCs were further reassessed after cluster analysis for the greatest difference comparison. In both phases, children's respiratory health was assessed by ISAAC-derived questionnaires. Indoor CO2 concentrations and building characteristics of the DCC were evaluated in both phases, using complementary methods. Mixed effect models were used to analyze the data. In phase I, which included 3,186 children (mean age 3.1 ± 1.5 years), indoor CO2 concentration in the DCC rooms was associated with reported wheezing in the past 12 months (27.5 %) (adjusted odds ratio (OR) for each increase of 200 ppm 1.04, 95 % CI 1:01 to 1:07). In phase II, the association in the subsample of 1,196 children seen in 19 out of the initial 45 DCCs was not significant (adjusted OR 1.02, 95 % CI 0.96 to 1.08). Indoor CO2 concentration was inversely associated with the practices of opening windows and internal doors and with higher wind velocity. A positive trend was observed between CO2 and prevalence of reported asthma (4.7 %). |
Is expression of metastasis-associated gene-1 associated with bone invasion and tumor stage in human pituitary adenomas? | Metastasis associated gene-1 (MTA1), was initially discovered in aggressive human cancer cell lines and has been subsequently associated with the invasiveness and metastatic potential of cancer cells. In the present study, we evaluated the expression levels of MTA1 in a cohort of human pituitary tumors (n=95) and examined the relationship between MTA1 expression and the pathological, clinical and aggressiveness of these tumors. MTA1 was expressed at significantly higher levels in large tumors and in those with higher tumor grade. It was also observed that tumors that had invaded the suprasellar bones and tumors that destructed the sella had significantly higher levels than those without bone involvement (p<005). Although there did not appear to exist any relationship between MTA1 and cystic lesions in the tumors, endocrine-active tumors, namely those secreting prolactin, growth hormone, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) had significantly lower MTA1 transcript levels than inactive tumors. | Exposure to fine particulate air pollution is associated with increased cardiovascular morbidity and mortality. We previously demonstrated that exposure to dilute diesel exhaust causes vascular dysfunction in humans. We conducted a study to determine whether exposure to ambient particulate matter causes vascular dysfunction. Twelve male patients with stable coronary heart disease and 12 age-matched volunteers were exposed to concentrated ambient fine and ultrafine particles (CAPs) or filtered air for 2 hr using a randomized, double-blind cross-over study design. We measured peripheral vascular vasomotor and fibrinolytic function, and inflammatory variables-including circulating leukocytes, serum C-reactive protein, and exhaled breath 8-isoprostane and nitrotyrosine-6-8 hr after both exposures. Particulate concentrations (mean +/- SE) in the exposure chamber (190+/-37 microg/m(3)) were higher than ambient levels (31+/-8 microg/m(3)) and levels in filtered air (0.5+/-0.4 microg/m(3); p<0.001). Chemical analysis of CAPs identified low levels of elemental carbon. Exhaled breath 8-isoprostane concentrations increased after exposure to CAPs (16.9+/-8.5 vs. 4.9+/-1.2 pg/mL, p<0.05), but markers of systemic inflammation were largely unchanged. Although there was a dose-dependent increase in blood flow and plasma tissue plasminogen activator release (p<0.001 for all), CAPs exposure had no effect on vascular function in either group. |
Is duration of extracorporeal membrane oxygenation a poor predictor of hospital survival? | Venovenous extracorporeal membrane oxygenation (ECMO) is increasingly used in patients with respiratory failure. In patients without the option of lung transplantation, prognostication is challenging. We hypothesized that duration of ECMO therapy is inversely correlated with the chance of recovery and therefore hospital survival. A single-center retrospective register analysis was performed. All bridge-to-recovery venovenous ECMO patients without option for lung transplantation treated between October 2010 and September 2015 were included. A total of 175 patients (mean age, 51.61 ± 2.11 years) were detected. Medium time on ECMO was 9.26 ± 1.91 days. Time on ECMO was not significantly shorter in survivors compared to nonsurvivors (8.23 ± 2.04 and 10.15 ± 3.07, respectively; P = .327). Rate of hospital survival and time on ECMO did not correlate (P = .103). The predictive value of ECMO duration on hospital survival was 0.503 in a receiver operating characteristic analysis. | Plasma levels of pancreatic polypeptide (PP) rise upon food intake. Although other pancreatic islet hormones, such as insulin and glucagon, have been extensively investigated, PP secretion and actions are still poorly understood. The release of PP upon glucose stimulation and the effects of PP on glucagon and insulin secretion were analyzed in isolated pancreatic islets. Expression of PP receptor (PPYR1) was investigated by immunoblotting, quantitative RT-PCR on sorted pancreatic islet cells, and immunohistochemistry. In isolated mouse pancreatic islets, glucose stimulation increased PP release, while insulin secretion was up and glucagon release was down. Direct exposure of islets to PP inhibited glucagon release. In mouse islets, PPYR1 protein was observed by immunoblotting and quantitative RT-PCR revealed PPYR1 expression in the FACS-enriched glucagon alpha-cell fraction. Immunohistochemistry on pancreatic sections showed the presence of PPYR1 in alpha-cells of both mouse and human islets, while the receptor was absent in other islet cell types and exocrine pancreas. |
Does laparoscopic cholecystectomy for biliary dyskinesia in children provide durable symptom relief? | The purpose of this study was to determine the effectiveness of laparoscopic cholecystectomy in children with biliary dyskinesia. Reports of children with an abnormal cholecystokinin (CCK)-stimulated HIDA scan between January 2001 and July 2006 who underwent laparoscopic cholecystectomy were reviewed. Postoperatively, a 23-item Likert scale, symptom questionnaire was administered to parents. Sixty-four children with chronic abdominal pain and no gallstones on ultrasound had an abnormal CCK-HIDA scan. Twenty-three children (median age, 14 years; 16 girls), with mean (SD) ejection fraction of 17% (8), underwent laparoscopic cholecystectomy and were further analyzed. Preoperatively, these children had right upper quadrant/epigastric pain (78%), nausea (52%), vomiting (43%), and generalized abdominal pain (22%) lasting for a median of 3 months (range, 1 month to 2.5 years). Median postoperative follow-up was 2.7 years. Sixteen (70%) parents completed the questionnaire. Of those who responded, 63% indicated that their children had no abdominal pain, 87% had no vomiting, and 69% had no nausea in the month preceding the questionnaire. Overall, 67% of parents indicated that their children's symptoms were completely relieved after cholecystectomy, whereas 7% indicated that the symptoms were not relieved. | : Finding appropriate seed cells for bone tissue engineering remains a significant challenge. Considering that skin is the largest organ, we hypothesized that human bone morphogenetic protein receptor type IB (BmprIB)+ dermal cells could have enhanced osteogenic capacity in the healing of critical-sized calvarial defects in an immunodeficient mouse model. In this study, immunohistochemical staining revealed that BmprIB was expressed throughout reticular dermal cells; the positive expression rate of BmprIB was 3.5% ± 0.4% in freshly separated dermal cells, by flow cytometry. Furthermore, in vitro osteogenic capacity of BmprIB+ cells was confirmed by osteogenic-related staining and marker gene expression compared with unsorted dermal cells. In vivo osteogenic capacity was demonstrated by implantation of human BmprIB+ cell/coral constructs in the treatment of 4-mm diameter calvarial defects in an immunodeficient mouse model compared with implantation of unsorted cell/coral constructs and coral scaffold alone. These results indicate that the selective cell population BmprIB from human dermis is a promising osteogenic progenitor cell that can be a large-quantity and high-quality cell source for bone tissue engineering and regeneration. |
Does soluble CD40 ligand induce human coronary artery smooth muscle cells proliferation and migration? | Clinical data have shown that an increased level of serum soluble CD40 ligand (sCD40L) is associated with atherosclerogenesis. We hypothesize that sCD40L induces proliferation and migration of vascular smooth muscle cells (VSMCs) through activation of matrix metalloproteinases (MMPs). Human VSMCs were treated with sCD40L (1 or 5 microg/mL). Cell proliferation and migration were studied using a nonradioactive cell proliferation assay (MTT) and a modified Boyden chamber combined with a scrape-wound assay, respectively. Messenger RNA (mRNA) and protein levels of MMP-2 and MMP-9 were measured with real-time polymerase chain reaction and enzyme-linked immunosorbent assays. Neutralizing antibodies against MMP-2 or MMP-9 were used to evaluate their effects on sCD40L-induced cell proliferation and migration. MTT assay showed a 35% increase in cell proliferation in the high-dose (5 microg/mL) sCD40L-treated group. Cell migration was also increased by 33% (Transwell assay) to 3-fold (scrape-wound assay) after high-dose sCD40L treatment. When cells were treated with 5 microg/mL of sCD40L for 24 hours, significant decreases in MMP-2 and increases in MMP-9 mRNA and protein levels were observed. Neutralizing antibodies against MMP-9 effectively blocked sCD40L-induced cell proliferation and migration. | For patients with small bowel obstruction (SBO), who do not have strangulation obstruction or other contraindications, long tube decompression has been successful in 75% in two studies. In a 1995 prospective randomized study, comparing nasogastric suction (short tube) with long tube decompression, the short tube was successful in 51% and the long tube was successful in 75%. Using upper gastrointestinal endoscopy, a long tube can be advanced into the jejunum in 20 minutes, so the delay in function has been eliminated. There were 35 patients with 37 episodes of SBO. From 1983 to 1988, three tubes then available were advanced endoscopically into the jejunum in 17 patients. From 1989 to 2002, an improved tube designed for endoscopic placement was used in 20 patients. From 1983 to 1988 using three tubes, long tube decompression was successful in 12 of 17 (70%); from 1989 to 2002 with the improved tube, decompression was successful in 18 of 20 (90%). |
Is progranulin increased in human and murine lipodystrophy? | Lipodystrophies (LD) are genetic or acquired disorders sharing the symptom of partial or complete adipose tissue deficiency and a dysregulation of adipokines including leptin and adiponectin. Progranulin, an adipokine with proinflammatory and insulin resistance-inducing characteristics, has not been investigated in LD so far. Circulating progranulin was determined in LD patients (N=37) and in age-, gender-, and body mass index-matched healthy control subjects (N=37). Additionally, we investigated progranulin expression in an LD mouse model as compared to wild-type mice. Moreover, we elucidated circulating progranulin before and during metreleptin supplementation in 10 patients with LD. Median [interquartile range] circulating progranulin was increased in patients with LD (82.9 [25.9] μg/l) as compared to controls (73.6 [22.8] μg/l) (p=0.005). C-reactive protein (CRP) remained an independent and positive predictor of progranulin in multivariate analysis. Progranulin mRNA was significantly upregulated in all adipose tissue depots, i.e. visceral, subcutaneous, and brown adipose tissue, and in muscle of LD animals versus wild-type mice. Progranulin levels did not significantly change during metreleptin supplementation. | Conventional optimal MRI is unremarkable in 20%-30% of patients with intractable focal epilepsy. These MRI-negative patients are the most challenging in surgical programs. Our aim was to evaluate the yield and utility of quantitative MRI with novel contrasts in MRI-negative patients with refractory focal epilepsy, who were potential surgical candidates. Ninety-three consecutive potential surgical candidates with refractory focal epilepsy, 44 with temporal lobe epilepsy, and 49 with frontal lobe epilepsy as determined with ictal scalp video-EEG; and normal optimal conventional MRI, including hippocampal volumes and T2 measures were investigated with quantitative MRI contrasts. The contrasts comprised fast fluid attenuated inversion recovery based T2 measurement (FFT2), double inversion recovery (DIR), magnetization transfer ratio (MTR), and voxel-based morphometry of gray matter (VBM). Voxel-based analyses of whole brain data were used to compare each patient with a control group. In patients with a putative single focus on scalp video-EEG telemetry, 16% had concordant FFT2 abnormalities, as did 16% with DIR, 5% with MTR and 9% with VBM. The greatest agreement in the localization of abnormalities was between FFT2 and DIR. Altogether, 31% patients had a focal abnormality with at least one contrast in the lobe of seizure onset. Signal changes outside the lobe of the putative focus were found with FFT2 in 36% patients, with DIR in 42%, with MTR in 6% and with VBM in 7%. |
Does l-Carnitine prevent the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease? | Prognosis of heart failure with preserved ejection fraction (HFpEF) remains poor because of unknown pathophysiology and unestablished therapeutic strategy. This study aimed to identify a potential therapeutic intervention for HFpEF through metabolomics-based analysis. Metabolomics with capillary electrophoresis time-of-flight mass spectrometry was performed using plasma of Dahl salt-sensitive rats fed high-salt diet, a model of hypertensive HFpEF, and showed decreased free-carnitine levels. Reassessment with enzymatic cycling method revealed the decreased plasma and left-ventricular free-carnitine levels in the HFpEF model. Urinary free-carnitine excretion was increased, and the expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was down-regulated in the left ventricle (LV) and kidney in the HFpEF model. L-Carnitine was administered to the hypertensive HFpEF model. L-Carnitine treatment restored left-ventricular free-carnitine levels, attenuated left-ventricular fibrosis and stiffening, prevented pulmonary congestion, and improved survival in the HFpEF model independent of the antihypertensive effects, accompanied with increased expression of fatty acid desaturase (FADS) 1/2, rate-limiting enzymes in forming arachidonic acid, and enhanced production of arachidonic acid, a precursor of prostacyclin, and prostacyclin in the LV. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced collagen production with increased FADS1/2 expression and enhanced production of arachidonic acid and prostacyclin. L-Carnitine-induced increase of arachidonic acid was canceled by knock-down of FADS1 or FADS2 in cultured cardiac fibroblasts. Serum free-carnitine levels were decreased in HFpEF patients. | Studies suggest ultraviolet (UV) A1 phototherapy is efficacious and safe in treating a variety of skin disorders. However, most reports evaluating the benefits of UVA1 phototherapy have been from Europe, focusing on a predominantly Caucasian population. Darker skin types have been evaluated only sparingly; none the less, it is widely held that these patients respond poorly to UVA1 phototherapy due to increased pigmentation. We aim to compare efficacy (clinical improvement scores) of UVA1 phototherapy among Fitzpatrick skin types. A retrospective analysis of 101 patients receiving UVA1 treatment at the University of Texas Southwestern Medical Center in Dallas, TX was performed. Data on Fitzpatrick skin type and cumulative UVA1 doses were collected. Clinical improvement scores based on body surface area, erythema, induration, sclerosis, pigmentation, and symptoms of pain or pruritus were obtained. In the population studied, with morphoea and scleroderma being the most frequent diagnoses, improvement scores from UVA1 phototherapy and mean cumulative UVA1 doses were not significantly different among the Fitzpatrick skin types evaluated. Furthermore, little or no correlation was found between improvement score and skin type. |
Does above-real-time training ( ARTT ) improve transfer to a simulated flight control task? | The aim of this study was to measure the effects of above-real-time-training (ARTT) speed and screen resolution on a simulated flight control task. ARTT has been shown to improve transfer to the criterion task in some military simulation experiments. We tested training speed and screen resolution in a project, sponsored by Defence Research and Development Canada, to develop components for prototype air mission simulators. For this study, 54 participants used a single-screen PC-based flight simulation program to learn to chase and catch an F-18A fighter jet with another F-18A while controlling the chase aircraft with a throttle and side-stick controller. Screen resolution was varied between participants, and training speed was varied factorially across two sessions within participants. Pretest and posttest trials were at high resolution and criterion (900 knots) speed. Posttest performance was best with high screen resolution training and when one ARTT training session was followed by a session of criterion speed training. | The aim of this study was to evaluate osteopontin (OPN) mRNA expression in eutopic endometrium and plasma OPN levels in patients with endometriosis. A total of 79 patients with histologically confirmed endometriosis and 43 patients without endometriosis participated in this study. OPN mRNA expression in endometrial tissues was measured by real-time quantitative polymerase chain reaction (PCR) and plasma concentrations of OPN were quantified using a specific commercial sandwich enzyme-linked immunosorbent assays (ELISA). Osteopontin mRNA expression in endometrial tissue was significantly higher in women with endometriosis than in controls (P = 0.010). The mean plasma levels of OPN (mean +/- S.E.M.) in patients with endometriosis and controls were 407.31 +/- 37.80 ng/mL and 165.84 +/- 19.29 ng/mL, respectively (P < 0.001). Receiver operating characteristic (ROC) analysis for plasma OPN revealed an area under the curve (AUC) of 0.894, with a sensitivity of 93.0%, specificity of 72.4%, positive likelihood ratio of 3.37, and negative likelihood ratio of 0.1 using a cut-off value of 167.68 ng/mL. |
Are erectile dysfunction and premature ejaculation the most frequently self-reported sexual concerns : profiles of 9,536 men calling a helpline? | To describe the range of sexual problems, as reported by men calling a help-line and to investigate factors associated with help seeking behaviour. The study included all calls between 1999 and 2004. The information used for analysis comprised caller's demographic characteristics, the sexual problem reported, previous doctor contacts, coexisting physical and mental health problems. Erectile dysfunction (ED) and premature ejaculation (PE) were the most frequently reported problems (57 and 19.2% respectively). ED-reporting callers were older (OR 0.63 for the ages of 50-59 yrs), with co-morbidities (OR 1.75) and in stable relationship (OR 0.46), while PE-reporting callers were younger (OR 5.83 for the ages of 20-29 yrs), relatively healthy and more likely single (OR 2.62 and OR 2.92 respectively). Type and duration of sexual concern, age, coexisting health problems and marital status relate significantly (p<0.01) with willingness to seek medical help. | Syndromic forms of osteosarcoma (OS) account for less than 10% of all recorded cases of this malignancy. An individual OS predisposition is also possible by the inheritance of low penetrance alleles of tumor susceptibility genes, usually without evidence of a syndromic condition. Genetic variants involved in such a non-syndromic form of tumor predisposition are difficult to identify, given the low incidence of osteosarcoma cases and the genetic heterogeneity of patients. We recently mapped a major OS susceptibility QTL to mouse chromosome 14 by comparing alpha-radiation induced osteosarcoma in mouse strains which differ in their tumor susceptibility. Tumor-specific allelic losses in murine osteosacoma were mapped along chromosome 14 using microsatellite markers and SNP allelotyping. Candidate gene search in the mapped interval was refined using PosMed data mining and mRNA expression analysis in normal osteoblasts. A strain-specific promoter variant in Rb1 was tested for its influence on mRNA expression using reporter assay. A common Rb1 allele derived from the BALB/cHeNhg strain was identified as the major determinant of radiation-induced OS risk at this locus. Increased OS-risk is linked with a hexanucleotide deletion in the promoter region which is predicted to change WT1 and SP1 transcription factor-binding sites. Both in-vitro reporter and in-vivo expression assays confirmed an approx. 1.5 fold reduced gene expression by this promoter variant. Concordantly, the 50% reduction in Rb1 expression in mice bearing a conditional hemizygous Rb1 deletion causes a significant rise of OS incidence following alpha-irradiation. |
Does sulforaphane prevent Neuronal Apoptosis and Memory Impairment in Diabetic Rats? | To explore the effects of sulforaphane (SFN) on neuronal apoptosis in hippocampus and memory impairment in diabetic rats. Thirty male rats were randomly divided into normal control, diabetic model and SFN treatment groups (N = 10 in each group). Streptozotocin (STZ) was applied to establish diabetic model. Water Morris maze task was applied to test learning and memory. Tunel assaying was used to detect apoptosis in hippocampus. The expressions of Caspase-3 and myeloid cell leukemia 1(MCL-1) were detected by western blotting. Neurotrophic factor levels and AKT/GSK3β pathway were also detected. Compared with normal control, learning and memory were apparently impaired, with up-regulation of Caspase-3 and down-regulation of MCL-1 in diabetic rats. Apoptotic neurons were also found in CA1 region after diabetic modeling. By contrast, SFN treatment prevented the memory impairment, decreased the apoptosis of hippocampal neurons. SFN also attenuated the abnormal expression of Caspase-3 and MCL-1 in diabetic model. Mechanically, SFN treatment reversed diabetic modeling-induced decrease of p-Akt, p-GSK3β, NGF and BDNF expressions. | The aim of this study was to determine whether the diagnostic yield of thyroid fine-needle aspirations (FNAs) changes over the course of residency training. We identified 5418 ultrasound-guided thyroid nodule FNAs performed in our radiology department from 2004 through 2012. For each FNA, we recorded if the FNA was performed by a resident and if so the name of the resident and supervising attending radiologist. For each resident, we determined the level of training based on their graduation year from our residency program and the date of the FNA as well as prior surgical training and if they completed subsequent interventional radiology fellowship. Pathology reports were reviewed, and FNAs were classified as diagnostic or nondiagnostic (ND). Generalized mixed models were used to assess ND rate with postgraduate years, including residents with and without prior surgical training or if they subsequently completed an interventional radiology fellowship. Of the 5418 thyroid FNAs, 3164 (58.4%) were performed by a radiology resident under the direct supervision of an attending physician. There was a significant decrease in ND rate as postgraduate years increased (P < .05). A significant decrease in ND rate was found as postgraduate years increased for residents without prior surgical training (P = .0007) or subsequent training in interventional radiology (P = .0014); however, no significant decrease was found for residents with surgical training (P = .37) or completing an interventional radiology fellowship (P = .08). In addition, no significant difference was found for ND rate between postgraduate year 4 (PGY4) and PGY5 (P > .05). |
Does endoscopic transphenoidal surgery for acromegaly improve quality of life? | Acromegaly has important effects on quality of life (QOL). This is the first study to measure QOL in acromegalic patients after endoscopic transsphenoidal surgery (ETSS). We prospectively collected the RAND-36, Center for Epidemiologic Studies Depression (CES-D), and Pituitary QOL validated questionnaires and patients' demographics, clinical presentation, endocrine laboratory results, radiological studies, development of complications and remission rates from 20 consecutive acromegalic patients who had undergone endoscopic transphenoidal surgery. The eleven females and nine males had an average age of 42 years; 90 percent had macroadenomas and 70% had cavernous sinus invasion on their preoperative imaging. Ninety percent had improved symptoms post-operatively and 80% stated that treatment improved their QOL. Biochemically, 35% were cured, 35% had discordant results and 30% were not cured, while pan-hypopituitarism occurred in 4 patients. Physical health subscales and pituitary-related symptoms were similar to norms. "Social," "emotional health," and "energy levels" were significantly lower than norms. Seventy percent stated that their relationship with their physician "very much so" affected their quality of life. Pan hypopituitarism and adjuvant therapy were the most significant predictors of lower QOL subscale scores. | Malaria is a one of the most important infectious diseases and is caused by parasitic protozoa of the genus Plasmodium. Previously, quantitative characterization of the P. falciparum transcriptome demonstrated that the strictly controlled progression of these parasites through their intra-erythrocytic developmental cycle is accompanied by a continuous cascade of gene expression. Although such analyses have proven immensely useful, the correlations between abundance of transcripts and their cognate proteins remain poorly characterized. Here, we present a quantitative time-course analysis of relative protein abundance for schizont-stage parasites (34 to 46 hours after invasion) based on two-dimensional differential gel electrophoresis of protein samples labeled with fluorescent dyes. For this purpose we analyzed parasite samples taken at 4-hour intervals from a tightly synchronized culture and established more than 500 individual protein abundance profiles with high temporal resolution and quantitative reproducibility. Approximately half of all profiles exhibit a significant change in abundance and 12% display an expression peak during the observed 12-hour time interval. Intriguingly, identification of 54 protein spots by mass spectrometry revealed that 58% of the corresponding proteins--including actin-I, enolase, eukaryotic initiation factor (eIF)4A, eIF5A, and several heat shock proteins--are represented by more than one isoform, presumably caused by post-translational modifications, with the various isoforms of a given protein frequently showing different expression patterns. Furthermore, comparisons with transcriptome data generated from the same parasite samples reveal evidence of significant post-transcriptional gene expression regulation. |
Does mR Elastography demonstrate Increased Brain Stiffness in Normal Pressure Hydrocephalus? | Normal pressure hydrocephalus is a reversible neurologic disorder characterized by a triad of cognitive impairment, gait abnormality, and urinary incontinence that is commonly treated with ventriculoperitoneal shunt placement. However, multiple overlapping symptoms often make it difficult to differentiate normal pressure hydrocephalus from other types of dementia, and improved diagnostic techniques would help patient management. MR elastography is a novel diagnostic tool that could potentially identify patients with normal pressure hydrocephalus. The purpose of this study was to assess brain stiffness changes in patients with normal pressure hydrocephalus compared with age- and sex-matched cognitively healthy individuals. MR elastography was performed on 10 patients with normal pressure hydrocephalus and 21 age- and sex-matched volunteers with no known neurologic disorders. Image acquisition was conducted on a 3T MR imaging scanner. Shear waves with 60-Hz vibration frequency were transmitted into the brain by a pillowlike passive driver. A novel postprocessing technique resistant to noise and edge artifacts was implemented to determine regional brain stiffness. The Wilcoxon rank sum test and linear regression were used for statistical analysis. A significant increase in stiffness was observed in the cerebrum (P = .001), occipital lobe (P < .001), parietal lobe (P = .001), and the temporal lobe (P = .02) in the normal pressure hydrocephalus group compared with healthy controls. However, no significant difference was noted in other regions of the brain, including the frontal lobe (P = .07), deep gray and white matter (P = .43), or cerebellum (P = .20). | Donor-specific transfusion (DST) and a brief course of anti-CD154 monoclonal antibody (mAb) induces permanent islet and prolonged skin allograft survival in mice. Induction of skin allograft survival requires the presence of CD4 cells and deletion of alloreactive CD8 cells. The specific roles of CD4 and CD4CD25 cells and the mechanism(s) by which they act are not fully understood. We used skin and islet allografts, a CD8 T cell receptor (TCR) transgenic model system, and in vivo depleting antibodies to analyze the role of CD4 cell subsets in regulating allograft survival in mice treated with DST and anti-CD154 mAb. Deletion of CD4 or CD25 cells during costimulation blockade induced rapid rejection of skin but only minimally shortened islet allograft survival. Deletion of CD4 or CD25 cells had no effect upon survival of healed-in islet allografts, and CD25 cell deletion had no effect upon healed-in skin allograft survival. In the TCR transgenic model, DST plus anti-CD154 mAb treatment deleted alloreactive CD8 T cells, and anti-CD4 mAb treatment prevented that deletion. In contrast, injection of anti-CD25 mAb did not prevent alloreactive CD8 T cell deletion. |
Are toker cells of the nipple commonly associated with underlying sebaceous glands but not with lactiferous ducts? | Toker cells are clear cells present in the squamous epithelium of the nipple of some women. In contrast to squamous epithelium, they are cytokeratin 7 (CK7) positive. The origin of these cells is not completely understood. It has been suggested that they may represent abortive glands or migratory ductal cells; and may be precursors of Paget's disease of the nipple. Our aim was to investigate the incidence and distribution of Toker cells and their relationship with lactiferous ducts. We examined nipple sections from 100 consecutive mastectomies performed at Charing Cross hospital. New sections were stained for CK7 using the immunoperoxidase technique. Toker cells were identified in 11 cases. They were always clustered within the squamous epithelium superficial to sebaceous glands with no relationship with lactiferous ducts. Two cases in the study had Paget's disease and these were not associated with underlying sebaceous glands. | While the anticholinergic activity of medications has been linked to cognitive decline, few studies have linked anticholinergic burden with falls in older people. We evaluated the relationship between anticholinergic burden and recurrent and injurious falls among community-dwelling older adults. This case-control study was performed on 428 participants aged ≥65 years, 263 cases with two or more falls or one injurious fall in the preceding 12 months, and 165 controls with no falls in the preceding 12 months. Anticholinergic burden was determined using the anticholinergic cognitive burden (ACB) scale. Upper and lower limb functional abilities were assessed with timed up and go (TUG), functional reach (FR) and grip strength (GS). Logistic regression analysis was employed to calculate the mediation effect of TUG, FR and GS on ACB associated falls. Univariate analysis revealed a significant association between an ACB score of ≥1 with falls (OR, 1.8; 95% CI; 1.1-3.0; p=0.01) and significantly poorer TUG and FR. The association between ACB≥1 and falls was no longer significant after adjustment for either TUG (OR for ACB associated falls, 1.4; 95% CI, 0.88-2.4; p=0.14) or FR (OR for ACB associated falls, 1.4; 95% CI, 0.89-2.4, p=0.12) but remained significant with GS. |
Is complex penetrating duodenal injuries : less better? | The traditional management of complex penetrating duodenal trauma (PDT) has been the use of elaborate temporizing and complex procedures such as the pyloric exclusion and duodenal diverticulization. We sought to determine whether a simplified surgical approach to the management of complex PDT injuries improves clinical outcome. A retrospective review of all consecutive PDT from 2003 to 2012 was conducted. Patients were divided into three groups according to a simplified surgical algorithm devised following the local experience at a regional Level I trauma center. Postoperative duodenal leaks were drained externally either via traditional anterior drainage or via posterior "retroperitoneal laparostomy" as an alternate option. There were 44 consecutive patients with PDT, and 41 of them (93.2%) were from gunshot wounds. Seven patients were excluded owing to early intraoperative death secondary to associated devastating traumatic injuries. Of the remaining 36 patients, 7 (19.4%) were managed with single-stage primary duodenal repair with definitive abdominal wall fascial closure (PDR + NoDC group). Damage-control laparotomy was performed in 29 patients, (80.5%) in which primary repair was performed in 15 (51.7%) (PDR + DC group), and the duodenum was over sewn and left in discontinuity in 14 (48.3%). Duodenal reconstruction was performed after primary repair in 2 of 15 cases and after left in discontinuity in 13 of 14 cases (DR + DC group). The most common complication was the development of a duodenal fistula in 12 (33%) of 36 cases. These leaks were managed by traditional anterior drainage in 9 (75%) of 12 cases and posterior drainage by retroperitoneal laparostomy in 3 (25%) of 12 cases. The duodenal fistula closed spontaneously in 7 (58.3%) of 12 cases. The duodenum-related mortality rate was 2.8%, and the overall mortality rate was 11.1%. | : Diagnostic criteria for bronchiolitis are variable. : To study how the risk factors for recurrent wheezing and asthma vary by different definitions of bronchiolitis. : Viral etiology and atopic characteristics were studied in 259 hospitalized wheezing children (median age, 14 months; range, 0-36 months). The data were analyzed according to age (<6, <12, <24 and <36 months) and whether they had a history or no history of a previous wheezing episode. Sixteen viruses were detected by conventional and molecular methods. Atopic characteristics included the presence of eczema, specific and total IgE responses, blood eosinophil count, and modified asthma predictive index. : Evidence of respiratory virus infection was found in 93% of the cases and allergic sensitization in 26% of the cases. Rhinovirus infections and atopic characteristics (sensitization, blood eosinophil count, and modified asthma predictive index) increased by age and were significantly more common in children with recurrent wheezing episodes than in first-time wheezers in age categories of <24 and <36 months (P < 0.05 for all). |
Does technical challenge encountered during deployment of the ovation abdominal aortic stent-graft system? | To describe technical challenges encountered using the Ovation endograft for abdominal aortic aneurysms and suggest tips and maneuvers for successful management. Deployment of the Ovation's unsupported main body is often associated with the anteroposterior arrangement of the limb gates instead of the usual side-by-side configuration, rendering contralateral catheterization challenging. Successful catheterization of the contralateral limb can be confirmed by lateral deviation of the ipsilateral stiff guidewire caused by balloon inflation within the contralateral limb. Moreover, failure to cannulate the contralateral limb gate due to persistent impingement of the guidewire or compromise of the inflated rings can be overcome using the transbrachial antegrade approach. | Signaling via B cell receptor (BCR) and Toll-like receptors (TLRs) results in activation of B cells with distinct physiological outcomes, but transcriptional regulatory mechanisms that drive activation and distinguish these pathways remain unknown. Two hours after ligand exposure RNA-seq, ChIP-seq and computational methods reveal that BCR- or TLR-mediated activation of primary resting B cells proceeds via a large set of shared and a smaller subset of distinct signal-selective transcriptional responses. BCR stimulation resulted in increased global recruitment of RNA Pol II to promoters that appear to transit slowly to downstream regions. Conversely, lipopolysaccharide (LPS) stimulation involved an enhanced RNA Pol II transition from initiating to elongating mode accompanied by greater H3K4me3 activation markings compared to BCR stimulation. These rapidly diverging transcriptomic landscapes also show distinct repressing (H3K27me3) histone signatures, mutually exclusive transcription factor binding in promoters, and unique miRNA profiles. |
Is derangement of the E-cadherin/catenin complex involved in transformation of differentiated to anaplastic thyroid carcinoma? | Anaplastic thyroid cancer arises, or transforms, from pre-existing differentiated thyroid cancer. E-cadherin functions as a cell-cell adhesion molecule that complexes with catenin proteins for function. The objective of this study was to evaluate the change in E-cadherin/beta-catenin expression in the transformation of differentiated to anaplastic thyroid carcinoma. A tissue microarray was constructed from 12 anaplastic thyroid tumors and their adjacent associated differentiated foci. Immunohistochemistry was used to evaluate tumor expression of E-cadherin and beta-catenin. There was decreased expression of E-cadherin and beta-catenin by the anaplastic tumors when compared with the differentiated thyroid tumors from which they evolved. The expression of E-cadherin and beta-catenin was 92% and 67%, respectively, by the differentiated thyroid carcinoma, and 17% and 50%, respectively, by the anaplastic tumors. | Hyperglycemia generates reactive oxygen species and prevents isoflurane-induced preconditioning. The authors tested the hypothesis that scavenging reactive oxygen species with N-acetylcysteine will restore protection against myocardial infarction produced by isoflurane in vivo. Barbiturate-anesthetized dogs (n = 45) were instrumented for measurement of systemic hemodynamics. Myocardial infarct size and coronary collateral blood flow were measured with triphenyltetrazolium staining and radioactive microspheres, respectively. All dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Dogs were randomly assigned to receive an infusion of 0.9% saline or 15% dextrose in water to increase blood glucose concentrations to 600 mg/dl (hyperglycemia) in the absence or presence of isoflurane (1.0 minimum alveolar concentration) with or without pretreatment with N-acetylcysteine (150 mg/kg i.v.) in six experimental groups. Isoflurane was discontinued, and blood glucose concentrations were allowed to return to baseline values before left anterior descending coronary artery occlusion. Myocardial infarct size was 27 +/- 2% (n = 8) of the left ventricular area at risk in control experiments. Isoflurane significantly (P < 0.05) decreased infarct size (13 +/- 2%; n = 7). Hyperglycemia alone did not alter infarct size (29 +/- 3%; n = 7) but abolished the protective effect of isoflurane (25 +/- 2%; n = 8). N-Acetylcysteine alone did not affect infarct size (28 +/- 2%; n = 8) but restored isoflurane-induced cardioprotection during hyperglycemia (10 +/- 1%; n = 7). |
Does activation of Serotonin 2C Receptors in Dopamine Neurons inhibit Binge-like Eating in Mice? | Neural networks that regulate binge eating remain to be identified, and effective treatments for binge eating are limited. We combined neuroanatomic, pharmacologic, electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of 5-hydroxytryptamine (5-HT) 2C receptor (5-HT We showed that 5-HT stimulates DA neural activity through a 5-HT | Thromboembolic disease (TED) after knee arthroplasty occurs infrequently in Iran. The aim of this study was to examine the incidence of TED in patients with osteoarthritis undergoing knee replacement in Southern Iran while on prophylaxis. In a case series study from January to December 2012, 100 consecutive total knee arthroplasty (TKA) candidates were evaluated for TED by clinical evaluation and Doppler sonography preoperatively and 2 months postoperatively and by clinical evaluation one year after surgery. The patients in this study randomly received either warfarin or enoxaparin prophylactically. A total of 77 women and 23 men with mean age of 67 years (52-82 years) entered the study. The average hemoglobin drop of 2.7 g with warfarin and 3.3 with enoxaparin was observed. No case of TED, pulmonary embolus (PE), major bleeding, post-thrombotic syndrome, or hemarthrosis was observed. |
Does epigallocatechin Gallate extend the Therapeutic Window of Recombinant Tissue Plasminogen Activator Treatment in Ischemic Rats? | Ischemic stroke is the leading cause of death and disability worldwide. To date, recombinant tissue plasminogen activator (rt-PA) remains the only safe and effective pharmaceutical treatment for brain ischemia, but delayed rt-PA administration leads to hyperperfusion, which severely limits its clinical efficacy. In this study, we investigated the effect of epigallocatechin gallate (EGCG) in extending the therapeutic window of rt-PA using a rat middle cerebral artery occlusion (MCAO) model. Simultaneous treatment of EGCG and rt-PA significantly recovered the neurobehavioral deficit, when administered even 4 hours after MCAO. Pathological examinations on the ischemic brain samples revealed that EGCG significantly alleviated the common side effects of delayed rt-PA treatment, including brain infarction, cerebral edema, and blood-brain barrier disruption. We further found that EGCG exerted its protective functions against delayed rt-PA through upregulation of plasminogen activator inhibitor-1, as well as downregulation of matrix metalloproteinases. | Methotrexate has been steroid sparing for some patients with chronic sarcoidosis. We wished to determine whether methotrexate can be steroid sparing in the first year of corticosteroid therapy in sarcoidosis. Patients with new onset, symptomatic disease within four weeks of starting on prednisone were randomized to receive either methotrexate or placebo for the next year. They were seen monthly and prednisone dosage was tapered following a pre-determined schedule. Of 24 patients enrolled, only 15 received at least six months of therapy. Since methotrexate appears to take six months to be effective, only patients who completed six or more months of therapy were evaluated. The amount of prednisone per day decreased for both groups: methotrexate (First 6 months: Median 26 (Range 15-37) mg/day); Second 6 months 8 (1-22) mg/day, p < 0.01) and placebo (First 6 Months 28 (24-33) mg/day; Second 6 months 16 (11-22) mg/day, p < 0.02), with less prednisone used for the methotrexate patients versus placebo in the last six months (p < 0.01). There was also less weight gain for those patients receiving methotrexate. There was no difference in toxicity between methotrexate and placebo. The difference between methotrexate versus placebo was not seen when all patients (including the dropouts) were analyzed. |
Does perfusion MDCT enable early detection of therapeutic response to antiangiogenic therapy? | The objective of our study was to determine whether perfusion CT can be used to detect early changes in therapeutic response to antiangiogenic therapy in an animal tumor model. Twenty-five rats implanted with R3230 mammary adenocarcinoma (diameter, 1.2-2.0 cm) randomly received 7.5 or 30 mg/kg of an antiangiogenic agent, sorafenib, by daily gavage for 4 (n = 4), 9 (n = 9), or 14 (n = 5) days. Seven untreated animals served as a control group. Perfusion MDCT was performed at days 0, 4, 9, and 14 with 0.4 mL of ioversol (350 mg/mL) and included four 5-mm slices covering the entire tumor volume. Changes in tumor growth were determined by volumetric analysis of CT data. Serial changes in tumor volume and blood flow were assessed and correlated with pathology findings. All control tumors grew larger (from 2.0 +/- 0.7 cm(3) at day 0 to 5.9 +/- 1.0 cm(3) at day 14), whereas all treated tumors shrank (from 2.5 +/- 1.1 to 2.1 +/- 1.0 cm(3)), with a statistically significant rate of growth or shrinkage in both groups (p < 0.05). Although perfusion in the control tumors changed little from day 0 to day 14 (day 0, 18.1 +/- 9.2 mL/min/100 g; day 4, 15.8 +/- 5.6; day 9, 21.7 +/- 12.2; day 14, 27.7 +/- 34), in the sorafenib group, the mean blood flow was significantly lower at day 4 (5.2 +/- 3.2 mL/min/100 g, 77% decrease), day 9 (6.4 +/- 4.0 mL/min/100 g, 66% decrease), and day 14 (6.3 +/- 5.2 mL/min/100 g, 83% decrease) compared with day 0 (23.8 +/- 11.6 mL/min/100 g) (p < 0.05). Poor correlation was seen between changes in blood flow and tumor volume for days 0-9 (r(2) = 0.34), 4-9 (r(2) = 0.0004), and 9-14 (r(2) = 0.16). However, when comparing day 4 images with days 9 and 14 images, seven of 14 (50%) sorafenib-treated tumors had focal areas of new perfusion that correlated with areas of histopathologic viability despite the fact that these tumors were shrinking in size from day 4 onward (day 4, 2.18 +/- 0.8 cm(3); day 9, 1.98 +/- 0.8 cm(3)). | Previous findings are inconsistent; yet, converging evidence suggests an association between schizophrenia (SZ) and the impairment of posttranscriptional regulation of brain development through microRNA (miRNA) systems. This study aims to (1) compare the overall frequency of 121 rare variants (RVs) in 59 genes associated with the miRNA system in genome-wide association studies (GWAS)-derived data including 768 SZ cases and 1348 healthy controls and validated in an independent GWAS data including 1802 SZ cases and 1447 controls; (2) profile genome-wide miRNA expression in blood collected from 15 early-onset SZ (EOS) cases and 15 healthy controls; and (3) construct a miRNA-messenger RNA (mRNA) regulatory network using our previous genome-wide mRNA expression data generated from a separate sample of 18 EOS cases and 12 healthy controls. Our findings indicate that: (1) In genes associated with the control of miRNAs, there are approximately 50% more RVs in SZ cases than in controls (P ≤ 2.62E-10); (2) The observed lower miRNA activity in EOS patients compared with the healthy controls suggests that miRNAs are abnormally downregulated; (3) There exists a predicted regulatory network among some downregulated miRNAs and some upregulated mRNAs. |
Does topical N-acetylcysteine reduce interleukin-1-alpha in tear fluid after laser subepithelial keratectomy? | To evaluate the effect of topical N-acetylcysteine (NAC) on interleukin 1-alpha (IL-1alpha) levels in tear fluid after myopic laser subepithelial keratectomy (LASEK) and its possible role in modulating corneal wound healing. Twenty-six eyes of 13 patients who underwent myopic LASEK were divided into 2 groups. Group 1 (n=10 eyes) was used as a control group. All patients received topical lomefloxacin and dexamethasone postoperatively. Additionally, patients in Group 2 received topical NAC for 1 month postoperatively. Tear fluid samples were collected with microcapillary tubes preoperatively, on the first and on the fifth postoperative day, and the release of IL-1alpha in tear fluid was calculated. Haze grading and confocal microscopic examination were performed at 1 and 3 months postoperatively. The mean IL-1-alpha release values were 0.285-/+0.159 pg/min in Group 1 and 0.235-/+0.142 pg/min in Group 2 preoperatively. In Group 1, the values were 0.243-/+0.155 pg/min on day 1 and 0.164-/+0.125 pg/min on day 5. In Group 2, the mean IL-1alpha release values were 0.220-/+0.200 pg/min on day 1 and 0.080-/+0.079 pg/min on day 5. The difference between the groups was significant only for day 5 (p<0.05). Mean corneal haze score and grey scale value in confocal microscopy were significantly higher (p<0.05) in Group 1 at 1 month. However, at 3 months there was no difference between groups (p>0.05). | Cardiac mass and volumes are often elevated in athletes, but it is not known whether moderate physical activity is also associated with cardiac dilatation and hypertrophy in a healthy adult population. In total, 1096 adults (54% female, median age 39 years) without cardiovascular disease or cardiomyopathy-associated genetic variants underwent cardiac magnetic resonance imaging to determine biventricular volumes and function. Physical activity was assessed using a validated activity questionnaire. The relationship between cardiac parameters and activity was assessed using multiple linear regression adjusting for age, sex, race, and systolic blood pressure. Logistic regression was performed to determine the effect of activity on the likelihood of subjects having cardiac dilatation or hypertrophy according to standard cardiac magnetic resonance normal ranges. Increasing physical activity was associated with greater left ventricular (LV) mass (β=0.23; P<0.0001) and elevated LV and right ventricular volumes (LV: β=0.26, P<0.0001; right ventricular: β=0.26, P<0.0001). Physical activity had a larger effect on cardiac parameters than systolic blood pressure (0.06≤β≤0.21) and a similar effect to age (-0.20≤β≤-0.31). Increasing physical activity was a risk factor for meeting imaging criteria for LV hypertrophy (adjusted odds ratio 2.1; P<0.0001), LV dilatation (adjusted odds ratio 2.2; P<0.0001), and right ventricular dilatation (adjusted odds ratio 2.2; P<0.0001). |
Do validation of Duruöz Hand Index in patients with tetraplegia? | Cross-sectional, clinical measurement. To investigate the validity of the Duruöz Hand Index (DHI) in the assessment of hand function in patients with tetraplegia. A total of 40 patients with tetraplegia participated. Patients' upper extremities were assessed on the level of 'body function and structure' [The American Spinal Cord Injury Association (ASIA) Impairment Scale (AIS) 2000 revised criteria, upper extremity motor score (UEMS), neurologic level of injury and visual analogue scale of hand function (VAS-HF)], 'activity' [DHI and Quadriplegia index of function-short form (QIF-SF)] and 'body function and structure, activity and participation' [Health Survey Short Form-36 (SF-36)] according to International Classification of Function. The DHI showed significant correlations with UEMS, AIS, QIF-SF, VAS-HF, physical functioning and physical compound summary scores of SF-36. | This study examines the ABCG1-mediated cholesterol efflux and intracellular cholesterol transport by studying the ABCG1 localization and function in macrophages. HEK 293 cell overexpressing ABCG1, RNA interference, or macrophages from ABCG1 or ABCG4 knockout mice were used. ABCG1 but not ABCG4 had a major role in the increased cholesterol mass efflux produced by treatment of macrophages with LXR activators. In 293 cells, ABCG1 was found in the plasma membrane, Golgi, and recycling endosomes. In contrast, in basal macrophages, ABCG1 was predominantly intracellular, and redistributed to the plasma membrane after LXR activation. LXR activation increased macrophage cholesterol efflux to high-density lipoprotein (HDL), low-density lipoprotein (LDL), and cyclodextrin in an ABCG1-dependent fashion. Suppression of ABCG1 expression increased cholesteryl ester formation and decreased SREBP2 target gene expression in macrophages, even in the absence of HDL acceptors. |
Does budesonide improve decreased airway conductance in infants with respiratory symptoms? | Inhaled corticosteroids (ICS) are commonly used to treat wheezing disorders in children, but few studies have investigated the effect of ICS on lung function in infants. We evaluated the efficacy of inhaled budesonide for decreased specific airway conductance (sGaw) as an indication of bronchial obstruction in very young children with recurrent cough and/or wheeze. PATIENTS, DESIGN AND INTERVENTIONS: Functional residual capacity (FRC) and sGaw of steroid-naive children aged 3-26 months with respiratory symptoms were measured using an infant whole-body plethysmograph. Clinically indicated bronchoscopy was performed in 79% of the patients to exclude anatomical abnormalities before randomisation. Children with abnormal lung function and respiratory symptoms were randomised into two treatment groups, receiving either inhaled budesonide (400 microg/day) or placebo with NebuChamber for 6 weeks. Inhaled terbutaline 0.25 mg/dose was used as a rescue medication. Lung function measurements were repeated after 6 weeks. Lung function. 44 children with a median age of 11.3 months (range 3.7-25.9) completed the study. Median sGaw improved from a z score of -3.6 to -1.2 (p<0.001) in the budesonide group and from -3.2 to -2.6 (p = 0.033) in the placebo group; between group difference p = 0.014. Improvement in sGaw was more pronounced in children with atopy (p = 0.017). Symptom-free days increased in both the budesonide and placebo groups with no difference between groups. | The aim of the present study was to assess the association between the pre-operative plasma fibrinogen level and the adjacent organ involvement in advanced gastric cancer. A total of 923 pre-operative plasma samples were obtained from 923 patients diagnosed clinically as having advanced gastric cancer, and fibrinogen levels were measured by immunoassay. Associations between fibrinogen levels and clinicopathologic findings (depth of tumor, adjacent organ involvement, and lymph node metastasis), along with survival were examined by univariate and multivariate analyses. Tumor size, tumor depth, and the presence of lymph node metastasis were found to be positively correlated with the preoperative plasma fibrinogen levels (P<0.001). Fifty (5.4%) patients had adjacent organ involvement. Lymphatic invasion (P<0.001), tumor size (P<0.001), clinical T (depth of invasion) stage (P<0.001), and clinical nodal stage (P=0.018) were found to be associated with adjacent organ involvement. Univariate and multivariate regression analyses showed that a preoperatively elevated plasma fibrinogen level was associated with adjacent organ involvement (P<0.001, 0.028), and Kaplan-Meier analysis showed that it was associated with poorer survival (P<0.001). |
Are most partial domains in proteins alignment and annotation artifacts? | Protein domains are commonly used to assess the functional roles and evolutionary relationships of proteins and protein families. Here, we use the Pfam protein family database to examine a set of candidate partial domains. Pfam protein domains are often thought of as evolutionarily indivisible, structurally compact, units from which larger functional proteins are assembled; however, almost 4% of Pfam27 PfamA domains are shorter than 50% of their family model length, suggesting that more than half of the domain is missing at those locations. To better understand the structural nature of partial domains in proteins, we examined 30,961 partial domain regions from 136 domain families contained in a representative subset of PfamA domains (RefProtDom2 or RPD2). We characterized three types of apparent partial domains: split domains, bounded partials, and unbounded partials. We find that bounded partial domains are over-represented in eukaryotes and in lower quality protein predictions, suggesting that they often result from inaccurate genome assemblies or gene models. We also find that a large percentage of unbounded partial domains produce long alignments, which suggests that their annotation as a partial is an alignment artifact; yet some can be found as partials in other sequence contexts. | To analyze serum periostin and liver stiffness in postoperative biliary atresia (BA). A total of 60 BA patients and 14 controls were enrolled. Serum periostin levels were analyzed by ELISA. Liver stiffness measurement was determined by transient elastography. Biliary atresia patients had significantly higher periostin and liver stiffness values than controls. Serum periostin levels were remarkably increased in BA patients with jaundice compared to those without jaundice. Moreover, serum periostin was correlated with liver stiffness. |
Does missense Variant in MAPK Inactivator PTPN5 be Associated with Decreased Severity of Post-Burn Hypertrophic Scarring? | Hypertrophic scarring (HTS) is hypothesized to have a genetic mechanism, yet its genetic determinants are largely unknown. The mitogen-activated protein kinase (MAPK) pathways are important mediators of inflammatory signaling, and experimental evidence implicates MAPKs in HTS formation. We hypothesized that single-nucleotide polymorphisms (SNPs) in MAPK-pathway genes would be associated with severity of post-burn HTS. We analyzed data from a prospective-cohort genome-wide association study of post-burn HTS. We included subjects with deep-partial-thickness burns admitted to our center who provided blood for genotyping and had at least one Vancouver Scar Scale (VSS) assessment. After adjusting for HTS risk factors and population stratification, we tested MAPK-pathway gene SNPs for association with the four VSS variables in a joint regression model. In addition to individual-SNP analysis, we performed gene-based association testing. Our study population consisted of 538 adults (median age 40 years) who were predominantly White (76%) males (71%) admitted to our center from 2007-2014 with small-to-moderate-sized burns (median burn size 6% total body surface area). Of 2,146 SNPs tested, a rare missense variant in the PTPN5 gene (rs56234898; minor allele frequency 1.5%) was significantly associated with decreased severity of post-burn HTS (P = 1.3×10-6). In gene-based analysis, PTPN5 (P = 1.2×10-5) showed a significant association and BDNF (P = 9.5×10-4) a borderline-significant association with HTS severity. | To evaluate the drug interaction between fosamprenavir (FPV) and esomeprazole (ESO) after repeated doses in healthy adults. Subjects received ESO 20 mg once daily (qd) for 7 days followed by either ESO 20 mg qd + FPV 1400 mg twice daily (bid) or ESO 20 mg qd + FPV 700 mg bid + ritonavir (RTV) 100 mg bid for 14 days in arms 1 and 2, respectively. After a 21- to 28-day washout, subjects received either FPV 1400 mg bid for 14 days (arm 1) or FPV 700 mg bid + RTV 100 mg bid for 14 days (arm 2). Pharmacokinetic sampling was conducted on the last day of each treatment. Simultaneous coadministration of ESO 20 mg qd with either FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid had no effect on steady-state amprenavir pharmacokinetics. The only effect on plasma ESO exposure was a 55% increase in area under the plasma concentration-time curve during a dosing interval, tau[AUC0-tau], after coadministration of ESO 20 mg qd with FPV 1400 mg bid. |
Do functional crosstalk between the mitochondrial PTP and KATP channels determine arrhythmic vulnerability to oxidative stress? | Mitochondrial permeability transition pore (mPTP) opening is a terminal event leading to mitochondrial dysfunction and cell death under conditions of oxidative stress (OS). However, mPTP blockade with cyclosporine A (CsA) has shown variable efficacy in limiting post-ischemic dysfunction and arrhythmias. We hypothesized that strong feedback between energy dissipating (mPTP) and cardioprotective (mKATP) channels determine vulnerability to OS. Guinea pig hearts (N = 61) were challenged with H2O2 (200 μM) to elicit mitochondrial membrane potential (ΔΨm) depolarization. High-resolution optical mapping was used to measure ΔΨm or action potentials (AP) across the intact heart. Hearts were treated with CsA (0.1 μM) under conditions that altered the activity of mKATP channels either directly or indirectly via its regulation by protein kinase C. mPTP blockade with CsA markedly blunted (P < 0.01) OS-induced ΔΨm depolarization and delayed loss of LV pressure (LVP), but did not affect arrhythmia propensity. Surprisingly, prevention of mKATP activation with the chemical phosphatase BDM reversed the protective effect of CsA, paradoxically exacerbating OS-induced ΔΨm depolarization and accelerating arrhythmia onset in CsA treated compared to untreated hearts (P < 0.05). To elucidate the putative molecular mechanisms, mPTP inhibition by CsA was tested during conditions of selective PKC inhibition or direct mKATP channel activation or blockade. Similar to BDM, the specific PKC inhibitor, CHE (10 μM) did not alter OS-induced ΔΨm depolarization directly. However, it completely abrogated CsA-mediated protection against OS. Direct pharmacological blockade of mKATP, a mitochondrial target of PKC signaling, equally abolished the protective effect of CsA on ΔΨm depolarization, whereas channel activation with 30 μM Diazoxide protected against ΔΨm depolarization (P < 0.0001). Conditions that prevented mKATP activation either directly or indirectly via PKC inhibition led to accelerated ΔΨm depolarization and early onset of VF in response to OS. Investigation of the electrophysiological substrate revealed accelerated APD shortening in response to OS in arrhythmia-prone hearts. | Anal complaints, caused not by haemorrhoids but by anal folds, fissures or perianal thrombosis, are probably too often and wrongly attributed to haemorrhoids by patients and self-treated. It was the aim of this study to find out how frequently patients with anal complaints make this false assumption and how successful their self treatment is. 458 consecutive patients referred between May and November 2001 with unclear abdominal and/or anal symptoms were investigated by a standardized questionnaire/interview, including any experience with wet compresses, haemorrhoidal ointments or results of a doctor's treatment of haemorrhoids. They were then examined by procto-coloscopy. The findings were documented on the questionnaire and the data stored in an computer. 344 of the 548 patients (63 %) believed that they had haemorrhoids, 184 (34 %) did not think so, and 20 (3 %) left the question unanswered. Haemorrhoids were found to be present in 18 % and 13 %, respectively. Bleeding, pain, itching and burning sensation around the anus were the most common symptoms in both groups. 151 of the 184 patients who did not think they had haemorrhoids (82 %) had been previously treated by a doctor for "haemorrhoids". 28 % of this group of patients and 36 % of those thought to have haemorrhoids had similar results with wet compresses, creams or ointments, and the two groups were also similar regarding the number found to have anal disease. |
Is b lymphopenia in uremia related to an accelerated in vitro apoptosis and dysregulation of Bcl-2? | Lymphopenia has been described in patients with chronic renal failure (CRF). It is postulated that the decline in lymphocytes is due to accelerated apoptosis. We investigated whether dysregulation of programmed cell death plays a role in the immunodeficiency described in CRF. Peripheral blood lymphocytes (PBL) from pre-dialysis uraemic patients (nHD) and haemodialysed patients (HD) were cultured with no stimulus for 96 h. Apoptosis of lymphocytes was measured by propidium iodide staining and flow cytometry. Expression of Fas and Bcl-2 was also analysed by flow cytometry. Peripheral blood B cells were significantly lower in pre-dialysis and haemodialysis uraemic patients compared to control. Lymphocytes from both groups of patients had a higher rate of apoptosis in vitro than those from healthy controls. This effect was more pronounced in B lymphocytes and a significant correlation between the B lymphopenia and the percentage of apoptotic B cells after 48 h of culture without stimulus was observed. The increased lymphocyte apoptosis in CRF was accompanied by a significantly lower in vitro Bcl-2 expression. However, Fas did not seem to play a role in spontaneous lymphocyte apoptosis in end-stage renal disease. | Various studies indicate that serotonin regulates impulsivity and the inhibitory control of aggression. Aggression is also known to be modified by sex hormones, which exert influence on serotonergic neurotransmission. The present study aimed to elucidate potential interactions between human aggression, the inhibitory serotonergic 5-HT(1A) receptor, and sex hormones. Thirty-three healthy volunteers (16 women, aged 26.24 +/- 5.5 yr) completed a validated questionnaire incorporating five dimensions of aggression. Subsequently, all subjects underwent positron emission tomography with the radioligand [carbonyl-(11)C]WAY-100635 to quantify 5-HT(1A) binding potentials (BP(ND)s) in the prefrontal cortex, limbic areas, and midbrain. Also, plasma levels of testosterone, 17beta-estradiol and sex hormone-binding globulin (SHBG) were measured. Relations between aggression scores, regional 5-HT(1A) BP(ND)s, and hormone levels were analyzed using correlations, multivariate analyses of variance, and linear regressions. Statistical analyses revealed higher 5-HT(1A) receptor BP(ND)s in subjects exhibiting higher aggression scores in prefrontal (all P < 0.041) and anterior cingulate cortices (P = 0.016). More aggressive subjects were also characterized by lower SHBG levels (P = 0.015). Moreover, higher SHBG levels were associated with lower 5-HT(1A) BP(ND)s in frontal (P = 0.048) and cingulate cortices (all P < 0.013) and in the amygdala (P = 0.03). |
Are rodent-specific alternative exons more frequent in rapidly evolving genes and in paralogs? | Alternative splicing is an important mechanism for generating functional and evolutionary diversity of proteins in eukaryotes. Here, we studied the frequency and functionality of recently gained, rodent-specific alternative exons. We projected the data about alternative splicing of mouse genes to the rat, human, and dog genomes, and identified exons conserved in the rat genome, but missing in more distant genomes. We estimated the frequency of rodent-specific exons while controlling for possible residual conservation of spurious exons. The frequency of rodent-specific exons is higher among predominantly skipped exons and exons disrupting the reading frame. Separation of all genes by the rate of sequence evolution and by gene families has demonstrated that rodent-specific cassette exons are more frequent in rapidly evolving genes and in rodent-specific paralogs. | Previous studies have demonstrated that the administration of antibiotics to patients before performing diagnostic testing for periprosthetic joint infection (PJI) can interfere with the accuracy of test results. Although a single-institution study has suggested that alpha-defensin maintains its concentration and sensitivity even after antibiotic treatment, this has not yet been demonstrated in a larger multiinstitutional study. (1) For the evaluation of PJI, is prior antibiotic administration associated with decreased alpha-defensin levels? (2) When prior antibiotics are given, is alpha-defensin a better screening test for PJI than the traditional tests (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], fluid white blood cells, fluid polymorphonuclear cells [PMNs], and fluid culture)? This retrospective study included data from 106 hip and knee arthroplasties with Musculoskeletal Infection Society-defined PJI from four centers. Of the 106 patients in this study, 30 (28%) were treated with antibiotics for PJI before diagnostic workup (ABX group), and 76 (72%) were not treated before the diagnostic workup (NO-ABX group). There were no differences in age, sex, joint, culture-negative rate, or bacteriology between groups. The patients in the ABX group had antibiotics initiated by physicians who commenced care before assessment for PJI by the treating surgeon's service. We compared the alpha-defensin levels and sensitivity between the ABX and NO-ABX groups. Additionally, the sensitivity of the alpha-defensin test was compared to that of traditional tests for PJI among patients on antibiotics. The administration of antibiotics before performing the alpha-defensin test for PJI was not associated with a decreased median alpha-defensin level (ABX group, median 4.2 [range, 1.79-12.8 S/CO] versus NO-ABX, median 4.9 [range, 0.5-16.8 S/CO], difference of medians: 0.68 S/CO [95% confidence interval {CI}, -0.98 to 1.26], p = 0.451). Furthermore, the alpha-defensin test had a higher sensitivity (100%; 95% CI, 88.4%-100.0%) in diagnosing PJI among patients on antibiotics when compared with the ESR (69.0% [95% CI, 49.17%-84.72%], p = 0.001), the CRP (79.3% [95% CI, 60.3%-92.0%], p = 0.009), the fluid PMN% (79.3% [95% CI, 60.3%-92.0%), p = 0.009), and fluid culture (70.0% [95% CI, 50.6%-85.3%], p = 0.001). |
Do cardiomyocytes derived from embryonic stem cells resemble cardiomyocytes of the embryonic heart tube? | After formation of the linear heart tube a chamber-specific program of gene expression becomes active that underlies the formation of the chamber myocardium. To assess whether this program is recapitulated in in vitro differentiated embryonic stem cells, we performed qualitative and quantitative analyses of cardiogenesis in vivo and in vitro. Gene expression profiles were made by in situ hybridisation and real-time PCR and electrophysiological profiles by patch clamp analyses of cardiomyocytes derived from time series of differentiating HM1 mouse embryonic stem cells and from embryonic and adult mouse hearts. In embryoid bodies the in situ patterns of expression of alpha-myosin heavy chain, myosin light chain 2a and sarcoendoplasmic reticulum calcium ATPase 2a were similar to that of the heart muscle-specific marker gene cardiac troponin I. Myosin light chain 2v was expressed in part of the cardiac troponin I-expressing area, indicating heterogeneity within the cardiac cell population. Atrial natriuretic factor expression, indicative of the chamber-type program, could only very occasionally be detected by in situ hybridisation. Quantitative reverse transcriptase PCR showed that all cardiac genes, most notably atrial natriuretic factor, were expressed at relatively low levels, similar to those in embryonic hearts at embryonic day 8.75-9. Analysis of the electrophysiological characteristics of embryonic stem cell-derived cardiomyocytes showed an increase of the upstroke velocity and a shorter duration of the action potential during prolonged differentiation in vitro. When embryonic mouse heart compartments of embryonic day 12.5 were used as a reference, the electrophysiological characteristics of a substantial part of the embryonic stem cell-derived cardiomyocytes were most reminiscent to those observed in the embryonic outflow tract. | Data regarding the prevalence and types of drug-related problems (DRPs) among neurology inpatients is sparse. The objective of this study was to characterise the types of DRPs seen among neurology inpatients and furthermore to study factors affecting the acceptance of clinical pharmacologists' and pharmacists' recommendations for improving drug safety. 1,263 consecutive inpatient cases in a Swiss university hospital neurology unit were assessed for the presence of DRPs over 12 months. Treating neurologists' acceptance of the resulting recommendations was also recorded. Primary outcome measures were types of DRP, recommendations made by clinical pharmacologists and number of recommendations accepted. Factors potentially associated with acceptance were studied using univariate and multivariate generalised estimating equation modelling. Twenty-nine percent of cases demonstrated one or more DRPs. DRPs were the cause of admission in 10 cases (0.8%). In total 494 DRPs were identified and 467 recommendations given, of which 62% were accepted. Factors associated with an increased likelihood of acceptance were prescriptions involving regularly administered drugs (odds ratio [OR] 2.57 95% confidence interval [CI] 1.73-3.80), adverse drug events (OR 2.5; 95% CI 1.29-5.06), known drug side-effect (OR 1.85; 95% CI 1.06-3.22), high-risk drug-drug interactions (OR 3.22; 95% CI 1.07-9.69) and interventions involving changing a drug (OR 2.71; 95% CI 1.17-6.25). |
Does serine protease inhibitor aprotinin ameliorate renal injury in a rat model of ischemia-perfusion injury? | Renal ischemia-reperfusion (I/R) injury may occur after renal transplantation, thoracoabdominal aortic surgery, and renal artery interventions. To investigate the therapeutic effects of aprotinin on tissue protection against I/R injury in a rat model. N-acetylcysteine (NAC), a potent antioxidant, was also tested to assess the experimental model. Twenty-four rats were categorized into 3 groups of 8 rats each: those receiving isotonic sodium chloride solution (control group); NAC, 150 mg/kg; and aprotinin, 40,000 KIU/kg. The animals underwent unilateral nephrectomy after 60 minutes of warm ischemia and 60 minutes of reperfusion of the kidney. Malondialdehyde, a lipid peroxidation marker, and antioxidant glutathione levels were measured in the kidney parenchyma. Tissue samples were obtained for histologic analysis. Compared with the control group, the NAC group demonstrated significantly low levels of malondialdehyde (P = .04) and high levels of glutathione (P = .01). At histopathologic analysis, less acute tubular necrosis (ATN) and cellular swelling was noted in the NAC group (P = .002 and P = .005, respectively). In the aprotinin group, histopathologic analysis revealed less tissue damage in terms of ATN (P < .001, cellular swelling (P < .001), and vacuolysis (P = .002). Compared with the NAC group, ATN (P = .01), vacuolysis (P = .04), and congestion (P = .05) were significantly less in the aprotinin group. | Most human microbiota studies focus on bacteria inhabiting body surfaces, but these surfaces also are home to large populations of viruses. Many are bacteriophages, and their role in driving bacterial diversity is difficult to decipher without the use of in vitro ecosystems that can reproduce human microbial communities. We used chemostat culture systems known to harbor diverse fecal bacteria to decipher whether these cultures also are home to phage communities. We found that there are vast viral communities inhabiting these ecosystems, with estimated concentrations similar to those found in human feces. The viral communities are composed entirely of bacteriophages and likely contain both temperate and lytic phages based on their similarities to other known phages. We examined the cultured phage communities at five separate time points over 24 days and found that they were highly individual-specific, suggesting that much of the subject-specificity found in human viromes also is captured by this culture-based system. A high proportion of the community membership is conserved over time, but the cultured communities maintain more similarity with other intra-subject cultures than they do to human feces. In four of the five subjects, estimated viral diversity between fecal and cultured communities was highly similar. |
Does 5-year evaluation of electronic medical record flag alert for patients warranting secondary prevention of coronary heart disease? | To assess the effect of flag alerts that were placed in electronic medical records on patients' adherence with National Cholesterol Education Program (NCEP) guidelines for secondary prevention of coronary heart disease. A secondary objective was to identify the proportion of patients who were prescribed lipid-lowering agents and assess the barriers of patients who did not reach low-density lipoprotein cholesterol (LDL) goals 5.6 years after the intervention. Retrospective analysis of a prospective medical record intervention. University-based primary care clinic. Eighty-nine adult patients with atherosclerotic vascular disease. For each patient identified as needing secondary prevention for coronary heart disease according to NCEP guidelines, flags were inserted into the patient's electronic medical record. Baseline patient data were collected. After 5.6 years, we performed a retrospective analysis. At that time, 72 patients were evaluated; 17 were lost to follow-up. Fifty-four percent of patients (39 of 72 patients) had reached their LDL goal compared with 25% (16 of 64 patients for whom complete lipid panels had been obtained) at baseline (p=0.001). The proportion of patients prescribed lipid-lowering agents rose from 16% at baseline to 75% at follow-up (p=0.0001). However, 33 patients (46%) were above their LDL goal levels at follow-up. Reasons for failure to reach LDL goal were as follows: drug dosage not titrated (10 patients [30%]), adverse drug reaction (four patients [12%]), planned to adjust therapy in the future (three patients [9%]), high drug cost (two patients [6%]), drug contraindicated (two patients [6%]), and non-compliance (one patient [3%]). In 11 patients (33%), the reason for failure was not addressed in the progress notes. Thus, inadequate drug dosage titration (dosage not titrated, planned to adjust therapy, and reason not addressed [assume no action]) occurred in more than 70% of these patients. | Early acute kidney injury (AKI) following trauma is associated with multiorgan failure and mortality. Leukotrienes have been implicated both in AKI and in acute lung injury. Activated 5-lipoxygenase (5-LO) colocalizes with 5-LO-activating protein (FLAP) in the first step of leukotriene production following trauma and hemorrhagic shock (T/HS). Diversion of postshock mesenteric lymph, which is rich in the 5-LO substrate of arachidonate, attenuates lung injury and decreases 5-LO/FLAP associations in the lung after T/HS. We hypothesized that mesenteric lymph diversion (MLD) will also attenuate postshock 5-LO-mediated AKI. Rats underwent T/HS (laparotomy, hemorrhagic shock to a mean arterial pressure of 30 mm Hg for 45 minutes, and resuscitation), and MLD was accomplished via cannulation of the mesenteric duct. Extent of kidney injury was determined via histology score and verified by urinary neutrophil gelatinase-associated lipocalin assay. Kidney sections were immunostained for 5-LO and FLAP, and colocalization was determined by fluorescence resonance energy transfer signal intensity. The end leukotriene products of 5-LO were determined in urine. AKI was evident in the T/HS group by derangement in kidney tubule architecture and confirmed by neutrophil gelatinase-associated lipocalin assay, whereas MLD during T/HS preserved renal tubule morphology at a sham level. MLD during T/HS decreased the associations between 5-LO and FLAP demonstrated by fluorescence resonance energy transfer microscopy and decreased leukotriene production in urine. |
Does ethnomedical aspects of the commonly used toothbrush stick in Ethiopia? | To determine the botanical identity, cytotoxicity, and antibacterial property of the commonly used toothbrush sticks in Ethiopia. Research laboratories of the departments of Biology and Chemistry, Addis Ababa University between December 1993 and May 1995. The study was performed by purchasing the commonly used toothbrush sticks from street markets in various towns of Ethiopia. Voucher specimens were collected and their botanical identity was determined following floral keys. The toothbrush sticks were ground in a mill and soaked in absolute methanol for 24 hours and filtered. The filtrates were dried in a rotary evaporator and the crude extracts were stored at 4 degrees C. The crude methanol extracts were used to test their antibacterial activity by impregnating into filter paper discs and placing on test plates of Staphylococcus aureus and Bacillus cerues. Their lethality to brine shrimp (Artemia salina) was performed following standard procedures. Twenty different species of plant used as toothbrush were collected and their botanical identity determined. Crude methanol extracts of only Agave sisalana, Birbira and Hypericum revolutum test concentrations up to 500 micrograms/ml showed weak toxicity to brine shrimp. All the extracts showed antibacterial activity against Staphylococcus aureus and Bacillus cereus by agar diffusion method. | In animal models, maternal obesity (OB) leads to augmented risk of offspring OB. While placental function is influenced by maternal habitus, the effect of maternal obesity on the interacting zones of the placenta [the labyrinth (LZ), junctional (JZ) and metrial gland (MG)] remains unknown. Using a rat maternal obesity model, we conducted transcriptomic profiling of the utero-placental compartments and fetal liver (FL) at dpc 18.5, in conjunction with analyses of mRNA expression of key thyroid hormone (TH) signaling genes in the placenta, fetus and weanling offspring. |
Are lobar microbleeds associated with a decline in executive functioning in older adults? | Normal aging is associated with a decline in cognitive abilities, particularly in the domains of psychomotor speed and executive functioning. However, 'aging,' per se, is not a cause of cognitive decline but rather a variable that likely captures multiple accumulating biological changes over time that collectively affect mental abilities. Recent work has focused on the role of cerebrovascular disease as one of the biological changes. In the current study, we examined whether lobar microbleeds - magnetic resonance imaging (MRI) signal voids due to hemosiderin deposits secondary to cerebral amyloid angiopathy - are associated with cognitive decline in normal aging. Previous studies that reported a relationship between the presence of lobar microbleeds and decreased cognitive abilities have been primarily cross-sectional. Here, we used a retrospective longitudinal design to examine whether the presence of lobar microbleeds is associated with the rate of cognitive decline among non-demented older adults. Participants came from an ongoing longitudinal community-based aging study, in which subjects are evaluated at 18-24 months intervals and received a full medical, neurological, and neuropsychological examination at each of the follow-up visits. Gradient echo MRI scans were available on 197 non-demented participants (mean age: 84.15 ± 5.02 years). Microbleeds were rated visually on axial view and divided into subcortical (basal ganglia, cerebellum) and lobar (frontal, temporal, parietal, occipital lobe) regions, and confirmed with coronal and sagittal views to exclude artifacts. Cognition was assessed with a neuropsychological battery, providing summary scores for memory, language, executive, and visuospatial abilities. Using general estimating equations (GEE), we compared cognition cross-sectionally between individuals with 2 or more (n = 11) and fewer than 2 (n = 186) lobar microbleeds and examined longitudinal cognitive change beginning 9.47 ± 3.13 years before the MRI scan. Subjects with 2 or more lobar microbleeds had worse executive functioning at the visit closest to the MRI scan (β = -0.044; p < 0.001) and had a faster decline in executive function over time (β = -0.072; p = 0.012) than subjects with fewer than 2 lobar microbleeds. The two groups were similar in age at scan date, education, ethnicity, sex distribution, and cognitive performance at first visit. | Allergic asthma is an inflammatory lung disease caused by a T(H)2-driven immune response. However, intranasal exposures to soluble antigen lead to mucosal tolerance, and the mechanism involved in generation of T(H)2 responses to inert inhaled allergens is unknown. The aim of this study was to investigate whether CD1d-restricted natural killer T (NKT) cells can contribute to the induction of T(H)2-dependent allergic asthma in a mouse model. To investigate the effect of NKT cells on the development of asthma, NKT cell ligand, alpha-galactosylceramide (alphaGC), was used with antigens. We intranasally sensitized Balb/c mice with various combinations of antigen and alphaGC for 3 consecutive days and challenged them 2 weeks later with an aerosol of ovalbumin. NKT cell-deficient or T(H) cell-deficient mice were immunized by administering ovalbumin and alphaGC together, and ovalbumin inhalation. Only when immunized with ovalbumin plus alphaGC, airway hyperreactivity, airway eosinophils, elevated IgE level, and T(H)2-cytokine production were observed in Balb/c mice. Ovalbumin alone, alphaGC alone, or BSA plus alphaGC-immunized mice did not induce asthma. Studies in NKT cell-deficient, or CD4(+) T-cell-deficient mice intranasally exposed to ovalbumin plus alphaGC did not show the development of asthma. An increase of NKT cells in bronchoalveolar lavage was observed in the pathologic states. |
Does trazodone improve the results of cognitive behaviour therapy of primary insomnia in non-depressed patients? | Cognitive behaviour therapy (CBT) of primary insomnia is frequently combined with various pharmacological treatments, including sedative antidepressants. The present study was undertaken to evaluate the clinical efficacy of CBT, singly and combined with trazodone pharmacotherapy, for primary insomnia. Randomised, comparative clinical trial, at a single academic medical centre. Twenty outpatients (15 women, 5 men) with chronic primary insomnia were randomly assigned to CBT or CBT +100mg trazodone and treated for 8 weeks. The treatment outcome was estimated by mean changes from baseline in self-reported clinical scales, sleep continuity data and sleep architecture parameters. All patients perceived significant subjective sleep improvements. Sleep latency significantly shortened (p=0.03), sleep efficiency increased (p=0.004) and the total sleep time was significantly prolonged (p=0.006) after the CBT treatment in both groups. Sleep architecture showed that the combined approach (CBT + trazodone) resulted in a significant increase in slow wave sleep duration compared to treatment by CBT only (p=0.04). | This study was designed to analyze porcine plasma and peritoneal fluid for concentration differences of angiogenic molecular mediators and to determine local peritoneal sites of production of these molecules. The peritoneum is now recognized as a dynamic cellular membrane with important functions, including antigen presentation; transport and movement of fluid, solutes, and particulate matter across serosal cavities; and secretion of glycosaminoglycans, extracellular matrix proteins, proinflammatory cytokines, and growth factors. The mechanisms of the peritoneal response to injury and the factors that determine the outcome of the reactive or reparative processes of the peritoneum remain poorly defined. Domestic swine (n = 12) underwent percutaneous diagnostic peritoneal lavage to obtain preincision peritoneal fluid for biochemical analysis. Open biopsy samples of parietal peritoneum and omentum were obtained for immunochemical and molecular analysis. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) levels were quantitated by enzyme-linked immunosorbent assay, and nitrite/nitrate (NOx) measured by nonenzymatic assay. Sections of formalin-fixed tissue were stained for immunoreactivity to VEGF, bFGF, and nitric oxide synthase (NOS). Frozen homogenized peritoneum and omentum were prepared for isolation of protein and RNA. An endothelial growth assay was created using human umbilical vein endothelial cells cultured with peritoneal fluid with or without anti-VEGF or anti-bFGF antibodies. The mean plasma concentrations of VEGF, bFGF, and NOx were 20 +/- 5 pg/mL, 35 +/- 9 pg/mL, and 4.5 +/- 1.3 microm, compared with mean peritoneal fluid concentrations of 395 +/- 75 pg/mL, 486 +/- 72 pg/mL, and 35.0 +/- 8.8 mum respectively (P < 0.05 for each molecule). Immunochemistry demonstrated VEGF, bFGF, and NOS protein in mesothelium, submesothelium, and omentum. The use of Western blotting and reverse transcription polymerase chain reaction confirmed peritoneal and omental presence of VEGF and NOS-2. The use of endothelial bioassay documented peritoneal fluid angiogenic activity, which was inhibited by addition of neutralizing antibody to VEGF or bFGF. |
Do long-term efficacy of the Baerveldt 250 mm2 compared with the Baerveldt 350 mm2 implant? | To investigate the long-term surgical outcomes of the Baerveldt 250 mm2 versus Baerveldt 350 mm2 glaucoma drainage implants (GDIs) (Abbott Laboratories Inc., Abbott Park, IL) in the treatment of refractory glaucoma. Comparative case study. A total of 89 consecutive eyes in 86 patients treated at Dean McGee Eye Institute between January 2006 and December 2008. We retrospectively reviewed patient data from the following postoperative visits: 1 week, 1 month, 2 months, 3 months, 6 months, and every 3 months thereafter. Postoperative complications were also recorded. The mean follow-up time was 40 months (range, 2-78 months) for the Baerveldt 250 mm2 group and 31 months (range, 3-75 months) for the Baerveldt 350 mm2 group. The primary outcome measure was surgical success. Secondary outcome measures included visual acuity (VA), intraocular pressure (IOP), and number of medications. There was no difference in surgical success (P=0.98). No significant differences were observed in VA measured using the logarithm of the minimum angle of resolution (logMAR) scale, IOP, and number of medications at the last visit (P=0.09, 0.23, and 0.82, respectively). Complication and failure rates were comparable (P=0.82 and 0.64, respectively). | Transcriptome analysis may provide means to investigate the underlying genetic causes of shared and divergent phenotypes in different populations and help to identify potential targets of adaptive evolution. Applying RNA sequencing to whole male Drosophila melanogaster from the ancestral tropical African environment and a very recently colonized cold-temperate European environment at both standard laboratory conditions and following a cold shock, we seek to uncover the transcriptional basis of cold adaptation. In both the ancestral and the derived populations, the predominant characteristic of the cold shock response is the swift and massive upregulation of heat shock proteins and other chaperones. Although we find ~25 % of the genome to be differentially expressed following a cold shock, only relatively few genes (n = 16) are up- or down-regulated in a population-specific way. Intriguingly, 14 of these 16 genes show a greater degree of differential expression in the African population. Likewise, there is an excess of genes with particularly strong cold-induced changes in expression in Africa on a genome-wide scale. |
Does estradiol bound to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro? | Insulin (INS) resistance associated with hyperestrogenemias occurs in gestational diabetes mellitus, polycystic ovary syndrome, ovarian hyperstimulation syndrome, estrogen therapies, metabolic syndrome, and obesity. The mechanism by which INS and estrogen interact is unknown. We hypothesize that estrogen binds directly to INS and the insulin receptor (IR) producing INS resistance. To determine the binding constants of steroid hormones to INS, the IR, and INS-like peptides derived from the IR; and to investigate the effect of estrogens on the binding of INS to its receptor. Ultraviolet spectroscopy, capillary electrophoresis, and NMR demonstrated estrogen binding to INS and its receptor. Horse-radish peroxidase-linked INS was used in an ELISA-like procedure to measure the effect of estradiol on binding of INS to its receptor. Binding constants for estrogens to INS and the IR were determined by concentration-dependent spectral shifts. The effect of estradiol on INS binding to its receptor was determined by shifts in the INS binding curve. Estradiol bound to INS with a K d of 12 × 10(-9) M and to the IR with a K d of 24 × 10(-9) M, while other hormones had significantly less affinity. Twenty-two nanomolars of estradiol shifted the binding curve of INS to its receptor 0.8 log units to the right. | Patients suffering traumatic brain and chest wall injuries are often difficult to liberate from the ventilator yet best timing of tracheostomy remains ill-defined. While prior studies have addressed early versus late tracheostomy, they generally suffer from the use of historical controls, which cannot account for variations in management over time. Propensity scoring can be utilized to identify controls from the same patient population, minimizing impact of confounding variables. The purpose of this study was to determine outcomes associated with early versus late tracheostomy by application of propensity scoring. Patients requiring intubation within 48h and receiving tracheostomy from January 2010 to June 2012 were identified. Early tracheostomy (ET) was a tracheostomy performed by the fifth hospital day. ET patients were matched to late tracheostomy patients (LT, tracheostomy after day 5) using propensity scoring and compared for multiple outcomes. Cost for services was calculated using average daily billing rates at our institution. One hundred and six patients were included, 53 each in the ET (mean day tracheostomy=4) and the LT (mean day tracheostomy=10) cohorts. The average age was 47 years and 94% suffered blunt injury, with an average NISS of 23.7. Patients in the ET group had significantly shorter TICU LOS (21.4 days vs. 28.6 days, p<0.0001) and significantly fewer ventilator days (16.7 days vs. 21.9, p<0.0001) compared to the LT group. ET patients also had significantly less VAP (34% vs. 64.2%, p=0.0019). |
Is platelet vitamin D receptor reduced in osteoporotic patients? | It is well known that vitamin D plays an important role in maintaining bone homeostasis and in regulating calcium absorption. The active form of vitamin D interacts with its receptor the VDR that is expressed in multiple tissues and it is involved in platelets (PLTs) function. In the present study we evaluate PLTs' VDR expression in osteoporotic as opposed to healthy subjects. We enrolled in the study 77 women with postmenopausal osteoporosis, 33 healthy women of childbearing age, 49 healthy men, and 11 healthy women matched with patients for age and postmenopausal period. Thirty-nine patients had had one femoral fracture occurred after the age of fifty and attributable to primary osteoporosis. Bone mineral density, markers of bone metabolism and VDR levels were measured in all the subjects. Our data show that VDR level is lower in patients as respect to controls and is positively correlated with bone density, but not with markers of bone metabolism. We also found a decrease in the phosphorus levels in patients without differences in vitamin D levels and in the dietary calcium intake. | Neuromuscular blocking agents (NMBAs) bind the nicotinic acetylcholine receptor α1 (nAChRα1) that also contributes to inflammatory signaling. Thus, the author hypothesized that the use of NMBA mitigates lung injury by improving ventilator synchrony and decreasing inflammatory responses. Lung injury was induced by intratracheal instillation of hydrogen chloride in rats that were randomized to receive no NMBA with evidence of asynchronous ventilation (noNMBA/aSYNC, n = 10); no NMBA with synchronous ventilation (noNMBA/SYNC, n = 10); cisatracurium (CIS, n = 10); or pancuronium (PAN, n = 10). Mechanical ventilation was set at a tidal volume of 6 ml/kg and positive end-expiratory pressure 8 cm H2O for 3 h. Human lung epithelial, endothelial, and CD14⁺ cells were challenged with mechanical stretch, lipopolysaccharide, lung lavage fluids (bronchoalveolar lavage fluid), or plasma obtained from patients (n = 5) with acute respiratory distress syndrome, in the presence or absence of CIS or small-interfering RNA and small hairpin RNA to attenuate the cell expression of nAChRα1. The use of CIS and PAN improved respiratory compliance (7.2 ± 0.7 in noNMBA/aSYNC, 6.6 ± 0.5 in noNMBA/SYNC, 5.9 ± 0.3 in CIS, and 5.8 ± 0.4 cm H2O/l in PAN; P < 0.05), increased PaO2 (140 ± 54, 209 ± 46, 269 ± 31, and 269 ± 54 mmHg, respectively, P < 0.05), and decreased the plasma levels of tumor necrosis factor-α (509 ± 252 in noNMBA, 200 ± 74 in CIS, and 175 ± 84 pg/ml in PAN; P < 0.05) and interleukin-6 (5789 ± 79, 1608 ± 534, and 2290 ± 315 pg/ml, respectively; P < 0.05). The use of CIS and PAN or silencing the receptor nAChRα1 resulted in decreased cytokine release in the human cells in response to a variety of stimuli mentioned earlier. |
Is the incidence of parametrial tumor involvement in select patients with early cervix cancer too low to justify parametrectomy? | To determine the incidence of parametrial involvement in a select group of patients with early cervical cancer. We retrospectively reviewed the records of patients with cervical cancer and a maximum tumor diameter of 2 cm, infiltration depth<10 mm and negative pelvic lymph nodes who underwent a radical hysterectomy in two university hospitals. In addition, the literature was reviewed. 103 patients were identified in our databases that met the abovementioned criteria. In two of these patients (1.94%), parametrial involvement was found. Both patients had LVSI. Literature review revealed 696 patients described in three studies that satisfied the selection criteria. Three (0.43%) of these patients had parametrial involvement. In patients with early stage cervical carcinoma, tumor size<2 cm, infiltration depth<10 mm, negative pelvic lymph nodes and absent LVSI the risk of parametrial involvement is 0.63%. | Interleukin-8 (IL-8), a potent chemoattractant for neutrophils, has been implicated in the pathogenesis of Alzheimer's disease (AD). The ability of individuals to produce high levels of IL-8 is partially determined by the IL-8 -251 T/A polymorphism. Therefore, we investigated the association between this polymorphism and AD in a Chinese population. Additionally, in light of the stimulatory effect of homocysteine on the production of IL-8, we also sought to determine whether the methylenetetrahydrofolate reductase (MTHFR) gene 677 C/T variant, a genetic modifier of the serum homocysteine level, may interact with the IL-8 -251 polymorphism in determining the AD risk. Genotyping of 198 AD patients and 240 matched controls was performed by PCR-RFLP. The presence of the MTHFR 677 C/T and 677 T/T genotypes conferred a marginally significant increase in the risk for AD (OR = 1.666, 95% CI = 1.022-2.715, and OR = 1.892, 95% CI = 1.124-3.187) and the presence of the IL-8 -251 polymorphism was not associated with AD. However, the OR for AD associated with joint occurrence of the MTHFR 677 T/T and the IL-8 -251 A/A genotypes was 2.512 (95% CI = 1.151-5.483). |
Does inhibition of c-Jun NH2-terminal kinase or extracellular signal-regulated kinase improve lung injury? | Although in vitro studies have determined that the activation of mitogen-activated protein (MAP) kinases is crucial to the activation of transcription factors and regulation of the production of proinflammatory mediators, the roles of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in acute lung injury have not been elucidated. Saline or lipopolysaccharide (LPS, 6 mg/kg of body weight) was administered intratracheally with a 1-hour pretreatment with SP600125 (a JNK inhibitor; 30 mg/kg, IO), or PD98059 (an MEK/ERK inhibitor; 30 mg/kg, IO). Rats were sacrificed 4 hours after LPS treatment. SP600125 or PD98059 inhibited LPS-induced phosphorylation of JNK and ERK, total protein and LDH activity in BAL fluid, and neutrophil influx into the lungs. In addition, these MAP kinase inhibitors substantially reduced LPS-induced production of inflammatory mediators, such as CINC, MMP-9, and nitric oxide. Inhibition of JNK correlated with suppression of NF-kappaB activation through downregulation of phosphorylation and degradation of IkappaB-alpha, while ERK inhibition only slightly influenced the NF-kappaB pathway. | We investigated interindividual differences in the shape, slope and setpoint of the pituitary-thyroid axis (PTA) in normal persons. Based on these physiological data we propose a novel bivariate concept for the interpretation of thyroid function tests which is less biased by interindividual differences in the PTA than the currently used univariate approach. In two separate trials (A and B), healthy volunteers were given small, increasing doses of T3 (7.5-45 micrograms/day orally) over 5 days. The regulation characteristics of the individual PTAs and the effects of age and gender were assessed by general linear regression models. In addition, serum samples were collected from normal persons to establish the proposed bivariate approach for the interpretation of thyroid function tests. The regulatory characteristics of the PTA were determined in a total of 21 normal volunteers (eight females, 13 males; age 24-49 years). Single blood samples were collected from 257 normal volunteers. The participants had no history of pituitary or thyroid disease. Free and total thyroid hormone and TSH concentrations were determined in the serum. All samples from one person were analysed in the same assay in duplicate. A log-linear relationship between T3 and TSH was found to describe best the individual PTA (multiple r = 0.96). However, significant differences in the setpoint (P < 0.001) and to a lesser degree in the slope (P < or = 0.05) of the PTA were detected; this variability was not dependent on age or gender. Since these findings invalidate the assumptions on which the current univariate interpretation of thyroid function tests is based, we propose a novel model for the evaluation of thyroid function tests derived from the experimentally determined shape and average slope of the PTA. |
Do chronic rhinosinusitis patients with polyps or polypoid mucosa have a greater burden of illness? | Recent studies suggest chronic rhinosinusitis without nasal polyposis (CRSsNP) and CRS with nasal polyposis (CRScNP) represent distinct pathological entities. The aim of this study was to determine whether patients with CRSsNP, CRScNP, and polypoid CRS could be distinguished by clinical features, radiologic extent of disease or use of medications. New patients with CRS (n = 126) were enrolled in a prospective outcomes study. Rhinoscopic evaluation was used to classify patients. The relationship between disease phenotype and clinical parameters was examined. Facial pain/pressure/headache was more prevalent in CRSsNP than CRScNP (p = 0.01). Nasal obstruction and hyposmia/ anosmia were more prevalent in CRScNP than CRSsNP (p = 0.025 and 0.01, respectively). Intermediate symptom prevalence was found in polypoid CRS. Multivariate analysis confirmed that prior surgery, CT scan score, and male gender were independent predictors of polyp/polypoid phenotype. Allergic status was unrelated to CRS classification. Medication use was higher in CRScNP patients than in CRSsNP patients. | The crosstalk between skeletal muscle (SkM) and beta cells plays a role in diabetes aetiology. In this study, we have investigated whether SkM-released exosome-like vesicles (ELVs) can be taken up by pancreatic beta cells and can deliver functional cargoes. Mice were fed for 16 weeks with standard chow diet (SCD) or with standard diet enriched with 20% palmitate (HPD) and ELVs were purified from quadriceps muscle. Fluorescent ELVs from HPD or SCD quadriceps were injected i.v. or intramuscularly (i.m.) into mice to determine their biodistributions. Micro (mi)RNA quantification in ELVs was determined using quantitative real-time RT-PCR (qRT-PCR)-based TaqMan low-density arrays. Microarray analyses were performed to determine whether standard diet ELVs (SD-ELVs) and high palmitate diet ELVs (HPD-ELVs) induced specific transcriptional signatures in MIN6B1 cells. In vivo, muscle ELVs were taken up by pancreas, 24 h post-injection. In vitro, both SD-ELVs and HPD-ELVs transferred proteins and miRNAs to MIN6B1 cells and modulated gene expressions whereas only HPD-ELVs induced proliferation of MIN6B1 cells and isolated islets. Bioinformatic analyses suggested that transferred HPD-ELV miRNAs may participate in these effects. To validate this, we demonstrated that miR-16, which is overexpressed in HPD-ELVs, was transferred to MIN6B1 cells and regulated Ptch1, involved in pancreas development. In vivo, islets from HPD mice showed increased size and altered expression of genes involved in development, including Ptch1, suggesting that the effect of palm oil on islet size in vivo was reproduced in vitro by treating beta cells with HPD-ELVs. |
Do gold nanoparticles induce apoptosis in MCF-7 human breast cancer cells? | Gold nanoparticles have recently been investigated with respect to biocompatibility according to their interactions with cells. The purpose of this study was to examine cytotoxicity and apoptosis induction by well-characterized gold nanoparticles in human breast epithelial MCF-7 cells. Apoptosis was assessed by TUNEL, cytotoxicity by MTT assay and caspase 3, 9, p53, Bax and Bcl expression by real-time PCR assays. Gold nanoparticles at up to 200 μg/mL for 24 hours exerted concentration-dependent cytotoxicity and significant upregulation of mRNA expression of p53, bax, caspase-3 and caspase-9, whereas expression of anti- apoptotic bcl-2 was down-regulated. | The metabolic syndrome (MetS), characterized by central obesity, lipid and insulin dysregulation, and hypertension, is a precursor state for cardiovascular disease. The purpose of this analysis was to determine whether low serum sex hormone levels or clinical androgen deficiency (AD) predict the development of MetS. Data were obtained from the Massachusetts Male Aging Study, a population-based prospective cohort of 1709 men observed at three time points (T1, 1987-1989; T2, 1995-1997; T3, 2002-2004). MetS was defined using a modification of the ATP III guidelines. Clinical AD was defined using a combination of testosterone levels and clinical signs and symptoms. The association between MetS and sex hormone levels or clinical AD was assessed using relative risks (RR), and 95% confidence intervals (95% CI) were estimated using Poisson regression models. Analysis was conducted in 950 men without MetS at T1. Lower levels of total testosterone and SHBG were predictive of MetS, particularly among men with a body mass index (BMI) below 25 kg/m2 with adjusted RRs for a decrease in 1 sd of 1.41 (95% CI, 1.06-1.87) and 1.65 (95% CI, 1.12-2.42). Results were similar for the AD and MetS association, with RRs of 2.51 (95% CI, 1.12-5.65) among men with a BMI less than 25 compared with an RR of 1.22 (95% CI, 0.66-2.24) in men with a BMI of 25 or greater. |
Do motivational brochures increase the number of medicare-eligible persons with diabetes making therapeutic footwear claims? | This study tests the hypothesis that Medicare beneficiaries at high risk of foot complications who are mailed a motivational brochure describing the Medicare diabetes-related therapeutic footwear benefit will increase their therapeutic footwear-related Medicare claims. In this quasi-experimental study, a motivational brochure was mailed in the summer of 1997 to 5,872 Medicare beneficiaries in Washington, Alaska, and Idaho who were identified as being at high risk for foot-related claims on the basis of their prior Medicare claims history. Beneficiaries were identified through footwear claims made in these states-and also in three comparison states (Oregon, Montana, and Wyoming)-during the 18 months before and after the mailing. Linear regression was used to compare the number of persons making claims in the intervention states with the comparison states before, at the time of, and after the mailing. Before the intervention, the number of persons making claims was increasing in the non-intervention states and decreasing in the intervention states. During the first month after the intervention mailing, the number of persons making claims remained nearly the same in non-intervention states, but increased 13 persons per month in intervention states (95% CI 3.5-11 persons/month). After the intervention, the number of persons making claims continued to increase similarly in both intervention and non-intervention states. | Multidrug resistance (MDR) develops in nearly all patients with colon cancer. The reversal of MDR plays an important role in the success of colon cancer chemotherapy. One of the commonest mechanisms conferring MDR is the suppression of apoptosis in cancer cells. This study investigated the sensitivity of cryptotanshinone (CTS) and dihydrotanshinone (DTS), two lipophilic tanshinones from a traditional Chinese medicine Salvia miltiorrhiza, in apoptosis-resistant colon cancer cells. Cell viability was measured by MTT assay. Cell cycle distribution and apoptosis were determined by flow cytometry. Protein levels were analyzed by western blot analysis. The formation of acidic vesicular organelles was visualized by acridine orange staining. Experimental results showed that multidrug-resistant colon cancer cells SW620 Ad300 were sensitive to both CTS and DTS in terms of cell death, but with less induction of apoptosis when compared with the parental cells SW620, suggesting that other types of cell death such as autophagy could occur. Indeed, the two tanshinones induced more LC3B-II accumulation in SW620 Ad300 cells with increased autophagic flux. More importantly, cell viability was increased after autophagy inhibition, indicating that autophagy induced by the two tanshinones was pro-cell death. Besides, the cytotoxic actions of the two tanshinones were p53-independent, which could be useful in inhibiting the growth of apoptosis-resistant cancer cells with p53 defects. |
Is peroxynitrite-induced oxidation of plasma lipids enhanced in stable hemodialysis patients? | The relationship between end-stage renal disease (ESRD), hemodialysis, and oxidative stress is controversial. To determine whether ESRD causes oxidative stress, we measured basal levels of plasma F2-isoprostanes as a marker of lipid peroxidation in vivo, and peroxynitrite-stimulated formation of F2-isoprostanes, as a marker of the oxidizibility of plasma lipids in vitro, before and after routine hemodialysis. Total plasma F2-isoprostanes were measured by gas chromatography-mass spectrometry (GC-MS) before and after the oxidation of plasma lipids with the peroxynitrite-generating compound, 3-morpholino-sydnonimine (SIN-1), in 23 patients with ESRD patients undergoing regular hemodialysis, and 14 controls. Plasma vitamin E concentrations were measured by high-performance liquid chromatography (HPLC). There was no difference in basal plasma concentrations of F2-isoprostanes in the ESRD group prior to hemodialysis, 246 +/- 20 pg/mL, compared to controls, 252 +/- 28 pg/mL, or immediately on completion of hemodialysis, 236 +/- 14 pg/mL. Incubation of control plasma with SIN-1 caused the formation of F2-isoprostanes with plasma concentrations increasing to 987 +/- 54 pg/mL at 6 hours. The formation of F2-isoprostanes stimulated by SIN-1 was markedly enhanced in the plasma obtained from patients undergoing hemodialysis at 1861 +/- 174 pg/mL, P < 0.001, and SIN-1-induced formation of F2-isoprostanes was further increased in plasma obtained immediately after hemodialysis at 2437 +/- 168 pg/mL, P < 0.001. Incubation of plasma with SIN-1 resulted in the net consumption of vitamin E. | This article compares judgments about the treatment of Dukes' B2 and C colon cancer made by general surgeons to those of internists and family practitioners. Physician and practice variables were specialty, affiliation with a Community Clinical Oncology Program (CCOP) hospital, time in practice, professional centrality (level of participation in cancer information networks), solo practice, and number of colon cancer patients. Data are combined from national probability samples of CCOP- and non-CCOP-affiliated physicians. This study focused on 1,138 internists, family physicians, and general surgeons who participated in decision making for patients diagnosed with Dukes' B2 or C stage colon cancer. Judgments were elicited using brief vignettes. Judgments of adjuvant therapy are classified as (a) consistent with the National Institutes of Health Consensus Conference recommendations (experimental for Dukes' B2, accepted for Dukes' C); (b) accepted treatment for both stages; or (c) experimental for both stages. Multinomial logit analyses were used to examine the association of practice setting and physician characteristics to judgments of treatment. Surgeons and CCOP-affiliated physicians were more likely to endorse the NIH consensus conference position. Surgeons, younger physicians, and those in group practice were more likely to approve of chemotherapy for both cancer stages. The most common position (chemotherapy experimental) was more likely from nonsurgeons, solo practitioners, and non-CCOP physicians. |
Does duration of well-controlled core temperature correlate with neurological outcome in patients with post-cardiac arrest syndrome? | Detailed procedures for optimal therapeutic hypothermia (TH) have yet to be established. We examined how duration of well-controlled core temperature within the first 24 hours after cardiac arrests (CA) correlated with neurological outcomes of successfully resuscitated out-of-hospital CA (OHCA) patients. OHCA patients who survived over 24 hours and treated with TH were included. Core temperature was measured every hour. Physicians intended to maintain temperature at 33 °C ± 1 °C for 24 hours. Cerebral performance categories (CPC) of patients at 6 months were recorded and patients were retrospectively divided into favorable (CPC1,2) and poor (CPC3-5) neurological outcome groups. Total time while the core temperature reached to 33 °C ± 1 °C within the first 24 hours after CA was measured and this duration was defined that of well-controlled temperature. receiver-operating characteristic analysis was performed on duration of well-controlled temperature to select the optimal cutoff value. Neurological outcome predictors were investigated by logistic regression analysis. Fifty-six patients were included. Optimal cutoff value of duration of well-controlled temperature was 18 hours. Ratio of male sex, witnessed by emergency medical service (EMS) personnel, first electrocardiogram as shockable, and duration of well-controlled core temperature ≥ 18 h of favorable neurological outcome group (n = 21) were significantly larger than that of poor neurological outcome group (n = 35). Logistic regression analysis identified "witnessed by EMS", "performed bystander CPR," and "the duration ≥ 18 h" as independent predictors of favorable neurological outcome. | Cancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colonic fibroblasts. Cell cycle analysis and cell proliferation assays were performed to evaluate the inhibitory effect of sunitinib in vitro. Western-blot analysis was performed to evaluate variations in the levels of phosphorylated platelet-derived growth factor receptor β (PDGFR-β), Akt, and ERK proteins. Co-injection of SW620 cells and colonic fibroblasts in nude mice was employed to test anti-growth efficacy in vivo. Sunitinib was found to effectively inhibit the growth of primary colonic fibroblasts. Low-dose sunitinib blocked the PDGF-BB-induced cell proliferation and PDGFR-β signaling. Co-injection of SW620 cells and colonic fibroblasts in nude mice generated greater tumor volumes than single injection of SW620 cells. Sunitinib treatment inhibited the SW620 cell+colonic fibroblast tumor growth more effectively than treatment of 5-fluorouracil. |
Is prevention of arterial stiffening by using low-dose atorvastatin in diabetes associated with decreased malondialdehyde? | Without affecting the lipid profile, a low-dose treatment with atorvastatin contributes to the reduction of oxidative stress, inflammation, and adverse cardiovascular events in diabetes. In this study, we investigated whether low-dose atorvastatin exerts any beneficial effect on vascular dynamics in streptozotocin (STZ)-induced diabetes in male Wistar rats. Diabetes was induced using a single tail-vein injection of STZ at 55 mg kg-1. The diabetic rats were treated daily with atorvastatin (10 mg kg-1 by oral gavage) for 6 weeks. They were also compared with untreated age-matched diabetic controls. Arterial wave reflection was derived using the impulse response function of the filtered aortic input impedance spectra. A thiobarbituric acid reactive substances measurement was used to estimate the malondialdehyde content. The high plasma level of total cholesterol in the diabetic rats did not change in response to this low-dose treatment with atorvastatin. Atorvastatin resulted in a significant increase of 15.4% in wave transit time and a decrease of 33.5% in wave reflection factor, suggesting that atorvastatin may attenuate the diabetes-induced deterioration in systolic loads imposed on the heart. This was in parallel with its lowering of malondialdehyde content in plasma and aortic walls in diabetes. Atorvastatin therapy also prevented the diabetes-related cardiac hypertrophy, as evidenced by the diminished ratio of left ventricular weight to body weight. | Lymph node size as a prognostic parameter has not been investigated well in the past. Recent data, however, have indicated that this parameter could be even more important than the lymph node count. Based on the results of earlier studies, we analyzed the lymph node size and number of node-negative colon cancer patients with regard to survival. Data from 115 node-negative cases of colon cancer were analyzed. Lymph nodes with diameters ≤5 mm were defined as small, and all other lymph nodes were classified as intermediate/large in size and labeled LN5. All of the cases were categorized according to the number of LN5s. The LN5 very low (LN5vl) group included cases with less than two LN5s. All of the other cases were assigned to the LN5 low/high (LN5l/h) group. The overall survival analysis revealed significantly worse outcomes for the LN5vl group, with a mean survival of 34 months compared to the LN5l/h group, with a mean survival of 40 months (P = 0.022). After adjusting for the pT1/2 and pT3/4 stages, we still found a significant outcome difference (P = 0.012). Multivariate analysis identified LN5vl and T-stage as being independently correlated with the outcome. The vast majority of LN5vl cases (91 %) were located in the left colon. The location itself, however, was not prognostic (P = 0.478). |
Is a common variant in RAB27A gene associated with fractional exhaled nitric oxide levels in adults? | Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium. We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 × 10(-7) ) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10(-7) ) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values. | To reduce the risk of postoperative spinal instability or deformity, unilateral laminectomy (UL) has been recommended to remove spinal space-occupying lesions. The purpose of this study was to determine whether there were any advantages of UL for removal of spinal cord tumors. From May 1995 to May 2010, 94 patients with spinal cord tumors, who underwent tumor removal via UL in our institute, were enrolled in this study. Intramedullary spinal cord tumors were excluded. Simple radiographs were obtained for accessing the restoration of the spinal column. Spinal magnetic resonance imaging (MRI) was also obtained during the follow-up period to evaluate tumor recurrence. There were 51 women and 43 men; their mean age was 47.8 years (range, 9-83 years). The mean follow-up period was 52.6 months (range, 24 month-16 years). The sites of the tumors were cervical in 21 cases, thoracic in 37, lumbar in 33, and sacral in 3. These cases included 85 intradural extramedullary (IDEM) and 9 extradural (ED) lesions. IDEM tumors consisted mainly of neurilemmomas (56.3%) and meningiomas (22.3%).Tumors were totally removed in 80 cases and subtotally removed in 14 cases. Postoperative neurological status was improved in 53 cases, unchanged in 31 cases, and worsened in 10 cases. During follow-up, MRI showed tumor recurrence in 4 patients. Histopathologically, three cases were meningiomas and one case was neurilemmoma. None of the patients showed spinal instability or kyphotic deformity at last follow-up. |
Does synthetic inhibitor of matrix metalloproteinases ( batimastat ) reduce prostate cancer growth in an orthotopic rat model? | Increased concentrations of metalloproteinases are associated with the invasive and metastatic behavior of several human malignant tumors. Normally, enzymatic activity is tightly regulated by nonspecific mechanisms and specific inhibitors. The aim of the study was to determine the potential of a synthetic metalloproteinase inhibitor, batimastat, to show its in vitro effect on MatLyLu cancer cells and its in vivo effect on tumor growth in orthotopic cancer (R3327 Dunning tumor) in rats. In vitro, a dose response curve of batimastat was generated over 4 days using the MTT assay. Prostate cancer was injected in vivo in male Copenhagen rats by inoculating R3327 Dunning tumor cells (MatLyLu) into the ventral prostatic lobe of 30 rats. Each of 10 rats received batimastat (30 mg/kg body weight) or vehicle administered once a day by i.p. application beginning the day of cell inoculation. Ten rats remained untreated. The effect on local tumor growth was evaluated by measuring tumor weights 20 days after tumor cell inoculation. Significant inhibition of tumor cell proliferation in vitro occurred at 400 and 4,000 ng/ml batimastat. After orthotopic cell inoculation, tumors grew to mean weights of 18.9 g in the control group without treatment, to 22.3 g in the vehicle group, and to 11.1 g in the treated group. In comparison to the control group and to the vehicle group, tumor weights increased significantly less under treatment with batimastat. | To estimate the prevalence of asthma, allergic rhinitis, and atopic dermatitis among school children in the region of Primorsko-goranska County in Croatia, and compare the results with data from other countries. The study was conducted during the 2001-2002 school year, in complete adherence to the Phase One protocol of the International Study of Asthma and Allergies in Childhood (ISAAC). The target population comprised two age groups (6-7 and 13-14 years) in the region of Primorsko-Goranska County in Croatia. Data were collected using standardized ISAAC written questionnaire and asthma video questionnaire. There were 1,634 participating children in the 6-7 age group (response rate 80.3%) and 2,194 participating children in the 13-14 age group (response rate 89.8%). Estimated 12-month prevalence rates of symptoms were: wheezing 9.7% and 8.4%, allergic rhinitis symptoms 16.9% and 17.5%, allergic rhinoconjunctivitis symptoms 5.6% and 6.7%, and atopic dermatitis symptoms 5.4% and 3.4%, for younger and older age group, respectively. |
Does next-generation sequencing survey of biliary tract cancer reveal the association between tumor somatic variants and chemotherapy resistance? | Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum-based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. | Adolescents in Vietnam have a low level of sexual activity, but this may increase with urbanisation and economic development. The aim of this analysis is to understand trends in correlates of permissive attitudes towards premarital sex among Vietnamese adolescents using an ecological framework. Data from the Survey Assessment of Vietnamese Youth from 2003 (n = 7584) and 2009 (n = 10,044) were analysed using multivariable logistic regressions to examine associations between permissive attitudes towards premarital sex and demographic and contextual factors among adolescents aged 14 to 25. Correlates of having permissive attitudes towards premarital sex in both 2003 and 2009 included being male, older age, living in an urban area, living in the North, having ever used the Internet and perceiving that people in the community were having premarital sex. Variables that were significant in 2009 but not in 2003 included socio-economic status and belonging to an ethnic minority. Statistically significant changes in associations between 2003 and 2009 were observed for age, socio-economic status and belonging to an ethnic minority. |
Do contributions of gut bacteria to Bacillus thuringiensis-induced mortality vary across a range of Lepidoptera? | Gut microbiota contribute to the health of their hosts, and alterations in the composition of this microbiota can lead to disease. Previously, we demonstrated that indigenous gut bacteria were required for the insecticidal toxin of Bacillus thuringiensis to kill the gypsy moth, Lymantria dispar. B. thuringiensis and its associated insecticidal toxins are commonly used for the control of lepidopteran pests. A variety of factors associated with the insect host, B. thuringiensis strain, and environment affect the wide range of susceptibilities among Lepidoptera, but the interaction of gut bacteria with these factors is not understood. To assess the contribution of gut bacteria to B. thuringiensis susceptibility across a range of Lepidoptera we examined larval mortality of six species in the presence and absence of their indigenous gut bacteria. We then assessed the effect of feeding an enteric bacterium isolated from L. dispar on larval mortality following ingestion of B. thuringiensis toxin. Oral administration of antibiotics reduced larval mortality due to B. thuringiensis in five of six species tested. These included Vanessa cardui (L.), Manduca sexta (L.), Pieris rapae (L.) and Heliothis virescens (F.) treated with a formulation composed of B. thuringiensis cells and toxins (DiPel), and Lymantria dispar (L.) treated with a cell-free formulation of B. thuringiensis toxin (MVPII). Antibiotics eliminated populations of gut bacteria below detectable levels in each of the insects, with the exception of H. virescens, which did not have detectable gut bacteria prior to treatment. Oral administration of the Gram-negative Enterobacter sp. NAB3, an indigenous gut resident of L. dispar, restored larval mortality in all four of the species in which antibiotics both reduced susceptibility to B. thuringiensis and eliminated gut bacteria, but not in H. virescens. In contrast, ingestion of B. thuringiensis toxin (MVPII) following antibiotic treatment significantly increased mortality of Pectinophora gossypiella (Saunders), which was also the only species with detectable gut bacteria that lacked a Gram-negative component. Further, mortality of P. gossypiella larvae reared on diet amended with B. thuringiensis toxin and Enterobacter sp. NAB3 was generally faster than with B. thuringiensis toxin alone. | A large proportion of interstitial fibroblasts actually originate from tubular epithelial cells via the epithelial-to-mesenchymal transition (EMT) in renal fibrogenesis. Transforming growth factor-beta1 (TGF-beta1) is capable of initiating and completing the entire EMT course. Bone morphogenetic protein-7 (BMP-7) is a member of the TGF-beta superfamily. Recent studies indicate that BMP-7 could reverse established renal fibrosis in mice, primarily through counteracting TGF-beta1-mediated EMT. Therefore, we tested the hypothesis that BMP-7 functions by antagonizing profibrogenic events that are induced by TGF-beta1 in cultured human renal proximal tubular epithelial (HK-2) cells. Cultured HK-2 cells were treated with TGF-beta1 (3 ng/mL) or a combination of TGF-beta1 and BMP-7 (100-400 ng/mL) for 48 hours. Morphological changes were assessed by phase contrast microscopy. The expression of alpha-smooth muscle actin (alpha-SMA), E-cadherin, fibronectin, collagen I and connective tissue growth factor (CTGF) was analyzed by immunofluorescence, reverse transcriptase polymerase chain reaction and Western blotting. Incubation of HK-2 cells with 3 ng/mL TGF-beta1 for 48 hours induced EMT, in association with decreased E-cadherin expression, increased alpha-SMA, fibronectin, collagen I and CTGF expression, and loss of epithelial morphology. BMP-7 inhibited all these effects in a dose-dependent manner. In addition, 200 ng/mL BMP-7 reversed TGF-beta1-induced EMT, in association with reexpression of endogenous E-cadherin. |
Are copper surfaces associated with significantly lower concentrations of bacteria on selected surfaces within a pediatric intensive care unit? | Health care-associated infections result in significant patient morbidity and mortality. Although cleaning can remove pathogens present on hospital surfaces, those surfaces may be inadequately cleaned or recontaminated within minutes. Because of copper's inherent and continuous antimicrobial properties, copper surfaces offer a solution to complement cleaning. The objective of this study was to quantitatively assess the bacterial microbial burden coincident with an assessment of the ability of antimicrobial copper to limit the microbial burden associated with 3 surfaces in a pediatric intensive care unit. A pragmatic trial was conducted enrolling 1,012 patients from 2 high acuity care units within a 249-bed tertiary care pediatric hospital over 12 months. The microbial burden was determined from 3 frequently encountered surfaces, regardless of room occupancy, twice monthly, from 16 rooms, 8 outfitted normally and 8 outfitted with antimicrobial copper. Copper surfaces were found to be equivalently antimicrobial in pediatric settings to activities reported for adult medical intensive care units. The log10 reduction to the microbial burden from antimicrobial copper surfaced bed rails was 1.996 (99%). Surprisingly, introduction of copper objects to 8 study rooms was found to suppress the microbial burden recovered from objects assessed in control rooms by log10 of 1.863 (73%). | Tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical results in medullary thyroid carcinoma (MTC) patients. However, the considerable variability in patient response to treatment with TKIs remains largely unexplained. There is evidence that it could be due, at least in part, to alterations in genes associated with the disease via their effect on the expression of TKI targets. The objective of this study was to evaluate the influence of RAS mutations on the expression levels in MTC tumors of eight key TKI target proteins. We assessed by immunohistochemistry the expression of EGFR, KIT, MET, PDGFRB, VEGF, VEGFR1, VEGFR2, and VEGFR3 in a series of 84 primary MTC tumors that had previously been molecularly characterized, including 14 RAS-positive, 18 RET(M918T)-positive, and 24 RET(C634)-positive tumors, as well as 15 wild-type tumors with no mutations in the RET or RAS genes. In contrast to RET-positive tumors, RAS-positive tumors expressed neither PDGFRB nor MET (p=0.0060 and 0.047, respectively). Similarly, fewer RAS-positive than RET-related tumors expressed VEGFR3 (p=0.00062). Finally, wild-type tumors expressed VEGF more often than both RAS- and RET-positive tumors (p=0.0082 and 0.011, respectively). |
Does upregulation of ID2 antagonize arsenic trioxide-induced antitumor effects in cancer cells? | Arsenic trioxide (ATO) strongly induces apoptosis and differentiation in acute promyelocytic leukemia, and induces cell cycle arrest in most solid tumors. Although many signaling pathways are involved in its antitumor mechanism, a detailed investigation of the transforming growth factor beta-bone morphogenetic protein signaling pathway has not been performed. A microarray containing 113 genes associated with the pathway was used to screen important molecules that participate in the antitumor effects of ATO. The expression levels of the inhibitors of DNA binding-2 (ID2) in 4 different types of cancer cells were determined by quantitative reverse transcription PCR and Western blotting. Human esophageal squamous cell carcinoma cell line Eca109 and pancreatic carcinoma cell line BxPC3 cells were transfected with siRNAs targeting ID2 and scrambled control siRNA. Cell proliferation was evaluated by methyl thiazolyl tetrazolium assay. Eighteen upregulated and 12 downregulated genes were identified. After verification at the transcriptional and translational levels in 4 different cancer cells, ID2 was identified as an ATO antitumor-associated protein. In addition, specific silencing of ID2 could enhance ATO-induced cell proliferation inhibition in cancer cells. | Asymmetric patterns of frontal brain activity and brain corticotropin-releasing hormone (CRH) systems have both been separately implicated in the processing of normal and abnormal emotional responses. Previous studies in rhesus monkeys demonstrated that individuals with extreme right frontal asymmetric brain electrical activity have high levels of trait-like fearful behavior and increased plasma cortisol concentrations. In this study we assessed cerebrospinal fluid (CSF) CRH concentrations in monkeys with extreme left and extreme right frontal brain electrical activity. CSF was repeatedly collected at 4, 8, 14, 40, and 52 months of age. Monkeys with extreme right frontal brain activity had increased CSF CRH concentrations at all ages measured. In addition, individual differences in CSF CRH concentrations were stable from 4 to 52 months of age. |
Does patient-prosthesis mismatch in patients undergoing bioprosthetic aortic valve implantation increase risk of reoperation for structural valve deterioration? | Patient-prosthesis mismatch has been identified as a risk factor for mortality after aortic valve replacement and for structural valve deterioration (SVD) in patients receiving a bioprosthetic aortic valve. The aim of the present study was to compare the incidence of aortic valve bioprosthesis replacement for SVD in patients with mismatch to a population without mismatch. Three hundred eighty-seven adult patients who underwent aortic valve replacement with a bioprosthesis from 1974 to 2009 were retrospectively reviewed. Mismatch was considered to be present if the anticipated indexed effective orifice area was <0.70 cm(2) /m(2) . The median follow-up period was 7.2 years. Follow-up was 97% complete. Patient-prosthesis mismatch was present in 12% of the study population (n = 47). Ten-year freedom from reoperation for aortic bioprosthesis replacement was 74.3 ± 3.2%. During follow-up, 111 patients underwent reoperation for aortic bioprosthesis replacement. Causes of aortic bioprosthesis replacement were SVD of the bioprosthesis (n = 96), paravalvular leak (n = 10), and acute endocarditis (n = 5). According to unadjusted Kaplan-Meier analysis, patients with mismatch had a higher incidence of aortic bioprosthesis replacement for SVD when compared with patients without mismatch (log rank test: p 0.05). This result was confirmed by multivariable Cox regression analysis, which identified two independent predictors of aortic bioprosthesis replacement for SVD: patients' age (hazard ratio (HR) 0.967) and patient-prosthesis mismatch (HR 2.161). | Tuberculosis has a staggering influence on world health, resulting in nearly 2 million deaths per year. The influence of glucocorticoids during Mycobacterium tuberculosis infection has been under investigation for decades; however, the identity of mycobacterial factors and the mechanism by which glucocorticoids are tissue specifically regulated to influence immune function during acute granuloma formation are unknown. One factor implicated in initiating immunopathology during M. tuberculosis infection is trehalose-6,6'-dimycolate (TDM), a glycolipid component of the mycobacterial cell wall. Intravenous administration of TDM causes inflammatory responses in lungs of mice similar to M. tuberculosis infection and has been used as a successful model to examine proinflammatory regulation and early events involved in the manifestation of pathology. |
Does novel cryoprotectant significantly improve the post-thaw recovery and quality of HSC from CB? | Hematopoietic stem cells (HSC) have traditionally been frozen using the cryoprotectant DMSO in dextran-40, saline or albumin. However, the process of freezing and thawing results in loss of HSC numbers and/or function. This study investigated the use of CryoStor for the freezing of HSC from cord blood (CB). CB donations (n = 30) were collected under an Institutional Ethics Committee-approved protocol, volume reduced and frozen using three different methods of cryoprotection. Aliquots were frozen with either 10% DMSO in dextran-40, 10% DMSO in CryoStor or 5% DMSO in CryoStor. Prior to freezing samples were separated for nucleated cell (NC) and CD34+ counts and assessment of CD34+ viability. Aliquots were frozen and kept in vapor phase nitrogen for a minimum of 72 h. Vials were rapidly thawed at 37 degrees C and tested for NC and CD34+ counts and CD34+ viability and colony-forming unit (CFU) assay. Cells frozen with CryoStor in 10% DMSO had significantly improved NC (P < 0.001), CD34+ recovery, viable CD34+ (P < 0.001) and CFU numbers (P < 0.001) compared with dextran in 10% DMSO. CryoStor in 5% DMSO resulted in significantly improved NC (P < 0.001) and CFU (P < 0.001). | Gastrokine-1 is a novel protein that plays an important role in the maintenance of the integrity of the gastric mucosa. However, whether Helicobacter pylori infection and non-steroidal anti-inflammatory drugs, which are known to cause gastric mucosal injuries, affect gastrokine-1 expression in the gastric mucosa is unknown. The aim of the present study was to determine gastric mucosal expression of gastrokine-1 in patients with Helicobacter pylori infection or long-term non-steroidal anti-inflammatory drug administration. A total of 40 patients with functional dyspepsia (20 with Helicobacter pylori-negative chronic gastritis, and 20 with Helicobacter pylori-positive chronic gastritis), and 37 Helicobacter pylori-negative long-term non-steroidal anti-inflammatory drug users (26 with aspirin, 11 with selective cyclooxygenase-2 inhibitors) were selected. In addition, 20 Helicobacter pylori-negative healthy volunteers were recruited as controls. All subjects underwent endoscopies with biopsies taken from the antrum and the sites with lesions. Gastric mucosal changes were detected endoscopically and histologically, and gastrokine-1 protein expression in the antral mucosa was analyzed by immunohistochemistry. Expression of gastrokine-1 protein was decreased in Helicobacter pylori-positive chronic gastritis compared with Helicobacter pylori-negative subjects and the healthy controls. Similarly, gastrokine-1 expression in non-steroidal anti-inflammatory drug users was also decreased, compared with the healthy controls, but there was no significant difference in gastrokine-1 expression between the aspirin group and selective cyclooxygenase-2 inhibitor group. Moreover, gastrokine-1 expression levels tended to be associated with the severity of chronic gastritis. |
Do advanced glycation end products increase expression of S100A8 and A9 via RAGE-MAPK in rat dental pulp cells? | Advanced glycation end products (AGE) are involved in the progression of diabetic complications. Although our previous reports show that AGE increased dental pulp calcification, AGE accumulation is also associated with inflammation. This study examined AGE effect on the expression of inflammation factors using rat dental pulp tissues and cell cultures. Receptor for AGE (RAGE), S100A8, S100A9, and interleukin (IL)-1β were selected as inflammation parameters. Rat dental pulp cells were cultured and treated with AGE, and the effects were determined by real-time PCR. An anti-RAGE antibody or MAPK pathway inhibitors (PD98059, SB203580, and SP60012) were used to investigate AGE signaling pathway. The mRNA levels of RAGE, S100A8, S100A9, and IL-1β were higher in diabetic pulp tissues. AGE increased mRNA expressions of S100A8, S100A9, and IL-1β in cultured dental pulp cells. In the presence of anti-RAGE antibody, AGE did not increase in S100A8 or S100A9 expressions. The AGE-induced increases in S100A8 and S100A9 were inhibited by PD98059 and SB203580, respectively. | Development of an improved MR sequence for examining the lung. T2 weighted ultra-short turbo spin echo sequences were used in five individuals with variations in echo times, delayed triggering and echo intervals. To reduce movement artifacts all examinations were carried out with ECG and respiratory triggering. The sequences giving optimal image quality were then employed in 19 patients having various pulmonary abnormalities. Image resolutions, artifacts, image contrasts and diagnostic value were then judged by two observers and compared with CT. In the first study, a diastole-triggered UTSE sequence with the shortest echo proved optimal (TE = 90 ms, TR = 2-4 s, echo = 9 ms, turbo factor = 19). In the patient series studied, MRT was inferior to CT with regard to resolution and number of artifacts, but better in respect of contrast and diagnostic value. |
Are measurement errors in polymerase chain reaction a confounding factor for a correct interpretation of 5-HTTLPR polymorphism effects on lifelong premature ejaculation : a critical analysis of a previously published meta-analysis of six studies? | To analyze a recently published meta-analysis of six studies on 5-HTTLPR polymorphism and lifelong premature ejaculation (PE). Calculation of fraction observed and expected genotype frequencies and Hardy Weinberg equilibrium (HWE) of cases and controls. LL,SL and SS genotype frequencies of patients were subtracted from genotype frequencies of an ideal population (LL25%, SL50%, SS25%, p = 1 for HWE). Analysis of PCRs of six studies and re-analysis of the analysis and Odds ratios (ORs) reported in the recently published meta-analysis. Three studies deviated from HWE in patients and one study deviated from HWE in controls. In three studies in-HWE the mean deviation of genotype frequencies from a theoretical population not-deviating from HWE was small: LL(1.7%), SL(-2.3%), SS(0.6%). In three studies not-in-HWE the mean deviation of genotype frequencies was high: LL(-3.3%), SL(-18.5%) and SS(21.8%) with very low percentage SL genotype concurrent with very high percentage SS genotype. The most serious PCR deviations were reported in the three not-in-HWE studies. The three in-HWE studies had normal OR. In contrast, the three not-in-HWE studies had a low OR. | Expression of osteopontin correlates with tumor progression and metastasis. The mechanisms by which osteopontin promotes tumor cell survival remain unclear. Here we used short-hairpin RNA-mediated gene silencing to investigate the antitumor effects by osteopontin depletion in hepatocellular carcinoma (HCC). We applied polyethylenimine nanoparticles to deliver a short-hairpin RNA for depletion of osteopontin expression in HCC cells. Tumorigenicity and metastatic potentials of HCC cells were studied in vitro and in nude mice. Nuclear factor-kappaB (NF-kappaB) activation was analyzed by gel shift assay and luciferase analysis. The expressions of integrins were examined by real-time reverse-transcription polymerase chain reaction. Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay and mitochondrial membrane potential analysis. Down-regulation of osteopontin inhibited HCC cell growth, anchorage-independent growth, adhesion with fibronectin and invasion through extracellular matrix in vitro, and suppressed tumorigenicity and lung metastasis in nude mice. Osteopontin silencing resulted in suppression of alphav, beta1, and beta3 integrin expressions, blockade of NF-kappaB activation, inhibition of Bcl-2/Bcl-xL and XIAP expressions, increase of Bax expression, and induction of a mitochondria-mediated apoptosis. Furthermore, down-regulation of osteopontin inhibited drug-induced NF-kappaB activation and sensitized HCC cells to chemotherapeutic agents in vitro, which led to complete regression of HCC xenografts in nude mice. |
Does the laryngeal mask airway prevent supraglottic leak during ventilation through an uncuffed cricothyroidotomy? | A 'cannot intubate-cannot ventilate' situation requires emergency insertion of an infraglottic surgical airway. We present a case of postoperative macroglossia requiring emergency insertion of an uncuffed percutaneous cricothyroidotomy tube. The supraglottic leak was eliminated by the insertion of a laryngeal mask airway with an occluded 15-mm connector. A 49-yr-old man underwent clipping of a left posterior inferior cerebellar artery aneurysm and his tracheal tube was removed postoperatively. Two hours later, he became dyspneic and developed significant macroglossia. After application of topical anesthesia, direct laryngoscopy, oral fibreoptic bronchoscopy and laryngeal mask insertion were unsuccessful. The patient became progressively hypoxemic, pulseless electrical activity ensued, and cardiopulmonary resuscitation was initiated. An uncuffed percutaneous cricothyroidotomy tube was inserted. Oxygenation and hemodynamics were restored. As the cricothyroidotomy tube was uncuffed, there was a large supraglottic leak with manual ventilation. A laryngeal mask airway was inserted and the cuff was inflated. The 15-mm connector was occluded by a piece of tape. Subsequently, there was no further supraglottic leak with manual ventilation. He was taken to operating room and a surgical tracheotomy was performed. | Aging and chronic alcohol consumption are both modifiers of DNA methylation, but it is not yet known whether chronic alcohol consumption also alters DNA hydroxymethylation, a newly discovered epigenetic mark produced by oxidation of methylcytosine. Furthermore, it has not been tested whether aging and alcohol interact to modify this epigenetic phenomenon, thereby having an independent effect on gene expression. Old (18 months) and young (4 months) male C57BL/6 mice were pair-fed either a Lieber-DeCarli liquid diet with alcohol (18% of energy) or an isocaloric Lieber-DeCarli control diet for 5 weeks. Global DNA hydroxymethylation and DNA methylation were analyzed from hepatic DNA using a new liquid chromatography-tandem mass spectrometry method. Hepatic mRNA expression of the Tet enzymes were measured via quantitative real-time polymerase chain reaction. In young mice, mild chronic alcohol exposure significantly reduced global DNA hydroxymethylation compared with control mice (0.22 ± 0.01 vs. 0.29 ± 0.06%, p = 0.004). Alcohol did not significantly alter hydroxymethylcytosine levels in old mice. Old mice fed the control diet showed decreased global DNA hydroxymethylation compared with young mice fed the control diet (0.24 ± 0.02 vs. 0.29 ± 0.06%, p = 0.04). This model suggests an interaction between aging and alcohol in determining DNA hydroxymethylation (pinteraction = 0.009). Expression of Tet2 and Tet3 was decreased in the old mice relative to the young (p < 0.005). |
Is sTAT3 Overactivated in Gastric Cancer Stem-Like Cells? | Gastric cancer (GC) is widely associated with chronic inflammation. The pro inflammatory microenvironment provides conditions that disrupt stem/progenitor cell proliferation and differentiation. The signal transducer and activator of transcrip- tion-3 (STAT3) signaling pathway is involved in inflammation and also contributes to the maintenance of embryonic stem cell (ESCs) pluripotency. Here, we have investi- gated the activation status of STAT3 in GC stem-like cells (GCSLCs). In this experimental research, CSLCs derived from the human GC cell line MKN-45 and patient specimens, through spheroid body formation, character- ized and then assayed for the STAT3 transcription factor expression in mRNA and protein level further to its activation. Spheroid cells showed higher potential for spheroid formation than the pa- rental cells. Furthemore, stemness genes NANOG, c-MYC and SOX-2 were over expressed in spheroids of MKN-45 and in patient samples. In MKN-45 spheroid cells, epithelial mesenchymal transition (EMT) related markers CDH2, SNAIL2, TWIST and VIMENTIN were upregulated (P<0.05), but we observed no change in expression of the E-cadherin epithelial marker. These cells exhibited more resistance to docetaxel (DTX) when compared with parental cells (P<0.05) according to the MTS assay. Al- though immunostaining and Western blotting showed expression of the STAT3 pro- tein in both spheroids and parents, the mRNA level of STAT3 in spheroids was higher than the parents. Nuclear translocation of STAT3 was accompanied by more intensive phospho-STAT3 (p-STAT3) in spheroid structures relative to the parent cells accord- ing to flow cytometry analysis (P<0.05). | This study investigated the effect of time of day on endurance exercise capacity in a warm environment. Nine males cycled to exhaustion at 65% .VO2peak in an ambient temperature of 35 degrees C (60% relative humidity) at 0645 h (AM) and 1845 h (PM). Rectal temperature (Tc), skin temperature (Tsk), and heart rate (HR) were recorded and blood and expired air samples collected at rest every 5 min during exercise and during recovery. Time to exhaustion was longer in the AM trial (45.8 +/- 10.7 min) than in the PM trial (40.5 +/- 9.0 min; P = 0.009). Resting Tc was lower in the AM trial and remained lower for the first 25 min of exercise (P < 0.001). Tc was not different between trials at the point of exhaustion (AM = 38.7 +/- 0.9 degrees C, PM = 38.8 +/- 0.6 degrees C; P = 0.847). Tsk followed a similar pattern, being lower at rest (P = 0.003) and during the initial stages of exercise (P < 0.05) in the AM trial but not different at exhaustion (P = 0.896). The rate of rise of Tc tended to be greater in the AM trial (P = 0.052), and the rate of rise of Tsk (P = 0.032) and of body heat content (P = 0.009) was also greater in the AM trial. HR was initially higher in the PM trial, but there was no difference at exhaustion. There were no differences between trials in blood glucose concentration or plasma volume change. |
Do low serum 25-hydroxyvitamin D concentrations associate with non-alcoholic fatty liver disease in adolescents independent of adiposity? | Non-alcoholic fatty liver disease (NAFLD) and serum 25-hydroxyvitamin D (s25[OH]D) concentrations are both associated with adiposity and insulin resistance (IR) and thus may be pathogenically linked. We aimed to determine the prevalence of vitamin D deficiency in adolescents with NAFLD and to investigate the prospective and cross-sectional associations between s25[OH]D concentrations and NAFLD. Participants in the population-based West Australian Pregnancy (Raine) Cohort had seasonally adjusted s25(OH)D concentrations determined at ages 14 and then 17 years. NAFLD was diagnosed at 17 years using liver ultrasonography. Associations were examined after adjusting for potential confounders. Odds ratios (ORs) and confidence intervals (CIs) are reported per standard deviation in s25(OH)D concentrations. NAFLD was present in 16% (156/994) of adolescents. The majority of participants with NAFLD had either insufficient (51%) or deficient (17%) vitamin D status. s25(OH)D concentrations at 17 years were inversely associated with risk of NAFLD (OR 0.74, 95% CI 0.56, 0.97; P = 0.029), after adjusting for sex, race, physical activity, television/computer viewing, body mass index, and IR. The effect of s25(OH)D concentrations at 17 years was minimally affected after further adjusting for s25(OH)D concentrations at 14 years (OR 0.76, 95% CI 0.56, 1.03; P = 0.072). | The proteasome is the proteolytically active core of the ubiquitin-proteasome system, which regulates vital processes and which can cause various diseases when it malfunctions. Therefore, the proteasome has become an attractive target for pharmaceutical interventions. Inhibition of the cardiac proteasome by specific proteasome inhibitors has been shown to attenuate cardiac hypertrophy and ischaemia reperfusion injury of the heart. We have resolved the cardiac proteasome into its subtypes and have addressed the key question of how proteasome inhibitors affect single cardiac proteasomal subtypes. The 20S proteasome from rat heart was dissected into three different subpopulations (groups I-III), each comprising 4-7 different subtypes. The major group (group II) comprises standard proteasome subtypes; the two minor subpopulations (groups I and III) contain intermediate proteasome subtypes. All subtypes exhibit chymotrypsin-, trypsin-, and caspase-like activity but to different degrees. We have tested the effect of two common proteasome inhibitors on the chymotrypsin-like activity of all subtypes: 20-30 nmol/L MG132 caused 50% inhibition of all subtypes from groups I and II, whereas 100 nmol/L was necessary to affect group III subtypes to the same extent. However, another inhibitor, bortezomib (VELCADE), already used clinically, inhibited 50% of the activity of group III proteasome subtypes even below 20 nmol/L, a concentration showing almost no effect on group I and II proteasome subtypes. The caspase-like activity of group II proteasome subtypes was not affected by MG132 and was inhibited by bortezomib only at concentrations above 100 nmol/L. |
Does a genetic fusion GDNF-C fragment of tetanus toxin prolong survival in a symptomatic mouse ALS model? | Amyotrophic Lateral Sclerosis (ALS) is a paralyzing disorder that kills individuals within three to five years of onset without any possibility for effective treatment. One proposed therapy has been the use of neurotrophic factors to inhibit the apoptosis of motorneurones. At the present, one way to deliver neurotrophic factors after intramuscular injection to the motor neurones is through the use of adenoviral vectors. An alternative strategy is the use of the atoxic C fragment of tetanus toxin (TTC) as a neurotrophic factor carrier for motorneurones. We have produced the recombinant protein fusion Glial Derived Neurotrophic Factor and C fragment of tetanus toxin (GDNF-TTC) and we have tested its antiapoptotic activity in degeneration culture cells and in the symptomatic SOD;{G93A} transgenic animal model for ALS. We demonstrated that GDNF-TTC induces the neuronal survival Akt kinase pathway in mouse cortical culture neurons and~maintains its antiapoptotic neuronal activity in Neuro2A cells. Moreover, we have found that genetic fusion is able to increase survival by 9 days and improves life quality in symptomatic ALS animal models. | A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk factor for developing diabetes and is associated with insulin resistance and atherosclerosis. In this work, we have examined the impact of serum ANGPTL2 on improving cardiovascular (CV) risk stratification in patients with type 2 diabetes. A prospective, monocentric cohort of consecutive type 2 diabetes patients (the SURDIAGENE cohort; total of 1353 type 2 diabetes patients; 58% men, mean ± SD age 64 ± 11 years) was followed for a median of 6.0 years for death as primary endpoint and major adverse CV events (MACE; i.e. CV death, myocardial infarction or stroke) as a secondary endpoint. Patients with end-stage renal disease, defined as a requirement for dialysis or a history of kidney transplantation, were excluded. Patients were grouped into quartiles according to ANGPTL2 concentrations at inclusion: <11.2 (Q1), 11.2-14.7 (Q2), 14.8-19.5 (Q3) or >19.5 (Q4) ng/ml. During follow up, 367 patients (representing 4.5% of the total person-years) died and 290 patients (representing 3.7% of the total person-years) presented with MACE. Both the survival and MACE-free survival rates were significantly different between ANGPTL2 quartiles (logrank 82.12, p < 0.0001 for death; and logrank 65.14, p < 0.0001 for MACE). Patients with ANGPTL2 concentrations higher than 19.5 ng/ml (Q4) had a significantly higher risk of death and MACE than those with ANGPTL2 levels of 19.5 ng/ml or less (Q1-3) (HR for death 2.44 [95% CI 1.98, 3.00], p < 0.0001; HR for MACE 2.43 [95% CI 1.92, 3.06], p < 0.0001) after adjustment for sex, age and established CV risk factors. Using ANGPTL2 concentrations, prediction of the risk of mortality, as assessed by integrated discrimination improvement (IDI), was significantly improved (IDI 0.006 ± 0.002, p = 0.0002). |
Does met promote the formation of double minute chromosomes induced by Sei-1 in NIH-3T3 murine fibroblasts? | Sei-1 is an oncogene capable of inducing double minute chromosomes (DMs) formation. DMs are hallmarks of amplification and contribute to oncogenesis. However, the mechanism of Sei-1 inducing DMs formation remains unelucidated. DMs formation significantly increased during serial passage in vivo and gradually decreased following culture in vitro. micro nuclei (MN) was found to be responsible for the reduction. Of the DMs-carrying genes, Met was found to be markedly amplified, overexpressed and highly correlated with DMs formation. Inhibition of Met signaling decreased the number of DMs and reduced the amplification of the DMs-carrying genes. We identified a 3.57Mb DMs representing the majority population, which consists of the 1.21 Mb AMP1 from locus 6qA2 and the 2.36 Mb AMP2 from locus 6qA2-3. We employed NIH-3T3 cell line with Sei-1 overexpression to monitor and characterize DMs in vivo and in vitro. Array comparative genome hybridization (aCGH) and fluorescence in situ hybridization (FISH) were performed to reveal amplification regions and DMs-carrying genes. Metaphase spread was prepared to count the DMs. Western blot and Met inhibition rescue experiments were performed to examine for involvement of altered Met signaling in Sei-1 induced DMs. Genomic walking and PCR were adopted to reveal DMs structure. | Current clinical tools to identify lacunar infarct patients at risk of deterioration are inadequate, and imaging techniques to predict fluctuation and deterioration would be of value. We sought to determine the occurrence of MRI perfusion-weighted imaging (PWI) abnormalities in lacunes, and whether they help predict clinical and radiological outcome. Patients with lacunar stroke or TIA were selected from a prospective MR imaging study. MRI was performed within 24 h of the event and follow-up imaging completed at 30 or 90 days. Baseline perfusion maps were qualitatively assessed and infarct volumes measured. Early clinical deterioration (NIHSS worsening of > or = 3 points within 72 h of event) and 90-day modified Rankin Scale score (mRS) were recorded. Twenty-two patients were included. Fifteen (68.2%) had abnormal PWI at the site of the diffusion-weighted imaging lesion. Patients with abnormal PWI were more likely to have stroke than TIA as their index event (RR 2.2, 95% CI 0.9-5.2, p = 0.02). Early clinical deterioration occurred in 4 patients (18.2%), all of whom had abnormal PWI. PWI lesions were not associated with a higher 90-day NIHSS or mRS score, nor did they predict infarct volume growth. |
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