Datasets:

reginaboateng

/

pubmedqa_cleaned

like 0

Damaged, necrotic, or apoptotic hepatocytes release damage-associated molecular patterns that initiate sterile inflammation, and liver inflammation drives liver injury and fibrosis. Here we identified hepatic nuclear factor kappa B (NF-κB)-inducing kinase (NIK), a Ser/Thr kinase, as a novel trigger of fatal liver inflammation. NIK is activated by a broad spectrum of stimuli. It was up-regulated in injured livers in both mice and humans. In primary mouse hepatocytes, NIK overexpression stimulated, independently of cell injury and death, release of numerous chemokines and cytokines that activated bone marrow-derived macrophages (BMDMs). BMDMs in turn secreted proapoptotic molecules that stimulated hepatocyte apoptosis. Hepatocyte-specific expression of the NIK transgene triggered massive liver inflammation, oxidative stress, hepatocyte apoptosis, and liver fibrosis, leading to weight loss, hypoglycemia, and death. Depletion of Kupffer cells/macrophages reversed NIK-induced liver destruction and death.

Does mouse hepatocyte overexpression of NF-κB-inducing kinase ( NIK ) trigger fatal macrophage-dependent liver injury and fibrosis?

Members of the Ewing sarcoma family of tumors (ESFT) contain tumor-associated translocations that give rise to oncogenic transcription factors, most commonly EWS/FLI1. EWS/FLI1 plays a dominant role in tumor progression by modulating the expression of hundreds of target genes. Here, the impact of EWS/FLI1 inhibition, by RNAi-mediated knockdown, on cellular signaling was investigated using mass spectrometry-based phosphoproteomics to quantify global changes in phosphorylation. This unbiased approach identified hundreds of unique phosphopeptides enriched in processes such as regulation of cell cycle and cytoskeleton organization. In particular, phosphotyrosine profiling revealed a large upregulation of STAT3 phosphorylation upon EWS/FLI1 knockdown. However, single-cell analysis demonstrated that this was not a cell-autonomous effect of EWS/FLI1 deficiency, but rather a signaling effect occurring in cells in which knockdown does not occur. Conditioned media from knockdown cells were sufficient to induce STAT3 phosphorylation in control cells, verifying the presence of a soluble factor that can activate STAT3. Cytokine analysis and ligand/receptor inhibition experiments determined that this activation occurred, in part, through an IL6-dependent mechanism. Taken together, the data support a model in which EWS/FLI1 deficiency results in the secretion of soluble factors, such as IL6, which activate STAT signaling in bystander cells that maintain EWS/FLI1 expression. Furthermore, these soluble factors were shown to protect against apoptosis.

Does phosphoproteomic profiling reveal IL6-mediated paracrine signaling within the Ewing sarcoma family of tumors?

Onset of sexual activity during adolescence is common in Vanuatu, however access to comprehensive sexual and reproductive health (SRH) information is limited. Improving adolescents' knowledge about SRH is necessary to improve health outcomes, however little is known about the information needs and preferences of adolescents in the Pacific to inform policy and programs in this region. Sixty-six focus group discussions were conducted with 341 male and female adolescents aged 15-19 years from rural and urban communities on two islands of Vanuatu. Twelve key-informant interviews were also conducted with policymakers and health service providers. Data were analysed thematically using an inductive approach. Much of the SRH information targeting adolescents focused on sexually transmitted infections and HIV. While this information was valued, important gaps were identified including prevention of pregnancy, condom use, puberty, sexuality and relationships. Peer educators and health workers were adolescents' preferred sources of information because they were considered knowledgeable and trustworthy. Parents were not a common source but were preferred, particularly by girls, despite considerable socio-cultural barriers. Schools were an important but underutilised source of information, as were a range of media sources.

Are `` These issues n't talked about at home '' : a qualitative study of the sexual and reproductive health information preferences of adolescents in Vanuatu?

In this study we sought to determine whether a Titin peptide fragment can serve as a clinical biomarker for changes in muscle mass. Mass spectrometry was used to identify Titin fragment in urine. An antibody against this Titin sequence was raised and used to develop a competitive ELISA assay for measurement in serum. Rat tissue extractions in the presence or absence of a series of proteases of interest were used to identify its enzymatic origin. A rat model of dexamethasone (DEX) induced muscle atrophy and a human 56-day bed rest study with and without vibration therapy were used to assess biological and clinical relevance. A technically robust ELISA measuring the Titin fragment was developed against a Titin peptide fragment identified in human urine. The fragment was shown to be produced primarily by MMP-2 cleavage of Titin. In the rat muscle DEX induced atrophy model, Titin-MMP2 fragment was decreased in the beginning of DEX treatment, and then significantly increased later on during DEX administration. In the human bed rest study, the Titin-MMP2 fragment was initially decreased 11.9 (±3.7) % after 1day of bed rest, and then gradually increased ending up at a 16.4 (±4.6) % increase at day 47.

Does measurement of a MMP-2 degraded Titin fragment in serum reflect changes in muscle turnover induced by atrophy?

It has been proposed that hepatitis B virus (HBV) sub-genotype A1 infections have mild outcomes and a low risk of drug-resistance among patients infected with human immunodeficiency virus (HIV) receiving lamivudine-containing antiretroviral therapy (ART) without tenofovir in Africa. The virologic expression of HBV sub-genotype A1 coinfection was studied over 12 months in HIV-positive adults starting stavudine/lamivudine/nevirapine in Malawi, using Sanger, deep, clonal, and single full-genome sequencing for the sensitive characterization of HBV resistance-associated mutations (RAMs). Among 1117 subjects, 133 (12%) tested HBsAg-positive. After starting ART, retention rates were 96/133 (72%) at 6 months and 54/133 (41%) at 12 months. Based upon the last available follow-up, 92/96 (96%) subjects achieved HIV-1 RNA <40 copies/mL, 48/96 (50%) showed HBV DNA <14 IU/mL, and 24/96 (25%) acquired HBV RAMs. At 6 months, M204I was detected in 8/46 (17%) and 16/17 (94%) subjects using Sanger and deep sequencing, respectively. At 12 months, all viremic patients had multiple resistance and compensatory mutations coexisting on the same HBV genomes. Comparing HBeA-positive (67/133, 50%) with HBeAg-negative subjects, 64/67 (96%) vs 35/66 (55%) showed baseline HBV DNA >2000 IU/mL (P = .0006), 39/47 (17%) vs 9/49 (82%) had persistent HBV DNA detection during follow-up (P < .0001), and 23/47 (49%) vs 2/49 (4%) acquired HBV RAMs (P < .0001). Baseline HBV DNA levels were median 8.1 vs 5.3 log10 IU/mL in subjects with vs those without treatment-emergent RAMs (P < .0001).

Is hepatitis B virus sub-genotype A1 infection characterized by high replication levels and rapid emergence of drug resistance in HIV-positive adults receiving first-line antiretroviral therapy in Malawi?

As next-generation sequencing (NGS) becomes a major sequencing platform in clinical diagnostic laboratories, it is critical to identify artifacts that constitute baseline noise and may interfere with detection of low-level gene mutations. This is especially critical for applications requiring ultrasensitive detection, such as molecular relapse of solid tumors and early detection of cancer. We recently observed a ~10-fold higher frequency of C:G > T:A mutations than the background noise level in both wild-type peripheral blood and formalin-fixed paraffin-embedded samples. We hypothesized that these might represent cytosine deamination events, which have been seen using other platforms. To test this hypothesis, we pretreated samples with uracil N-glycosylase (UNG). Additionally, to test whether some of the cytosine deamination might be a laboratory artifact, we simulated the heat associated with polymerase chain reaction thermocycling by subjecting samples to thermocycling in the absence of polymerase. To test the safety of universal UNG pretreatment, we tested known positive samples treated with UNG. UNG pretreatment significantly reduced the frequencies of these mutations, consistent with a biologic source of cytosine deamination. The simulated thermocycling-heated samples demonstrated significantly increased frequencies of C:G > T:A mutations without other baseline base substitutions being affected. Samples with known mutations demonstrated no decrease in our ability to detect these after treatment with UNG.

Is cytosine deamination a major cause of baseline noise in next-generation sequencing?

The pH at the surface of healthy human skin is around 5. Cleansing the skin with soap increases the pH of the skin, which then returns to a more acidic pH within a few hours. However, the effects of skin cleansing with soap over a long time on the pH regulatory system is still unclear. We compared the pH of the skin between users of a soap-based cleanser and of a mild-acidic cleanser prior to and following the cleansing. This study had two groups of subjects, one group who had used a soap-based cleanser for more than 5 years and the other group who had used a mild-acidic cleanser for more than 5 years. The pH on the inner forearm of each subject was measured prior to and for 6 h after cleansing with a soap bar. There were no differences between the pH of the skin these two groups prior to cleansing, immediately after cleansing or in the pH recovery rate for 6 h.

Does the long-term use of soap affect the pH-maintenance mechanism of human skin?

In the present study, we investigated the potential effect of aliskiren on smooth muscle cell (SMC) migration in response to prorenin. Cultured human SMCs were incubated with angiotensinogen (ANG) (1.5 × 10(-7)M) and increasing concentrations of aliskiren (10(-6)-10(-5)M). After 24 h, SMC migration was assessed by Boyden's chamber chemotactic assay using prorenin as chemotactic factor (10(-8)M). The effect of aliskiren on RhoA and Rac activity was also determined by G-LISA assay and the lamellipodia formation by rhodamine-phalloidin staining. Changes in cell morphology were recorded in real-time using the iCelligence system. Aliskiren determined, at 10(-5)M, a significant inhibition of SMC migration induced by prorenin (-66.4 ± 18.1%; p < 0.05), while no significant effect was observed when PDGF-BB was utilized as chemotactic agent. Aliskiren also reduced Rac-GTP levels in response to prorenin (-54.2 ± 5.4%) without affecting the RhoA-GTP levels. Finally, aliskiren inhibited both the lamellipodia formation and morphological changes induced by prorenin with no significant effect on PDGF-BB activity.

Does aliskiren inhibit prorenin-induced human aortic smooth muscle cell migration?

Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancer patients, including children homozygous for the CYP2C19*17 gain-of-function allele. A linear mixed effect model compared voriconazole dose-corrected trough concentrations (n = 142) among CYP2C19 diplotypes in 33 patients (aged 1-19 years). Voriconazole pharmacokinetics was described by a two-compartment model with Michaelis-Menten elimination. Age (p = 0.05) and CYP2C19 diplotype (p = 0.002) were associated with voriconazole concentrations. CYP2C19*17 homozygotes never attained therapeutic concentrations, and had lower dose-corrected voriconazole concentrations (median 0.01 μg/ml/mg/kg; p = 0.02) than CYP2C19*1 homozygotes (median 0.07 μg/ml/mg/kg). Modeling indicates that higher doses may produce therapeutic concentrations in younger children and in those with a CYP2C19*17/*17 diplotype.

Do voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes?

This study investigated whether cholesterol levels influence the expression and function of drug transporters and whether statin treatments could alter this by reducing plasma low-density lipoprotein cholesterol levels. The mRNA expression and function of OATP1B1, ABCB1 and ABCG2 were assessed in peripheral blood mononuclear cells (PBMCs) of healthy subjects and from patients with familial hypercholesterolemia (FH) before and after statin treatment by real-time PCR and flow cytometric assay, respectively. The effects of statin exposure and cholesterol depletion in PBMCs and in cell lines were assessed. ABCG2 expression and activity in PBMCs in patients with FH were 2-fold and 26-fold higher, respectively, than those of the healthy subjects (p < 0.001 for both). Statin treatment decreased ABCG2 expression and function in patients with FH. Depletion of cholesterol ex vivo reduced ABCG2 expression in PBMCs and reduced ABCG2 activity in liver and colon cells.

Are expression and activity of ABCG2 , but not ABCB1 or OATP1B1 , associated with cholesterol levels : evidence from in vitro and in vivo experiments?

Do teenage girls with a history of menstrual irregularity and/or elevated androgen levels in adolescence exhibit an increased risk of polycystic ovary syndrome (PCOS) and/or infertility later on in adulthood?

Are irregular menstruation and hyperandrogenaemia in adolescence associated with polycystic ovary syndrome and infertility in later life : Northern Finland Birth Cohort 1986 study?

The current standard of care for glioblastoma (GBM) involves a combination of surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance to temozolomide is largely mediated by expression of the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation of MSH6 and other mismatch repair proteins plays an important role in temozolomide resistance. Here, we investigate endogenous MSH6 mutations in GBM, anaplastic oligodendroglial tumor tissue, and corresponding brain tumor-initiating cell lines (BTIC). MSH6 sequence and MGMT promoter methylation were determined in human tumor samples and BTICs. Sensitivity to temozolomide was evaluated in vitro using BTICs in the absence and presence of O(6)-benzylguanine to deplete MGMT. The influence of MGMT and MSH6 status on in vivo sensitivity to temozolomide was evaluated using intracranial BTIC xenografts. We identified 11 previously unreported mutations in MSH6 in nine different glioma samples and six paired BTIC lines from adult patients. In addition, MSH6 mutations were documented in three oligodendrogliomas and two treatment-naïve gliomas, both previously unreported findings. These mutations were found to influence the sensitivity of BTICs to temozolomide both in vitro and in vivo, independent of MGMT promoter methylation status.

Do novel MSH6 mutations in treatment-naïve glioblastoma and anaplastic oligodendroglioma contribute to temozolomide resistance independently of MGMT promoter methylation?

The association between blood types and ovarian reserve is investigated in this study. As an index of ovarian reserve, women with a follicle stimulat- ing hormone (FSH) level of ≥10 mIU/ml in the early follicular phase were designated as having diminished ovarian reserve. In this prospective study, early follicular phase serum FSH and estradiol levels and blood types were evaluated in 500 patients who were admitted to the Infertility Department of Ministry of Health Etlik Zübeyde Hanım Women's Health Training and Research Hospital between January 2012 and June 2012. Women with serum FSH level <10 mIU/ml formed group I, and women with serum FSH ≥10 mIU/ml formed group II. The prevalence of blood types in each group and their associa- tion with ovarian reserve were analyzed. Out of 500 patients, 438 women were in group I, while 62 women were in group II. There was no statistically significant difference among the two groups in terms of blood group proportions (p=0.69), this did not change after age adjustment (p=0.77). The presence of A antigen (in A and AB blood type) (p=0.91), the blood type O (p=0.70), and the blood type B (p=0.51) were not statistically related to ovarian reserve after age adjustment. There was also no statistically significant correlation between rhesus factor and ovarian reserve after age adjustment (p=0.83). The only factor that affected ovarian reserve was age of patients (p=0.006).

Is only female age , and not blood type , associated with ovarian reserve?

Type 1 endometrial cancer (EC) is typically sex hormone sensitive; however, most women diagnosed with EC have already gone through menopause. Several studies have reported that the postmenopausal ovary is hormonally active, and estradiol (E2) production from the ovaries persists for as much as 10 years beyond menopause. The aim of this study was to evaluate whether sex steroid production from the ovaries contributes to the pathogenesis of type 1 EC. This was a prospective study of 53 women treated for EC (28 cases of type 1 disease and 25 cases of type 2 disease). Serum specimens were collected from the peripheral and ovarian veins of participants undergoing bilateral oophorectomy. The sex steroid hormone levels and hormonal milieu on cervical cytology were evaluated as maturation value (MV). In addition, the degree of stromal hyperplasia of the ovary was evaluated histologically. Although the E2 levels of the peripheral veins did not show any significant differences [8.2 (5.1-12.4) vs 7.4 (5.1-11.7) pg/mL, respectively; P < 0.05], the patients with type 1 EC had a higher E2 level in the ovarian vein than those with type 2 EC [25 (13.8-42.5) vs 15 (10.0-23.0) pg/mL, respectively; P < 0.05]. There were also no significant differences in the rate of moderate to marked hyperplasia of the ovarian stroma between the groups; however, the thickness of the ovarian cortex demonstrated a correlation with the ovarian E2 level. In addition, the MV displayed a strong correlation with the ovarian E2 level, but not the peripheral E2 level.

Do postmenopausal patients with endometrial cancer of type 1 have elevated serum estradiol levels in the ovarian vein?

Penehyclidine hydrochloride (PHC) is a new anticholinergic drug, which has been shown to have a good curative effect for sepsis. Beta arrestins have been demonstrated to play important roles in sepsis. This study is to investigate the effects of PHC on pulmonary microvascular permeability and on expressions of beta arrestins in lung injury induced by the cecal ligation and puncture (CLP) procedure. Thirty healthy female mice were randomly divided into three groups (n = 10 each): sham operation group (control group), CLP group (CLP group), and PHC 0.45 mg/kg group (PHC group). In the PHC group, mice were given an intraperitoneal injection of PHC 0.45 mg/kg 1 h before surgery. Mice in the other two groups received an intraperitoneal injection of the same volume of normal saline. At 12 h after surgery, serum and bronchoalveolar lavage fluid were collected to examine lung permeability index. The lung tissue samples were collected to examine expressions of myosin light chain kinase (MLCK), vascular endothelial-cadherin (VE-cadherin), vascular cell adhesion molecule 1 (VCAM-1), myeloperoxidase (MPO), NF-κB, and beta arrestins. Compared with the control group, pulmonary microvascular permeability, MPO activity, NF-κB, VCAM-1, and MLCK expressions were significantly increased, whereas VE-cadherin and beta-arrestin protein expressions were obviously decreased in CLP group. Furthermore, compared with the CLP group, PHC group markedly decreased pulmonary microvascular permeability, MPO activity, NF-κB, VCAM-1, and MLCK expressions, and increased expressions of VE-cadherin and beta arrestins.

Does penehyclidine hydrochloride decrease pulmonary microvascular permeability by upregulating beta arrestins in a murine cecal ligation and puncture model?

To investigate the impact of antiangiogenic monotherapy and photodynamic therapy (PDT) as add-on strategy on retinal morphology, and to analyse prognostic biomarkers for visual outcome and retreatment frequency in neovascular age-related macular degeneration (nAMD). 255 patients participating in the MONT BLANC study were evaluated. Patients were randomised to receive as-needed ranibizumab monotherapy or combination therapy (verteporfin PDT and ranibizumab). Outcome measures included visual acuity (VA), retinal morphology assessed by optical coherence tomography and retreatment frequency. The proportion of scans showing intraretinal cysts (IRC) or subretinal fluid (SRF) decreased more intensively in the combination than in the monotherapy group. Pigment epithelial detachments (PED) decreased significantly only in the combination group. Patients with IRC presented the lowest initial VA, and IRC had the strongest negative predictive value for functional improvement in both groups. SRF showed a predictive value for a higher number of ranibizumab injections (combination, +0.9; monotherapy, +0.8) and a higher number of PDT treatments in the combination group (+0.3). PED was associated with a higher number of ranibizumab injections only in the monotherapy group (+1.2).

Are intraretinal cysts the most relevant prognostic biomarker in neovascular age-related macular degeneration independent of the therapeutic strategy?

Poor quality of life (QoL) is a feature of people with Parkinson's disease (PD) who develop dementia. The relationship between mild cognitive impairment in PD (PD-MCI) and QoL is less clear. To address this, we studied the impact of varying severities of cognitive impairment on QoL in a cohort of non-demented patients with early PD. Patients with newly diagnosed PD (n = 219) and age and sex matched healthy controls (n = 99) completed a schedule of neuropsychological tests, in addition to scales assessing QoL (PDQ-39), depression, sleep, neuropsychiatric symptoms and a clinical examination. The Movement Disorder Society criteria were used to define and classify PD-MCI. Participants with PD-MCI were significantly older than those with normal cognition, had more severe motor symptoms, scored higher for depression and had poorer quality of life. Logistic regression showed that mild cognitive impairment, independent of other factors, was an indicator of poorer QoL. Using cognitive performance 2.0 standard deviations (SD) below normative data as a cut-off to define PD-MCI, there was a significant difference in QoL scores between patients with PD-MCI and those classified as having normal cognition. Subjects with less severe mild cognitive impairment did not exhibit significant differences in QoL.

Does severity of mild cognitive impairment in early Parkinson 's disease contribute to poorer quality of life?

The gene p8 was initially described in pancreatic tissue during acute experimental pancreatitis, a disease that is characterized by a systemic immune response. Although early reports suggested that p8 affects leukocyte migration during acute pancreatitis (AP), no studies revealing its immune-modulatory effects have been performed. We investigated the composition of the cellular immune system in naive p8 knockout (p8(−/−)) mice and compared with matched wild-type mice during pancreatitis. In young mice, there were no relevant differences in the composition of peripheral and splenic CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD11b(+)Gr-1(-), and Gr-1 cells. In mature p8(−/−) mice, increased splenic CD4CD25FoxP3 cells, spleen siderosis, and increased marginal zones in the splenic white pulp were found. During AP, peripheral and splenic CD3(+) and CD3CD4 declined stronger in the p8(−/−) mice. The spleen of the p8(−/−) mice showed severe hypoplasia of the white pulp and mild hyperplasia of the red pulp. This was associated with a significantly increased rate of apoptosis.

Does p8 Deficiency cause siderosis in spleens and lymphocyte apoptosis in acute pancreatitis?

Neoadjuvant chemotherapy is established in the management of most resectable esophageal and esophagogastric junction adenocarcinomas. However, assessing the downstaging effects of chemotherapy and predicting response to treatment remain challenging, and the relative importance of tumor stage before and after chemotherapy is debatable. We analyzed consecutive resections for esophageal or esophagogastric junction adenocarcinomas performed at two high-volume cancer centers in London between 2000 and 2010. After standard investigations and multidisciplinary team consensus, all patients were allocated a clinical tumor stage before treatment, which was compared with pathologic stage after surgical resection. Survival analysis was conducted using Kaplan-Meier analysis and Cox regression analysis. Among 584 included patients, 400 patients (68%) received neoadjuvant chemotherapy. Patients with downstaged tumors after neoadjuvant chemotherapy experienced improved survival compared with patients without response (P < .001), and such downstaging (hazard ratio, 0.43; 95% CI, 0.31 to 0.59) was the strongest independent predictor of survival after adjusting for patient age, tumor grade, clinical tumor stage, lymphovascular invasion, resection margin status, and surgical resection type. Patients downstaged by chemotherapy, compared with patients with no response, experienced lower rates of local recurrence (6% v. 13%, respectively; P = .030) and systemic recurrence (19% v. 29%, respectively; P = .027) and improved Mandard tumor regression scores (P = .001). Survival was strongly dictated by stage after neoadjuvant chemotherapy, rather than clinical stage at presentation.

Does tumor stage after neoadjuvant chemotherapy determine survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction?

To determine whether platelet-specific collagen receptor glycoprotein VI (GP6) gene variants are associated with recurrent miscarriages (RM). Genetic association study. Tertiary care referral hospital. A total of 200 women with at least three unexplained spontaneous abortions before 20 weeks of gestation and 300 healthy parous women. Determination of variants of GP6 single-nucleotide polymorphisms (SNPs) namely; rs1671153, rs1654410, rs1654419, and rs1613662 was based on polymerase chain reaction-restriction fragment-length polymorphism. Genotypes and haplotypes frequencies were compared in RM case subjects versus control subjects. We observed significantly higher occurrence of rare alleles of SNPs in GP6, namely, rs1671153, rs1654410, rs1654419, and rs1613662, among RM cases, revealing risk association for fetal losses. The synergistic effects of haplotype combinations were also evaluated and showed that four haplotypes G-T-G-G, T-C-A-A, G-C-G-A, and G-T-A-A were more prevalent among RM cases, revealing increased risk for fetal losses. In silico analysis revealed that GP6 has an impact on biologic pathways and significant influence in collagen binding. Gene-gene interaction network analysis revealed that GP6 consisted of a total of 25 interactions with 13 genes in the human genome.

Do platelet-specific collagen receptor glycoprotein VI gene variants affect recurrent pregnancy loss?

This study compared the pharmacokinetics of a single dose of 1% testosterone solution after application to the inner arm or the axilla as application sites for transdermal testosterone therapy. Healthy, not pregnant, premenopausal women, 18 to 45 years of age with a body mass index of 20 to 28 kg/m(2) were enrolled into a single-center, open-label, randomized, 2-way crossover study. Serum total testosterone (TT), free testosterone (fT), and sex hormone binding globulin concentrations were measured. Pharmacokinetic parameters determined from serum TT and fT included area under the serum concentration versus time curve from time zero (pre-dose) until 72 hours post-dose (AUC0-72), Cmax, and Tmax. Descriptive statistics were performed on serum concentrations of TT and fT for each site. ANOVA was performed on AUC0-72 and Cmax. A single-dose application of 1% testosterone solution to the inner arm and the axilla produced clear increases in TT and fT. Slower and lower increases in TT and fT were observed after treatment to the inner arm. Based on baseline-corrected AUC versus time curves, the bioavailability of 1% testosterone solution was increased 2-fold for the axilla compared with the inner arm.

Does application site affect the pharmacokinetics of topical testosterone applied to the axilla compared with the inner arm?

Minimally invasive parathyroidectomy for primary hyperparathyroidism is dependent on preoperative localization, commonly with ultrasound and sestamibi imaging. This study sought to determine if preoperative serum calcium and parathyroid hormone (PTH) levels correlate with localization sensitivity and positive predictive value (PPV). This is a retrospective analysis of a prospective database of 1,910 patients with primary hyperparathyroidism from 2002 to 2013, who had surgeon-performed ultrasound and/or sestamibi for preoperative localization. The sensitivity and PPV of ultrasound and sestamibi were analyzed by degree of preoperative serum calcium and parathyroid hormone level perturbation. In 1,910 parathyroidectomy patients, ultrasound was localizing in 1,411 of 1,644 (86%) and sestamibi in 802 of 1,165 (69%) (p < 0.01). The PPV of ultrasound was 1,135 of 1,411 (80%) and sestamibi was 705 of 802 (88%) (p < 0.01). Using logistic regression analysis, there was statistically significant positive correlation between localization and preoperative serum calcium for both sestamibi (odds ratio [OR] 1.21 [95% CI 1.00 to 1.47; p < 0.05]) and ultrasound (OR 1.29 [95% CI 1.03 to 1.60; p < 0.05]). There was a weak, but statistically significant positive correlation of PTH with sestamibi localization (OR 1.00 [95% CI 1.00 to 1.01; p < 0.05]). There was no statistically significant correlation between the PPV and serum calcium or PTH for either study. When patients were divided into quartiles of preoperative serum calcium and PTH levels, localization rates and PPV of both ultrasound and sestamibi increased with higher calcium and PTH levels. Surgeon-performed ultrasound had higher localization rates than sestamibi, with lower calcium and PTH values. Sestamibi demonstrated higher PPV values across all quartiles.

Does the biochemical severity of primary hyperparathyroidism correlate with the localization accuracy of sestamibi and surgeon-performed ultrasound?

In the last decade, reactive oxygen species (ROS) production has been shown to occur upon T-cell receptor (TCR) stimulation and to affect TCR-mediated signalling. However, the exact reactive species that are produced, how ROS are generated and their requirement for T-cell activation, proliferation or cytokine production remain unclear, especially in the case of primary human T cells. Moreover, several groups have questioned that ROS are produced upon TCR stimulation. To shed some light onto this issue, we specifically measured superoxide production upon TCR ligation in primary human and mouse T lymphocytes. We showed that superoxide is indeed produced and released into the extracellular space. Antioxidants, such as superoxide dismutase and ascorbate, abolished superoxide production, but surprisingly did not affect activation, proliferation and cytokine secretion in TCR-stimulated primary human T cells. It has been suggested that T cells produce ROS via the NADPH oxidase 2 (NOX2). Therefore, we investigated whether T-cell activation is affected in NOX2-deficient mice (gp91phox-/-). We found that T cells from these mice completely lack inducible superoxide production but display normal upregulation of activation markers and proliferation.

Is tCR-triggered extracellular superoxide production required for T-cell activation?

To examine the in vitro effects of LL37 on the expression of vascular endothelial growth factor (VEGF) in human pulp cells and to identify the intracellular signalling pathway involved. Pulp cells at passage 6 were treated with 10 μg mL(-1) synthesized LL37, and an inhibition assay was performed with MAPK or NF-κB inhibitors to determine the possible signalling pathway. VEGF mRNA, VEGF protein and phosphorylated ERK1/2 levels were determined by real-time PCR, ELISA and Western blot, respectively. Data were analysed using t-tests. LL37 significantly increased both the mRNA and protein levels of VEGF in pulp cells (P < 0.01). However, pre-treatment with an ERK kinase inhibitor suppressed these increases. Furthermore, the inhibitor blocked LL37-induced ERK1/2 phosphorylation.

Does lL37 induce VEGF expression in dental pulp cells through ERK signalling?

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.

Are cDKN2A ( p16 ) and HRAS frequently mutated in vulvar squamous cell carcinoma?

To determine the association between ocular sun exposure measured by conjunctival ultraviolet (UV) autofluorescence and myopic refractive error in young adults. Cross-sectional study. setting: Population-based cohort in Western Australia. study population: Total of 1344 mostly white subjects aged 19-22 years in the Western Australian Pregnancy Cohort (Raine) Eye Health Study. observation procedures: Cycloplegic autorefraction, conjunctival ultraviolet autofluorescence photography, participant questionnaire. main outcome measures: Prevalence of myopic refractive error (spherical equivalent less than -0.50 diopters) and area of conjunctival ultraviolet autofluorescence in mm(2). There was an inverse relationship between myopic refractive error and ocular sun exposure, with more than double the prevalence of myopia in the lowest quartile of conjunctival autofluorescence than the highest quartile (33.0% vs 15.6%). Median area of autofluorescence was significantly lower in myopic than in nonmyopic subjects (31.9 mm(2) vs 47.9 mm(2), P < .001). These differences remained significant after adjustment for age, sex, parental history of myopia, and subject level of education. The use of corrective lenses did not explain the lower conjunctival autofluorescence observed in myopic subjects.

Is myopia in young adults inversely related to an objective marker of ocular sun exposure : the Western Australian Raine cohort study?

Acrolein is a reactive aldehyde present in high amounts in coal, wood, paper, and tobacco smoke. It is also generated endogenously by lipid peroxidation and the oxidation of amino acids by myeloperoxidase. In animals, acrolein exposure is associated with the suppression of circulating progenitor cells and increases in thrombosis and atherogenesis. The purpose of this study was to determine whether acrolein exposure in humans is also associated with increased cardiovascular disease (CVD) risk. Acrolein exposure was assessed in 211 participants of the Louisville Healthy Heart Study with moderate to high (CVD) risk by measuring the urinary levels of the major acrolein metabolite-3-hydroxypropylmercapturic acid (3-HPMA). Generalized linear models were used to assess the association between acrolein exposure and parameters of CVD risk, and adjusted for potential demographic confounders. Urinary 3-HPMA levels were higher in smokers than nonsmokers and were positively correlated with urinary cotinine levels. Urinary 3-HPMA levels were inversely related to levels of both early (AC133(+)) and late (AC133(-)) circulating angiogenic cells. In smokers as well as nonsmokers, 3-HPMA levels were positively associated with both increased levels of platelet-leukocyte aggregates and the Framingham Risk Score. No association was observed between 3-HPMA and plasma fibrinogen. Levels of C-reactive protein were associated with 3-HPMA levels in nonsmokers only.

Is acrolein exposure associated with increased cardiovascular disease risk?

Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and resistance to therapies. Recent studies have reported that HCC may be derived not only from adult hepatocytes and hepatoblasts but also hepatic stem/progenitors. In this context, HepaRG cells may represent a suitable cellular model to study stem/progenitor cancer cells and the retrodifferentiation of tumor-derived hepatocyte-like cells. Indeed, they differentiate into hepatocyte- and biliary-like cells. Moreover, tumor-derived HepaRG hepatocyte-like cells (HepaRG-tdHep) differentiate into both hepatocyte- and biliary-like cells through a hepatic progenitor. In this study we report the mechanisms and molecular effectors involved in the retrodifferentiation of HepaRG-tdHep into bipotent progenitors. Gene expression profiling was used to identify genomic changes during the retrodifferentiation of HepaRG-tdHep into progenitors. We demonstrated that gene expression signatures related to a poor-prognosis HCC subclass, proliferative progenitors, or embryonic stem cells were significantly enriched in HepaRG progenitors derived from HepaRG-tdHep. HepaRG-tdHep retrodifferentiation is mediated by crosstalk between transforming growth factor beta 1 (TGFβ1) and inflammatory cytokine pathways (e.g., tumor necrosis factor alpha [TNFα] and interleukin 6 [IL6]). Signatures related to TNFα, IL6, and TGFβ activation pathways are induced within the first hour of retrodifferentiation. Moreover, specific activation or inhibition of these signaling pathways allowed us to determine that TNFα and IL6 contribute to the loss of hepatic-specific marker expression and that TGFβ1 induces an epithelial-to-mesenchymal transition of HepaRG-tdHep. Interestingly, the retrodifferentiation process is blocked by the histone deacetylase inhibitor trichostatin A, opening new therapeutic opportunities.

Do inflammatory cytokines promote the retrodifferentiation of tumor-derived hepatocyte-like cells to progenitor cells?

Various designs of braces including hinged and nonhinged models are used to provide external support of the ankle. Hinged ankle braces supposedly allow almost free dorsiflexion and plantar flexion of the foot in the sagittal plane. It is unclear, however, whether this additional degree of freedom affects the stabilizing effect of the brace in the other planes of motion. To investigate the dynamic and passive stabilizing effects of 3 ankle braces, 2 hinged models that provide free plantar flexion-dorsiflexion in the sagittal plane and 1 ankle brace without a hinge. Crossover study. University Movement Analysis Laboratory. Seventeen healthy volunteers (5 women, 12 men; age = 25.4 ± 4.8 years; height = 180.3 ± 6.5 cm; body mass = 75.5 ± 10.4 kg). We dynamically induced foot inversion on a tilting platform and passively induced foot movements in 6 directions via a custom-built apparatus in 3 brace conditions and a control condition (no brace). Maximum inversion was determined dynamically using an in-shoe electrogoniometer. Passively induced maximal joint angles were measured using a torque and angle sensor. We analyzed differences among the 4 ankle-brace conditions (3 braces, 1 control) for each of the dependent variables with Friedman and post hoc tests (P < .05). Each ankle brace restricted dynamic foot-inversion movements on the tilting platform as compared with the control condition, whereas only the 2 hinged ankle braces differed from each other, with greater movement restriction caused by the Ankle X model. Passive foot inversion was reduced with all ankle braces. Passive plantar flexion was greater in the hinged models as compared with the nonhinged brace.

Does biomechanical comparison of 3 ankle brace with and without free rotation in the sagittal plane?

Remission, the primary goal of treatment for major depressive disorder (MDD), is the absence of significant signs or symptoms and the return to a state of normal functioning. A recent study found that the level of brain-derived neurotrophic factor (BDNF) increased after antidepressant treatment in remitted patients. This study evaluated serum BDNF levels in MDD patients with chronic maintenance treatment, and compared these between remission and nonremission groups. Serum BDNF levels were measured in 34 MDD patients and 35 healthy controls. The severity of depression was measured using the Hamilton Depression Rating Scale (Ham-D). The MDD patients were divided into remission and nonremission groups according to a cutoff total Ham-D score of either ≤7 or ≤6. Serum BDNF levels differed significantly between the remission, nonremission, and healthy control groups (P<0.05). The Bonferroni post hoc test confirmed that serum BDNF levels were significantly lower in the nonremission group than in the healthy-control group (P<0.05), but did not differ significantly between the remission and healthy-control groups.

Are lower serum brain-derived neurotrophic factor levels associated with failure to achieve remission in patients with major depression after escitalopram treatment?

Cerebral ischemia upregulates aquaporin-4 expression, increases blood-brain barrier (BBB) permeability, and induces brain edema. Mesenchymal stem cells (MSCs) can repress inflammatory cytokines and show great potential for ischemic stroke therapy. However, the effect of MSCs regarding the protection of ischemia-induced BBB break down is unknown. We test whether MSCs therapy protects BBB integrity and explore the molecular mechanisms of aquaporin-4 on BBB integrity. Two hundred and twenty-eight adult CD1 male mice underwent 90 minutes transient middle cerebral artery occlusion and received 2 × 10(5) MSCs intracranial transplantation. The neurological severity score was improved and both ischemia-induced brain edema and BBB leakage were reduced in MSC-treated mice. MSCs therapy reduced astrocyte apoptosis and inhibited ischemia-induced aquaporin-4 upregulation. In addition, small-interfering RNA knockdown of aquaporin-4 after cerebral ischemia effectively reduced aquaporin-4 expression, brain edema, BBB leakage, and astrocyte apoptosis. Conditional medium from lipopolysaccharide (LPS)-activated microglia enhanced aquaporin-4 expression, p38 and JNK phosphorylation, and apoptosis of cultured astrocytes. MSC treatment reduced the expression of inflammatory cytokines in LPS-activated microglia, and subsequently reduced aquaporin-4 expression and apoptosis of astrocytes. Knockdown of aquaporin-4 in cultured astrocytes also reduced apoptosis. Treatment with p38 and JNK inhibitors showed that p38, but not the JNK signaling pathway, was responsible for the aquaporin-4 upregulation.

Do mesenchymal stem cells maintain blood-brain barrier integrity by inhibiting aquaporin-4 upregulation after cerebral ischemia?

Two-dimensional speckle tracking echocardiography (2DSTE) has been used widely in research, but rarely in clinical practice because data acquisition and analysis are time-consuming. By reducing the acquisition and analysis time, 3-dimensional STE may improve clinical impact. We investigated the feasibility of 3DSTE myocardial deformation, with comparison to 2DSTE. Transthoracic 3DSTE and 2DSTE were performed in 230 adults (138 men, 51 ± 14 years, and 142 hypertension, 10 heart failure and 78 normotensive subjects). The variables of LV deformation were analyzed using EchoPAC software. The 3D LV longitudinal (LS) analysis was feasible in 84.9% of the study subjects, which was lower than the 2D analysis (97.2%). The success rates for circumferential strain (CS) and radial strain (RS) were similar between the 2D and 3D techniques. All magnitude of strains measured by 2DSTE and 3DSTE were significantly correlated. The magnitude of 3D LS and CS was lower, but the 3D RS is higher than that of 2DSTE (-18.5 ± 2.8 vs. -21.2 ± 3.5; 20.8 ± 4.1 vs. 21.7; and 50.0 ± 11.2 vs. 37.7 ± 12.6, respectively). Strains measured by 3DSTE exhibited stronger correlation with LV ejection fraction (EF) than that by 2DSTE. In inter- and intra-observer reproducibility for 3D LS, CS, RS and AS were acceptable. The mean time of analysis for LV volume, EF and strains was 116s by 3DSTE, which was significantly shorter than that by 2DSTE (5 min, P<0.0001).

Is three-dimensional speckle strain echocardiography more accurate and efficient than 2D strain in the evaluation of left ventricular function?

To compare single- with double-layer closure of the uterus for the risk of uterine rupture in women attempting vaginal birth after one prior caesarean delivery. Cohort study. Sweden. From a total of 19 604 nulliparous women delivered by caesarean section in the years 2001-2007, 7683 women attempting vaginal birth in their second delivery were analysed. Data from population-based registers were linked to hospital-based registers that held data from maternity and delivery records. Logistic regression was used to estimate the risk of uterine rupture after single- or double-layer closure of the uterus. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). Uterine rupture. Uterine rupture during labour occurred in 103 (1.3%) women. There was no increased risk of uterine rupture when single- was compared with double-layer closure of the uterus (OR 1.17; 95% CI 0.78-1.76). Maternal factors associated with uterine rupture were: age ≥35 years and height ≤160 cm. Factors from the first delivery associated with uterine rupture in a subsequent delivery were: infection and giving birth to an infant large for gestational age. Risk factors from the second delivery were induction of labour, use of epidural analgesia, and a birthweight of ≥4500 g.

Is the risk of uterine rupture increased with single- compared with double-layer closure : a Swedish cohort study?

Mannose-binding lectin (MBL) is a protein of the innate immune system that participates in host defense and the tissue injury/repair process, enhancing the clearance of apoptotic cells by macrophages. The aim is to characterize the relationship between pre-transplant MBL levels, histological lesions and number of apoptotic cells in early surveillance renal allograft biopsies. Consecutive renal transplant recipients were recruited and MBL levels were classified into tertiles. The first tertile was considered the low MBL group. Surveillance biopsies were done during the first 6 months and were evaluated according to Banff criteria. Renal inflammatory infiltrates were studied by immunohistochemical techniques. Apoptosis was studied using morphological methods in renal tubular cells and was expressed as the number of apoptotic cells/mm(2). MBL was determined in 126 patients and a surveillance biopsy with sufficient tissue was obtained in 41 of them. Patients with low pre-transplant MBL levels showed a higher acute Banff index (3.14 ± 1.96 vs. 1.88 ± 1.56, p = 0.044) and an increased proportion of biopsies with tubular cell apoptosis The proportion of biopsies with tubular cell apoptosis was higher in patients with low pre-transplant MBL levels in comparison with patients with high MBL levels (4.3 ± 3.6 versus 0.2 ± 0.9 p = 0.012) and increased interstitial number of inflammatory cells and significantly the macrophages/mm(2) (109 ± 118 vs. 32 ± 46; p = 0.04).

Are low serum mannose-binding lectin levels associated with inflammation and apoptosis in early surveillance allograft biopsies?

C-reactive protein (CRP) levels predict incident and recurrent cardiovascular disease (CVD) events; however, associations between CRP and pre-clinical atherosclerosis is less certain. Since high concentrations of high-density lipoprotein cholesterol (HDL-C) are inversely associated with CVD risk, we investigated whether HDL-C modified the association between CRP concentration and measures of preclinical atherosclerosis. Data were analyzed from a Korean occupational cohort of 12,030 male subjects who underwent a cardiac computed tomography (CT) estimation of coronary artery calcification (CAC) score and an assessment of CVD risk factors. Logistic regression was used to describe associations between CRP and measures of pre-clinical atherosclerosis, such as CAC scores >0. As many as 1351 (11.2%) participants had a CAC score>0. CRP was stratified into 3 groups based on clinical category: <1 mg/L, 1 to <2 mg/L, and ≥ 2 mg/dL. In the bottom CRP group, 907/8697 (10.4%) of subjects had a CAC score >0, compared with 242/1943 (12.5%) in the middle group and 202/1396 (14.5%) in the top CRP group (p < 0.0001). After adjustment for multiple CVD risk factors, there was a positive association between CRP and CAC score>0 (OR between top and bottom CRP groups, 1.41 [1.04, 1.90], p = 0.027) in the lowest HDL-C quartile but not in the highest HDL-C (OR between top and bottom CRP group, 0.80 [0.46, 1.39], p = 0.425).

Do hDL-C levels modify the association between C-reactive protein and coronary artery calcium score?

The COMFORT behaviour scale (COMFORT-B scale) is widely used in paediatric intensive care units to assess young children's pain and distress. It is also used to assess the impact of treatment interventions, but little is known on the scale's sensitivity to detect changes between before and after measurements following an intervention. This study explored the sensitivity to change of the COMFORT-B scale. COMFORT-B scores, originally and prospectively collected as part of standard care, were retrieved from the digital patient data management system. We analysed scores obtained in 747 paired observations, i.e., before and after a pharmacological intervention in 180 paediatric intensive care patients between September 2009 and September 2010. The mean scores before and after an intervention were 20.0 [standard deviation (SD) 3.7] and 14.1 (SD 4.7), respectively. Multilevel regression analysis showed a 6-point mean decline after an intervention (p < 0.0001). The magnitude of this decline was not statistically significantly related to number and type of interventions or time between assessments. In almost three-quarters of cases (74%), the COMFORT-B score dropped to below 17 after a pharmacological intervention, indicating good responsiveness.

Does the COMFORT behaviour scale detect clinically meaningful effects of analgesic and sedative treatment?

With rising obesity rates in children, it is increasingly difficult to differentiate between type 1 and type 2 diabetes mellitus (T1DM, T2DM) on clinical grounds alone. Using C-peptide as a method of classifying diabetes mellitus (DM) has been suggested. This study aimed to find a correlation between fasting C-peptide level and DM types in children and adolescents. A total of 223 diabetic children, newly diagnosed at 5 hospitals between January 2001 and December 2012, were enrolled in this study. Initial DM classification was based on clinical and laboratory data including fasting C-peptide at diagnosis; final classification was based on additional data (pancreatic autoantibodies, human leukocyte antigen type, and clinical course). Of 223 diabetic children, 140 were diagnosed with T1DM (62.8%) and the remaining 83 with T2DM (37.2%). The mean serum C-peptide level was significantly lower in children with T1DM (0.80 ng/mL) than in children with T2DM (3.91 ng/mL). Among 223 children, 54 had a serum C-peptide level <0.6 ng/mL; they were all diagnosed with T1DM. The proportion of children with T2DM increased in accordance with C-peptide level. Forty-nine of 223 children had a C-peptide level >3.0 ng/mL; 48 of them (97.9%) were diagnosed with T2DM.

Is fasting serum C-peptide useful for initial classification of diabetes mellitus in children and adolescents?

BRAT1 (BRCA1-associated ATM activator 1) interacts with both BRCA1, ATM and DNA-PKcs, and has been implicated in DNA damage responses. However, based on our previous results, it has been shown that BRAT1 may be involved in cell growth and apoptosis, besides DNA damage responses, implying that there are undiscovered functions for BRAT1. Using RNA interference against human BRAT1, we generated stable BRAT1 knockdown cancer cell lines of U2OS, Hela, and MDA-MA-231. We tested cell growth properties and in vitro/in vivo tumorigenic potentials of BRAT1 knockdown cells compared to control cells. To test if loss of BRAT1 induces metabolic abnormalities, we examined the rate of glycolysis, ATP production, and PDH activity in both BRAT1 knockdown and control cells. The role of BRAT1 in growth signaling was determined by the activation of Akt/Erk, and SC79, Akt activator was used for validation. By taking advantage of BRAT1 knockdown cancer cell lines, we found that loss of BRAT1 expression significantly decreases cell proliferation and tumorigenecity both in vitro and in vivo. Cell migration was also remarkably lowered when BRAT1 was depleted. Interestingly, glucose uptake and production of mitochondrial ROS (reactive oxygen species) are highly increased in BRAT1 knockdown HeLa cells. Furthermore, both basal and induced activity of Akt and Erk kinases were suppressed in these cells, implicating abnormality in signaling cascades for cellular growth. Consequently, treatment of BRAT1 knockdown cells with Akt activator can improve their proliferation and reduces mitochondrial ROS concentration.

Does bRAT1 deficiency cause increased glucose metabolism and mitochondrial malfunction?

Sophocarpine, a tetracyclic quinolizidine alkaloid derived from Sophora alopecuroides L., has been documented that it can suppress pro-inflammatory cytokines synthesis in alleviating nonalcoholic steatohepatitis (NASH) in vivo. Toll-like receptor 4 (TLR4) is a pattern recognition receptor whose activation results in the production of several pro-inflammatory cytokines. It has been reported that TLR4 is upregulated in nonalcoholic fatty liver disease and plays an important role in the pathogenesis of NASH. This study aimed to examine the changes of TLR4 and its signaling pathways in sophocarpine's anti-inflammatory process on experimental NASH in vitro. Primary hepatocytes were isolated, and oleic acid-induced steatosis model was established. Cell Counting Kit-8 assay was used to detect the number of metabolically active mitochondria and viable cells. Immunocytochemistry analysis was applied to evaluating pro-inflammatory cytokines synthesis. Total RNA and protein were extracted for real-time polymerase chain reaction and Western blot detection. Enhanced expression of TLR4 was observed in oleic acid-induced steatotic hepatocytes. Sophocarpine suppressed pro-inflammatory cytokines synthesis and reduced the expression of TLR4 in steatotic hepatocytes. Expression of TLR4 and pro-inflammatory cytokines recovered after sophocarpine was removed. Moreover, sophocarpine restrained the activation of nuclear factor-kappaB (NF-κB), c-Jun-N-terminal kinase (JNK), and Extracellular regulated protein kinases (ERK) signaling pathways in the anti-inflammatory process.

Does sophocarpine attenuate toll-like receptor 4 in steatotic hepatocytes to suppress pro-inflammatory cytokines synthesis?

Hypocalcemia is the most common complication after total thyroidectomy. Some patients need to stay in the hospital for monitoring of hypocalcemic symptoms and serum calcium levels for several days. We investigated the efficacy and safety of using early postoperative parathyroid hormone (PTH) results for early discharge after thyroidectomy. A retrospective cohort study of 2 sequential groups of patients undergoing total thyroidectomy between January 2010 and March 2013 was undertaken. Patients were divided into 2 groups. In Group 1 (before June 2011), patients had daily monitoring of serum calcium level and hypocalcemic symptoms. They were discharged when calcium level was static and asymptomatic. Postoperative PTH was not utilized for discharge plan. In Group 2 (after June 2011), postoperative PTH and calcium level on day 1 were utilized to dictate subsequent management and discharge plan. Of the 107 patients reviewed, 54 (50.5%) were in Group 1 and 53 (49.5%) were in Group 2. A total of 51 (47.7%) patients developed hypocalcemia. The two groups were comparable in demographic data, early postoperative PTH value, rate of hypocalcemia, the need for oral calcium and vitamin D supplements and rate of permanent hypoparathyroidism. Fewer patients in Group 2 experienced hypocalcemic symptoms, p=0.005. None of the patients in Group 2 needed intravenous calcium supplement (p=0.003). The median postoperative hospital stay for Group 1 was 4 days and for Group 2 was 1 day (p<0.0001).

Does postoperative PTH monitoring of hypocalcemia expedite discharge after thyroidectomy?

Single-incision laparoscopic colectomy (SILC) is one of several promising operation choices. Our previous study demonstrated that SILC with a self-made glove-port system both improves the feasibility of SILC and decreases the cost expense of surgery. Because the incision site for SILC could be made at either the umbilicus or McBurney's point, we are interested in whether the incision site affects the outcomes of patients, which is a less explored topic. The purpose of this study is not only to show the results of SILC with a self-made glove-port system for supporting its feasibility, but also to compare the short-term surgical outcomes between SILC with the incision made at the umbilicus and at McBurney's point. We collected and reviewed the medical records of patients who received SILC with a self-made glove-port system for tumors in the left side of the colon from August 2009 to March 2011. All operations were performed by a single surgeon. Comparisons of the demographic characteristics, perioperative data, and clinical outcomes between umbilical and McBurney's SILCs were performed. Postoperative pain was assessed by a visual analog scale and opiate demand. In total, 61 patients were enrolled in this retrospective study. Five of 48 (10.4%) tumors in the umbilical SILC group and 5 of 13 (38.5%) tumors in the McBurney's SILC group were located below the peritoneal reflection. The tumor location was significantly different between these two groups (P=.015). Patients in the umbilical SILC group had significantly higher frequency of opiate demand than those in the McBurney's SILC group (0.4±0.7 versus 1.4±1.8, respectively; P=.002).

Does the application of McBurney 's single-incision laparoscopic colectomy alleviate the response of patients to postoperative wound pain?

Bortezomib-induced peripheral neuropathy (BIPN) is a significant neurotoxicity, requiring dose reduction or the delay of treatment. In a multicentre trial including 97 % Caucasians and 3 % Asians, BIPN was shown to occur less frequently in cases in which bortezomib was administered subcutaneously. Considering the different pharmacokinetics between Caucasians and Asians, we analysed BIPN according to the administration route, specifically in Korean myeloma patients. We surveyed the prescribed anticonvulsants for the treatment of BIPN and analysed the data after stratifying the results by the cumulative dose of bortezomib. Exclusion criteria were as follows: treated with <2 doses of bortezomib, change in the administration route during the treatment, or receiving anticonvulsants for other reasons prior to bortezomib administration. A total of 101 patients were enrolled; 60 were treated with bortezomib and dexamethasone, and 37 were treated with bortezomib, melphalan, and prednisolone. The median number of treatment courses was four for each regimens. The median exposure to bortezomib for all patients was 19 mg/m(2). Progression-free survival (PFS) and overall survival rates were not statistically different between the groups. There was no difference in the proportion of patients requiring medical treatment (p = 0.388). After stratifying the results, BIPN developed less frequently when bortezomib was administered subcutaneously rather than intravenously in patients receiving more than 23.4 mg/m(2) of bortezomib (p < 0.05).

Is bortezomib-associated peripheral neuropathy requiring medical treatment decreased by administering the medication by subcutaneous injection in Korean multiple myeloma patients?

Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function. To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity. Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens. Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression.

Does blockade of the programmed death-1 pathway restore sarcoidosis CD4 ( + ) T-cell proliferative capacity?

Despite recent advancements in post-cardiac arrest resuscitation, the optimal measurement of postarrest outcome remains unclear. We hypothesized that Cerebral Performance Category score can predict the long-term outcome of postarrest survivors who received targeted temperature management during their postarrest hospital care. Retrospective chart review. Two academic medical centers from May 2005 to December 2012. The medical records of 2,417 out-of-hospital and in-hospital patients post cardiac arrest were reviewed to identify 140 of 582 survivors who received targeted temperature management. None. The Cerebral Performance Category scores at hospital discharge were determined by three independent abstractors. The 1-month, 6-month, and 12-month survival of these patients was determined by reviewing hospital records and querying the Social Security Death Index and by follow-up telephone calls. The association of unadjusted long-term survival and adjusted survival with Cerebral Performance Category was calculated. Of the 2,417 patients who were identified to have undergone cardiac arrest, 24.1% (582/2,417) were successfully resuscitated, of whom 24.1% (140/582) received postarrest targeted temperature management. Overall, 42.9% of patients (60/140) were discharged with Cerebral Performance Category 1, 27.1% (38/140) with Cerebral Performance Category 2, 18.6% (26/140) with Cerebral Performance Category 3, and 11.4% (16/140) with Cerebral Performance Category 4. Cerebral Performance Category 1 survivors had the highest long-term survival followed by Cerebral Performance Categories 2 and 3, with Cerebral Performance Category 4 having the lowest long-term survival (p < 0.001, log-rank test). We found that Cerebral Performance Category 3 (hazard ratio = 3.62, p < 0.05) and Cerebral Performance Category 4 (hazard ratio = 12.73, p < 0.001) remained associated with worse survival after adjusting for age, gender, race, shockable rhythm, time to targeted temperature management initiation, total duration of resuscitation, withdrawal of care, and location of arrest.

Does cerebral performance category at hospital discharge predict long-term survival of cardiac arrest survivors receiving targeted temperature management*?

To determine the impact of prostate size on positive surgical margin (PSM) rates after robot-assisted radical prostatectomy (RARP) and the preoperative factors associated with PSM. In all, 1229 men underwent RARP by a single surgeon, from 2005 to August of 2013. Excluded were patients who had transurethral resection of the prostate, neoadjuvant therapy, clinically advanced cancer, and the first 200 performed cases (to reduce the effect of learning curve). Included were 815 patients who were then divided into three prostate size groups: <31 g (group 1), 31-45 g (group 2), >45 g (group 3). Multivariate analysis determined predictors of PSM and biochemical recurrence (BCR). Console time and blood loss increased with increasing prostate size. There were more high-grade tumours in group 1 (group 1 vs group 2 and group 3, 33.9% vs 25.1% and 25.6%, P = 0.003 and P = 0.005). PSM rates were higher in prostates of <45 g with preoperative PSA levels of >20 ng/dL, Gleason score ≥7, T3 tumour, and ≥3 positive biopsy cores. In group 1, preoperative stage T3 [odds ratio (OR) 3.94, P = 0.020] and ≥3 positive biopsy cores (OR 2.52, P = 0.043) were predictive of PSM, while a PSA level of >20 ng/dL predicted the occurrence of BCR (OR 5.34, P = 0.021). No preoperative factors predicted PSM or BCR for groups 2 and 3.

Is number of positive preoperative biopsy cores a predictor of positive surgical margins ( PSM ) in small prostates after robot-assisted radical prostatectomy ( RARP )?

Targeting the energy storing white adipose tissue (WAT) by pharmacological and dietary means in order to promote its conversion to energy expending "brite" cell type holds promise as an anti-obesity approach. Present study was designed to investigate/revisit the effect of capsaicin on adipogenic differentiation with special reference to induction of "brite" phenotype during differentiation of 3T3-L1 preadipocytes. Multiple techniques such as Ca2+ influx assay, Oil Red-O staining, nutrigenomic analysis in preadipocytes and matured adipocytes have been employed to understand the effect of capsaicin at different doses. In addition to in-vitro experiments, in-vivo studies were carried out in high-fat diet (HFD) fed rats treated with resiniferatoxin (RTX) (a TRPV1 agonist) and in mice administered capsaicin. TRPV1 channels are expressed in preadipocytes but not in adipocytes. In preadipocytes, both capsaicin and RTX stimulate Ca2+ influx in dose-dependent manner. This stimulation may be prevented by capsazepine, a TRPV1 antagonist. At lower doses, capsaicin inhibits lipid accumulation and stimulates TRPV1 gene expression, while at higher doses it enhances accumulation of lipids and suppresses expression of its receptor. In doses of 0.1-100 µM, capsaicin promotes expression of major pro-adipogenic factor PPARγ and some of its downstream targets. In concentrations of 1 µM, capsaicin up-regulates anti-adipogenic genes. Low-dose capsaicin treatment of 3T3-L1 preadipocytes differentiating into adipocytes results in increased expression of brown fat cell marker genes. In white adipose of mice, capsaicin administration leads to increase in browning-specific genes. Global TRPV1 ablation (i.p. by RTX administration) leads to increase in locomotor activity with no change in body weight.

Does capsaicin induce `` brite '' phenotype in differentiating 3T3-L1 preadipocytes?

Cytochrome c (Cyt c) is an apoptosis-initiating protein when released into the cytoplasm of eukaryotic cells and therefore a possible cancer drug candidate. Although proteins have been increasingly important as pharmaceutical agents, their chemical and physical instability during production, storage, and delivery remains a problem. Chemical glycosylation has been devised as a method to increase protein stability and thus enhance their long-lasting bioavailability. Three different molecular weight glycans (lactose and two dextrans with 1 kD and 10 kD) were chemically coupled to surface exposed Cyt c lysine (Lys) residues using succinimidyl chemistry via amide bonds. Five neo-glycoconjugates were synthesized, Lac4-Cyt-c, Lac9-Cyt-c, Dex5(10kD)-Cyt-c, Dex8(10kD)-Cyt-c, and Dex3(1kD)-Cyt-c. Subsequently, we investigated glycoconjugate structure, activity, and stability. Circular dichroism (CD) spectra demonstrated that Cyt c glycosylation did not cause significant changes to the secondary structure, while high glycosylation levels caused some minor tertiary structure perturbations. Functionality of the Cyt c glycoconjugates was determined by performing cell-free caspase 3 and caspase 9 induction assays and by measuring the peroxidase-like pseudo enzyme activity. The glycoconjugates showed ≥94% residual enzyme activity and 86 ± 3 to 95 ± 1% relative caspase 3 activation compared to non-modified Cyt c. Caspase 9 activation by the glycoconjugates was with 92 ± 7% to 96 ± 4% within the error the same as the caspase 3 activation. There were no major changes in Cyt c activity upon glycosylation. Incubation of Dex3(1 kD)-Cyt c with mercaptoethanol caused significant loss in the tertiary structure and a drop in caspase 3 and 9 activation to only 24 ± 8% and 26 ± 6%, respectively. This demonstrates that tertiary structure intactness of Cyt c was essential for apoptosis induction. Furthermore, glycosylation protected Cyt c from detrimental effects by some stresses (i.e., elevated temperature and humidity) and from proteolytic degradation. In addition, non-modified Cyt c was more susceptible to denaturation by a water-organic solvent interface than its glycoconjugates, important for the formulation in polymers.

Does chemical glycosylation of cytochrome c improve physical and chemical protein stability?

ErbB family receptor tyrosine kinases (ErbBs) play a role in cell adhesion and migration and are frequently overexpressed in esophageal squamous cell carcinomas (ESCCs) or esophageal adenocarcinomas (EACs). Targeting ErbBs by tyrosine kinase inhibitors (TKIs) may therefore limit esophageal cancer cell migration. Here, we studied the impact of TKIs on ErbB dimerization, cell signaling pathways, and cell migration in three esophageal cell lines: OE21 (ESCC), OE33 (EAC), and Het-1A (non-neoplastic esophageal epithelium). In OE21 cells, the TKIs erlotinib, gefitinib, and lapatinib slightly affected epidermal growth factor receptor EGFR/EGFR, but not EGFR/HER2 dimerization as detected by in situ proximity ligation assay (in situ PLA). Still, TKIs inhibited ERK1/2, Akt, STAT3, and RhoA activity in OE21 cells, as assessed by Western blot, antibody arrays, and Rho GTPase effector pull-down assays. This was accompanied by reduced OE21 cell migration, induction of focal adhesions, and actin cytoskeleton reorganization, as shown by Oris™ migration assay and focal adhesion kinase (FAK)/phalloidin staining. In contrast, in OE33 cells, only lapatinib decreased STAT5, Src family kinase (SFK), and FAK activity as well as β-catenin expression. This impeded cell migration and induced morphological changes in OE33 cells. No alterations were seen for the non-neoplastic Het-1A cells. Thus, we identified the ErbB signaling network as regulator of esophageal cancer cell's actin cytoskeleton, focal adhesions, and cell migration. ErbB targeted TKIs therefore also limit ESCC and EAC cell motility and migration.

Do erbB targeting inhibitors repress cell migration of esophageal squamous cell carcinoma and adenocarcinoma cells by distinct signaling pathways?

Hyperhomocysteinemia (HHcy) is associated with kidney disease and leads to atherosclerosis and thrombosis. Paraoxonase 1 (Pon1), a hydrolase that participates in homocysteine (Hcy) metabolism and is carried in the circulation on high-density lipoprotein, has also been linked to kidney disease and atherothrombosis. Pon1-knockout mice are susceptible to atherosclerosis and exhibit a kidney-associated phenotype, polyuria or urine dilution. We hypothesize that HHcy and Pon1 deficiency are toxic to kidney function because they impair metabolic pathways important for normal kidney homeostasis. We examined changes in the mouse kidney proteome induced by Pon1 gene deletion and dietary HHcy, using 2D IEF/SDS-PAGE gel electrophoresis and MALDI-TOF mass spectrometry. We found that the expression of ten mouse kidney proteins was altered by the Pon1(-/-) genotype or HHcy. Proteins involved in metabolism of lipid (ApoA-I), protein (Hspd1), carbohydrate (Pdhb, Fbp1-isoform2, Eno1), and energy (Ndufs8, Ldhd) were down-regulated. Proteins involved in lipid transport (Pebp1), oxidative stress response (Prdx2), and cellular detoxification (Glo1) were up-regulated. The kidney proteins altered by HHcy or Pon1 are also altered in renal disease.

Do paraoxonase 1 deficiency and hyperhomocysteinemia alter the expression of mouse kidney proteins involved in renal disease?

Endophytic bacteria do have several potential applications in medicine and in other various sectors of biotechnology including agriculture. Bacterial endophytes need to be explored for their potential applications in agricultural biotechnology. One of the potential applications of bacterial endophytes in agricultural is to enhance the growth of the agricultural crops. Hence, this study was undertaken to explore the plant growth promoting potential application of bacterial endophytes. The objective of this study was to examine the effect of endophytic bacteria from mangrove tree (Rhizophora apiculata Blume) for their efficacy in promoting seedling growth in rice. Eight endophytic bacterial isolates (EBIs) isolated from twig and petiole tissues of the mangrove were identified based on their 16S ribosomal ribonucleic acid (rRNA) gene sequence homology. Separately, surface sterilized paddy seeds were treated with cell-free broth and cell suspension of the EBIs. Rice seedlings were analyzed by various bioassays and data was recorded. The gene sequences of the isolates were closely related to two genera namely, Bacillus and Pantoea. Inoculation of EBIs from R. apiculata with rice seeds resulted in accelerated root and shoot growth with significant increase in chlorophyll content. Among the isolates, Pantoea ananatis (1MSE1) and Bacillus amyloliquefaciens (3MPE1) had shown predominance of activity. Endophytic invasion was recognized by the non-host by rapid accumulation of reactive oxygen species (ROS) and was counteracted by the production of hydrogen peroxide (H2O2) and lipid peroxide. The results demonstrated that EBIs from mangrove tree can increase the fitness of the rice seedlings under controlled conditions.

Do culturable bacterial endophytes isolated from Mangrove tree ( Rhizophora apiculata Blume ) enhance seedling growth in Rice?

This study is to investigate the mechanisms by which macrophage-activating lipopeptide-2 (MALP-2) induces heme oxygenase (HO)-1, a cytoprotective enzyme that catalyzes the degradation of heme, in human monocytes. Human monocytic THP-1 cells were cultured for transient transfection with plasmids and stimulation with MALP-2 for indicative time intervals. After incubation with MALP-2, cells were collected and disrupted, before being tested for promoter activity using luciferase assay. For analysis of proteins, immunoreactive bands were detected using an enhanced chemiluminescence Western blotting system, and the band intensity was measured by densitometryic analysis. For the detection of co-immunoprecipitation, SDS-PAGE was performed and the membranes were probed using respective antibodies. To investigate the cellular localization of NF-E2-related factor 2 (Nrf2), cells underwent immunofluorescence staining and confocal microscopy, and were analyzed using electrophoretic mobility shift assay. MALP-2-induced HO-1 expression and promoter activity were abrogated by transfection with dominant negative (DN) plasmids of TLR2 and TLR6, or their neutralizing antibodies. However, inhibition of MyD88 or transfection with the DN-MyD88 was insufficient to attenuate HO-1 expression. In contrast, mutation or silencing of MyD88 adapter-like (Mal) by DN-Mal or siRNA almost completely blocked HO-1 induction. Btk, c-Src and PI3K were also involved in MALP-2-induced HO-1 expression, as revealed by specific inhibitors LFM-A13, PP1 and LY294002, or by transfection with siRNA of c-Src. MALP-2-induced activation of PI3K was attenuated by transfection with DN mutant of Mal, and by pretreatment with LFM-A13 or PP1. Furthermore, MALP-2 stimulated the translocation of Nrf2 from the cytosol to the nucleus and Nrf2 binding to the ARE site in the HO-1 promoter, which could also be inhibited by pretreatment with a PI3K inhibitor, LY294002.

Does macrophage-activating lipopeptide-2 require Mal and PI3K for efficient induction of heme oxygenase-1?

Chronic cytomegalovirus (CMV) infection has been associated with immunosenescence and immunoactivation in the general population. In human immunodeficiency virus type 1 (HIV-1)-infected people, CMV coinfection, in addition to residual HIV replication and microbial translocation, has been proposed as a key factor in sustaining immune activation, even in individuals with a controlled HIV load. Patients from the ICONA Study with at least 1 CMV immunoglobulin G (IgG) test available without active CMV disease were included in the analysis. AIDS-defining event or AIDS-related death and severe non-AIDS-defining event or non-AIDS-related death were taken as clinical progression end points. Independent predictors of CMV were identified by multivariable logistic regression. Probabilities of reaching the end points were estimated by survival analyses. A total of 6111 subjects were included, of whom 5119 (83.3%) were CMV IgG positive at baseline. Patients with CMV IgG positivity at baseline were more likely to develop a severe non-AIDS-defining event/non-AIDS-related death (adjusted hazard ratio [HR], 1.53 [95% confidence interval {CI}, 1.08-2.16]. In particular, CMV seropositivity was an independent risk factor for cardiovascular and cerebrovascular diseases (adjusted HR, 2.27 [95% CI, .97-5.32]).

Is cytomegalovirus coinfection associated with an increased risk of severe non-AIDS-defining events in a large cohort of HIV-infected patients?

Diabetic nephropathy (DN) is a common complication in diabetics. Recent evidence suggests that neutrophil-lymphocyte ratio (NLR) affects the development and acceleration of some diabetic complications. Scholars have rarely investigated the relationship between DN and NLR. This study aims to evaluate the relationship between DN and NLR and estimate whether or not NLR is a reliable marker for early-stage DN. The study included 253 patients with type 2 diabetes mellitus, 115 of whom have early-stage DN. The control group was composed of 210 healthy age- and sex-matched subjects. The NLR values of the patients with diabetes were significantly higher than those of the healthy controls (P < 0·001), and the NLR values of the patients with early-stage DN were higher than those of the patients without DN (P < 0·001). Logistic regression analysis showed that the risk predictors of DN include NLR, creatinine, total cholesterol, systolic blood pressure, HbA1c and insulin resistance. NLR (P = 0·004, EXP(B) = 2·088, 95% CI = 1·271-3·429) levels positively correlated with DN. The DN odds ratio increased by a factor of 2·088 (95% CI, 1·271-3·429) for every one unit increase in NLR.

Is neutrophil-lymphocyte ratio a reliable predictive marker for early-stage diabetic nephropathy?

Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown. The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients. We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families.

Is the prevalence of CHD7 missense versus truncating mutations higher in patients with Kallmann syndrome than in typical CHARGE patients?

An oligonucleotide termed 'T-oligo' having sequence homology with telomere overhang has shown cytotoxicity in multiple cancers. We have demonstrated that T-oligo can induce apoptosis in androgen independent prostate cancer cell line DU-145. In this report, we evaluate the use of star-shaped tetraspermine (SSTS) for delivery of T-oligo. SSTS was synthesized from spermine and its intrinsic cytotoxicity towards DU-145 cells was compared with spermine and branched polyethyleneimine (bPEI). Atomistic molecular dynamic (MD) simulations were conducted to understand binding and complexation of spermine and SSTS with T-oligo. Complexation was also determined using gel electrophoresis and SYBR gold assay. Complexes were characterized for size, cellular uptake and antiproliferative effect. SSTS exhibited significantly lower toxicity than spermine and bPEI. Its affinity towards T-oligo was significantly higher than spermine as determined by experimental studies and confirmed by MD simulations and it formed stable complexes (TONPs) with T-oligo. TONPs facilitated cellular uptake and nuclear accumulation of T-oligo and their cytotoxic potential was observed at concentration several folds lower than that required for T-oligo alone.

Does star-shaped tetraspermine enhance cellular uptake and cytotoxicity of T-oligo in prostate cancer cells?

To examine the relationship between lexical tone perception and melodic pitch perception in Mandarin-speaking cochlear implant (CI) users and to investigate the influence of previous acoustic hearing on CI users' speech and music perception. Lexical tone perception and melodic contour identification (MCI) were measured in 21 prelingual and 11 postlingual young (aged 6-26 years) Mandarin-speaking CI users. Lexical tone recognition was measured for four tonal patterns: tone 1 (flat F0), tone 2 (rising F0), tone 3 (falling-rising F0), and tone 4 (falling F0). MCI was measured using nine five-note melodic patterns that contained changes in pitch contour, as well as different semitone spacing between notes. Lexical tone recognition was generally good (overall mean = 81% correct), and there was no significant difference between subject groups. MCI performance was generally poor (mean = 23% correct). MCI performance was significantly better for postlingual (mean = 32% correct) than for prelingual CI participants (mean = 18% correct). After correcting for outliers, there was no significant correlation between lexical tone recognition and MCI performance for prelingual or postlingual CI participants. Age at deafness was significantly correlated with MCI performance only for postlingual participants. CI experience was significantly correlated with MCI performance for both prelingual and postlingual participants. Duration of deafness was significantly correlated with tone recognition only for prelingual participants.

Do melodic pitch perception and lexical tone perception in Mandarin-speaking cochlear implant users?

Human induced pluripotent stem cells (iPSCs) play an important role in disease modeling and drug testing. However, the current methods are time-consuming and lack an isogenic control. This study sought to establish an efficient technology to generate human PSC-based disease models with isogenic control. The ion channel genes KCNQ1 and KCNH2 with dominant negative mutations causing long QT syndrome types 1 and 2, respectively, were stably integrated into a safe harbor AAVS1 locus using zinc finger nuclease technology. Patch-clamp recording revealed that the edited iPSC-derived cardiomyocytes (iPSC-CMs) displayed characteristic long QT syndrome phenotype and significant prolongation of the action potential duration compared with the unedited control cells. Finally, addition of nifedipine (L-type calcium channel blocker) or pinacidil (KATP-channel opener) shortened the action potential duration of iPSC-CMs, confirming the validity of isogenic iPSC lines for drug testing in the future.

Does genome editing of isogenic human induced pluripotent stem cells recapitulate long QT phenotype for drug testing?

To study the reasons that the seedless fruits of Siraitia grosvenorii developed to smaller ones. The differences of fruit expanding, gene expressing and cell development were investigated between the triploid and diploid fruits from two strains F050 and F049. The results showed the expanding of triploid fruits was stopped about 20 days after artificial pollination, 10 days earlier than the diploid fruits. Meanwhile, it was also investigated that aux expressing level in the triploid fruits was greatly higher than that in diploid fruits, while its ipt, cyt-p450, spds, cycB, cycD1, cycD3, cdkA, cdkB, exp and xth expressing level were greatly lower than that in diploid fruits. The majority of sarcocarp cells of the triploid fruits kept in the stage of small ones comparing with the diploid fruits.

Do [ Reasons that seedless fruits of Siraitia grosvenorii become small ]?

A computerized physician order entry (CPOE) system with embedded clinical decision support can reduce medication errors in hospitals, but might increase the time taken to generate orders. We aimed to quantify the effects of temporal (month, day of week, hour of shift) and other factors (grade of doctor, prior experience with the system, alert characteristics, and shift type) on the time taken to generate a prescription order. A large university teaching hospital using a locally developed CPOE system with an extensive audit database. We retrospectively analyzed prescription orders from the audit database between August 2011 and July 2012. The geometric mean time taken to generate a prescription order within the CPOE system was 11.75 s (95% CI 11.72 to 11.78). Time to prescribe was most affected by the display of high-level (24.59 s (24.43 to 24.76); p<0.001) or previously unseen (18.87 s (18.78 to 18.96); p<0.001) alerts. Prescribers took significantly less time at weekends (11.29 s (11.23 to 11.35)) than on weekdays (11.88 s (11.84 to 11.91); p<0.001), in the first (11.25 s (11.16 to 11.34); p<0.001) and final (11.56 s (11.47 to 11.66); p<0.001) hour of their shifts, and after the first month of using the system.

Do temporal and other factors that influence the time doctors take to prescribe using an electronic prescribing system?

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it is still lacking effective prognostic biomarkers so far. Previous results of the iTRAQ-based quantitative proteomics study (iTRAQ-2DLC-MS/MS) have shown that α-methylacyl-CoA racemase (AMACR) might be a promising prognostic biomarker for the early recurrence/metastasis of hepatocellular carcinoma (HCC). Here a large-scale cohort clinical study was performed to evaluate its prognostic potential. HCC samples from patients (n=158) were used for the construction of tissue microarray. The expression level of AMACR was determined by immunohistochemical staining. A large-scale cohort clinical study between the expression of AMACR and some major clinical parameter has been performed to assess the prognostic potential of AMACR for the early recurrence/metastasis of HCC. Some important clinical parameters such as α-fetoprotein, tumour numbers, dissemination to regional lymph nodes, tumour capsule and portal vein tumour thrombosis are significantly associated with the low expression of AMACR. The expression of AMACR was an independent factor for the survival of patients with HCC. The median survival time was 17 months in the low-expression group compared with 45 months in the high-expression group.

Does α-Methylacyl-CoA racemase ( AMACR ) serve as a prognostic biomarker for the early recurrence/metastasis of HCC?

To evaluate the immediate effects of indirect moxibustion, a traditional local thermal therapy, on renal hemodynamics by using Doppler ultrasonography (US). Prospective observational study of postintervention changes in several variables. Gifu University Hospital, Gifu, Japan. Eleven healthy persons (7 men and 4 women; mean age±standard deviation, 32.6±5.7 years) were enrolled. Indirect moxibustion was applied for 4 minutes to bilateral lower back acupuncture points (BL23). Each participant received 3 successive treatments. The main outcome measurement was resistive index (RI) in the renal segmental arteries. Blood flow variables, including RI, were measured for 6 renal segmental arteries by Doppler US at rest (baseline), immediately after completion of moxibustion (post 1), and 10 minutes later (post 2). Participants were monitored for adverse events during the intervention. The mean RI was 0.578±0.037 at baseline, 0.546±0.027 at post 1, and 0.547±0.032 at post 2. RI decreased significantly between post 1 and baseline (95% confidence interval [CI], -0.053 to -0.011; p=0.003) and between post 2 and baseline (95% CI, -0.052 to -0.009; p=0.005). No adverse events, such as burns, were observed.

Does traditional thermal therapy with indirect moxibustion decrease renal arterial resistive index?

Korean red ginseng (ginseng, Panax ginseng C.A. Meyer) has traditionally been used in the treatment of most ageing-related diseases, such as obesity, diabetes, and dyslipidemia, but the mechanism of the effects is unclear. The aim of this study was to determine the effects of ginseng on obesity in a mouse model of female obesity (obese female db/db mouse) and to investigate the mechanism of anti-obesity effects. After female db/db (B6.Cg-m Lepr(db)/++/J) mice were treated with 5% (w/w) ginseng for 13 weeks, variables and parameters of obesity and disorders related to obesity were examined. Blood vessel density and the expression of genes involved in angiogenesis were also measured. Mice treated with ginseng for 13 weeks had less body weight and lower adipose tissue mass compared to control, untreated mice. The size of adipocytes was smaller in visceral adipose tissues of ginseng-treated mice. Obesity-related complications, such as hepatic steatosis, hypertriglyceridemia, and hyperglycemia, were markedly improved in treated mice. Blood vessel density was lower in visceral adipose tissue sections from treated mice than those from control mice. Concomitantly, mRNA levels for VEGF-A and FGF-2 were lower in both visceral adipose tissue from treated mice and treated 3T3-L1 cells compared to those from untreated controls. Protein levels for VEGF were also lower in visceral adipose tissue from treated mice. In contrast, ginseng increased mRNA expression of genes responsible for energy expenditure and fatty acid β-oxidation in visceral adipose tissue during ginseng-induced weight reduction.

Does ginseng treatment reverse obesity and related disorders by inhibiting angiogenesis in female db/db mice?

We have described cerebrospinal fluid (CSF) myeloid microvesicles (MVs) as a marker of microglia activation during neuroinflammation in Alzheimer disease (AD), and characterized their ability to produce toxic amyloid β1-42 (Aβ1-42 ) oligomers from aggregated or soluble substrate. The aim of this study is to investigate the association of CSF myeloid MVs with neuroimaging, clinical, and paraclinical data in AD and mild cognitive impairment (MCI). We collected CSF from 106 AD patients, 51 MCI patients, and 29 neurologically healthy controls. We examined CSF myeloid MV content and AD markers. A subgroup of 34 AD and 21 MCI patients underwent structural and diffusion tensor MRI. Higher levels of myeloid MVs were found in the CSF of AD patients and MCI patients converting within 3 years relative to controls, but also, at a lower level, in MCI patients not converting to AD. CSF myeloid MVs were associated with Tau but not with Aβ1-42 CSF levels. CSF MVs levels correlated with white matter (WM) tract damage in MCI, and with hippocampal atrophy in AD.

Are myeloid microvesicles in cerebrospinal fluid associated with myelin damage and neuronal loss in mild cognitive impairment and Alzheimer disease?

Surgical debridement is often required to treat spinal infections. Successful surgery requires accurate localization of the active infections, however, current imaging technique still requires surgeons' experience to narrow the surgical fields to achieve less invasive procedures. To investigate the use of F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for successful surgical planning. Nine patients with suspected spinal infection underwent magnetic resonance imaging (MRI) and FDG-PET/CT before surgery to locate active foci of infections. The spinal structures were divided into seven compartments at each intervertebral disc level for a total of 315 compartments investigated. The same classification system was used to design operating fields for histological correlation. FDG-PET/CT diagnosed fewer compartments as active infection (34 compartments, 10.8%) than MRI (62 compartments, 19.7%, P  = 0.002). Surgical exploration was performed in 49 compartments, and demonstrated active infection in 25 compartments. The sensitivity / specificity of FDG-PET/CT was 100% / 79%, respectively, which was superior to those of MRI, 76% / 42%. Foci of active infection showed hypermetabolic activity with a SUVmax of 7.1 ± 2.6 (range, 3.0-12.7). Receiver operating characteristic (ROC) analysis indicated an optimal threshold for active spinal infection at a SUVmax of 4.2, corresponding to a sensitivity of 90.3% and specificity of 91.2%.

Does 18F-FDG-PET/CT better localize active spinal infection than MRI for successful minimally invasive surgery?

MicroRNA-222 (miR-222) has been shown to play a potential oncogenic role in bladder cancer. The aim of this study was to evaluate the expression of miR-222 in bladder cancer and its potential relevance to clinicopathological characteristics and patient survival. Surgical specimens of cancer tissue and adjacent normal tissue were obtained from 97 patients with bladder cancer. The relative expression levels of miR-222 in the cancer and the normal adjacent tissue were measured by quantitative reverse-transcriptase PCR. We analyzed their correlation with clinicopathological parameters and prognostic value. The expression level of miR-222 was significantly higher in tumor tissues than in corresponding non-cancerous tissues (5.46 ± 1.45 versus 1.92 ± 0.65, P <  0.0001), and a high expression of miR-222 was found to be significantly associated with tumor grade (P = 0.003) and tumor stage (P = 0.005). The miR-222 expression level was classified as high or low in relation to the median value (cutoff value = 5.15). Kaplan-Meier analysis showed that patients with higher levels of miR-222 had significantly poorer survival than those with lower expression of this miRNA in patients, with a 5-year overall survival of 29.53% and 52.75%, respectively (P = 0.0034). In the multivariate Cox proportional hazards analysis, which included miR-222 level, tumor grade, tumor stage, and tumor number, high miR-222 expression was independently associated with poor survival (P < 0.001; hazard ratio 6.17; 95% CI 2.33 to 10.39).

Is increased expression of miR-222 associated with poor prognosis in bladder cancer?

The integrity and evolution of lichen symbioses depend on a fine-tuned combination of algal and fungal genotypes. Geographically widespread species complexes of lichenized fungi can occur in habitats with slightly varying ecological conditions, and it remains unclear how this variation correlates with symbiont selectivity patterns in lichens. In an attempt to address this question, >300 samples were taken of the globally distributed and ecologically variable lichen-forming species complex Tephromela atra, together with closely allied species, in order to study genetic diversity and the selectivity patterns of their photobionts. Lichen thalli of T. atra and of closely related species T. grumosa, T. nashii and T. atrocaesia were collected from six continents, across 24 countries and 62 localities representing a wide range of habitats. Analyses of genetic diversity and phylogenetic relationships were carried out both for photobionts amplified directly from the lichen thalli and from those isolated in axenic cultures. Morphological and anatomical traits were studied with light and transmission electron microscopy in the isolated algal strains. Tephromela fungal species were found to associate with 12 lineages of Trebouxia. Five new clades demonstrate the still-unrecognized genetic diversity of lichen algae. Culturable, undescribed lineages were also characterized by phenotypic traits. Strong selectivity of the mycobionts for the photobionts was observed in six monophyletic Tephromela clades. Seven Trebouxia lineages were detected in the poorly resolved lineage T. atra sensu lato, where co-occurrence of multiple photobiont lineages in single thalli was repeatedly observed.

Does photobiont selectivity lead to ecological tolerance and evolutionary divergence in a polymorphic complex of lichenized fungi?

Left ventricular (LV) torsion is an important parameter of LV performance and can be influenced by several factors. Aim of this investigation was to evaluate whether QRS prolongation in left bundle branch block (LBBB) may influence global LV twist and twisting/untwisting rate in chronic systolic heart failure (HF) patients. We prospectively evaluated 30 healthy subjects (control group) and 100 chronic HF patients with severely impaired LV systolic function (ejection fraction ≤ 35%). Patients were divided into three groups according to QRS duration: A: QRS < 120 ms (n 49), B: 120 ≤ QRS ≤ 150 ms (n 28) and C: QRS > 150 ms (n 23). Patients in groups B and C presented LBBB. All subjects underwent standard trans-thoracic echocardiography and two-dimensional speckle-tracking echocardiography evaluation. Categorical variables were compared by the chi-square or the Fisher's exact test. Continuous variables were compared using the ANOVA test. Correlations between variables were analysed with linear regression. Control subjects presented higher torsion parameters, when compared with patients in any HF group. Among the three HF groups, no differences were detected in global twist (4.79 ± 3.54, 3.8 ± 3.0 and 4.15 ± 3.14 degrees, respectively), twist rate max (44.81 ± 25.03, 37.94 ± 19.09 and 37.61 ± 24.49 degrees s(-1), respectively) and untwist rate max (-36.31 ± 30.89, -27.68 ± 34.67 and -39.62 ± 26.27 degrees s(-1), respectively) (P>0.05 for all). At linear regression analysis, there was no relation between QRS duration and any torsion parameter (P>0.05 for all).

Does qRS duration in left bundle branch block affect left ventricular twisting in chronic systolic heart failure?

The appropriate management of patients with mitral regurgitation (MR) and left ventricular dysfunction (LVD) is controversial. The study aim was to determine whether the presence of contractile reserve (CR) assessed by dobutamine stress echocardiography (DSE) was associated with improved outcomes. Death and heart transplantation were analyzed as the primary outcomes associated with the presence of CR. A total of 125 consecutive patients (96 males, 29 females; mean age 60 +/- 12 years) with left ventricular ejection fraction (LVEF) < or = 35% and hemodynamically significant MR underwent DSE between 1999 and 2005. CR was defined as an increase in LVEF of > or = 10% during dobutamine infusion. Among 125 patients, 55 (43.0%) showed evidence of CR. Within five years after DSE, 24 patients (34.3%) in the CR- group and seven (12.7%) in the CR+ group had died or required heart transplantation (p < 0.01, log rank). After adjusting for age, baseline LVEF, NYHA class and moderate/severe tricuspid regurgitation (TR), CR remained an independent predictor of time to death or heart transplantation (HR 0.34; 95% CI: 0.15-0.76, p < 0.01). Improvement in the degree of MR was present at one year in 85.0% of CR+ patients, and in 62.5% of CR- patients (p = 0.03). An improvement of 5% in LVEF was noted in the CR+ group, compared to 0% in the CR- group (p = 0.04).

Does contractile reserve induced with dobutamine echocardiography predict outcome in patients with left ventricular dysfunction and mitral regurgitation?

Telomerase, a ribonucleoprotein enzyme mainly consisted of a catalytic protein subunit human telomerase reverse transcriptase (hTERT) and a human telomerase RNA component, is responsible for maintaining telomeres. Telomerase over-expression correlates significantly with tumors and is a prognostic marker. However, telomerase over-expression in breast cancers and the effect of telomerase inhibition as a candidate cancer therapy are unknown. We used the dominant-negative mutant of hTERT (DN-hTERT) to inhibit telomerase activity on human breast adenocarcinoma cell line MCF-7 by transfection. Telomeric repeat amplification protocol assays and real-time quantitative RT-PCR were performed to investigate telomerase activity as well as expression of hTERT. Telomere length was measured by the flow-fluorescence in situ hybridization assay. Cell proliferation was assessed by the WST-8 assay, and apoptosis was evaluated by flow cytometry. The tumor formation ability of MCF-7 cells was investigated by transplanting cells subcutaneously into BALB/c nude mice. Ectopic expression of DN-hTERT caused dramatically inhibition of telomerase activity and reduction of telomere length. Telomerase inhibition induced growth arrest and apoptosis of MCF7 cells in vitro and loss of tumorigenic properties in vivo.

Does inhibition of telomerase activity by dominant-negative hTERT retard the growth of breast cancer cells?

Management of cardiac surgery patients is a very standardized procedure in respective local institutions. Yet only very limited evidence exists concerning optimal indication, safety and efficacy of hemodynamic monitoring catecholamine and fluid therapy. Between April and May 2013, all 81 German anaesthesia departments involved in cardiac surgery care were asked to participate in a questionnaire addressing the institutional specific current practice in hemodynamic monitoring, catecholamine and volume therapy. 51 (63%) questionnaires were completed and returned. All participating centers used basic hemodynamic monitoring (i.e. invasive arterial blood pressure and central venous pressure), supplemented by transesophageal echocardiography. Pulmonary arterial catheter and calibrated trend monitoring devices were also routinely available. In contrast, non-calibrated trend monitoring and esophageal doppler ultrasound devices were not commonly in use. Cerebral oximetry is increasingly emerging, but lacks clear indications. The majority of patients undergoing cardiac surgery, especially in university hospitals, required catecholamines during perioperative care, In case of low cardiac output syndrome, dobutamine (32%), epinephrine (30%) or phosphodiesterase inhibitors (8%) were first choice. In case of hypotension following vasoplegia, norepinephrine (96%) represented the most common catecholamine. 88% of the participating centers reported regular use of colloid fluids, with hydroxyethyl starches (HES) being first choice (64%).

Does catecholamine and volume therapy for cardiac surgery in Germany -- result from a postal survey?

Low energy shock waves have been shown to induce angiogenesis, improve left ventricular ejection fraction and decrease angina symptoms in patients suffering from chronic ischemic heart disease. Whether there is as well an effect in acute ischemia was not yet investigated. Hind-limb ischemia was induced in 10-12 weeks old male C57/Bl6 wild-type mice by excision of the left femoral artery. Animals were randomly divided in a treatment group (SWT, 300 shock waves at 0.1 mJ/mm2, 5 Hz) and untreated controls (CTR), n = 10 per group. The treatment group received shock wave therapy immediately after surgery. Higher gene expression and protein levels of angiogenic factors VEGF-A and PlGF, as well as their receptors Flt-1 and KDR have been found. This resulted in significantly more vessels per high-power field in SWT compared to controls. Improvement of blood perfusion in treatment animals was confirmed by laser Doppler perfusion imaging. Receptor tyrosine kinase profiler revealed significant phosphorylation of VEGF receptor 2 as an underlying mechanism of action. The effect of VEGF signaling was abolished upon incubation with a VEGFR2 inhibitor indicating that the effect is indeed VEGFR 2 dependent.

Does low energy shock wave therapy induce angiogenesis in acute hind-limb ischemia via VEGF receptor 2 phosphorylation?

Accurate evaluation of the biological behavior of Gastrointestinal stromal tumor and careful selection of patients with a high risk for tumor recurrence are necessary. In the present study, we analyzed prognostic factors in patients with GIST. A total of 214 patients who had undergone curative resection of a localized primary gastric GIST without adjuvant therapy were enrolled in this retrospective study. Prognostic factors were analyzed. The growth pattern was classified as intramural, endoluminal, exoluminal, or mixed- type. On univariate and multivariate analyses, recurrence was predicted by exoluminal or mixed-type (hazard ratio [HR]=3.7, p=0.043), tumor size of >3.5 cm (HR=7.1, p=0.01), and mitotic rate of >5/50 high-power fields (HR=7.9, p<0.001).

Is macroscopic type a prognostic factor for recurrence-free survival after resection of gastric GIST?

To assess the identification accuracy of dynamic assessment (DA) of narrative ability in English for children learning English as a 2nd language. A DA task was administered to 54 children: 18 Spanish-English-speaking children with language impairment (LI); 18 age-, sex-, IQ- and language experience-matched typical control children; and an additional 18 age- and language experience-matched comparison children. A variety of quantitative and qualitative measures were collected in the pretest phase, the mediation phase, and the posttest phase of the study. Exploratory discriminant analysis was used to determine the set of measures that best differentiated among this group of children with and without LI. A combination of examiner ratings of modifiability (compliance, metacognition, and task orientation), DA story scores (setting, dialogue, and complexity of vocabulary), and ungrammaticality (derived from the posttest narrative sample) classified children with 80.6% to 97.2% accuracy.

Does dynamic assessment of narrative ability in English accurately identify language impairment in English language learners?

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.

Are adherence measurement and patient recruitment methods poor in intervention trials to improve patient adherence?

Spontaneous bacterial peritonitis (SBP) is associated with high mortality. Early paracentesis (EP) is essential for rapid diagnosis and optimal treatment. The aim of the study is to compare the outcomes of patients with SBP who received EP vs. delayed paracentesis (DP). Consecutive patients who were diagnosed with SBP (ascites neutrophil count ≥250 cells/mm(3) and clinical evidence of cirrhosis) <72 h from the first physician encounter at two centers were identified. EP was defined by receiving paracentesis <12 h and DP 12-72 h from hospitalization. Primary outcome was in-hospital mortality. The mean age of 239 patients with SBP was 53±10 years; mean Model for End-Stage Liver Disease (MELD) score was 22±9. In all, 98 (41%) patients who received DP had a higher in-hospital mortality (27% vs. 13%, P=0.007) compared with 141 (59%) who received EP. Furthermore, DP group had longer intensive care days (4.0±9.5 vs. 1.3±4.1, P=0.008), hospital days (13.0±14.7 vs. 8.4±7.4, P=0.005), and higher 3-month mortality (28/76, 37% vs. 21/98, 21%; P=0.03) compared with the EP group. Adjusting for MELD score ≥22 (adjusted odds ratio (AOR)=5.7, 95% confidence interval (CI)=1.8-18.5) and creatinine levels ≥1.5 mg/dl (AOR=3.2, 95% CI=1.4-7.2), DP was associated with increased in-hospital mortality (AOR=2.7, 95% CI=1.3-4.8). Each hour delay in paracentesis was associated with a 3.3% (95% CI=1.3-5.4%) increase in in-hospital mortality after adjusting for MELD score and creatinine levels.

Is delayed paracentesis associated with increased in-hospital mortality in patients with spontaneous bacterial peritonitis?

The aim of this study was to demonstrate the effect of low-level light therapy (LLLT) in an acute colitis model in mice. Low-level light therapy (LLLT) has been shown to be an effective treatment for various inflammatory processes such as oral mucositis and diabetic foot ulcers. Colitis was induced by dextran sodium sulfate (DSS) in mice in four blinded controlled studies (validation of model, efficacy study, and two studies for evaluation of optimal dose). LLLT was applied to the colon utilizing a small diameter endoscope with an LED-based light source in several wavelengths (440, 660, and 850 nm at 1 J/cm(2)) and then 850 nm at several doses (1, 0.5, 0.25, and 0.1 J/cm(2)). LLLT was initiated 1 day prior to induction of colitis and went on for the 6 day induction period as well as for the following 3-10 days. Dose was controlled by changing exposure time. Disease activity was scored endoscopically and by histopathological assessment. Statistically significant improvement in disease severity was observed in the treatment groups compared with the control groups. The three wavelengths used demonstrated efficacy, and a clear dose-response curve was observed for one of the wavelengths (850 nm). On day 11, colonoscopic scoring in the sham-treated mice increased from 7.9±1.3 to 12.2±2.2, while activity in all treated groups remained stable.

Does low-level light therapy induce mucosal healing in a murine model of dextran-sodium-sulfate induced colitis?

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.

Are toker cells of the nipple commonly associated with underlying sebaceous glands but not with lactiferous ducts?

Involved field radiotherapy (IFRT) after cytotoxic chemotherapy has become the standard of care in treating pediatric patients with Hodgkin lymphoma. However, recent interest in shrinking the treatment volume to involved node radiotherapy (INRT) may allow lower doses to critical organ structures. We dosimetrically compared IFRT and INRT treatment approaches. INRT treatment plans were retrospectively constructed from 17 consecutively treated pediatric patients identified with Hodgkin lymphoma who had been previously treated with conventional IFRT. The radiation doses delivered to organs-at-risk (OARs) with virtual INRT treatment plans based on INRT field design were then compared to the original IFRT treatment plans. Metrics for comparison included mean doses to organs and volumes of organ receiving at least 50% of the original prescription dose (V50%). A one-tailed, paired t-test was then performed to verify statistical significance at an alpha level of 0.05. All organs at risk compared in this investigation (kidneys, heart, thyroid, parotids, and lungs) had significantly lower doses of radiation with INRT when compared to IFRT (p<0.05). Furthermore, the volume of the breast receiving at least 50% of the initial prescription dose was statistically lower in the INRT plans.

Does involved-nodal radiation therapy lead to lower doses to critical organs-at-risk compared to involved-field radiation therapy?

Ibulocydine (IB), a novel prodrug of CDK inhibitor, has been reported to have anti-cancer effect in human hepatoma cells. In order to address its feasibility as a radiosensitizer to improve radiotherapeutic efficacy for human cancers, this study was designed. Human cancer cells of lung and colon were treated with IB and/or radiotherapy (RT). The cellular effects were assessed by CCK-8, clonogenic, flow cytometric, and western blotting assays. In vivo radiotherapeutic efficacy was evaluated using the xenograft mouse model. Combined treatment of IB and RT significantly reduced viability and survival fraction of the cells. Apoptotic cell death accompanied with activation of caspases, decrease in Bcl-2/Bax expression, loss of mitochondrial membrane potential (MMP) leading to release of cytochrome c into cytosol was observed. Recovery of Bcl-2 expression level by introducing Bcl-2 expressing plasmid DNA compromised the loss of MMP and apoptosis induced by IB and RT. In vivo therapeutic efficacy of combined treatment was verified in the xenograft mouse model, in which tumor growth was markedly delayed by RT with IB.

Does ibulocydine sensitize human cancers to radiotherapy by induction of mitochondria-mediated apoptosis?

Total hip replacement (THR) outcomes have been worse for patients with rheumatoid arthritis (RA) compared with those who have osteoarthritis (OA). Whether this remains true in contemporary patients with RA with a high use of disease-modifying and biologic therapy is unknown. The purpose of our study is to assess pain, function, and quality of life 2 years after primary THR, comparing patients with RA and patients with OA. Baseline and 2-year data were compared between validated patients with RA and patients with OA who were enrolled in a single-center THR registry between May 1, 2007, and February 25, 2011. There were 5666 eligible primary THR identified, of which 193 were for RA. RA THR had worse baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (44.8 vs 53.2, p < 0.001) and function (38.7 vs 49.9, p < 0.001) compared with OA. These differences remained after surgery: pain (88.4 vs 94.0, p < 0.001) and function (82.9 vs 91.8, p < 0.001). Patients with RA were as likely to have a significant improvement as patients with OA (Δ WOMAC > 10) in pain (94% vs 96%, p = 0.35) and function (95% vs 94%, p = 0.69), but were 4 times as likely to have worse function (WOMAC ≤ 60; 19% vs 4%, p < 0.001) and pain (12% vs 3%, p < 0.001). In multivariate logistic regression controlling for multiple potential confounders, RA increased the odds of poor postoperative function (OR 4.32, 95% CI 1.57-11.9), and in patients without a previous primary THR, worse postoperative pain (OR 3.17, 95% CI 1.06-9.53).

Are patients with rheumatoid arthritis more likely to have pain and poor function after total hip replacements than patients with osteoarthritis?

To investigate whether use of adalimumab decreases the frequency of attacks of anterior uveitis (AU) in patients with ankylosing spondylitis (AS). Consecutive patients with AS, visiting an outpatient clinic and treated for at least 12 weeks with adalimumab, were enrolled. The number of attacks of AU in the year before start and during treatment were assessed by patient history and ophthalmological controls. In the 77 patients a total of 52 AU attacks occurred in the year before baseline (68 attacks per 100 patient-yrs), whereas during adalimumab treatment 19 attacks were seen (14 per 100 patient-yrs; reduction rate 80%). Twenty-six patients with AU in the year before start of adalimumab treatment had recurrent attacks, with a median number of 2.0 AU attacks per year [interquartile range (IQR) 1.00-3.00], whereas during treatment this decreased to 10 patients with a median number of 0.56 attacks per year (IQR 0.30-0.75). Hence, the number of attacks per year decreased by 72% (p = 0.000).

Does adalimumab significantly reduce the recurrence rate of anterior uveitis in patients with ankylosing spondylitis?

Interleukin 22 (IL-22) plays an important role in the promotion of antimicrobial immunity. However, dysregulated IL-22 action leads to inflammation and is involved in autoimmune diseases, including systemic lupus erythematosus (SLE). IL-22 binding protein (IL-22BP) is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We investigated the expression and potential significance of serum and urinary IL-22BP levels in patients with SLE. A total of 112 patients with SLE and healthy control subjects participated in our study. Patients were classified according to kidney involvement and disease activity based on clinical and laboratory measures such as urinary sediment, proteinuria, kidney function, complement factor 3 (C3), C4, anti-dsDNA, disease activity index, and renal SLE disease activity index. The concentrations of IL-22BP and IL-22 were measured by ELISA. The expression of IL-22BP in the renal tissue was detected by immunohistochemistry. Patients with active renal disease had urinary levels of IL-22BP higher than (1) patients with active SLE but no renal involvement, (2) patients with a history of lupus nephritis in remission with no systemic disease activity and no history of renal involvement, and (3) control subjects. There was no difference in serum levels of IL-22BP among the groups. Urinary levels of IL-22BP in patients with active renal disease were positively correlated with SLE Disease Activity Index, Systemic Lupus International Collaborating Clinics renal activity score, and histological activity index. IL-22BP was highly expressed in renal tissue of patients with active renal disease. After 6 months of treatment, urinary IL-22BP levels decreased significantly in patients with complete response, but remained unchanged in those with partial or no response.

Do increased urinary interleukin 22 binding protein levels correlate with lupus nephritis activity?

Statins have been shown to possess antiinflammatory and immunomodulatory effects. In this study, we sought to determine if preoperative statin therapy is associated with a reduced frequency of postoperative acute respiratory distress syndrome (ARDS) in surgical populations at increased risk of developing ARDS. We performed a retrospective cohort evaluation of the association between preoperative statin therapy and early postoperative ARDS in patients undergoing elective high-risk thoracic and aortic vascular surgery. The association between preoperative statin therapy and postoperative ARDS was assessed using propensity-adjusted analyses to control for indication bias and confounding factors. Of 1845 patients, 722 were receiving preoperative statin therapy. One hundred twenty patients developed postoperative ARDS. Frequencies of ARDS among those receiving statin therapy versus those who were not was 7.2% and 6.1%, respectively (OR = 1.20; 95% CI, 0.83-1.75; P = 0.330). Neither the stratified propensity score analysis (pooled OR 0.93; 95% CI, 0.60-1.43) nor matched analysis (OR = 0.78; 95% CI, 0.48-1.27) identified a statistically significant association between preoperative statin administration and postoperative ARDS. When compared to matched controls, patients who developed postoperative ARDS did not differ in mortality (7.7% vs 8.8%, P = 0.51), hospital length of stay (21 days vs 15 days, P = 0.21), or ventilator-free days (24 days vs 25 days, P = 0.62).

Does preoperative statin administration protect against early postoperative acute respiratory distress syndrome : a retrospective cohort study?

In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase-sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type. A total of 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disk level. Two independent, clinically masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates. Relapsing MS (RMS) patients showed smaller SC GM areas than age- and sex-matched controls (p = 0.008) without significant differences in SC WM areas. Progressive MS patients showed smaller SC GM and SC WM areas compared to RMS patients (all p ≤ 0.004). SC GM, SC WM, and whole cord areas inversely correlated with EDSS (rho: -0.60, -0.32, -0.42, respectively; all p ≤ 0.001). The SC GM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, fluid-attenuated inversion recovery lesion load, T1 lesion load, SC WM area, number of SC T2 lesions, age, sex, and disease duration. Brain and spinal GM independently contributed to EDSS.

Does spinal cord gray matter atrophy correlate with multiple sclerosis disability?

In the presence of comorbidities the effectiveness of many cardioprotective strategies is blunted. The goal of this study was to assess in a hypertensive rat model if the early reperfusion with anti-hypertensive and pro-angiogenic Chromogranin A-derived peptide, Catestatin (CST:hCgA352-372; CST-Post), protects the heart via Reperfusion-Injury-Salvage-Kinases (RISK)-pathway activation, limiting infarct-size and apoptosis, and promoting angiogenetic factors (e.g., hypoxia inducible factor, HIF-1α, and endothelial nitric oxide synthase, eNOS, expression). The effects of CST-Post on infarct-size, apoptosis and pro-angiogenetic factors were studied in isolated hearts of spontaneously hypertensive rats (SHR), which underwent the following protocols: (a) 30-min ischemia and 120-min reperfusion (I/R); (b) 30-min ischemia and 20-min reperfusion (I/R-short), both with and without CST-Post (75 nM for 20-min at the beginning of reperfusion). In unprotected Wistar-Kyoto hearts, used as normal counterpart, infarct-size resulted smaller than in SHR. CST-Post reduced significantly infarct-size and improved post-ischemic cardiac function in both strains. After 20-min reperfusion, CST-Post induced S-nitrosylation of calcium channels and phosphorylation of RISK-pathway in WKY and SHR hearts. Yet specific inhibitors of the RISK pathway blocked the CST-Post protective effects against infarct in the 120-min reperfusion groups. Moreover, apoptosis (evaluated by TUNEL, ARC and cleaved caspase) was reduced by CST-Post. Importantly, CST-Post increased expression of pro-angiogenetic factors (i.e., HIF-1α and eNOS expression) after two-hour reperfusion.

Does catestatin increase the expression of anti-apoptotic and pro-angiogenetic factors in the post-ischemic hypertrophied heart of SHR?

Several studies have shown that contralateral prophylactic mastectomy (CPM) provides a disease-free and overall survival (OS) benefit in young women with estrogen receptor (ER)-negative breast cancer. We utilized the National Cancer Data Base to evaluate CPM's survival benefit for young women with early -stage breast cancer in the years that ER status was available. We selected 14,627 women ≤45 years of age with American Joint Committee on Cancer stage I-II breast cancer who underwent unilateral mastectomy or CPM from 2004 to 2006. Five-year OS was compared between those who had unilateral mastectomy and CPM using the Kaplan-Meier method and Cox regression analysis. A total of 10,289 (70.3 %) women underwent unilateral mastectomy and 4,338 (29.7 %) women underwent CPM. Median follow up was 6.1 years. After adjusting for patient age, race, insurance status, co-morbidities, year of diagnosis, ER status, tumor size, nodal status, grade, histology, facility type, facility location, use of adjuvant radiation and chemohormonal therapy, there was no difference in OS in women <45 years of age who underwent CPM compared towith those who underwent unilateral mastectomy (hazard ratio [HR] = 0.93; p = 0.39). In addition, Tthere was no improvement in OS in women <45 years of age with T1N0 tumors who underwent CPM versus unilateral mastectomy (HR = 0.85; p = 0.37) after adjusting for the aforementioned factors. Among women ≤45 years of age with ER-negative tumors who underwent CPM, there was no improvement in OS compared with women who underwent unilateral mastectomy (HR = 1.12; p = 0.32) after adjusting for the same aforementioned factors.

Does contralateral prophylactic mastectomy provide no survival benefit in young women with estrogen receptor-negative breast cancer?

Type 2 diabetes is known to be associated with elevated cardiovascular mortality. Pioglitazone improves blood pressure (BP) and pulse wave velocity (PWV), which is an arterial stiffness parameter. Arterial stiffness is closely associated with cardiovascular disease. However, PWV is correlated with BP. The cardio-ankle vascular index (CAVI) reflects arterial stiffness independent of BP. Pioglitazone improves PWV but reduces blood pressure. The aim of this study was to re-evaluate the effect of pioglitazone on arterial stiffness with CAVI. Sixty patients with type 2 diabetes mellitus and already on 500 mg/day of metformin received add-on therapy of pioglitazone 15 mg/day or glimepiride 1 mg/day for 6 months, during which time changes in their metabolic parameters and CAVI were observed. After 6 months of treatment, both pioglitazone (n=30) and glimepiride (n=30) improved fasting blood glucose and glycated hemoglobin. The changes in fasting blood glucose and glycated hemoglobin between the two groups were greater in the pioglitazone group. Systolic and diastolic BP was decreased in both groups, with no significant between-group differences. Only pioglitazone increased serum adiponectin levels, and the change in adiponectin between the pioglitazone and glimepiride groups was significantly different. CAVI was decreased significantly by pioglitazone but remained unchanged after treatment with glimepiride. The change in CAVI between the two groups was significantly different.

Does pioglitazone improve the cardio-ankle vascular index in patients with type 2 diabetes mellitus treated with metformin?

Alterations of adipocytokine levels and clinical parameters in non-alcoholic fatty liver disease (NAFLD) are crucial for the prognosis and complications of the diseases. However, the key adipocytokines independently associated with NAFLD have not been identified, and we aimed to investigate them. This study was conducted on a consecutive series of 210 Taiwanese NAFLD patients and 420 sex- and age-matched controls. Fatty liver was diagnosed by magnetic resonance spectroscopy. The enrolled subjects' body mass indexes, homeostasis model of assessment-insulin resistance, uric acid, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, blood pressure, metabolic syndrome (yes/no), alanine aminotransferase, aspartate aminotransferase-to-platelet ratio indexes, leptin, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) levels were analyzed to determine their association with NAFLD. Univariate analysis showed that all of the aforementioned factors were associated with NAFLD, whereas multivariate analysis revealed that only PAI-1 (odds ratio: 1.39, P = 0.039) was independently associated with NAFLD. Subgroup analysis showed that females consistently had higher leptin (P < 0.001) and adiponectin (P < 0.001) levels than males, whereas their PAI-1 levels were similar. Males with NAFLD had higher leptin but lower adiponectin levels than their subgroup counterparts (all P < 0.001). Among the female subgroups, hyperleptinemia and hypoadiponectinemia were only observed in the NAFLD patients ≥ 45 years.

Is plasminogen activator inhibitor-1 independently associated with non-alcoholic fatty liver disease whereas leptin and adiponectin vary between genders?

Continuous support from follicular CD4(+) T helper (Tfh) cells drives germinal center (GC) responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization. Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model.

Does germinal center B cell depletion diminish CD4+ follicular T helper cells in autoimmune mice?

To analyse if predictors of radiographic progression differ between patients treated with or without prednisolone in early rheumatoid arthritis (RA). Radiographs of hands and feet were assessed using the modified Sharp/van der Heijde score and radiographic progression was defined as an increase in the total Sharp score above 5.8 (the smallest detectable change). Prospective, randomised study of patients with early RA. Secondary level of care; six participating centres from southern Sweden; both urban and rural populations. In all, 225 patients, 64% women, with a diagnosis of RA according to the American College of Rheumatology criteria, were included if they were between 18 and 80 years of age and had a disease duration of less than 1 year. The patients were randomised to 7.5 mg prednisolone daily for 2 years (P-group; n=108) or no prednisolone (NoP-group; n=117) when they started with their first disease-modifying anti-rheumatic drug and were prospectively followed for 2 years. The frequency of patients with radiographic progression after 2 years was 26% in the P-group and 39% in the NoP-group (p=0.033). Relevant interactions between treatment and rheumatoid factor (RF) (p=0.061) and between treatment and anti-cyclic citrullinated peptide 2 (anti-CCP) (p=0.096) were found. RF and anti-CCP independently predicted radiographic progression only in the NoP-group, OR (95% CI) 9.4 (2.5 to 35.2), p=0.001 and OR (95% CI) 8.7 (2.5 to 31.3), p=0.001, respectively.

Do rheumatoid factor and anti-CCP predict progressive joint damage in patients with early rheumatoid arthritis treated with prednisolone : a randomised study?

Proteins from the ABC family (ATP-binding cassette) represent the largest known group of efflux pumps, responsible for transporting specific molecules across lipid membranes in both prokaryotic and eukaryotic organisms. In arthropods they have been shown to play a role in insecticide defense/resistance. The presence of ABC transporters and their possible association with insecticide transport have not yet been investigated in the mosquito Anopheles stephensi, the major vector of human malaria in the Middle East and South Asian regions. Here we investigated the presence and role of ABCs in transport of permethrin insecticide in a susceptible strain of this mosquito species. To identify ABC transporter genes we obtained a transcriptome from untreated larvae of An. stephensi and then compared it with the annotated transcriptome of Anopheles gambiae. To analyse the association between ABC transporters and permethrin we conducted bioassays with permethrin alone and in combination with an ABC inhibitor, and then we investigated expression profiles of the identified genes in larvae exposed to permethrin. Bioassays showed an increased mortality of mosquitoes when permethrin was used in combination with the ABC-transporter inhibitor. Genes for ABC transporters were detected in the transcriptome, and five were selected (AnstABCB2, AnstABCB3, AnstABCB4, AnstABCmember6 and AnstABCG4). An increased expression in one of them (AnstABCG4) was observed in larvae exposed to the LD50 dose of permethrin. Contrary to what was found in other insect species, no up-regulation was observed in the AnstABCB genes.

Are aBC transporters involved in defense against permethrin insecticide in the malaria vector Anopheles stephensi?

The molecular mechanisms underlying dysregulation of microRNAs have been documented in nasopharyngeal carcinoma (NPC). Our previous study demonstrated that plasma miR-124 was down-regulated in NPC using microarray analysis and quantitative PCR validation. Though growing studies showed that down-regulated miR-124 was closely related to tumourigenesis in various types of cancers, the role of miR-124 in NPC remains largely unknown. The expression level of miR-124 was evaluated in NPC cell lines and patient specimens using quantitative reverse transcription-PCR (Real-time qPCR). The clinicopathological significance of the resultant data was later analyzed. Then, we explored the role of miR-124 in NPC tumorigenesis by in vitro and in vivo experiments. Homo sapiens forkhead box Q1 (Foxq1) was confirmed as a novel direct target gene of miR-124 by the dual-luciferase assay and western bolt. We found that miR-124 was commonly down-regulated in NPC specimens and NPC cell lines. The expression of miR-124 was inversely correlation with clinical stages and marked on T stages. Then, the ectopic expression of miR-124 dramatically inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as tumor growth and metastasis in vivo. Furthermore, we identified Foxq1 as a novel direct target of miR-124. Functional studies showed that knockdown of Foxq1 inhibited cell growth, migration and invasion, whereas Foxq1 overexpression partially rescued the suppressive effect of miR-124 in NPC. In clinical specimens, Foxq1 was commonly up-regulated in NPC, and the level increased with clinical stages and T stages. Additionally, the level of Foxq1 was inversely correlated with miR-124.

Does miR-124 suppress tumor growth and metastasis by targeting Foxq1 in nasopharyngeal carcinoma?

Hashimoto's thyroiditis (HT) is considered to be a Th1-related autoimmune disease (AID). Recent studies revealed that Th17 lymphocytes (producing mostly IL-17, IL-21 and IL-22) play a major role in numerous AIDs commonly thought to be Th1 diseases. More recently, another subset of Th cells, which produce IL-22 and thus so-called Th-22, have been identified. Few data are available in the literature on the role of IL-22, the main soluble mediator of both Th17 and Th22 cells, in HT. Using IL-22 Quantikine ELISA Kit (lower limit of detection 0.7 pg/ml), we assayed serum levels of IL-22 in three groups of subjects: newly diagnosed HT patients (n=55, 5 males and 50 females, age 38±17 years), non-HT patients with nodular goiter (n=30, 4 males and 26 females, age 43±14 years) and an age- and sex-matched group of healthy individuals. HT patients were euthyroid and were not receiving any treatment. HT patients showed significantly higher levels of serum IL-22 (group A, 42±34 pg/ml) as compared to non-HT-goitrous patients (18±15 pg/ml; P<0.001) and healthy controls (20±13 pg/ml; P=0.014). Serum IL-22 levels did not differ between non-HT-goitrous patients and healthy controls (p=0.496). No significant correlation was found between serum levels of IL-22 and Tg-Ab, TPO-Ab or TSH in the HT patients.

Is serum interleukin-22 ( IL-22 ) increased in the early stage of Hashimoto 's thyroiditis compared to non-autoimmune thyroid disease and healthy controls?

Apart from transcription factors, little is known about the molecules that modulate the proliferation and differentiation of pancreatic endocrine cells. The early expression of tyrosine hydroxylase (TH) in a subset of glucagon(+) cells led us to investigate whether catecholamines have a role in beta cell development. We studied the immunohistochemical characteristics of TH-expressing cells in wild-type (Th (+/+) ) mice during early pancreas development, and analysed the endocrine pancreas phenotype of TH-deficient (Th (-/-) ) mice. We also studied the effect of dopamine addition and TH-inhibition on insulin-producing cells in explant cultures. In the mouse pancreas at embryonic day (E)12.5-E13.5, the ∼10% of early glucagon(+) cells that co-expressed TH rarely proliferated and did not express the precursor marker neurogenin 3 at E13.5. The number of insulin(+) cells in the Th (-/-) embryonic pancreas was decreased as compared with wild-type embryos at E13.5. While no changes in pancreatic and duodenal homeobox 1 (PDX1)(+)-progenitor cell number were observed between groups at E12.5, the number of neurogenin 3 and NK2 homeobox 2 (NKX2.2)-expressing cells was reduced in Th (-/-) embryonic pancreas, an effect that occurred in parallel with increased expression of the transcriptional repressor Hes1. The potential role of dopamine as a pro-beta cell stimulus was tested by treating pancreas explants with this catecholamine, which resulted in an increase in total insulin content and insulin(+) cells relative to control explants.

Is non-neural tyrosine hydroxylase , via modulation of endocrine pancreatic precursors , required for normal development of beta cells in the mouse pancreas?

Macrophage accumulation of cholesterol leads to foam cell formation which is a major pathological event of atherosclerosis. Recent studies have shown that microRNA (miR)-19b might play an important role in cholesterol metabolism and atherosclerotic diseases. Here, we have identified miR-19b binding to the 3'UTR of ATP-binding cassette transporter A1 (ABCA1) transporters, and further determined the potential roles of this novel interaction in atherogenesis. To investigate the molecular mechanisms involved in a miR-19b promotion of macrophage cholesterol accumulation and the development of aortic atherosclerosis. We performed bioinformatics analysis using online websites, and found that miR-19b was highly conserved during evolution and directly bound to ABCA1 mRNA with very low binding free energy. Luciferase reporter assay confirmed that miR-19b bound to 3110-3116 sites within ABCA1 3'UTR. MiR-19b directly regulated the expression levels of endogenous ABCA1 in foam cells derived from human THP-1 macrophages and mouse peritoneal macrophages (MPMs) as determined by qRT-PCR and western blot. Cholesterol transport assays revealed that miR-19b dramatically suppressed apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux, resulting in the increased levels of total cholesterol (TC), free cholesterol (FC) and cholesterol ester (CE) as revealed by HPLC. The excretion of (3)H-cholesterol originating from cholesterol-laden MPMs into feces was decreased in mice overexpressing miR-19b. Finally, we evaluated the proatherosclerotic role of miR-19b in apolipoprotein E deficient (apoE(-/-)) mice. Treatment with miR-19b precursor reduced plasma high-density lipoprotein (HDL) levels, but increased plasma low-density lipoprotein (LDL) levels. Consistently, miR-19b precursor treatment increased aortic plaque size and lipid content, but reduced collagen content and ABCA1 expression. In contrast, treatment with the inhibitory miR-19b antisense oligonucleotides (ASO) prevented or reversed these effects.

Does microRNA-19b promote macrophage cholesterol accumulation and aortic atherosclerosis by targeting ATP-binding cassette transporter A1?

Worldwide, each year, large numbers of women are referred for colposcopy following low-grade abnormal cervical cytology. Many have no visible abnormality on examination. The risk of cervical intra-epithelial neoplasia grade 2/3 (CIN2/3) in these women is low. It is unknown whether, for women, a normal colposcopy resolves the anxiety which often follows the receipt of an abnormal cytology result. We investigated the prevalence of adverse psychological outcomes over 30 months following a normal colposcopy. This cohort study was nested within the UK TOMBOLA randomized controlled trial. Women aged 20-59 years, with recent low-grade cytology, who had a satisfactory colposcopy examination and normal transformation zone, completed the Hospital Anxiety and Depression Scale (HADS) and Process Outcome Specific Measure (POSM) at recruitment and during follow-up (12, 18, 24 and 30 months post-recruitment). Outcomes included percentages reporting significant anxiety (HADS anxiety subscale score ≥11), significant depression (HADS depression subscale score ≥8) or worries about the result of the next cytology test, cervical cancer, having sex, future fertility and general health at each time point (point prevalence) and during follow-up (cumulative prevalence). The study included 727 women. All psychological measures (except depression) had high prevalence at recruitment, falling substantially by 12 months. During follow-up, the cumulative prevalence of significant anxiety was 27% and significant depression was 21%. The most frequently reported worry was that the next cytology test would be abnormal (cumulative prevalence of 71%; point prevalence of ≥50% at 12 and 18 months). The cumulative prevalence values of worries about cervical cancer, having sex and future fertility were 33%, 20% and 16%, respectively.

Does a normal colposcopy examination fail to provide psychological reassurance for women who have had low-grade abnormal cervical cytology?

Eph receptors, comprising the A- and B-subfamilies, are the largest family of receptor tyrosine kinases in the mammalian genome, and their function is critical for morphogenesis in a variety of contexts. Whereas signaling through B-type Ephs has been demonstrated to play a role in cleft lip and palate (CL/P), the involvement of A-type Ephs has not been examined in this context notwithstanding a recent genome-wide association study that identified the EPHA3 locus as a candidate for non-syndromic CL/P. Here, we present a systematic analysis of the gene expression patterns for the nine EphA receptors at progressive stages of mouse development and find that EphA3, EphA4, and EphA7 exhibit restricted overlapping patterns of expression during palate development. We find that homozygous mutation of EphA3 or compound homozygous mutation of EphA3 and EphA4 in mice does not result in defective midfacial development, supporting the possibility of redundant function with EphA7. We also document previously undescribed expression patterns in other tissues of the craniofacial complex including the lacrimal duct and salivary glands.

Does embryonic expression of EphA receptor genes in mice support their candidacy for involvement in cleft lip and palate?

MDC1A is a congenital neuromuscular disorder with developmentally complex and progressive pathologies that results from a deficiency in the protein laminin α2. MDC1A is associated with a multitude of pathologies, including increased apoptosis, inflammation and fibrosis. In order to assess and treat a complicated disease such as MDC1A, we must understand the natural history of the disease so that we can identify early disease drivers and pinpoint critical time periods for implementing potential therapies. We found that DyW mice show significantly impaired myogenesis and high levels of apoptosis as early as postnatal week 1. We also saw a surge of inflammatory response at the first week, marked by high levels of infiltrating macrophages, nuclear factor κB activation, osteopontin expression and overexpression of inflammatory cytokines. Fibrosis markers and related pathways were also observed to be elevated throughout early postnatal development in these mice, including periostin, collagen and fibronectin gene expression, as well as transforming growth factor β signaling. Interestingly, fibronectin was found to be the predominant fibrous protein of the extracellular matrix in early postnatal development. Lastly, we observed upregulation in various genes related to angiotensin signaling. We sought out to examine the dysregulation of various pathways throughout early development (postnatal weeks 1-4) in the DyW mouse, the most commonly used mouse model of laminin-deficient muscular dystrophy. Muscle function tests (stand-ups and retractions) as well as gene (qRT-PCR) and protein levels (western blot, ELISA), histology (H&E, picrosirius red staining) and immunohistochemistry (fibronectin, TUNEL assay) were used to assess dysregulation of matricelluar protieins.

Is dysregulation of matricellular proteins an early signature of pathology in laminin-deficient muscular dystrophy?

Tubuloglomerular feedback (TGF) is an important mechanism in control of signal nephron glomerular filtration rate. The oxidative stress in the macula densa, primarily determined by the interactions between nitric oxide (NO) and superoxide (O2-), is essential in maintaining the TGF responsiveness. However, few studies examining the interactions between and amount of NO and O2- generated by the macula densa during normal and hypertensive states. In this study, we used isolated perfused juxtaglomerular apparatus to directly measure the amount and also studied the interactions between NO and O2- in macula densa in both physiological and slow pressor Angiotensin II (Ang II)-induced hypertensive mice. We found that slow pressor Ang II at a dose of 600 ng kg(-1) min(-1) for two weeks increased mean arterial pressure by 26.1 ± 5.7 mmHg. TGF response increased from 3.4 ± 0.2 μm in control to 5.2 ± 0.2 μm in hypertensive mice. We first measured O2- generation by the macula densa and found it was undetectable in control mice. However, O2- generation by the macula densa increased to 21.4 ± 2.5 unit min(-1) in Ang II-induced hypertensive mice. We then measured NO generation and found that NO generation by the macula densa was 138.5 ± 9.3 unit min(-1) in control mice. The NO was undetectable in the macula densa in hypertensive mice infused with Ang II.

Does oxidative status in the macula densa modulate tubuloglomerular feedback responsiveness in angiotensin II-induced hypertension?

To date, Alphavirus infections and their most prominent member, chikungunya fever, a viral disease which first became apparent in Tanzania in 1953, have been very little investigated in regions without epidemic occurrence. Few data exist on burden of disease and socio-economic and environmental covariates disposing to infection. A cross-sectional seroprevalence study was undertaken in 1,215 persons from Mbeya region, South-Western Tanzania, to determine the seroprevalence of anti-Alphavirus IgG antibodies, and to investigate associated risk factors. 18% of 1,215 samples were positive for Alphavirus IgG. Seropositivity was associated with participant age, low to intermediate elevation, flat terrain and with IgG positivity for Rift Valley fever, Flaviviridae, and rickettsiae of the spotted fever group. When comparing the geographical distribution of Alphavirus seropositivity to that of Rift Valley fever, it was obvious that Alphaviruses had spread more widely throughout the study area, while Rift Valley fever was concentrated along the shore of Lake Malawi.

Does seroprevalence of alphavirus antibodies in a cross-sectional study in southwestern Tanzania suggest endemic circulation of chikungunya?