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Is obesity associated with increased postoperative complications after operative management of proximal humerus fractures?

Obesity has become a significant public health concern in the United States. The goal of this study was to assess the effect of obesity on postoperative complications after operative management of proximal humerus fractures by use of a national database. Patients who underwent operative management of a proximal humerus fracture were identified in a national database by Current Procedural Terminology codes for procedures in patients with International Classification of Diseases, Ninth Revision (ICD-9) codes for proximal humerus fracture, including (1) open reduction and internal fixation, (2) intramedullary nailing, (3) hemiarthroplasty, and (4) total shoulder arthroplasty. These groups were then divided into obese and nonobese cohorts by use of ICD-9 codes for obesity, morbid obesity, or body mass index >30. Each cohort was then assessed for local and systemic complications within 90 days and mortality within 2 years postoperatively. Odds ratios and 95% confidence intervals were calculated. From 2005 to 2011, 20,319 patients who underwent operative management of proximal humerus fractures were identified, including 14,833 (73.0%) open reduction and internal fixation, 1368 (9.2%) intramedullary nail, 3391 (16.7%) hemiarthroplasty, and 727 (3.6%) shoulder arthroplasty. Overall, 3794 patients (18.7%) were coded as obese, morbidly obese, or body mass index >30. In each operative group, obesity was associated with a substantial increase in local and systemic complications.

Obesity and its resultant medical comorbidities are associated with increased rates of postoperative complications after operative management of proximal humerus fractures. Obese patients for whom operative management of proximal humerus fractures is planned should be counseled preoperatively about their increased risk for postoperative complications.

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Is radiofrequency ablation a thyroid function-preserving treatment for patients with bilateral benign thyroid nodules?

To evaluate the efficacy and safety of radiofrequency (RF) ablation for treatment of bilateral thyroid nodules as well as preservation of thyroid function. Between January 2007 and October 2012, 18 patients (16 women and 2 men; mean age, 49.9 y; median age, 44 y; age range, 27-81 y) with bilateral thyroid nodules treated by RF ablation were included in this study. The inclusion criteria included bilateral thyroid nodules, pressure symptoms or cosmetic problems, cytologic confirmation of benignancy without atypical cells, and patient refusal of surgery. We used an RF generator (Cool-tip RF system [Covidien, Boulder, Colorado] or SSP-2000, Taewoong Medical Co, Ltd [Gyeonggi-do, Republic of Korea]) and an 18-gauge internally cooled electrode with 1-cm active tips (Cool-tip [Covidien] or Well-Point RF electrode [Taewoong Medical Co, Ltd]). RF ablation was conducted using the moving shot technique and a trans-isthmic approach. RF ablation was performed in separate sessions for nodules in each lobe. Follow-up ultrasound examinations were performed at 1-6 months, 6-12 months, and during the last month of follow-up. The diameter and volume of the nodule and clinical problems including cosmetic and symptom scores were evaluated before and after the procedure. The mean initial nodule size was 4.1 cm ± 1.9, although there was a significant decrease by the time of the last follow-up examination (range, 1-48 mo; mean, 18.1 mo ± 12.8; P < .001, 2.5 cm ± 1.4). The initial nodule volume was 24.4 mL ± 32.2 and was decreased at the last follow-up (6.3 mL ± 19.0, P < .001), with a mean volume reduction of 75.9% ± 19.0. The symptom (P < .001) and cosmetic (P < .001) scores were decreased. Serum hormone levels did not differ significantly before treatment and at the last follow-up (P > .05).

RF ablation improves cosmetic problems and symptoms and preserves thyroid function in patients with bilateral thyroid nodules.

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Does silence of MCL-1 upstream signaling by shRNA abrogate multiple myeloma growth?

Multiple myeloma (MM) is an incurable B-cell cancer with accumulated clonal abnormal plasma cells in bone marrow of patients. MCL-1 (myeloid cell leukemia sequence 1) protein is an anti-apoptotic molecule in MM cells and regulated by pro-inflammatory cytokine IL-6 and downstream signaling molecules STAT3, PI3K and MAPK. The purpose of this study is to investigate the effect of STAT3, PI3K and MAPK gene silence on MCL-1 expression in human MM cells and the consequence of cell survival. Lentivirus small hairpin RNA (shRNA) interference techniques were utilized to knock down STAT3, PI3K or MAPK genes. Gene and protein expression was quantified by quantitative real-time PCR and Western Blot. MM cell apoptosis was examined by annexin-V FITC/propidium iodide staining. Efficient silence of STAT3, PI3K, MAPK1 or MAPK2 gene robustly abrogated IL-6 enhanced MCL-1 expression and suppressed MM cell growth. Silencing STAT3 gene inhibited PI3K expression, silencing PI3K markedly abrogated STAT3 and MAPK production. Inhibition of MAPK2 gene by shMAPK2 suppressed STAT3, PI3K and MAPK1 expression in the cells. Silencing of STAT3, PI3K and MAPK2 together completely blocked MCL-1 expression in MM cells.

There is a syngeneic effect among the three independent STAT3, PI3K and MAPK2 survival-signaling pathways related to MCL-1 expression in MM cells. shRNAs silencing of STAT3, PI3K and MAPK2 together could provide an effective strategy to treat MM.

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Does pulse oximetry measure a lower heart rate at birth compared with electrocardiography?

To examine the effect of time after birth on heart rate (HR) measured by pulse oximetry (PO) (HRPO) and electrocardiography (ECG) (HRECG). HRECG and HRPO (collected at maximum sensitivity) were assessed in 53 term and preterm infants at birth. ECG electrodes and a PO sensor were attached as soon as possible and HRECG and HRPO were compared every 30 seconds from 1-10 minutes after birth. Data were compared using a Wilkinson signed-rank test. Clinical relevance (eg, HR <100 beats per minute [bpm] was tested using a McNemar test). Seven hundred fifty-five data pairs were analyzed. Median (IQR) gestational age was 37 (31-39) weeks. Mean (SD) starting time of PO and ECG data collection was 99 (33) vs 82 (26) seconds after birth (P = .001). In the first 2 minutes after birth, HRPO was significantly lower compared with HRECG (94 (67-144) vs 150 (91-153) bpm at 60 seconds (P < .05), 81 (60-109) vs 148 (83-170) bpm at 90 seconds (P < .001) and 83 (67-145) vs 158 (119-176) at 120 seconds (P < .001). A HR <100 bpm was more frequently observed with a PO than ECG in the first 2 minutes (64% vs 27% at 60 seconds (P = .05), 56% vs 26% at 90 seconds (P < .05) and 53% vs 21% at 120 seconds (P < .05). HR by ECG was verified by ultrasound for outflow from a subset of infants.

In infants at birth, HRPO is significantly lower compared with ECG with clinically important differences in the first minutes.

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Does brivaracetam differentially affect voltage-gated sodium currents without impairing sustained repetitive firing in neurons?

Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF). Brivaracetam investigations on the voltage-gated sodium current (I(Na)) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100-300 μM) experiments were performed in comparison with 100 μM carbamazepine (CBZ). Brivaracetam and CBZ reduced IN a in N1E-115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect I(Na) in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75-93%.

The lack of effect of BRV on SRF in neurons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties.

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Does ascorbic Acid ameliorate nicotine exposure induced impaired spatial memory performances in rats?

The long lasting behavioural and cognitive impairments in offspring prenatally exposed to nicotine have been confirmed in animal models. In the present study, we investigated the effect of ascorbic acid on prenatal nicotine exposure induced behavioral deficits in male offspring of rats. The pregnant Wistar dams were divided into four groups of six rats: control, vehicle control, nicotine and nicotine+ascorbic acid groups. The nicotine group received daily dose of subcutaneous injections of 0.96 mg/kg body weight (bw) nicotine free base throughout gestation. Pregnant dams in nicotine+ascorbic acid group were first given nicotine free base (0.96 mg/kg bw/day; subcutaneous route) followed by ascorbic acid (50 mg/kg bw/day, orally) daily throughout gestation. The cognitive function of male offspring of all the experimental groups was studied using Morris water maze test at postnatal day 40. Prenatal nicotine exposure altered spatial learning and memory in male offspring. However, treatment with ascorbic acid ameliorated these changes in rats.

Ascorbic acid supplementation was found to be effective in preventing the prenatal nicotine exposure induced cognitive deficits in rat offspring to some extent.

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Are glutathione s-transferase m1 and t1 gene polymorphisms associated with increased risk of gestational diabetes mellitus development?

The aim of this study was to investigate whether the glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) gene polymorphisms contributed to development of gestational diabetes mellitus (GDM). Fifty women with diagnosis of GDM and 50 control individuals without GDM or altered glucose intolerance during their pregnancy were enrolled in the study. Multiplex polimerase chain reaction-restriction fragment length polymorphism method was applied to determine the GSTM1 and GSTT1 gene polymorphisms. Genotypes were determined according to bands detected with the agarose gel electrophoresis. The difference in the frequencies of GSTM1 null genotypes between GDM and control groups was not statistically significant (60% and 54%, respectively). There was no statistically significant difference between GDM and control groups with respect to GSTT1 null genotype rates (22% and 20%, respectively).There was no statistically significant difference between GDM and control groups with respect to GSTT1 null genotype rates (22% and 20%, respectively).

This study shows no association between GST gene polymorphisms and GDM.

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Does heterologous expression of mutated HLA-G1 reduce alloreactivity of human dermal fibroblasts?

To engineer a stable HLA-G molecule and evaluate its immunomodulatory properties in transgenic human dermal fibroblasts (HDFs). A mutated HLA-G1 (mHLA-G1) molecule was generated by modifying the endoplasmic reticulum retrieval motif and 3'-untranslated region miRNA-binding sites of HLA-G1. Immunomodulatory properties of transgenic HDF-mHLA-G1 were evaluated in vitro. Stable mHLA-G1 expressing HDF cells were successfully generated and flow cytometry analysis revealed that mHLA-G1 efficiently localized to the cell surface. Natural killer cell-mediated cytolysis of HDF-mHLA-G1/green fluorescent protein (GFP) was reduced by 73% compared with HDF-GDP. HDF-mHLA-G1/GFP decreased phytohemagglutinin-activated peripheral blood mononuclear cell proliferation by 30% versus HDF-GFP.

We are the first to successfully create a human fibroblast source with reduced alloreactivity using a novel mHLA-G1 construct. This approach may be extended to other cell types including human embryonic stem cells for use in allogeneic transplantation for cell-based regenerative medicine applications.

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Does a cluster-randomized trial show telephone peer coaching for parents reduces children 's asthma morbidity?

Childhood asthma morbidity remains significant, especially in low-income children. Most often, asthma management is provided by the child's primary care provider. We sought to evaluate whether enhancing primary care management for persistent asthma with telephone-based peer coaching for parents reduced asthma impairment and risk in children 3 to 12 years old. Over 12 months, peer trainers provided parents with asthma management training by telephone (median, 18 calls) and encouraged physician partnership. The intervention was evaluated in a cluster-randomized trial of 11 intervention and 11 usual care pediatric practices (462 and 486 families, respectively). Patient outcomes were assessed by means of telephone interviews at 12 and 24 months conducted by observers blinded to intervention assignment and compared by using mixed-effects models, controlling for baseline values and clustering within practices. In a planned subgroup analysis we examined the heterogeneity of the intervention effect by insurance type (Medicaid vs other). After 12 months, intervention participation resulted in 20.9 (95% CI, 9.1-32.7) more symptom-free days per child than in the control group, and there was no difference in emergency department (ED) visits. After 24 months, ED visits were reduced (difference in mean visits/child, -0.28; 95% CI, -0.5 to -0.02), indicating a delayed intervention effect. In the Medicaid subgroup, after 12 months, intervention participation resulted in 42% fewer ED visits (difference in mean visits/child, -0.50; 95% CI, -0.81 to -0.18) and 62% fewer hospitalizations (difference in mean hospitalizations/child, -0.16; 95% CI, -0.30 to -0.014). Reductions in health care use endured through 24 months.

This pragmatic telephone-based peer-training intervention reduced asthma impairment. Asthma risk was reduced in children with Medicaid insurance.

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Is lipoprotein internalisation induced by oncogenic AMPK activation essential to maintain glioblastoma cell growth?

Metabolic adaptations are essential during tumour growth to maintain the high proliferation levels exhibited by cancer cells. In this study, we examined the transformations that occurred in the lipid metabolism in astrocytic tumours, and the possible role of the fuel-sensing enzyme AMPK. Metabolic targets might help design new and effective drugs for cancer. To accomplish this objective, we studied both mice and human astrocytic tumours. We first used a mouse model of astrocytoma driven by oncogenic H-RasV12 and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We then confirmed the results in human glioblastoma cell lines and in glioblastoma tissue samples from patients. We show that the high levels of activated AMPK, observed in astrocytic tumours, increase extracellular lipid internalisation and reduce energy expenditure by inhibiting 'de novo' fatty acid (FA) synthesis, which allows tumour cells to obtain building blocks and energy to be able to create new organelles and new cells.

Our findings demonstrate that AMPK plays a crucial role in glioblastoma cell growth and suggest that blocking lipoprotein receptors could potentially be used as a plausible therapeutic approach for these and other type of tumours with high levels of AMPK.

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Are tools for assessing the content of guidelines needed to enable their effective use -- a systematic comparison?

To ensure that clinical practice guidelines (CPGs) form a sound basis for decision-making in health care, it is necessary to be able to reliably assess and ensure their quality. This results in the need to assess the content of guidelines systematically, particularly with regard to the validity of their recommendations.The aim of the present analysis was to determine the suitability and applicability of frequently used assessment tools for evidence syntheses with regard to the assessment of guideline content. We conducted a systematic comparison and analysis of established tools for the assessment of evidence syntheses (guidelines, systematic reviews, health technology assessments). The tools analyzed were: ADAPTE, AGREE II, AMSTAR, GLIA and the INAHTA checklist. We analyzed methodological steps related to the assessment of the reliability and validity of guideline recommendations. Data were extracted and analyzed by two persons independently of one another. Widely used tools for the methodological assessment of evidence syntheses are not suitable for a comprehensive content-related assessment. They remain mostly at the level of assessment of the documentation of processes. Some tools assess selected content-related aspects, but operationalization is either unspecific or lacking.

None of the tools analyzed enables the structured and comprehensive assessment of the content of guideline recommendations with special regard to their reliability and validity. All tools contribute towards the judicious use of evidence syntheses by supporting their systematic development or assessment. However, further progress is needed, particularly with regard to the assessment of content quality. This includes comprehensive operationalization and documentation of the assessment process to ensure reliability and validity, and therefore to enable the effective use of trustworthy guidelines in the health care system.

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Is high blood eosinophil count a risk factor for future asthma exacerbations in adult persistent asthma?

Exacerbation-associated uncontrolled asthma represents a major public health problem. The relationship of elevated blood eosinophils to this process needs study. To determine whether a high blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma. By using electronic pharmacy and health care data from Kaiser Permanente Southern California, 2392 patients, ages 18 to 64 years, were identified who met the Health Effectiveness Data and Information Set 2-year criteria for persistent asthma, did not manifest chronic obstructive pulmonary disease and other major illnesses, and had a blood eosinophil determination in 2010. Exacerbations (primary outcome) were defined as asthma outpatient visits that required systemic corticosteroid dispensing within ±7 days or asthma emergency department visits or hospitalizations. A period of ≥8 days defined a new exacerbation. Multivariate modelling used negative binomial and Poisson regression to examine the association between a blood eosinophil count determined in 2010 and risk of exacerbations, and ≥7 short-acting β2-agonist (SABA) canisters dispensed (secondary outcome) in 2011 by adjusting for demographics, comorbidities, and asthma burden. The rate of asthma exacerbations in 2011 was 0.41 events per person year (95% CI, 0.37-0.45). Eosinophil count ≥400/mm(3) in 2010 was a risk factor for asthma exacerbations in 2011 (adjusted rate ratio 1.31 [95% CI, 1.07-1.60]; P = .009) and ≥7 SABA dispensed (adjusted risk ratio 1.17 [95% CI, 1.03-1.1.33]; P = .015).

A high blood eosinophil count is a risk factor for increased future asthma exacerbations and excessive short-acting β2-agonist use after adjustment of potential confounders in adults with persistent asthma, which suggests a higher disease burden in patients with asthma and with high blood eosinophil counts.

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Do phosphorus application and elevated CO2 enhance drought tolerance in field pea grown in a phosphorus-deficient vertisol?

Benefits to crop productivity arising from increasing CO2 fertilization may be offset by detrimental effects of global climate change, such as an increasing frequency of drought. Phosphorus (P) nutrition plays an important role in crop responses to water stress, but how elevated CO2 (eCO2) and P nutrition interact, especially in legumes, is unclear. This study aimed to elucidate whether P supply improves plant drought tolerance under eCO2. A soil-column experiment was conducted in a free air CO2 enrichment (SoilFACE) system. Field pea (Pisum sativum) was grown in a P-deficient vertisol, supplied with 15 mg P kg(-1) (deficient) or 60 mg P kg(-1) (adequate for crop growth) and exposed to ambient CO2 (aCO2; 380-400 ppm) or eCO2 (550-580 ppm). Drought treatments commenced at flowering. Measurements were taken of soil and leaf water content, photosynthesis, stomatal conductance, total soluble sugars and inorganic P content (Pi). Water-use efficiency was greatest under eCO2 when the plants were supplied with adequate P compared with other treatments irrespective of drought treatment. Elevated CO2 decreased stomatal conductance and transpiration rate, and increased the concentration of soluble sugars and relative water contents in leaves. Adequate P supply increased concentrations of soluble sugars and Pi in drought-stressed plants. Adequate P supply but not eCO2 increased root length distribution in deeper soil layers.

Phosphorus application and eCO2 interactively enhanced periodic drought tolerance in field pea as a result of decreased stomatal conductance, deeper rooting and high Pi availability for carbon assimilation in leaves.

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Do parental characteristics have a larger effect on children 's health behaviour than their body weight?

Parents take an important role in a child's development, but there is currently limited information on parental correlates with children's health behaviour. The purpose of this study, therefore, was to examine whether parental characteristics, such as body weight, TV consumption and sport participation, affect children's body weight and health behaviour. To examine the effects of parental characteristics on children's body weight and health behaviour, baseline data of 1,118 elementary school children (7.6 ± 0.4 years) participating in a school-based intervention in southwest Germany was used. Children's height and weight were measured and parent as well as child behaviour was assessed via questionnaire. BMI percentiles of children were positively associated with parental BMI (r = 0.2, p <0.01). Further, high parental TV time increased the odds for high TV time in children (OR mother= 2.2, OR father = 2.3) and parental club sport participation increased the odds for club sport participation in children (OR mother = 1.9, OR father = 1.7). The relationship between parental and child behaviour was stronger than the relationship between parental BMI and BMI percentiles of the child.

These results suggest that parental behaviour and role modeling provide an important contribution to childrens' health behaviour, especially at younger ages.

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Do elevated levels of preoperative circulating CD44⁺ lymphocytes and neutrophils predict poor survival for non-small cell lung cancer patients?

Certain circulating cells have been shown to predict the clinical outcome of several cancers. The objective of this study was to identify clinical, hematological and immunological predictors of prognosis in non-small cell lung cancer (NSCLC) patients. A retrospective study on a prevalent cohort of 225 NSCLC patients hospitalized at the Zhejiang Province Cancer Hospital (ZPCH) was conducted from August 1, 2006 to April 15, 2008. Circulating lymphocytes were measured by flow cytometry. WBC count and classification in peripheral blood were measured with a Coulter counter. We calculated the proportion of patients surviving after first hospital admission and hazard ratios (HR) using the Cox proportional hazards model. Elevated levels of preoperative circulating CD44(+) lymphocytes, WBCs and neutrophils indicated low cumulative survival. Clinical stage (HR: 2.292; 95% confidence interval (CI): 1.34-3.91, P=0.002), neutrophils (HR: 1.877; 95% CI: 1.34-2.62, P<0.001) and CD44(+) lymphocytes (HR: 1.018; 95% CI: 1.00-1.03, P=0.002) are independent predictors of survival in NSCLC patients, respectively. Elevated levels of CD44(+) lymphocytes and neutrophils correlated with distant metastasis and prognosis in NSCLC patients with stage III/IV, respectively.

CD44(+) lymphocytes along with neutrophils could serve as an independent prognostic marker for NSCLC patients.

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Does cardiac-specific ablation of synapse-associated protein SAP97 in mice decrease potassium currents but not sodium current?

Membrane-associated guanylate kinase (MAGUK) proteins are important determinants of ion channel organization in the plasma membrane. In the heart, the MAGUK protein SAP97, encoded by the DLG1 gene, interacts with several ion channels via their PDZ domain-binding motif and regulates their function and localization. The purpose of this study was to assess in vivo the role of SAP97 in the heart by generating a genetically modified mouse model in which SAP97 is suppressed exclusively in cardiomyocytes. SAP97(fl/fl) mice were generated by inserting loxP sequences flanking exons 1-3 of the SAP97 gene. SAP97(fl/fl) mice were crossed with αMHC-Cre mice to generate αMHC-Cre/SAP97(fl/fl) mice, thus resulting in a cardiomyocyte-specific deletion of SAP97. Quantitative reverse transcriptase-polymerase chain reaction, western blots, and immunostaining were performed to measure mRNA and protein expression levels, and ion channel localization. The patch-clamp technique was used to record ion currents and action potentials. Echocardiography and surface ECGs were performed on anesthetized mice. Action potential duration was greatly prolonged in αMHC-Cre/SAP97(fl/fl) cardiomyocytes compared to SAP97(fl/fl) controls, but maximal upstroke velocity was unchanged. This was consistent with the decreases observed in IK1, Ito, and IKur potassium currents and the absence of effect on the sodium current INa. Surface ECG revealed an increased corrected QT interval in αMHC-Cre/SAP97(fl/fl) mice.

These data suggest that ablation of SAP97 in the mouse heart mainly alters potassium channel function. Based on the important role of SAP97 in regulating the QT interval, DLG1 may be a susceptibility gene to be investigated in patients with congenital long QT syndrome.

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Does imaging DNA damage allow detection of preneoplasia in the BALB-neuT model of breast cancer?

A prominent feature of many human cancers is oncogene-driven activation of the DNA damage response (DDR) during early tumorigenesis. It has been shown previously that noninvasive imaging of the phosphorylated histone H2A variant H2AX, γH2AX, a DNA damage signaling protein, is possible using (111)In-labeled anti-γH2AX antibody conjugated to the cell-penetrating peptide transactivator of transcription (TAT). The purpose of this study was to investigate whether (111)In-anti-γH2AX-TAT detects the DDR during mammary oncogenesis in BALB-neuT mice. Mammary fat pads from BALB-neuT and wild-type mice (age, 40-106 d) were immunostained for γH2AX. (111)In-anti-γH2AX-TAT or a control probe was administered intravenously to BALB-neuT mice. SPECT was performed weekly and compared with tumor detection using palpation and dynamic contrast-enhanced MR imaging. γH2AX expression was elevated in hyperplastic lesions in the mammary fat pads of BALB-neuT mice aged 76-106 d, compared with normal fat pads from younger mice and carcinomas from older mice (13.5 ± 1.2 γH2AX foci/cell vs. 5.2 ± 1.5 [P < 0.05] and 3.4 ± 1.1 [P < 0.001], respectively). Serial SPECT imaging revealed a 2.5-fold increase in (111)In-anti-γH2AX-TAT accumulation in the mammary fat pads of mice aged 76-106 d, compared with control probe (P = 0.01). The median time to detection of neoplastic lesions by (111)In-anti-γH2AX-TAT (defined as >5% injected dose per gram of tissue) was 96 d, compared with 120 and 131 d for dynamic contrast-enhanced MR imaging and palpation, respectively (P < 0.001).

DDR imaging using (111)In-anti-γH2AX-TAT identified mammary tumors significantly earlier than MR imaging. Imaging the DDR holds promise for the detection of preneoplasia and as a technique for screening cancer-prone individuals.

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Does glioma-derived versican promote tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling?

Accumulation and infiltration of microglia/brain macrophages around and into glioma tissue promote tumor invasion and expansion. One tumor-promoting mechanism of microglia/brain macrophages is upregulation of membrane type 1 matrix metalloprotease (MT1-MMP), which promotes the degradation of extracellular matrix. MT1-MMP upregulation is induced by soluble factors released by glioma cells activating microglial Toll-like receptor 2 (TLR2). Versican identified by proteomics was silenced in glioma cells by short interference RNA and short hairpin RNA approaches and studied in vitro and after injection into mouse brains or organotypic brain slices. The splice variants V0/V1 of the endogenous TLR2 ligand versican are highly expressed in mouse and human glioma tissue. Versican-silenced gliomas induced less MT1-MMP expression in microglia both in vitro and in vivo, which resulted in smaller tumors and longer survival rates as compared with controls. Recombinant versican V1 induced significantly higher levels of MT1-MMP in wild-type microglia compared with untreated and treated TLR2 knockout microglial cells. Using glioma-injected organotypic brain slices, we found that the impact of versican signaling on glioma growth depended on the presence of microglia. Moreover, we found that TLR2 expression is upregulated in glioma-associated microglia but not in astrocytes. Additionally, an established TLR2 neutralizing antibody reduced glioma-induced microglial MT1-MMP expression as well as glioma growth ex vivo.

Our results show that versican released from glioma promotes tumor expansion through glioma-associated microglial/macrophage TLR2 signaling and subsequent expression of MT1-MMP. This signaling cascade might be a novel target for glioma therapies.

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Is care of patients undergoing vascular surgery at safety net public hospitals associated with higher cost but similar mortality to nonsafety net hospitals?

This study compared in-hospital mortality and resource utilization among vascular surgical patients at safety net public hospitals (SNPHs) with those at nonsafety net public hospitals (nSNPHs). The National Inpatient Sample (2003-2011) was queried to identify surgical patients with peripheral arterial disease (PAD), carotid stenosis, or nonruptured abdominal aorta aneurysm based on International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic and procedure codes. The cohort was then divided into SNPH and nSNPH groups according to the definition of SNPH used by the National Association of Public Hospitals. Clinical characteristics, length of stay, in-hospital mortality, and hospital charges were compared between groups. Advanced PAD was defined as that associated with rest pain or tissue loss. Statistical methods included bivariate χ(2) tests for categoric variables, t-tests for continuous variables, and multivariable linear and logistic regression to adjust for confounding variables (in-hospital mortality). We identified 306,438 patients operated on for PAD, carotid stenosis, and abdominal aortic aneurysm. Patients at SNPHs were younger, the percentage of female and minority patients was higher, and patients had a higher Elixhauser comorbidity index (P < .001). Nonelective admissions were more common among SNPH patients who presented with more advanced PAD (P > .05) and symptomatic carotid stenosis (P < .05). Patients at SNPHs had a significantly longer length of stay, higher hospital charges, and higher in-hospital mortality (P < .05 for all variables). Crude odds of mortality at SNPHs were 1.28 higher than at nSNPHs (95% confidence interval, 1.13-1.46; P < .001), but adjusted analyses revealed no statistically significant difference between the odds of in-hospital mortality at both hospital groups.

Patients undergoing vascular surgery at SNPHs, despite being younger, had higher comorbidities, presented more urgently with more advanced disease, and incurred higher costs than the SNPH cohort despite similar adjusted odds of in-hospital mortality. Delayed presentation and higher comorbidities are most likely related to poor access to routine and preventive health care for the SNPH patients.

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Does older age limit postbariatric surgery cognitive benefits : a preliminary investigation?

Bariatric surgery is associated with cognitive benefits, but the nature of such gains may be variable across demographically and clinically diverse persons. Older adults achieve less weight loss and resolution of fewer medical co-morbidities after surgery compared to younger patients and are also at heightened risk for nutritional deficiencies. However, no study has examined the influence of age on cognitive improvements after bariatric surgery. The objective of this study was to determine the effects of age on cognitive function postbariatric surgery. A total of 95 participants enrolled in the Longitudinal Assessment for Bariatric Surgery completed a computerized cognitive test battery before bariatric surgery and at 12-weeks and 12-months postoperatively. Baseline cognitive impairments were common. Significant improvements were found in attention/executive function and memory abilities 12-weeks and 12-months after surgery. Age was not associated with baseline cognitive test performance. Separate multivariable regression analyses controlling for baseline attention/executive function and memory also showed that age was not a significant predictor of 12-week or 12-month performances in these domains (P>.05 for all).

The present study provides preliminary evidence suggesting that older age does not preclude postbariatric surgery cognitive benefits. Prospective studies in more age diverse samples (i.e., up to 70 yr) are needed to determine whether bariatric surgery can reduce risk of age-related neurologic conditions like Alzheimer's disease and stroke.

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Is self-reported sleep disturbance associated with Alzheimer 's disease risk in men?

To study the association between self-reported sleep disturbances and dementia risk. Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1-40 and 1-42 were measured at ages 70, 77, and 82 years. Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Aβ levels.

Improving sleep quality may help reduce the neurodegenerative risk in older men.

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Does a group of segmental premotor interneurons regulate the speed of axial locomotion in Drosophila larvae?

Animals control the speed of motion to meet behavioral demands. Yet, the underlying neuronal mechanisms remain poorly understood. Here we show that a class of segmentally arrayed local interneurons (period-positive median segmental interneurons, or PMSIs) regulates the speed of peristaltic locomotion in Drosophila larvae. PMSIs formed glutamatergic synapses on motor neurons and, when optogenetically activated, inhibited motor activity, indicating that they are inhibitory premotor interneurons. Calcium imaging showed that PMSIs are rhythmically active during peristalsis with a short time delay in relation to motor neurons. Optogenetic silencing of these neurons elongated the duration of motor bursting and greatly reduced the speed of larval locomotion.

Our results suggest that PMSIs control the speed of axial locomotion by limiting, via inhibition, the duration of motor outputs in each segment. Similar mechanisms are found in the regulation of mammalian limb locomotion, suggesting that common strategies may be used to control the speed of animal movements in a diversity of species.

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Do plasma membrane-targeted PIN proteins drive shoot development in a moss?

Plant body plans arise by the activity of meristematic growing tips during development and radiated independently in the gametophyte (n) and sporophyte (2n) stages of the life cycle during evolution. Although auxin and its intercellular transport by PIN family efflux carriers are primary regulators of sporophytic shoot development in flowering plants, the extent of conservation in PIN function within the land plants and the mechanisms regulating bryophyte gametophytic shoot development are largely unknown. We have found that treating gametophytic shoots of the moss Physcomitrella patens with exogenous auxins and auxin transport inhibitors disrupts apical function and leaf development. Two plasma membrane-targeted PIN proteins are expressed in leafy shoots, and pin mutants resemble plants treated with auxins or auxin transport inhibitors. PIN-mediated auxin transport regulates apical cell function, leaf initiation, leaf shape, and shoot tropisms in moss gametophytes. pin mutant sporophytes are sometimes branched, reproducing a phenotype only previously seen in the fossil record and in rare natural moss variants.

Our results show that PIN-mediated auxin transport is an ancient, conserved regulator of shoot development.

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Do axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties?

Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies associated with mutations or copy number variations in over 70 genes encoding proteins with fundamental roles in the development and function of Schwann cells and peripheral axons. Here, we used iPSC-derived cells to identify common pathophysiological mechanisms in axonal CMT. iPSC lines from patients with two distinct forms of axonal CMT (CMT2A and CMT2E) were differentiated into spinal cord motor neurons and used to study axonal structure and function and electrophysiological properties in vitro. iPSC-derived motor neurons exhibited gene and protein expression, ultrastructural and electrophysiological features of mature primary spinal cord motor neurons. Cytoskeletal abnormalities were found in neurons from a CMT2E (NEFL) patient and corroborated by a mouse model of the same NEFL point mutation. Abnormalities in mitochondrial trafficking were found in neurons derived from this patient, but were only mildly present in neurons from a CMT2A (MFN2) patient. Novel electrophysiological abnormalities, including reduced action potential threshold and abnormal channel current properties were observed in motor neurons derived from both of these patients.

Human iPSC-derived motor neurons from axonal CMT patients replicated key pathophysiological features observed in other models of MFN2 and NEFL mutations, including abnormal cytoskeletal and mitochondrial dynamics. Electrophysiological abnormalities found in axonal CMT iPSC-derived human motor neurons suggest that these cells are hyperexcitable and have altered sodium and calcium channel kinetics. These findings may provide a new therapeutic target for this group of heterogeneous inherited neuropathies.

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Does gastroprotective effect of the iridoid fraction from Barleria prionitis leave on experimentally-induced gastric ulceration?

To study the gastroprotective effect and in vivo antioxidant potential of a standardized iridoid fraction from B. prionitis leaves (BPE) against different gastric ulcer models in rats. The standardized iridoid fraction from BPE at 50, 100, and 200 mg/kg body weight was administered orally, twice daily for 5 days for prevention from aspirin, ethanol, cold-restraint stress (CRS), and pylorus ligation (PL)-induced ulcers. Estimation of the antioxidant enzyme activity was carried out in a CRS-induced ulcer model, and various gastric secretion parameters including volume of gastric juice, acid output, and pH value were estimated in the PL-induced ulcer model. BPE showed a dose-dependent ulcer protective effect in PL (18.67%-66.26% protection), aspirin (24.65%-63.25% protection), CRS (20.77%-59.42% protection), and EtOH (16.93%-77.04% protection)-induced ulcers. BPE treatment in PL-rats showed a decrease in acid-pepsin secretion, and enhanced mucin and mucosal glycoproteins. However, BPE reduced the ulcer index with significant decrease in LPO (P < 0.01-0.001), SOD (P < 0.01-0.001), and an increase in CAT (P < 0.01-0.001), activity in the CRS-induced model.

The data shows that the iridoid fraction from BPE possesses anti-ulcerogenic and antioxidant potential.

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Does tetramethylpyrazine protect lymphocytes from radiation-induced apoptosis through nuclear factor-κB?

Radiation induces an important apoptosis response in irradiated organs. The objective of this study was to investigate the radioprotective effect of tetramethylpyrazine (TMP) on irradiated lymphocytes and discover the possible mechanism of protection. Lymphocytes were pretreated for 12 h with TMP (25-200 μmol·L(-1)) and then exposed to 4 Gy radiation. Cell apoptosis and the signaling pathway were analyzed. Irradiation increased cell death, DNA fragmentation, activated caspase activation and cytochrome c translocation, downregulated B-cell lymphoma 2 (Bcl-2) and up-regulated Bcl-2-associated X protein (Bax). Pretreated with TMP significantly reversed this tendency. Several anti-apoptotic characteristics of TMP, including the ability to increase cell viability, inhibit caspase-9 activation, and upregulate Bcl-2 and down-regulate Bax in 4Gy-irradiated lymphocytes were determined. Signal pathway analysis showed TMP could translate nuclear factor-κB (NF-κB) from cytosol into the nucleus.

The results suggest that TMP had a radioprotective effect through the NF-κB pathway to inhibit apoptosis, and it may be an effective candidate for treating radiation diseases associated with cell apoptosis.

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Is persistent insomnia associated with mortality risk?

Insomnia has been associated with mortality risk, but whether this association is different in subjects with persistent vs intermittent insomnia is unclear. Additionally, the role of systemic inflammation in such an association is unknown. We used data from a community-based cohort to determine whether persistent or intermittent insomnia, defined based on persistence of symptoms over a 6-year period, was associated with death during the following 20 years of follow-up. We also determined whether changes in serum C-reactive protein (CRP) levels measured over 2 decades between study initiation and insomnia determination were different for the persistent, intermittent, and never insomnia groups. The results were adjusted for confounders such as age, sex, body mass index, smoking, physical activity, alcohol, and sedatives. Of the 1409 adult participants, 249 (18%) had intermittent and 128 (9%) had persistent insomnia. During a 20-year follow-up period, 318 participants died (118 due to cardiopulmonary disease). In adjusted Cox proportional-hazards models, participants with persistent insomnia (adjusted hazards ratio [HR] 1.58; 95% confidence interval [CI], 1.02-2.45) but not intermittent insomnia (HR 1.22; 95% CI, 0.86-1.74) were more likely to die than participants without insomnia. Serum CRP levels were higher and increased at a steeper rate in subjects with persistent insomnia as compared with intermittent (P = .04) or never (P = .004) insomnia. Although CRP levels were themselves associated with increased mortality (adjusted HR 1.36; 95% CI, 1.01-1.82; P = .04), adjustment for CRP levels did not notably change the association between persistent insomnia and mortality.

In a population-based cohort, persistent, and not intermittent, insomnia was associated with increased risk for all-cause and cardiopulmonary mortality and was associated with a steeper increase in inflammation.

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Does vitamin E attenuate neurotoxicity induced by deltamethrin in rats?

The safety of Deltamethrin (DM) has been raised as a point of concern. The current investigation was envisaged to explore the responsiveness of oxidative stress parameters, DNA fragmentation and expression levels of TP53, cycloxygenase 2 (COX2) and cytochrome p4502E1 (CYP2E1) as toxicological endpoint in rats treated with DM. as well as attention was provided to the neuroprotective effect of vitamin E (VE). Four different groups of rats were used in this study, group I served as control, group II received DM (0.6 mg/kg BW), group III received both DM plus VE and finally group IV received VE only (200 mg/kg BW). The treatment regimen was extending for one month for all groups and the brain tissues were collected for further analysis. The obtained results showed a highly statistically significant increase in lipid peroxidation (LPO) content, nitric oxide concentration, and DNA fragmentation percentage and expression level of CYP2E1, TP53 and COX2 genes, in addition statistical significant reduction in total antioxidant capacity in DM treated group as compared to control were detected. Oral administration of VE attenuated the neurotoxic effects of DM through improvement of oxidative status, DNA fragmentation percentage and suppressing the expression level of CYP2E1, TP53 and COX2 genes.

From this study we concluded that VE supplementation has beneficial impacts on DM neurotoxicity in rats through its antioxidant and antiapoptotic properties.

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Does glial cell line-derived neurotrophic factor promote β-catenin phosphorylation and nuclear translocation in glioma cells?

Glial cell line-derived neurotrophic factor (GDNF) and N-cadherin interact to transduce intracellular signals. However, the specific molecular mechanisms of this interaction are unclear. This study attempted to detect changes in GDNF-induced β-catenin phosphorylation and nuclear translocation in C6 glioma cells. C6 glioma cells were treated with GDNF (70 ng/mL) and membrane and cytoplasmic proteins were extracted. A N-cadherin antibody was used for co-immunoprecipitation (co-IP). Western blot analysis using the co-IP protein was completed using antibodies for β-catenin, Src and β-actin. Immunocytochemistry was conducted with the same antibodies. To determine if Src induced phosphorylation of β-catenin Tyr-654, Western blot analysis was also performed on nuclear proteins from C6 cells treated with tyrosine kinase inhibitor PP2 using then p- β-catenin antibody. After induced by GDNF, C6 cell membrane β-catenin was phosphorylated at Tyr-654 and subsequently separated from the N-cadherin/β-catenin complex. Further study confirmed that the induction by GDNF significantly increased cytoplasmic and nuclear expression of phospho-β-catenin (Tyr-654) in C6 glioma cells. There was also an increase in the binding of non-receptor protein kinase Src with N-cadherin on the inner cell membrane surface. Src induced phosphorylation of β-catenin Tyr-654 induced by GDNF decreased significantly.

The results of our study demonstrate that GDNF increases the intracellular phosphorylation level of β-catenin through N-cadherin/Src signaling, which subsequently stimulates the nuclear translocation of β-catenin. This study provides a theoretical basis for us to reveal the role of biological mechanisms on glioma cell by GDNF.

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Does statin treatment affect cytokine release and phagocytic activity in primary cultured microglia through two separable mechanisms?

As the primary immune cells of the central nervous system, microglia contribute to development, homeostasis, and plasticity of the central nervous system, in addition to their well characterized roles in the foreign body and inflammatory responses. Increasingly, inappropriate activation of microglia is being reported as a component of inflammation in neurodegenerative and neuropsychiatric disorders. The statin class of cholesterol-lowering drugs have been observed to have anti-inflammatory and protective effects in both neurodegenerative diseases and ischemic stroke, and are suggested to act by attenuating microglial activity. We sought to investigate the effects of simvastatin treatment on the secretory profile and phagocytic activity of primary cultured rat microglia, and to dissect the mechanism of action of simvastatin on microglial activity. Simvastatin treatment altered the release of cytokines and trophic factors from microglia, including interleukin-1-β, tumour necrosis factor-α, and brain derived neurotrophic factor in a cholesterol-dependent manner. Conversely, simvastatin inhibited phagocytosis in microglia in a cholesterol-independent manner.

The disparity in cholesterol dependence of cytokine release and phagocytosis suggests the two effects occur through distinct molecular mechanisms. These two pathways may provide an opportunity for further refinement of pharmacotherapies for neuroinflammatory, neurodegenerative, and neuropsychiatric disorders.

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Are the Expression of RAC1 and Mineralocorticoid Pathway-Dependent Genes Associated With Different Responses to Salt Intake?

Rac1 upregulation has been implicated in salt-sensitive hypertension as a modulator of mineralocorticoid receptor (MR) activity. Rac1 could affect the expression of oxidative stress markers, such as hemoxigenase-1 (HO-1) or nuclear factor-B (NF-κB), and the expression of neutrophil gelatinase-associated lipocalin (NGAL), a cytokine upregulated upon MR activation. We evaluated RAC1 expression in relation of high salt intake and association with MR, NGAL, HO-1, and NF-κB expression, mineralo- and glucocorticoids levels, and inflammatory parameters. We studied 147 adult subjects. A food survey identified the dietary sodium (Na) intake. RAC1 expression was considered high or low according to the value found in normotensive subjects with low salt intake. We determined the gene expression of RAC1, MR, NGAL, HO-1, NF-κB, and 18S, isolated from peripheral leukocytes. We measured aldosterone, cortisol, sodium, potassium excretion, metalloproteinase (MMP9 y MMP2), and C-reactive protein. We identified 126 subjects with high Na-intake, 18 subjects had high, and 108 low-RAC1 expression. The subjects with high-RAC1 expression showed a significant increase in MR (P = 0.0002), NGAL (P < 0.0001) HO-1 (P = 0.0004), and NF-κB (P < 0.0001) gene expression. We demonstrated an association between RAC1 expression and MR (R sp 0.64; P < 0.0001), NGAL (R sp 0.48; P < 0.0001), HO-1 (R sp 0.53; P < 0.0001), and NF-κB (R sp0.52; P < 0.0001). We did not identify any association between RAC1 and clinical or biochemical variables.

RAC1 expression was associated with an increase in MR, NGAL, NF-κB, and HO-1 expression, suggesting that RAC1 could be a mediator of cardiovascular damage induced by sodium, and may also useful to identify subjects with different responses to salt intake.

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Are statin medications associated with a lower probability of having an abnormal screening prostate-specific antigen result?

To investigate how statin use is associated with the probability of having an abnormal screening prostate-specific antigen (PSA) result according to common PSA thresholds for biopsy (>2.5, >4.0, and >6.5 ng/mL). We conducted a cross-sectional study of 323,426 men aged ≥65 years who had a screening PSA test in 2003 at a Veterans Affairs facility. The primary predictor was the use of statin medications at the time of index screening PSA test. The main outcome was the screening PSA value. Poisson regressions were performed to calculate adjusted relative risks for having an abnormal screening PSA result according to statin usage. Percentages of men with PSA results exceeding commonly used thresholds of >2.5, >4.0, and >6.5 ng/mL were 21.0%, 7.6%, and 1.6%, respectively. These percentages decreased with statin use, increasing statin dose, duration of statin use, and potency of the statin. For example, after adjusting for age, the percentage of men having a PSA level >4.0 ng/mL ranged from 8.2% in non-statin users to 6.2% in men prescribed with >40 mg of simvastatin dose. Adjusted relative risks of having a PSA level >4.0 ng/mL were 0.89 (95% confidence interval [CI], 0.86-0.93), 0.87 (95% CI, 0.84-0.91), and 0.83 (95% CI, 0.80-0.87), respectively for men on simvastatin dose of 5-20, >20-40, and >40 mg vs non-statin users.

Statin use is associated with a reduction in the probability that an older man will have an abnormal screening PSA result, regardless of the PSA threshold. This reduction is more pronounced with higher statin dose, longer statin duration, and higher statin potency.

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Does systemic delivery of human bone marrow embryonic-like stem cells improve motor function of severely affected dystrophin/utrophin-deficient mice?

Embryonic-like stem cells (ELSCs) express embryonic stem cell-specific marker genes, such as SSEA-4, Oct-4 and Nanog, and can be induced to differentiate into cells of all 3 germ layers. Our preliminary data showed that ELSCs isolated from human bone marrow express multipotent antigen markers and differentiate into multinucleated myotube-like cells more efficiently than do mesenchymal stromal cells (MSCs) isolated from the same source. We investigated the therapeutic effect of ELSCs in dystrophin/utrophin double knock-out (dko) mice, one of the Duchenne muscular dystrophy animal models, by systemically transplanting them through tail-vein injection. ELSCs and MSCs were both isolated from human bone marrow. Two months after equal amounts of ELSCs or MSCs were injected through tail-vein injection, we evaluated skeletal muscle motor function and serum creatine kinase activity and measured dystrophin expression by means of immunostaining, Western blotting and semi-quantitative reverse transcriptase-polymerase chain reaction. ELSCs positive for Oct-4 and Nanog-3 expressed higher levels of SSEA-4, FZD-9 and CD105 and were induced to differentiate into myotube-like cells more efficiently than did MSCs in vitro. Transplantation of ELSCs through the tail vein improved motor function and decreased serum creatine kinase activity at 2 months after cell transplantation. In addition, dystrophin protein and messenger RNA were upregulated and the skeletal muscle histology was improved in these dko mice transplanted with ELSCs.

ELSCs could be more efficiently induced to differentiate into myotubes than were MSCs in vitro, and systematically transplanting ELSCs improved muscle motor function and muscle histology in dko mice.

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Is uRG4 overexpression correlated with cervical cancer progression and poor prognosis in patients with early-stage cervical cancer?

Upregulator of cell proliferation 4 (URG4) has been implicated in the oncogenesis of certain cancers. However, the correlation between URG4 expression and clinicopathological significance in human cancer remains unclear. Therefore, this study investigated its expression and clinicopathological significance in cervical cancer patients. URG4 expression was examined using quantitative PCR (qPCR) and western blotting in normal cervical epithelial cells, cervical cancer cells, and eight matched pairs of cervical cancer tissues and adjacent noncancerous tissues from the same patient. In addition, immunohistochemistry (IHC) was used to examine URG4 expression in paraffin-embedded tissues from 167 cervical cancer patients (FIGO stages Ib1-IIa2). Statistical analyses were performed to evaluate associations between URG4 expression and prognostic and diagnostic factors. URG4 was significantly upregulated in the cervical cancer cell lines and tissues compared with the normal cells and adjacent noncancerous cervical tissues. IHC revealed high URG4 expression in 59 out of the 167 (35.13%) cervical cancer specimens. Its expression was significantly correlated with clinical stage (P < 0.0001), tumour size (P = 0.012), T classification (P = 0.023), lymph node metastasis (P = 0.001) and vaginal involvement (P = 0.002). Patients with high URG4 expression, particularly those who received concurrent chemotherapy and radiotherapy (P < 0.0001), showed a shorter overall survival (OS) and disease-free survival (DFS) compared to those with the low expression of this protein. Multivariate analysis revealed that URG4 expression is an independent prognostic factor for cervical cancer patients.

Our results demonstrated that elevated URG4 protein expression is associated with a poor outcome in patients with early-stage cervical cancer. URG4 may be a novel prognostic marker and therapeutic target for the treatment of cervical cancer.

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Is fragmented QRS associated with frequency of premature ventricular contractions in patients without overt cardiac disease?

In this study, we aimed to demonstrate whether the presence of fragmented QRS (fQRS) is associated with the frequency of premature ventricular contractions (PVCs). We retrospectively analyzed 282 cases by 24-hour Holter monitorings (HMs) between August 2012 and February 2013. Firstly, the patients were divided into 2 groups with respect to presence of fQRS and then divided into 3 groups with respect to frequency of PVCs as Group 1: seldom PVC (<120 PVCs/day), Group 2: moderate-frequency PVC (120-720 PVCs/day), and Group 3: frequent PVC (>720 PVCs/day). We investigated the predictors of frequent PVCs by using multinomial logistic regression analysis. Ninety-eight patients had fQRS. There was no difference between the 2 groups with respect to body mass index, gender, hypertension, and diabetes mellitus. Patients with fQRS were older (54.9±15.6 vs. 47.0±16.3, p<0.001) and had more family history of coronary artery disease (25% vs. 13%, p=0.012). Patients with fQRS was more likely to be on aspirin therapy (28.6% vs. 10.4%, p<0.001) and have a larger left atrium diameter (33.5±5.7 vs. 30.4±5.8, p=0.001). Presence of fQRS was significantly associated with the frequency of PVCs (for frequent PVC 27.7% vs. 7.6%, p<0.001; for moderate-frequency PVC 18.4% vs. 11.4%, p=0.012); 26.2% of Group 1 (n=202) had fQRS, 46.2% of Group 2 (n=39) had fQRS, and 65.9% of Group 3 (n=41) had fQRS. In the multinomial regression analysis, only age (odds ratio: 4.24, 95% confidence interval 2.08-8.64, p=0.001) and fQRS (odds ratio: 2.11, 95% confidence interval 1.00-4.45, p=0.05) were predictors of frequent PVCs.

This study demonstrated that the presence of fQRS is associated with frequent PVCs in patients without overt structural heart disease.

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Does adjustment of sensitisation and challenge protocols restore functional and inflammatory responses to ovalbumin in guinea-pigs?

Inhalation of antigen in atopic asthma induces early (EAR) and late asthmatic responses (LARs), inflammatory cell infiltration and airways hyperresponsiveness (AHR). Previously, we have established a protocol of sensitisation and subsequent ovalbumin (Ova) inhalation challenge in guinea-pigs which induced these 4 features (Smith & Broadley, 2007). However, the responses of guinea-pigs to Ova challenge have recently declined, producing no LAR or AHR and diminished EAR and cells. By making cumulative modifications to the protocol, we sought to restore these features. Guinea-pigs were sensitised with Ova (i.p. 100 or 150 μg) on days 1 and 5 or days 1, 4 and 7 and challenged with nebulised Ova (100 or 300 μg/ml, 1h) on day 15. Airway function was measured in conscious guinea-pigs by whole-body plethysmography to record specific airway conductance (sGaw). Airway responsiveness to aerosolized histamine (0.3mM) was determined before and 24h after Ova challenge. Bronchoalveolar lavage was performed for total and differential inflammatory cell counts. Lung sections were stained for counting of eosinophils. Lack of AHR and LAR with the original protocol was confirmed. Increasing the Ova challenge concentration from 100 to 300 μg/ml restored AHR and eosinophils and increased the peak of the EAR. Increasing the number of sensitisation injections from 2 to 3 did not alter the responses. Increasing the Ova sensitisation concentration from 100 to 150 μg significantly increased total cells, particularly eosinophils. A LAR was revealed and lymphocytes and eosinophils increased when either the Al(OH)3 concentration was increased or the duration between the final sensitisation injection and Ova challenge was extended from 15 to 21 days.

This study has shown that declining allergic responses to Ova in guinea-pigs could be restored by increasing the sensitisation and challenge conditions. It has also demonstrated an important dissociation between EAR, LAR, AHR and inflammation.

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Is expression of growth arrest and DNA damage inducible 45a in human oral squamous cell carcinoma associated with tumor progression and clinical outcome?

The aim of this study was to examine the growth arrest and DNA damage-inducible (Gadd45a) expression and its role in tumor progression, invasion and metastasis in oral squamous cell carcinoma (OSCC). Growth arrest and DNA damage-inducible 45a distribution was detected by immunohistochemistry in tumor sections of 106 patients with primary OSCC and sections of adjacent pericancerous tissues from 60 patients among the 106. The association between the Gadd45a expression and clinical prognosis of OSCC were performed by statistical analysis. Gadd45a gene knockdown was performed in Tca8113 cells by small interfering ribonucleic acid treatment and its effects on cell cycle, and migration were detected by Flow Cytometric (Becton Dickinson, USA) and transwell chamber assay respectively.

The results showed that Gadd45a was redistributed to cytoplasm in poorly differentiated carcinoma from its nucleus location in normal tissue (P < 0.05). The expression of Gadd45a was significantly associated with lymph node metastasis, tumor stage and tumor histological grade (P < 0.05). Knockdown of Gadd45a gene abolished the G2/M arrest and increased migrating ability of Tca8113 cell (P < 0.05). The results indicate that Gadd45a play an important role in OSCC metastasis by affecting the bioactivity of the tumor cells, and its distribution may serve for the prediction of clinical outcome of OSCC.

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Does alteration of inflammatory response by shock wave therapy lead to reduced calcification of decellularized aortic xenografts in mice†?

Tissue-engineered xenografts represent a promising treatment option in heart valve disease. However, inflammatory response leading to graft failure and incomplete in vitro repopulation with recipient cells remain challenging. Shock waves (SWs) were shown to modulate inflammation and to enhance re-epithelialization. We therefore aimed to investigate whether SWs could serve as a feasible adjunct to tissue engineering. Porcine aortic pieces were decellularized using sodium deoxycholate and sodium dodecylsulphate and implanted subcutaneously into C57BL/6 mice (n = 6 per group). The treatment (shock wave therapy, SWT) group received SWs (0.1 mJ/mm(2), 500 impulses, 5 Hz) for modulation of inflammatory response directly after implantation; control animals remained untreated (CTR). Grafts were harvested 72 h and 3 weeks after implantation and analysed for inflammatory cytokines, macrophage infiltration and polarization, osteoclastic activity and calcification. Transmission electron microscopy (TEM) was performed. Endothelial cells (ECs) were treated with SWs and analysed for macrophage regulatory cytokines. In an ex vivo experimental set-up, decellularized porcine aortic valve conduits were reseeded with ECs with and without SWT (0.1 mJ/mm(2), 300 impulses, 3 Hz), fibroblasts as well as peripheral blood mononuclear cells (all human) and tested in a pulsatile flow perfusion system for cell coverage. Treated ECs showed an increase of macrophage migration inhibitory factor and macrophage inflammatory protein 1β, whereas CD40 ligand and complement component C5/C5a were decreased. Subcutaneously implanted grafts showed increased mRNA levels of tumour necrosis factor α and interleukin 6 in the treatment group. Enhanced repopulation with recipient cells could be observed after SWT. Augmented macrophage infiltration and increased polarization towards M2 macrophages was observed in treated animals. Enhanced recruitment of osteoclastic cells in proximity to calcified tissue was found after SWT. Consequently, SWT resulted in decreased areas of calcification in treated animals. The reseeding experiment revealed that fibroblasts showed the best coverage compared with other cell types. Moreover, SW-treated ECs exhibited enhanced repopulation compared with untreated controls.

SWs reduce the calcification of subcutaneously implanted decellularized xenografts via the modulation of the acute macrophage-mediated inflammatory response and improves the in vitro repopulation of decellularized grafts. It may therefore serve as a feasible adjunct to heart valve tissue engineering.

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Does multicenter immunohistochemical ALK-testing of non-small-cell lung cancer show high concordance after harmonization of techniques and interpretation criteria?

Detection of anaplastic lymphoma kinase (ALK)-gene rearrangements in non-small-cell lung cancer (NSCLC) is mainly performed by fluorescence in-situ hybridization (FISH). The question was raised if FISH might be replaced by immunohistochemistry (IHC) in a reliable and reproducible manner across different laboratories. After calibration of the staining instruments and training of the observers to binary interpretation (positive versus negative), 15 NSCLC were independently tested for ALK protein expression by IHC only in a multicenter setting (16 institutes). Each laboratory utilized the VENTANA ALK-D5F3 IHC assay. As demonstrated by FISH the samples displayed unequivocal ALK break-positivity (6×) and negativity (7×), as well as ALK positive-"borderline" character (2×), which is challenging for FISH diagnosis and thus was RT-PCR-confirmed. All seven ALK FISH-negative cases were homogenously scored as ALK-IHC negative. All 16 participants scored the two ALK positive-"borderline" samples as unequivocally positive according to their protein expression. Concordant IHC interpretation was also noticed in four of six unequivocal ALK break positive cases. In two of six some observers described a weak/heterogeneous ALK-IHC staining. This would have resulted in a subsequent ALK-testing (FISH/PCR) in a routine diagnostic setting.

This so-called "ALK-Harmonization-Study" shows for the first time that predictive semiquantitative IHC reveals reliable and reproducible results across several labs when methodology and interpretation are strictly defined and the pathologists are uniquely trained. The application of validated ALK IHC assays and its comparison to ALK-FISH is highly needed in future clinical trials. This might answer the question if ALK-IHC cannot only serve as a prescreening tool, but as a stand-alone test at least in cases displaying an unequivocally staining pattern as well as an alternative predictive test in samples with reduced FISH interpretability.

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Does the novel surfactant protein SP-H enhance the phagocytosis efficiency of macrophage-like cell lines U937 and MH-S?

Surfactant proteins (SP) secreted by alveolar type 2 cells, play an essential role in maintaining the air-liquid barrier of the lung and are also involved in the opsonisation and clearance of bacteria by phagocytes. We have recently described a novel surfactant protein, SP-H (SFTA3). Expression of SP-H was earlier demonstrated to be upregulated by LPS and negatively regulated by IL-1β and IL-23 in vitro. The influence of SP-H on phagocytosis was measured using a murine and a human phagocytic cell line and fluorescent latex beads. SP-H markedly increases phagocytosis in vitro in the murine-derived alveolar macrophage cell lines MH-S and in human-derived differentiated U937 cells.

It can be assumed that SP-H is involved in regulating phagocytic activity of macrophages. SP-H is a new player in pulmonary host defence.

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Does the rtPA increase MMP-9 activity in serum during ischaemic stroke?

To find the relationship between rtPA treatment vs. MMP-9 activity, MMP-3, and TIMP-1 serum levels related to patients' neurological status during acute ischaemic stroke (IS). 35 IS patients were enrolled. 14 of them underwent thrombolytic therapy with Actylise (rtPA group). The serum samples were obtained at 3 time-points for rtPA group (time-point 0: 1st-4th hour of stroke; time-point 1 - immediately after rtPA administration; time-point 2 - on day 5-7 from stroke onset). Remaining patients had venous blood collection at two time-points: time-point 1 - 5th-10th hour of stroke and time-point 2 - on day 5-7 of stroke. MMP-9 was analyzed with gelatin zymography, MMP-3 and TIMP-1 serum levels were analyzed with ELISA method. NIHSS improvement ratio (IR) was calculated as a difference between NIHSS score at the admission and discharge of patient. The active form of MMP-9 (86kDa) was not observed in any analyzed samples. Total MMP-9 activity was significantly elevated at time-point 1 in rtPA group in comparison with non-rtPA group. MMP-3 serum level significantly decreased during rtPA administration in comparison with non-rtPA group and it was restored at time-point 2. MMP-3 negatively correlated with IR values (p=0.06).

Thrombolysis applied for IS treatment increases MMP-9 activity in serum, however, rtPA does not facilitate the conversion of pro-MMP-9 into the active form. Our results also suggest the involvement of MMP-3 to the biochemical processes occurring during acute phase of IS.

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Does tRAIL receptor deletion in mice suppress the inflammation of nutrient excess?

Low-grade chronic inflammation is a cardinal feature of the metabolic syndrome, yet its pathogenesis is not well defined. The purpose of this study was to examine the role of TRAIL receptor (TR) signaling in the pathogenesis of obesity-associated inflammation using mice with the genetic deletion of TR. TR knockout (TR(-/-)) mice and their littermate wild-type (WT) mice were fed a diet high in saturated fat, cholesterol and fructose (FFC) or chow. Metabolic phenotyping, liver injury, and liver and adipose tissue inflammation were assessed. Chemotaxis and activation of mouse bone marrow-derived macrophages (BMDMϕ) was measured. Genetic deletion of TR completely repressed weight gain, adiposity and insulin resistance in FFC-fed mice. Moreover, TR(-/-) mice suppressed steatohepatitis, with essentially normal serum ALT, hepatocyte apoptosis and liver triglyceride accumulation. Gene array data implicated inhibition of macrophage-associated hepatic inflammation in the absence of the TR. In keeping with this, there was diminished accumulation and activation of inflammatory macrophages in liver and adipose tissue. TR(-/-) BMDMϕ manifest reduced chemotaxis and diminished activation of nuclear factor-κ B signaling upon activation by palmitate and lipopolysaccharide.

These data advance the concept that macrophage-associated hepatic and adipose tissue inflammation of nutrient excess requires TR signaling.

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Are hospitalisation costs for infant bronchiolitis up to 20 times higher if intensive care is needed?

Up to 3% of infants with bronchiolitis under 12 months of age are hospitalised, and up to 9% require intensive care. We evaluated the costs of bronchiolitis hospitalisation, with a special focus on whether infants needed intensive care. Baseline and cost data were retrospectively collected, using electronic hospital files, for 80 infants under 12 months old who were treated in the paediatric intensive care unit (PICU) for bronchiolitis during a 13-year period. We calculated the daily costs for patients admitted to the PICU and compared them with 104 admitted to inpatient wards and 56 outpatients treated in the emergency department. The mean hospitalisation cost for PICU patients was €8061 (95% CI 6193-9929), compared to €1834 (1649-2020) for other inpatients and €359 (331-387) for the outpatients. The hospitalisation cost per patient was associated with length of hospital stay, but not gender, age on admission or gestational age. There was no constant increase or decrease in hospitalisation costs during the study period.

The hospitalisation costs of infants treated in the PICU for bronchiolitis at <12 months of age were approximately four times more than for other inpatients and over 20 times more than for outpatients. Strategies are needed to reduce the need for intensive care.

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Is hospital readmission associated with poor survival after esophagectomy for esophageal cancer?

Hospital readmissions are costly and associated with inferior patient outcomes. There is limited knowledge related to readmissions after esophagectomy for malignancy. Our aim was to determine the impact on survival of readmission after esophagectomy. This cohort study utilizes Surveillance, Epidemiology, and End Results-Medicare data (2002 to 2009). Survival, length of stay, 30-day readmissions, and discharge disposition were determined. Multivariate logistic regression models were created to examine risk factors associated with readmission. In all, 1,744 patients with esophageal cancer underwent esophagectomy: 80% of patients (1,390) were male, and mean age was 73 years; 71.8% of tumors (1,251) were adenocarcinomas, and 72.5% (1,265) were distal esophageal tumors; 38% of patients (667) received induction therapy. Operative approach was transthoracic in 52.6% of patients (918) and transhiatal in 37.4% (653), and required complex reconstruction (intestinal interposition) in 9.9% (173). Stage distribution was as follows: stage I, 35.3% (616); stage II, 32.5% (566); stage III, 27.9% (487); and stage IV, 2.3% (40). Median length of stay was 13 days, hospital mortality was 9.3% (158 patients), and 30-day readmission rate was 18.6% (212 of 1,139 home discharges); 25.4% of patients (443) were discharged to institutional care facilities. Overall survival was significantly worse for patients who were readmitted (p < 0.0001, log rank test). Risk factors for readmission were comorbidity score of 3+, urgent admission, and urban residence.

Hospital readmissions after esophagectomy for cancer occur frequently and are associated with worse survival. Improved identification of patients at risk for readmission after esophagectomy can inform patient selection, discharge planning, and outpatient monitoring. Optimization of such practices may lead to improved outcomes at reduced cost.

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Does polyphenol-enriched diet prevent coronary endothelial dysfunction by activating the Akt/eNOS pathway?

The Mediterranean diet, rich in polyphenols, has shown to be cardioprotective. However the mechanisms involved remain unknown. We investigated whether supplementation with a pomegranate extract rich in polyphenols renders beneficial effects on coronary function in a clinically relevant experimental model and characterized the underlying mechanisms. Pigs were fed a 10-day normocholesterolemic or hypercholesterolemic diet. Half of the animals were given a supplement of 625 mg/day of a pomegranate extract (Pomanox; 200 mg punicalagins/day). Coronary responses to escalating doses of vasoactive drugs (acetylcholine, calcium ionophore, and sodium nitroprusside) and L-NG-monomethylarginine (endothelial nitric oxide-synthase inhibitor) were measured using flow Doppler. Akt/endothelial nitric oxide-synthase axis activation, monocyte chemoattractant protein-1 expression, oxidative deoxyribonucleic acid damage in the coronary artery, and lipoprotein resistance to oxidation were evaluated. In dyslipidemic animals, Pomanox supplementation prevented diet-induced impairment of endothelial relaxation, reaching vasodilatory values comparable to normocholesterolemic animals upon stimulation with acetylcholine and/or calcium ionophore. These beneficial effects were associated with vascular Akt/endothelial nitric oxide-synthase activation and lower monocyte chemoattractant protein-1 expression. Pomanox supplementation reduced systemic oxidative stress (higher high-density lipoprotein-antioxidant capacity and higher low-density lipoprotein resistance to oxidation) and coronary deoxyribonucleic acid damage. Normocholesterolemic animals elicited similar drug-related vasodilation regardless of Pomanox supplementation. All animals displayed a similar vasodilatory response to sodium nitroprusside and L-NG-monomethylarginine blunted all vasorelaxation responses except for sodium nitroprusside.

Pomanox supplementation hinders hyperlipemia-induced coronary endothelial dysfunction by activating the Akt/endothelial nitric oxide-synthase pathway and favorably counteracting vascular inflammation and oxidative damage.

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Is malnutrition a prognostic factor in patients with hepatocellular carcinoma ( HCC )?

Malnutrition is a common, hence frequently underdiagnosed condition in patients with liver cirrhosis as well as in patients with cancer and has been shown to have a negative impact on survival in these patients. Frequently applied screening tools including anthropometric measurements or laboratory parameters to screen for malnutrition are not suitable for patients with liver cirrhosis with additional pathophysiological mechanisms leading to hypoalbuminemia and edema. Prospective data on the prevalence and prognostic impact of malnutrition in patients with HCC are scarce. Fifty-one consecutive patients with hepatocellular carcinoma were prospectively enrolled into this study and screened for malnutrition by anthropometric measurements, the MNA score, the NRS score, laboratory work-up, and BIA measurement. The results of the different screening tools were compared to each other and with the BIA assessment and correlated with the outcome of patients. The calculation of a body mass index (BMI) was not suitable to identify malnourished patients with HCC. The MNA identified 19, the NRS score 17 patients at a risk for malnutrition. BIA revealed a reduction in relative body cell mass in 12 patients. Univariate Cox regression analyses identified tumor stage, MNA score, and phase angle obtained by BIA as significant factors with influence on survival. Multivariate analyses confirmed the phase angle at a cut-off of 4.8 to be an independent factor.

A significant proportion of patients with HCC is malnourished or at risk for malnutrition. Screening questionnaires and BIA measurement are superior to pure anthropometric measurements to identify the condition that negatively influences survival. The phase angle derived from body impedance analysis is an independent prognostic factor in patients with HCC.

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Is histiocytoid Sweet syndrome infiltrated predominantly by M2-like macrophages?

Histiocytoid Sweet syndrome (HSS) is a rare variant of Sweet syndrome (SS). The nature of histiocytoid cells is still uncertain. We sought to offer a comprehensive overview on clinical features of HSS and further information on immunohistochemical phenotype of the infiltrate. The clinical, histologic, and immunohistochemical features of 12 of our patients with HSS and all cases retrieved through a PubMed search were analyzed. Lesions consisted of erythematous-violaceous papules and plaques, randomly distributed mostly on the trunk and the limbs. Three patients had myelodysplastic syndrome and 1 had a monoclonal gammopathy. The infiltrate was mainly composed of CD68(+)CD163(+)myeloperoxidase(+)myeloid cell nuclear differentiation antigen(+)CD117(-)CD15(-)CD34(-), a phenotype suggestive of M2-like macrophages. A few mature neutrophils and lymphocytes were also present. Review of all HSS cases showed no sex predominance and no extracutaneous infiltrates; inconstant presence of fever and blood neutrophilia; association with hematologic or solid neoplasms (26%), autoimmune conditions (12%), and infectious diseases (10%); and good response to steroid treatment, with rare relapses or recurrences.

The study includes a limited case series. The pathogenesis of the disease remains to be clarified.

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Is sinR a mutational target for fine-tuning biofilm formation in laboratory-evolved strains of Bacillus subtilis?

Bacteria often form multicellular, organized communities known as biofilms, which protect cells from a variety of environmental stresses. During biofilm formation, bacteria secrete a species-specific matrix; in Bacillus subtilis biofilms, the matrix consists of protein polymers and exopolysaccharide. Many domesticated strains of B. subtilis have a reduced ability to form biofilms, and we conducted a two-month evolution experiment to test whether laboratory culturing provides selective pressure against biofilm formation in B. subtilis. Bacteria grown in two-month-long batch culture rapidly diversified their biofilm-forming characteristics, exhibiting highly diverse colony morphologies on LB plates in the initial ten days of culture. Generally, this diversity decreased over time; however, multiple types of colony morphology remained in our final two-month-old populations, both under shaking and static conditions. Notably, while our final populations featured cells that produce less biofilm matrix than did the ancestor, cells overproducing biofilm matrix were present as well. We took a candidate-gene approach to identify mutations in the strains that overproduced matrix and found point mutations in the biofilm-regulatory gene sinR. Introducing these mutations into the ancestral strain phenocopied or partially phenocopied the evolved biofilm phenotypes.

Our data suggest that standard laboratory culturing conditions do not rapidly select against biofilm formation. Although biofilm matrix production is often reduced in domesticated bacterial strains, we found that matrix production may still have a fitness benefit in the laboratory. We suggest that adaptive specialization of biofilm-forming species can occur through mutations that modulate biofilm formation as in B. subtilis.

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Does ancient DNA provide new insight into the maternal lineages and domestication of Chinese donkeys?

The donkey (Equus asinus) is an important domestic animal that provides a reliable source of protein and method of transportation for many human populations. However, the process of domestication and the dispersal routes of the Chinese donkey are still unclear, as donkey remains are sparse in the archaeological record and often confused with horse remains. To explore the maternal origins and dispersal route of Chinese donkeys, both mitochondrial DNA D-loop and cytochrome b gene fragments of 21 suspected donkey remains from four archaeological sites in China were amplified and sequenced. Molecular methods of species identification show that 17 specimens were donkeys and three samples had the maternal genetic signature of horses. One sample that dates to about 20,000 years before present failed to amplify. In this study, the phylogenetic analysis reveals that ancient Chinese donkeys have high mitochondrial DNA diversity and two distinct mitochondrial maternal lineages, known as the Somali and Nubian lineages. These results indicate that the maternal origin of Chinese domestic donkeys was probably related to the African wild ass, which includes the Nubian wild ass (Equus africanus africanus) and the Somali wild ass (Equus africanus somaliensis). Combined with historical records, the results of this study implied that domestic donkeys spread into west and north China before the emergence of the Han dynasty. The number of Chinese domestic donkeys had increased primarily to meet demand for the expansion of trade, and they were likely used as commodities or for shipping goods along the Silk Road during the Tang Dynasty, when the Silk Road reached its golden age.

This study is the first to provide valuable ancient animal DNA evidence for early trade between African and Asian populations. The ancient DNA analysis of Chinese donkeys also sheds light on the dynamic process of the maternal origin, domestication, and dispersal route of ancient Chinese donkeys.

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Do a critical analysis of secondary overtriage to a Level I trauma center?

Trauma centers often receive transfers from lower-level trauma centers or nontrauma hospitals. The aim of this study was to analyze the incidence and pattern of secondary overtriage to our Level I trauma center. We performed a 2-year retrospective analysis of all trauma patients transferred to our Level I trauma center and discharged within 24 hours of admission. Reason for referral, referring specialty, mode of transport, and intervention details were collected. Outcomes measures were incidence of secondary overtriage as well as requirement of major or minor procedure. Major procedure was defined as surgical intervention in the operating room. Minor procedures were defined as procedures performed in the emergency department. A total of 1,846 patients were transferred to our Level I trauma center, of whom 440 (24%) were discharged within 24 hours of admission. The mean (SD) age was 35 (21) years, 72% were male, and mean (SD) Injury Severity Score (ISS) 4 (4). The most common reasons for referral were extremity fractures (31%), followed by head injury (23%) and soft tissue injuries (13%).Of the 440 patients discharged within 24 hours, 380 (86%) required only observation (268 of 380) or minor procedure (112 of 380). Minor procedures were entirely consisted of fracture management (n = 47, 42%) and wound care (n = 65, 58%). The mean (SD) interfacility transfer distance was 45 (46) miles. Mean (SD) hospital charges per transfer were $12,549 ($5,863).

A significant number of patients transferred to our trauma center were discharged within 24 hours; most of them required observation and/or minor procedures. Appropriately increasing primary hospital resources, in addition to interhospital outreach in the form of education or telemedicine, should be considered to decrease the number of avoidable transfers.

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Is fibromyalgia associated with coronary heart disease : a population-based cohort study?

We examined whether patients with a diagnosis of fibromyalgia have an increased risk of coronary heart disease (CHD), compared with age- and sex-matched control patients. We hypothesized that patients diagnosed with fibromyalgia are at increased risk of adverse coronary events. Using a matched-cohort study design, we analyzed data retrieved from the Longitudinal Health Insurance Database 2000 released by the National Health Research Institute, Taiwan. The Longitudinal Health Insurance Database 2000 includes medical claims data and registration files for 1 million enrollees randomly selected from the 2000 Registry for Beneficiaries (n = 23.72 million) of the National Health Insurance program. Patients treated for fibromyalgia at least once a month for 3 consecutive months following their initial diagnosis were enrolled in our study. The primary end point was the composite of CHD events, including percutaneous coronary interventions and coronary artery bypass grafting procedures. A propensity score was estimated by a logistic regression method, in which the fibromyalgia status was regressed on baseline prognostic factors. The hazard ratios and the 95% confidence intervals were estimated using multivariate Cox proportional-hazards regression models while adjusting for the propensity score. After adjusting for the propensity score, the patients with fibromyalgia showed a significantly higher subsequent risk of a CHD event (hazard ratio, 2.11; 95% confidence interval, 1.46-3.05; P < 0.001) than the patients without fibromyalgia.

An association between fibromyalgia and CHD appears to exist.

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Do serum miRNA biomarkers serve as a fingerprint for proliferative diabetic retinopathy?

Diabetic retinopathy (DR) is a retinopathy resulting from diabetes mellitus (DM) which was classified into non-proliferative DR (NPDR) and proliferative DR (PDR). Without an early screening and effective diagnosis, patients with PDR will develop serious complications. Therefore, we sought to identify special serum microRNAs (miRNAs) that can serve as a novel non-invasive screening signature of PDR and test its specificity and sensitivity in the early diagnosis of PDR. In total, we obtained serum samples from 90 PDR cases, 90 matched NPDR patients and 20 controls. An initial screening of miRNA expression was performed through TaqMan Low Density Array (TLDA). The candidate miRNAs were validated by individual reverse transcription quantitative real-time PCR (RT-qPCR) arranged in an initial and a two-stage validation sets. Moreover, additional double-blind testing was performed in 20 patients clinically suspected of having DR to evaluate the diagnostic value and accuracy of the serum miRNA profiling system in predicting PDR. Three miRNAs were significantly increased in patients with PDR compared with NPDR after the multiple stages. The areas under the receiver operating characteristic (ROC) curves of the validated three-serum miRNAs signature were 0.830, 0.803 and 0.873 in the initial and two validation sets, respectively. Combination of miR-21, miR-181c, and miR-1179 possessed a moderate ability to discrimination between PDR and NPDR with an area under ROC value of 0.89. The accuracy rate of the three-miRNA profile as PDR signature was 82.6%.

These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of PDR. These biomarkers could serve as a dynamic monitoring factor for detecting the progression of PDR from NPDR.

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Does the usage of overtube have a favorable effect on endoscopic submucosal dissection?

Endoscopic submucosal dissection (ESD) may be very time consuming, and depending on the anesthesia, the contents of the stomach may reflux to the esophagus and cause the patient to aspirate. To prevent these situations, many practitioners suggest using an overtube, but no study has been done to evaluate the effect of the use of an overtube while performing the ESD procedure. Our aim was to investigate the effects of performing an upper gastrointestinal ESD with and without overtube. Records of patients who underwent ESD were evaluated for histopathological results, complications, speed of dissection, dosages of anesthetic medications, and number of suctions performed during the procedure. The patients were classified into two depending on whether an overtube was used or not. There were a total of 58 patients on which 63 upper gastrointestinal ESD procedures were performed. Regarding age, gender, localization of the lesions, duration of the procedures, dosage of propofol, histopathological results, rate of complete resection, and rate of en-bloc resection, there was no difference between the two groups (p > 0,05). But the size of the lesions, the size of the resected specimen, and the speed of dissection were statistically different in two groups (p = 0.018, p < 0.001, p < 0.001, respectively).The need for suction during the procedure was much lower in the overtube group than those with no overtube (p < 0.001).

We conclude that using an overtube during an upper gastrointestinal ESD decreases the need for suction, favors the speed of dissection, and eases the comfort of the procedure.

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Do dehydroepiandrosterone and its sulfate predict the 5-year risk of coronary heart disease events in elderly men?

The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory. This study tested the hypothesis that serum DHEA and DHEA-S are predictors of major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events in a large cohort of elderly men. We used gas and liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based Osteoporotic Fractures in Men study in Sweden (2,416 men, ages 69 to 81 years). Complete cardiovascular clinical outcomes were available from national Swedish registers. During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality.

Low serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men.

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Does aeromonas piscicola AH-3 express an extracellular collagenase with cytotoxic properties?

The aim of this study was to investigate the presence and the phenotypic expression of a gene coding for a putative collagenase. This gene (AHA_0517) was identified in Aeromonas hydrophila ATCC 7966 genome and named colAh. We constructed and characterized an Aeromonas piscicola AH-3::colAh knockout mutant. Collagenolytic activity of the wild-type and mutant strains was determined, demonstrating that colAh encodes for a collagenase. ColAh-collagen interaction was assayed by Far-Western blot, and cytopathic effects were investigated in Vero cells. We demonstrated that ColAh is a gluzincin metallopeptidase (approx. 100 kDa), able to cleave and physically interact with collagen, that contributes for Aeromonas collagenolytic activity and cytotoxicity. ColAh possess the consensus HEXXH sequence and a glutamic acid as the third zinc binding positioned downstream the HEXXH motif, but has low sequence similarity and distinct domain architecture to the well-known clostridial collagenases. In addition, these results highlight the importance of exploring new microbial collagenases that may have significant relevance for the health and biotechnological industries.

Collagenases play a central role in processes where collagen digestion is needed, for example host invasion by pathogenic micro-organisms. We identified a new collagenase from Aeromonas using an integrated in silico/in vitro strategy. This enzyme is able to bind and cleave collagen, contributes for AH-3 cytotoxicity and shares low similarity with known bacterial collagenases. This is the first report of an enzyme belonging to the gluzincin subfamily of the M9 family of peptidases in Aeromonas. This study increases the current knowledge on collagenolytic enzymes bringing new perspectives for biotechnology/medical purposes.

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Does preoperative anemia increase postoperative morbidity in elective cranial neurosurgery?

Preoperative anemia may affect postoperative mortality and morbidity following elective cranial operations. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was used to identify elective cranial neurosurgical cases (2006-2012). Morbidity was defined as wound infection, systemic infection, cardiac, respiratory, renal, neurologic, and thromboembolic events, and unplanned returns to the operating room. For 30-day postoperative mortality and morbidity, adjusted odds ratios (ORs) were estimated with multivariable logistic regression. Of 8015 patients who underwent elective cranial neurosurgery, 1710 patients (21.4%) were anemic. Anemic patients had an increased 30-day mortality of 4.1% versus 1.3% in non-anemic patients (P < 0.001) and an increased 30-day morbidity rate of 25.9% versus 14.14% in non-anemic patients (P < 0.001). The 30-day morbidity rates for all patients undergoing cranial procedures were stratified by diagnosis: 26.5% aneurysm, 24.7% sellar tumor, 19.7% extra-axial tumor, 14.8% intra-axial tumor, 14.4% arteriovenous malformation, and 5.6% pain. Following multivariable regression, the 30-day mortality in anemic patients was threefold higher than in non-anemic patients (4.1% vs 1.3%; OR = 2.77; 95% CI: 1.65-4.66). The odds of postoperative morbidity in anemic patients were significantly higher than in non-anemic patients (OR = 1.29; 95% CI: 1.03-1.61). There was a significant difference in postoperative morbidity event odds with a hematocrit level above (OR = 1.07; 95% CI: 0.78-1.48) and below (OR = 2.30; 95% CI: 1.55-3.42) 33% [hemoglobin (Hgb) 11 g/dl].

Preoperative anemia in elective cranial neurosurgery was independently associated with an increased risk of 30-day postoperative mortality and morbidity when compared to non-anemic patients. A hematocrit level below 33% (Hgb 11 g/dl) was associated with a significant increase in postoperative morbidity.

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Does endothelin-Bone morphogenetic protein type 2 receptor interaction induce pulmonary artery smooth muscle cell hyperplasia in pulmonary arterial hypertension?

Endothelin receptor antagonists improve pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2) predispose to PAH. Here, we sought to determine whether there might exist interactions between these 2 signaling pathways and their effect on the acquisition of the altered phenotype of pulmonary artery smooth muscle cells (PA-SMCs) observed in PAH. Expression of BMPR2, of the BMP agonist BMP4, and of the BMP antagonists gremlin1 and gremlin2 was evaluated in lungs and in PA-SMCs from 6 PAH patients and 14 controls treated with endothelin-1. Endothelin-1 pre-treated PA-SMCs were assessed for proliferation, apoptosis, and downstream signaling activation of Smad1/5/8 and p38 mitogen-activated protein kinase (p38(MAPK)) after BMP2 treatment. In PA-SMCs from PAH patients, expression of BMPR2 and BMP4 decreased, whereas expression of gremlin1 and gremlin2 increased compared with controls. Treatment of control PA-SMCs with endothelin-1 induced a dose-dependent increase in gremlin1 and gremlin2, whereas BMPR2 and BMP4 expression decreased, reaching similar levels as those observed in PAH cells. In control PA-SMCs, endothelin-1 pre-treatment reduced inhibitor of DNA binding 1 (Id1) expression and Smad1/5/8 activation induced by BMP2, whereas it enhanced p38(MAPK) activation. Moreover, BMP2 decreased serum-induced proliferation and increased the pro-apoptotic Bax/Bcl-2 ratio. These effects were attenuated by endothelin-1 pre-treatment. Endothelin-1 did not alter BMPR2 signaling in PA-SMCs from PAH patients.

Endothelin-1 downregulates canonical BMPR2 signaling. This is related to decreased BMPR2 and increased anti-BMP gremlin expression associated with increased activation of p38(MAPK) and results in PA-SMC proliferation.

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Do long-term results from the Contura multilumen balloon breast brachytherapy catheter phase 4 registry trial?

To describe the long-term outcomes from a completed, multi-institutional phase 4 registry trial using the Contura multilumen balloon (CMLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer. Three hundred forty-two evaluable patients were enrolled by 23 institutions between January 2008 and February 2011. All patients received 34 Gy in 10 fractions, delivered twice daily. Rigorous target coverage and normal tissue dose constraints were observed. The median follow-up time was 36 months (range, 1-54 months). For the entire patient cohort of 342 patients, 10 patients experienced an ipsilateral breast tumor recurrence (IBTR). Eight of these IBTR were classified as true recurrences/marginal miss (TRMM), and 2 were elsewhere failures (EF). Local recurrence-free survival was 97.8% at 3 years. For the entire cohort, 88% of patients had good to excellent overall cosmesis. The overall incidence of infection was 8.5%. Symptomatic seroma was reported in only 4.4% of patients. A separate analysis was performed to determine whether improved outcomes would be observed for patients treated at high-volume centers with extensive brachytherapy experience. Three IBTR were observed in this cohort, only 1 of which was classified as a TRMM. Local recurrence-free survival at high-volume centers was 98.1% at 3 years. Overall cosmetic outcome and toxicity were superior in patients treated at high-volume centers. In these patients, 95% had good to excellent overall cosmesis. Infection was observed in only 2.9% of patients, and symptomatic seroma was reported in only 1.9%.

Use of the CMLB for APBI delivery is associated with acceptable long-term local control and toxicity. Local recurrence-free survival was 97.8% at 3 years. Significant (grade 3) toxicity was uncommon, and no grade 4 toxicity was observed. Treatment at high-volume centers was associated with decreased late toxicity.

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Does selenium status in pregnancy influence children 's cognitive function at 1.5 years of age?

Selenium deficiency has been shown to affect the neurological development in animals, but human research in this area is scarce. We aimed to assess the impact of selenium status during pregnancy on child development at 1.5 years of age. This prospective cohort study was nested into a food and micronutrient supplementation trial (MINIMat) conducted in rural Bangladesh. Using inductively coupled plasma mass spectrometry, we measured selenium concentrations in erythrocyte fraction of blood collected from 750 mothers at gestational week 30, and calculated μg per g hemoglobin. A revised version of Bayley Scales of Infant Development was used to assess children's mental and psychomotor development. A Bangladeshi version of MacArthur's Communicative Development Inventory was used to assess language comprehension and expression. Linear regression analyses adjusted for multiple covariates were used to assess the associations. Maternal erythrocyte selenium concentrations varied considerably, from 0.19 to 0.87 μg/g hemoglobin (median 0.46 μg/g hemoglobin), and were associated with developmental measures. An increase in erythrocyte selenium by 0.50 μg/g hemoglobin was associated with an increase in children's language comprehension by 3.7 points (0.5 standard deviations; 95% confidence interval: 0.40, 7.1; p = 0.028). The same increase in erythrocyte selenium corresponded to an increase in the girls' psychomotor development by 12 points (0.9 standard deviation; 95% confidence interval: 4.3, 19; p = 0.002), but much less in boys.

Low prenatal selenium status seems to be disadvantageous for children's psychomotor and language development. Further studies are needed to elucidate the underlying mechanisms of these effects.

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Does dexmedetomidine reduce atrial fibrillation after lung cancer surgery?

To evaluate whether the use of intraoperative dexmedetomidine (DEX) during lung cancer surgery may reduce the incidence of postoperative atrial fibrillation (POAF). A retrospective study. Academic hospital. Seven hundred three adult patients with non-small-cell lung cancer. Patients younger than 18 years of age with a history of atrial fibrillation were excluded. Episodes of atrial fibrillation were identified from electronic medical records and consisted of cardiology consultations, electrocardiogram records, and use of anti-arrhythmic medications within the postoperative admission time. The Wilcoxon rank sum test was used to evaluate the difference in a continuous variable between patient groups. Fisher's exact test or the chi-square test was used to evaluate the association between 2 categorical variables. Logistic regression models were used for multivariate analysis. Overall POAF incidence was 136 of 703 (19.35%), with a mean onset of 3.01±2.03 days after surgery. Among patients, 204 (29.02%) received DEX intraoperatively. Male gender and age were strong predictors of POAF. POAF incidence was comparable between patients who were (n=93, 21.1%) and were not (n=43, 18.6%) treated with DEX (p=0.46). The mean onset time of arrhythmia was similar in both groups (DEX users: 2.93±2.49 days; non-DEX users: 3.05±1.79 days; p=0.146).

These results were similar to those published elsewhere on POAF incidence and risk factors. This study could not confirm the hypothesis that the intraoperative use of DEX is associated with a reduced rate of POAF after thoracic surgery for lung cancer.

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Does extracorporeal shockwave therapy improve short-term functional outcomes of shoulder adhesive capsulitis?

The treatment of adhesive capsulitis is a dilemma for orthopaedic rehabilitation specialists. In this study, we assessed whether extracorporeal shockwave therapy (ESWT) improves the functional outcome of primary shoulder adhesive capsulitis. In this prospective, randomized, controlled, single-blind clinical trial, we enrolled 40 patients with primary adhesive capsulitis to assess whether ESWT can improve the functional outcome of primary adhesive capsulitis better than oral steroid therapy. Patients were allocated to the oral steroid group or ESWT group with randomization. Functional outcome evaluations were performed using the Constant Shoulder Score (CSS) and Oxford Shoulder Score. Both groups showed significant improvement in the Oxford Shoulder Score evaluation throughout the study period. In the ESWT group, the total CSS and range of motion (ROM) parameter of the CSS in the ESWT group showed significant improvement from the fourth week that was better than that in the steroid group; the activities–of–daily living (ADL) parameter of the CSS achieved significance and was better than that in the steroid group at the sixth week. For the steroid group, pain was significantly reduced from baseline to the fourth week of the study; ADL and ROM improved at the fourth to 12th week. For the ESWT group, ADL and ROM improvements were significant from baseline to the sixth week.

Our results showed that ESWT can be an alternative treatment, at least in the short-term, for primary adhesive capsulitis of the shoulder. In addition, all of the side effects of ESWT were transient and tolerable.

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Do collateral flow and brain changes on computed tomography angiography predict infarct volume on early diffusion-weighted imaging?

We investigated whether a computed tomography (CT)-based score could predict a large infarct (≥ 80 mL) on early diffusion-weighted magnetic resonance imaging (DWI). Acute stroke patients considered for endovascular therapy within 8 hours of the onset of symptoms were included. The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) was determined on noncontrast CT and computed tomography angiography source images (CTA-SI). Limited collateral flow was defined as less than 50% collateral filling on CTA-SI. Fifty-six patients were analyzed. National Institutes of Health Stroke Scale score was 20 (15-24) in the large infarct group and 16 (11-20) in the small infarct group (P = .049). ASPECTS on noncontrast CT and CTA-SI was 5 (3-8) and 3 (2-6) in the large infarct group and 9 (8-10) and 8 (7-9) in the small infarct group (both P < .001), respectively. Limited collateral flow was frequent in the large infarct group than in the small infarct group (92% vs. 11%, P < .001). Multivariate analysis found that CTA-SI ASPECTS less than or equal to 5 (odds ratio [OR], 40.55; 95% confidence interval [CI], 1.10-1493.44; P = .044) and limited collateral flow (OR, 114.64; 95% CI, 1.93-6812.79; P = .023) were associated with a large infarct. Absence of ASPECTS less than or equal to 5 and limited collateral flow on CTA-SI predicted absence of a large infarct with a sensitivity of .89, specificity of 1.00, positive predictive value of 1.00, and negative predictive value of .71.

Assessment of ASPECTS and collateral flow on CTA-SI may be able to exclude a patient with large infarct on early DWI.

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Do angiogenic microvascular endothelial cells release microparticles rich in tissue factor that promotes postischemic collateral vessel formation?

Therapeutic angiogenesis is a promising strategy for treating ischemia. Our previous work showed that endogenous endothelial tissue factor (TF) expression induces intracrine signaling and switches-on angiogenesis in microvascular endothelial cells (mECs). We have hypothesized that activated mECs could exert a further paracrine regulation through the release of TF-rich microvascular endothelial microparticles (mEMPs) and induce neovascularization of ischemic tissues. Here, we describe for the first time that activated mECs are able to induce reparative neovascularization in ischemic zones by releasing TF-rich microparticles. We show in vitro and in vivo that mEMPs released by both wild-type and TF-upregulated-mECs induce angiogenesis and collateral vessel formation, whereas TF-poor mEMPs derived from TF-silenced mECs are not able to trigger angiogenesis. Isolated TF-bearing mEMPs delivered to nonperfused adductor muscles in a murine hindlimb ischemia model enhance collateral flow and capillary formation evidenced by MRI. TF-bearing mEMPs increase angiogenesis operating via paracrine regulation of neighboring endothelial cells, signaling through the β1-integrin pathway Rac1-ERK1/2-ETS1 and triggering CCL2 (chemokine [C-C motif] ligand 2) production to form new and competent mature neovessels.

These findings demonstrate that TF-rich mEMPs released by microvascular endothelial cells can overcome the consequences of arterial occlusion and tissue ischemia by promoting postischemic neovascularization and tissue reperfusion.

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Does adenovirus-mediated NDRG2 inhibit the proliferation of human renal cell carcinoma cell line OS-RC-2 in vitro?

To investigate the inhibitory effects of adenovirus-mediated NDRG2 on the proliferation of human renal cell carcinoma cell line OS-RC-2 in vitro. NDRG2 was harvested by RT-PCR, confirmed by DNA sequencing, and then cloned into the eukaryotic expression vector pIRES2-EGFP, which encodes green fluorescent protein (GFP), to construct pIRES2-EGFP-NDRG2 plasmid. OS-RC-2 cells with NDRG2 negative expression were transfected with pIRES2-EGFP-NDRG2 plasmid. The growth of transfected OS-RC-2 cells was observed under light and fluorescence microscopes. After colony-forming cell assays, cell proliferation detection and MTT assays, the growth curves of cells in each group were plotted to investigate the inhibitory effects of adenovirus-mediated NDRG2 on the proliferation of OS-RC-2 cells. Cell cycle was determined by flow cytometry. Confocal laser scanning microscopy showed that NDRG2 protein was specifically located on subcellular organelle. A eukaryotic expression vector pIRES2-EGFP-NDRG2 was successfully constructed. After NDRG2 transfection, the growth of OS-RC-2 cells was inhibited. Flow cytometry showed that cells were arrested in S phase but the peak of cell apoptosis was not present, and confocal laser scanning microscopy showed that NDRG2 protein was located in mitochondrion.

NDRG2 can significantly inhibit the proliferation of OS-RC-2 cells in vitro and its protein is specifically expressed in the mitochondrion.

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Does introduction of an 8-aminooctanoic acid linker enhance uptake of 99mTc-labeled lactam bridge-cyclized α-MSH peptide in melanoma?

The purpose of this study was to examine the effects of amino acid, hydrocarbon, and polyethylene glycol (PEG) linkers on the melanoma targeting and imaging properties of (99m)Tc-labeled lactam bridge-cyclized HYNIC-linker-Nle-CycMSHhex (hydrazinonicotinamide-linker-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2) peptides. Four novel peptides (HYNIC-GGGNle-CycMSHhex, HYNIC-GSGNle-CycMSHhex, HYNIC-PEG2Nle-CycMSHhex, and HYNIC-AocNle-CycMSHhex) were designed and synthesized. The melanocortin-1 receptor binding affinities of the peptides were determined in B16/F1 melanoma cells. The biodistribution of (99m)Tc(ethylenediaminediacetic acid [EDDA])-HYNIC-GGGNle-CycMSHhex, (99m)Tc(EDDA)-HYNIC-GSGNle-CycMSHhex, (99m)Tc(EDDA)-HYNIC-PEG2Nle-CycMSHhex, and (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex were determined in B16/F1 melanoma-bearing C57 mice at 2 h after injection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex were further examined because of its high melanoma uptake. The inhibitory concentrations of 50% (IC50) for HYNIC-GGGNle-CycMSHhex, HYNIC-GSGNle-CycMSHhex, HYNIC-PEG2Nle-CycMSHhex, and HYNIC-AocNle-CycMSHhex were 0.7 ± 0.1, 0.8 ± 0.09, 0.4 ± 0.08, and 0.3 ± 0.06 nM, respectively, in B16/F1 melanoma cells. Among these four (99m)Tc-labeled peptides, (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex displayed the highest melanoma uptake (22.3 ± 1.72 percentage injected dose/g) at 2 h after injection. (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex exhibited high tumor-to-normal-organ uptake ratios except for the kidneys. The tumor-to-kidney uptake ratios of (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex were 3.29, 3.63, and 6.78 at 2, 4, and 24 h, respectively, after injection. The melanoma lesions were clearly visualized by SPECT/CT using (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex as an imaging probe at 2 h after injection.

High melanoma uptake and fast urinary clearance of (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex highlighted its potential for metastatic melanoma detection in the future.

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Does bRCAness predict resistance to taxane-containing regimens in triple negative breast cancer during neoadjuvant chemotherapy?

To provide optimal treatment of heterogeneous triple negative breast cancer (TNBC), we need biomarkers that can predict the chemotherapy response. We retrospectively investigated BRCAness in 73 patients with breast cancer who had been treated with taxane- and/or anthracycline-based neoadjuvant chemotherapy (NAC). Using multiplex, ligation-dependent probe amplification on formalin-fixed core needle biopsy (CNB) specimens before NAC and surgical specimens after NAC. BRCAness status was assessed with the assessor unaware of the clinical information. We obtained 45 CNB and 60 surgical specimens from the 73 patients. Of the 45 CNB specimens, 17 had BRCAness (38.6% of all subtypes). Of the 23 TNBC CNB specimens, 14 had BRCAness (61% of TNBC cases). The clinical response rates were significantly lower for BRCAness than for non-BRCAness tumors, both for all tumors (58.8% vs. 89.3%, P = .03) and for TNBC (50% vs. 100%, P = .02). All tumors that progressed with taxane therapy had BRCAness. Of the patients with TNBC, those with non-BRCAness cancer had pathologic complete responses significantly more often than did those with BRCAness tumors (77.8% vs. 14.3%, P = .007). After NAC, the clinical response rates were significant lower for BRCAness than for non-BRCAness tumors in all subtypes (P = .002) and in TNBC cases (P = .008). After a median follow-up of 26.4 months, 6 patients-all with BRCAness-had developed recurrence. Patients with BRCAness had shorter progression-free survival than did those with non- BRCAness (P = .049).

Identifying BRCAness can help predict the response to taxane, and changing regimens for BRCAness TNBC might improve patient survival. A larger prospective study is needed to further clarify this issue.

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Does classical swine fever virus induce oxidative stress in swine umbilical vein endothelial cells?

Classical swine fever virus (CSFV) infection causes significant losses of pigs, which is characterized by hemorrhage, disseminated intravascular coagulation and leucopenia. The swine vascular endothelial cell is a primary target cell for CSFV. The aim of this study was to determine the role of CSFV infection in inducing oxidative stress (OS) in vascular endothelial cells. We demonstrated that CSFV infection induced oxidative stress in swine umbilical vein endothelial cells (SUVECs), characterized by the induction of reactive oxygen species (ROS) production and the elevations of porcine antioxidant proteins thioredoxin (Trx), peroxiredoxin-6 (PRDX-6) and heme oxygenase-1 (HO-1) expression. Furthermore, cyclooxygenase-2 (COX-2), a pro-inflammatory protein related to oxidative stress, was up-regulated while anti-inflammatory protein peroxisome proliferator-activated receptor-γ (PPAR-γ), an important mediator in vascular functional regulation, was down-regulated in the CSFV infected cells. In addition, antioxidants showed significant inhibitory effects on the CSFV replication, indicating a close relationship between CSFV replication and OS induced in the host cells.

Our results indicated that CSFV infection induced oxidative stress in SUVECs. These findings provide novel information on the mechanism by which CSFV can alter intracellular events associated with the viral infection.

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Does e2F4 regulatory program predict patient survival prognosis in breast cancer?

Genetic and molecular signatures have been incorporated into cancer prognosis prediction and treatment decisions with good success over the past decade. Clinically, these signatures are usually used in early-stage cancers to evaluate whether they require adjuvant therapy following surgical resection. A molecular signature that is prognostic across more clinical contexts would be a useful addition to current signatures. We defined a signature for the ubiquitous tissue factor, E2F4, based on its shared target genes in multiple tissues. These target genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) experiments using a probabilistic method. We then computationally calculated the regulatory activity score (RAS) of E2F4 in cancer tissues, and examined how E2F4 RAS correlates with patient survival. Genes in our E2F4 signature were 21-fold more likely to be correlated with breast cancer patient survival time compared to randomly selected genes. Using eight independent breast cancer datasets containing over 1,900 unique samples, we stratified patients into low and high E2F4 RAS groups. E2F4 activity stratification was highly predictive of patient outcome, and our results remained robust even when controlling for many factors including patient age, tumor size, grade, estrogen receptor (ER) status, lymph node (LN) status, whether the patient received adjuvant therapy, and the patient's other prognostic indices such as Adjuvant! and the Nottingham Prognostic Index scores. Furthermore, the fractions of samples with positive E2F4 RAS vary in different intrinsic breast cancer subtypes, consistent with the different survival profiles of these subtypes.

We defined a prognostic signature, the E2F4 regulatory activity score, and showed it to be significantly predictive of patient outcome in breast cancer regardless of treatment status and the states of many other clinicopathological variables. It can be used in conjunction with other breast cancer classification methods such as Oncotype DX to improve clinical outcome prediction.

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Do long-term efficacy of the Baerveldt 250 mm2 compared with the Baerveldt 350 mm2 implant?

To investigate the long-term surgical outcomes of the Baerveldt 250 mm2 versus Baerveldt 350 mm2 glaucoma drainage implants (GDIs) (Abbott Laboratories Inc., Abbott Park, IL) in the treatment of refractory glaucoma. Comparative case study. A total of 89 consecutive eyes in 86 patients treated at Dean McGee Eye Institute between January 2006 and December 2008. We retrospectively reviewed patient data from the following postoperative visits: 1 week, 1 month, 2 months, 3 months, 6 months, and every 3 months thereafter. Postoperative complications were also recorded. The mean follow-up time was 40 months (range, 2-78 months) for the Baerveldt 250 mm2 group and 31 months (range, 3-75 months) for the Baerveldt 350 mm2 group. The primary outcome measure was surgical success. Secondary outcome measures included visual acuity (VA), intraocular pressure (IOP), and number of medications. There was no difference in surgical success (P=0.98). No significant differences were observed in VA measured using the logarithm of the minimum angle of resolution (logMAR) scale, IOP, and number of medications at the last visit (P=0.09, 0.23, and 0.82, respectively). Complication and failure rates were comparable (P=0.82 and 0.64, respectively).

With a mean follow-up of 40 and 31 months, no differences in surgical success, VA, IOP, number of medications at the last visit, and complication/failure rates were noted between the Baerveldt 250 mm2 and 350 mm2 GDIs, respectively. The size of the GDI may not be associated with surgical outcomes.

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Is self-reported body fat change in HIV-infected men a marker of decline in physical health-related quality of life with aging , independent of co-morbidity?

Self-perception of changes in body fat among HIV+ persons is associated with decreased health related quality of life in cross-sectional studies. The longitudinal impact of body fat changes on health related quality of life, while accounting for comorbidity and anatomic location or severity of body fat changes, is unknown. This was a longitudinal analysis of HIV+ and HIV- Multicenter AIDS Cohort Study (MACS) participants who completed questionnaires assessing self-perceived body fat changes (baseline visit) and a health related quality of life (Short Form-36) at baseline and then ≥5 years later. Relationships between body fat changes and change in Short Form-36 Physical and Mental Component Summary scores were investigated using mixed-model regression. We studied 270 HIV+ and 247 HIV- men. At baseline, ≥50% of HIV+ men reported body fat changes; physical component but not mental component summary scores were lower among HIV+ men who reported moderate/severe leg or abdominal fat changes (p<0.05). At follow-up, physical component summary scores were significantly lower among men with face, leg, or abdominal fat changes compared to men without perceived fat changes (p<0.05). No significant changes were seen in mental component scores by fat change location or severity. In the final model, body fat changes at any site or severity were significant predictors of a decline in physical component summary score (p<0.05), independent of demographics or comorbidities. Mental component summary score was not associated with body fat changes, but higher mental component summary score was associated with increasing age and time.

Negative self-perceived body fat changes were associated with decline in physical health related quality of life, independent of comorbidities, and may be a marker of an increased risk for physical function decline with aging.

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Does transcranial magnetic stimulation reveal cortical hyperexcitability in episodic cluster headache?

Evidence shows involvement of the cerebral cortex in the pathophysiology of cluster headache (CH). Here we investigated cortical excitability in episodic CH patients by using transcranial magnetic stimulation. In 25 patients with episodic CH and 13 healthy subjects we evaluated the motor cortical response to single-pulse (ie, motor threshold, input-output curves, cortical silent period) and paired-pulse (ie, intracortical facilitation, short intracortical inhibition) transcranial magnetic stimulation in both hemispheres. Thirteen patients were evaluated outside bout and the remaining 12 patients inside bout. Our results showed increased slope of the input-output curves after stimulation of both hemispheres in patients outside bout and in the hemisphere contralateral to the headache side in patients inside bout. Increased intracortical facilitation was observed in the hemisphere ipsilateral to the headache side in patients evaluated both outside and inside bout; reduced short intracortical inhibition was observed in patients inside bout ipsilateral to the side of pain. In conclusion, we provide evidence of increased cortical excitability in episodic CH both outside and inside bout, especially in the hemisphere ipsilateral to the side of headache attacks. Our results suggest that an abnormal regulation of cortical excitability could be involved in the pathophysiology of CH.

We investigated cortical excitability in episodic cluster headache by using transcranial magnetic stimulation, providing evidence of cortical hyperexcitability in patients both inside and outside bout. We suggest that an abnormal state of cortical excitability could be involved in the pathophysiology of the disease.

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Is motor cortical activity during motor tasks normal in patients with complex regional pain syndrome?

Motor dysfunction in complex regional pain syndrome (CRPS) is often considered a functional movement disorder. Earlier studies in patients with functional movement disorders found evidence of cortical inhibition during explicit but not implicit motor tasks, suggesting active inhibition from other brain areas. In this study, we explored whether active inhibition occurs in CRPS patients. We compared patients with CRPS with 2 control groups: healthy controls matched for age and sex, and patients whose hand was immobilized to treat a scaphoid fracture. We used transcranial magnetic stimulation to measure corticospinal excitability at rest and during motor imagery (explicit motor task) and motor observation (implicit motor task). Motor corticospinal excitation measured at rest and during implicit and explicit motor tasks was similar for CRPS patients and healthy controls. Patients with an immobilized hand showed an absence of motor cortical excitation of the corresponding hemisphere during motor imagery of tasks involving the immobilized hand, but not during motor observation. The normal motor cortical processing during motor imagery and motor observation found in the corresponding hemisphere of CPRS patients suggests that the nature of motor dysfunction in this condition differs from that described in literature for patients with functional paresis or under circumstances of limb immobilization.

This study shows that the nature of motor dysfunction in CRPS patients differs from that encountered in patients with functional paresis or under circumstances of limb immobilization. This information is important for patients and pain clinicians and could help prevent implementation of therapeutic strategies based on incorrect assumptions.

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Does peripheral group I metabotropic glutamate receptor activation lead to muscle mechanical hyperalgesia through TRPV1 phosphorylation in the rat?

Elevated glutamate levels within injured muscle play important roles in muscle pain and hyperalgesia. In this study, we hypothesized that protein kinase C (PKC)-dependent TRPV1 phosphorylation contributes to the muscle mechanical hyperalgesia following activation of Group I metabotropic glutamate receptors (mGlu1/5). Mechanical hyperalgesia induced by (R,S)-3,5-dihydroxyphenylglycine (DHPG), an mGlu1/5 agonist, in the masseter muscle was attenuated by AMG9810, a specific TRPV1 antagonist. AMG9810 also suppressed mechanical hyperalgesia evoked by pharmacologic activation of PKC. DHPG-induced mechanical hyperalgesia was suppressed by pretreatment with a decoy peptide that disrupted interactions between TRPV1 and A-kinase-anchoring protein (AKAP), which facilitates phosphorylation of TRPV1. In dissociated trigeminal ganglia, DHPG upregulated serine phosphorylation of TRPV1 (S800), during which DHPG-induced mechanical hyperalgesia was prominent. The TRPV1 phosphorylation at S800 was suppressed by a PKC inhibitor. Electrophysiologic measurements in trigeminal ganglion neurons demonstrated that TRPV1 sensitivity was enhanced by pretreatment with DHPG, and this was prevented by a PKC inhibitor, but not by a protein kinase A inhibitor. These results suggest that mGlu1/5 activation in masseter afferents invokes phosphorylation of TRPV1 serine residues including S800, and that phosphorylation-induced sensitization of TRPV1 is involved in masseter mechanical hyperalgesia. These data support a role of TRPV1 as an integrator of glutamate receptor signaling in muscle nociceptors.

This article demonstrates that activation of mGlu1/5 leads to phosphorylation of a specific TRPV1 residue via PKC and AKAP150 in trigeminal sensory neurons and that functional interactions between glutamate receptors and TRPV1 mediate mechanical hyperalgesia in the muscle tissue.

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Does lipopolysaccharide preconditioning induce neuroprotection against early brain injury after experimental subarachnoid hemorrhage?

Subarachnoid hemorrhage (SAH) is a devastating neurological injury associated with significant morbidity and mortality. We postulated that lipopolysaccharide (LPS) preconditioning induces neuroprotection against early brain injury (EBI) after experimental SAH. 72 male Sprague-Dawley rats (250 to 300 g) were used. SAH was produced by injecting autologous arterial blood into the pre-chiasmatic cistern. Rats were given an intraperitoneal injection of LPS 24 hours prior SAH. Matrix metalloproteinase 9 (MMP-9) protein expression was measured by western blot; apoptosis in the cerebral cortex were studied by terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) and 4'6-diamidino-2-phenylindole dihydrochloride (DAPI) staining at 24 h after SAH. Brain water content was also examined. MMP-9 expression was increased after SAH and decreased by LPS preconditioning at 24 h after SAH. The number of neuronal death in cortex was increased after SAH and decreased by LPS preconditioning. In addition, brain water content was attenuated by LPS preconditioning.

LPS preconditioning could modulate MMP-9 and therefore induce neuroprotection against EBI after experimental SAH.

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Is loss of N-cadherin associated with loss of E-cadherin expression and poor outcomes of liver resection in hepatocellular carcinoma?

Our previous study suggested that N-cadherin was downregulated in hepatocellular carcinoma (HCC). Our aim in this study was to investigate the correlation between N- and E-cadherin expression in HCC and its clinical significance. Eighty-six patients with HCC undergoing liver resection were retrospectively studied. N- and E-cadherin expression in HCC and adjacent liver tissue were investigated using immunohistochemistry and immunofluorescence. The correlation between the expression status of both cadherins and surgical outcomes was analyzed. In 23 patients negative for E-cadherin expression, 19 of them (82.6%) were also negative for N-cadherin expression. In 30 patients with heterogeneous expression of E-cadherin, 20 of them (66.7%) also had heterogeneous expression of N-cadherin. In 33 patients with uniformly positive expression of E-cadherin, 19 of them (57.6%) also had uniformly positive expression of N-cadherin. Therefore, there was a positive correlation between expression patterns of N- and E-cadherins. Concurrent loss of both N- and E-cadherin expressions was significantly associated with absence of the tumor capsule, vascular invasion, and poor differentiation. The 1- and 3-y disease-free survival rates were 27% and 9%, respectively, and the 1- and 3-y overall survival rates were 64.3% and 14.3%, respectively, in patients with concurrent loss of both cadherins, which were significantly worse than those with concurrent uniformly positive expression or heterogeneous expression of both cadherins.

Loss of N-cadherin was positively correlated with loss of E-cadherin in HCC. Concurrent loss of both N- and E-cadherin expressions was associated with poor surgical outcomes of HCC patients undergoing liver resection.

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Does the dual mTORC1 and mTORC2 inhibitor PP242 show strong antitumor activity in a pheochromocytoma PC12 cell tumor model?

To assess the activity of mTOR and downstream effector proteins in the mTOR pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) inhibitor (PP242) compared with that of mTOR complex 1 (mTORC1) inhibitor (rapamycin) using a xenograft tumor model. Pheochromocytoma PC12 cell were xenografted into nude mice. Animals were treated with PP242 and rapamycin. Mean tumor volume was compared across groups. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was used to detect apoptosis. Immunoblot analysis was performed to assess mTORC1/2 activity using p-Akt, p-S6, and p-4E-BP1. The expression of the antiapoptotic protein Bcl-2, pro-apoptotic protein Bax, and the mediator of angiogenesis vascular endothelial growth factor were also investigated. The mean tumor volume of PP242 was significantly lower than in other groups. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling results showed that PP242 markedly increased cell apoptosis compared with other groups. Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated p-Akt. We also observed that only PP242, but not rapamycin, significantly reduced Bcl-2 expression and markedly increased Bax expression. Rapamycin decreased vascular endothelial growth factor expression, but not nearly as striking as seen in the PP242 group.

Our study showed that PP242 showed strong antitumor activity in a pheochromocytoma PC12 cell tumor model. Based on our study, dual mTORC1/2 kinase inhibitors warrant further investigation as a potential treatment for malignant pheochromocytomas or paragangliomas.

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Does s100A3 suppression inhibit in vitro and in vivo tumor growth and invasion of human castration-resistant prostate cancer cells?

To investigate the role of S100A3 and the effect of S100A3 inhibition on human castration-resistant prostate cancer (CRPC) cells by using in vitro and in vivo functional assays. Using human CRPC cells (PC3 and DU145), S100A3 expression levels were assessed by reverse transcription-polymerase chain reaction and Western blot analysis. After S100A3-specific small interfering ribonucleic acid (RNA) treatment, cell viability was determined by Cell Counting Kit-8 assay, and apoptotic cell fractions were evaluated by flow cytometry. The invasive properties of these cells and the expression pattern of matrix metalloproteinases (MMPs) were assessed using transwell migration assays, reverse transcription-polymerase chain reaction, and gelatin zymography. Finally, the in vivo efficacy of S100A3 inhibition on human CRPC cells was investigated using human tumor xenograft models in nude mice. Human CRPC cells showed overexpression of S100A3, and its suppression reduced cell viability owing to apoptotic cell death. Additionally, S100A3 inhibition decreased the invasiveness of human CRPC cells. Moreover, MMP-2 and MMP-9 were downregulated in PC3, whereas only MMP-9 was downregulated in D145 after S100A3 inhibition. In human CRPC xenograft models, we noted a marked reduction in tumor growth in mice injected with S100A3 short hairpin RNA-transfected PC3 and DU145 cells.

Human CRPC cells showed upregulation of S100A3 expression, and S100A3 inhibition reduced tumor cell viability. S100A3 inhibition reduced invasion capability with downregulation of MMP expression. More importantly, S100A3 inhibition resulted in tumor growth suppression in human CRPC xenograft models, suggesting S100A3 could serve as a novel therapeutic target for the treatment of human CRPC.

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Does a common polymorphism within MSLN affect miR-611 binding site and soluble mesothelin levels in healthy people?

Soluble mesothelin related peptide (SMRP) was proposed as a promising diagnostic marker for malignant pleural mesothelioma (MPM). In a previous study, we found that rs1057147 within the 3' untranslated region of MSLN gene was associated with SMRP levels. Thus, we aimed to (1) confirm the previous association on a large series of volunteers and (2) test the hypothesis that the SNP could affect microRNA binding sites. The association analysis was verified in 759 subjects. Then, in silico predictions highlighted miR-611 and miR-887 as candidate miRNAs binding to the polymorphic site. Thus, chimeric constructs bearing the alternative alleles (G > A) were assayed alone or in cotransfection with the miRNA mimics, with dual luciferase reporter assay in non-MPM Met-5A cells. The miRNAs were also assayed by western blot analysis for their ability to down-regulate endogenous mesothelin in the MPM Mero-14 cell line. We confirmed that, among non-MPM volunteers, GG homozygotes have the lowest SMRP levels. When the genotype is taken into account, the specificity of SMRP as biomarker improves from 79.7% to 85.3%. Dual-luciferase assays showed a significantly lower reporter activity when the vector harbored the G allele as compared to A allele. miR-887 mimic caused a reduced reporter activity of vectors harboring A or G alleles, while miR-611 was effective only on the vector harboring the G allele. Transfection of these miRNAs into Mero-14 cells significantly reduced endogenous MSLN protein.

SMRP performance as diagnostic biomarker improved by considering the genotype rs1057147. This polymorphism most likely affects a binding site for miR-611.

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Is [ Ischemia an independent predictive factor of chronic renal failure after partial nephrectomy in a solitary kidney in patients without pre-operative renal insufficiency ]?

To assess the influence of vascular clamping and ischemia time on long-term post-operative renal function following partial nephrectomy (PN) for cancer in a solitary kidney. This is a retrospective study including 259 patients managed by PN between 1979 and 2010 in 13 centers. Clamping use, technique choice (pedicular or parenchymal clamping), ischemia time, and peri-operative data were collected. Pre-operative and last follow-up glomerular filtration rates were compared. A multivariate analysis using a Cox model was performed to assess the impact of ischemia on post-operative chronic renal failure risk. Mean tumor size was 4.0±2.3cm and mean pre-operative glomerular filtration rate was 60.8±18.9mL/min. One hundred and six patients were managed with warm ischemia (40.9%) and 53 patients with cold ischemia (20.5%). Thirty patients (11.6%) have had a chronic kidney disease. In multivariate analysis, neither vascular clamping (P=0.44) nor warm ischemia time (P=0.1) were associated with a pejorative evolution of renal function. Pre-operative glomerular filtration rate (P<0.0001) and blood loss volume (P=0.02) were significant independent predictive factors of long-term renal failure.

Renal function following PN in a solitary kidney seems to depend on non-reversible factors such as pre-operative glomerular filtration rate. Our findings minimize the role of vascular clamping and ischemia time, which were not significantly associated with chronic renal failure risk in our study.

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Does regional anesthesia improve outcome in patients undergoing proximal humerus fracture repair?

The purpose of this study was to examine functional outcomes following ORIF of displaced proximal humerus fractures in patients who received brachial plexus blocks compared to those who underwent general anesthesia. We retrospectively reviewed prospectively collected data on 92 patients. Patients were grouped according to anesthesia type: regional interscalene brachial plexus block, with or without general anesthesia, or general anesthesia alone. Patients were asked to complete the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and range of motion assessments at a minimum of 6-month follow-up. Plain radiographic films were obtained to assess fracture healing. Forty-five (48.9%) patients with 45 proximal humerus fractures received a regional anesthetic, while 47 (51.1%) patients with 48 proximal humerus fractures had general anesthesia. No significant differences existed in demographic information or fracture type. DASH scores at the most recent follow-up were significantly better in the regional block group (38.6) compared to the general anesthesia group (53.1) (p = 0.003). The regional block group had significantly better passive and active forward elevation and external rotation range and equivalent internal rotation (p = 0.002, 0.005, 0.002, and 0.507, respectively).

Patients who received regional anesthetic via a brachial plexus interscalene blocks had better functional outcomes and range of motion at the most recent clinical follow-up. Regional anesthesia provides patients with prolonged postoperative pain relief, which may allow for early mobilization, increasing the likelihood that the patient's function and range of motion will return to baseline.

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Are in patients with rheumatoid arthritis , Dickkopf-1 serum levels correlated with parathyroid hormone , bone erosions and bone mineral density?

The objective of this study is to compare the serum levels of Dickkopf-1 (DKK1), a natural inhibitor of Wnt signalling, with parathyroid hormone (PTH) and bone involvement in patients with rheumatoid arthritis (RA). This cross-sectional study includes 154 postmenopausal women with RA and 125 healthy controls. DKK1, 25OH vitamin D (25OHD), bone turnover markers, and PTH serum levels were measured by ELISA; lumbar spine and hip bone mineral density (BMD) and the erosion score were obtained. The RA patients and healthy controls were not significantly different in terms of age, body mass index, and 25OHD serum levels. The mean level of DKK1 and PTH were significantly higher in patients with RA than in healthy controls (172±68 [SD] vs. 96±55 pmoL/L, and 30±15 vs 22±11, respectively; p<0.0001). DKK1 serum levels were positively correlated with age (p<0.05) only in the healthy controls, while they were correlated with PTH serum levels only in the RA patients (p<0.0001). Among the RA patients, DKK1 levels adjusted for age, PTH and disease duration were significantly higher in patients with bone erosions (176 vs. 167 pmoL/L, respectively; p<0.05). DKK1 levels adjusted for age and PTH were negatively correlated with total hip BMD (p<0.05). In the RA patients not on treatment with bisphosphonates, DKK1 serum levels positively correlated with C-terminal telopeptides of type I collagene serum levels (p<0.05).

In patients with RA, serum levels of DKK1 are significantly increased, correlate with PTH and are associated with increased risk of bone erosions and osteoporosis. However, this finding deserves confirmation in a larger and more selected population.

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Does multimodal protocol reduce postoperative nausea and vomiting in patients undergoing Le Fort I osteotomy?

To assess the impact of a multimodal antiemetic protocol on postoperative nausea and vomiting (PONV) after Le Fort I osteotomy. Consecutive patients undergoing Le Fort I osteotomy with or without additional procedures at a single academic institution were recruited as the intervention cohort for an institutional review board-approved prospective clinical trial with a retrospective comparison group. The intervention cohort was managed with a multimodal antiemetic protocol, including total intravenous anesthesia; prophylactic ondansetron, steroids, scopolamine, and droperidol; gastric decompression at surgery end; opioid-sparing analgesia; avoidance of morphine and codeine; prokinetic erythromycin; and fluids at a minimum of 25 mL/kg. The comparison group consisted of consecutive patients from a larger study who underwent similar surgical procedures before protocol implementation. Data, including occurrence of PONV, were extracted from medical records. Data were analyzed in bivariate fashion with the Fisher exact and Wilcoxon rank-sum tests. Logistic regression was used to compare the likelihood of nausea and vomiting in the 2 cohorts after controlling for demographic and surgical characteristics. A P value less than .05 was considered significant. The intervention (n = 93) and comparison (n = 137) groups were similar in gender (58% and 65% female patients; P = .29), race (72% and 71% Caucasian; P = .85), age (median, 19 and 20 years old; P = .75), proportion of patients with known risk factors for PONV (P = .34), percentage undergoing bimaxillary surgery (60% for the 2 groups), and percentage for whom surgery time was longer than 180 minutes (63% and 59%; P = .51). Prevalence of postoperative nausea was significantly lower in the intervention group than in the comparison group (24% vs 70%; P < .0001). Prevalence of postoperative vomiting was likewise significantly lower in the intervention group (11% vs 28%; P = .0013). The likelihood that patients in the comparison group would develop nausea was 8.9 and that for vomiting was 3.7 times higher than in the intervention group.

This multimodal protocol was associated with substantially decreased prevalence of PONV in patients undergoing Le Fort I osteotomy.

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Is a high body mass index in esophageal cancer patients associated with adverse outcomes following esophagectomy?

There is no consensus about the impact of a high BMI on postoperative morbidity and survival after esophagectomy. The aim of this study was to determine the influence of a high BMI on postoperative complications and survival in a large cohort of esophageal cancer patients. From January 2006 to December 2012, 1,342 consecutive esophageal cancer patients who underwent esophagectomy were included in this study. Patients were divided into three groups: 950 patients were classified as normal BMI (BMI 18.5-24.9 kg/m(2)), 279 were classified as high BMI (BMI ≥ 25 kg/m(2)), and 113 as low BMI (BMI < 18.5 kg/m(2)). Multivariate logistic regression models were used to identify confounding factors associated with postoperative complications. The impact of BMI on overall survival (OS) was estimated by the Kaplan-Meier method and Cox proportional hazard models. The predominance of pathological type was esophageal squamous cell carcinoma (n = 1,280, 95.4 %). Overall morbidity, mortality, and hospital stay did not differ among groups. The incidence of pneumonia was higher in patients with high BMI compared with those with normal BMI (14.7 vs. 9.9 %, P = 0.025). However, chylothorax was less frequent in high-BMI group (0.4 % in high-BMI group, 3.1 % in normal group, and 3.5 % in low group, P = 0.011). Logistic regression analysis revealed high BMI was independently associated with decreased incidence of chylothorax [HR 0.86; 95 % confidence interval 0.76-0.97]. Overweight and obese patients had significantly better overall survival than underweight patients (median OS 55.6 vs. 32.5 months, P = 0.013), while the pathological stage was significantly higher in underweight patients (P = 0.001). In multivariate analysis, T status, N status, differentiation grade, and tumor length were identified as independent prognostic factors.

A high BMI is not associated with increased overall morbidity following esophagectomy; moreover, it is associated with decreased incidence of chylothorax. The better overall survival in patients with high BMI compared with those with low BMI might be due to a relatively low pathological stage. A high BMI should therefore not be a relative contraindication for esophagectomy.

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Are fascial closure after open abdomen : initial indication and early revisions decisive factors -- a retrospective cohort study?

The surgical treatment method in which the peritoneal cavity is opened anteriorly and deliberately left open, hence often called "open abdomen" has become the standard of care in damage-control procedures as well as in the management of intra-abdominal hypertension and in severe intra-abdominal sepsis. Whereas open abdomen has been closed in two stages traditionally, a modern trend is to close the fascial layers within the initial hospitalization to avoid complications like enterocutaneous fistula and hernia formation. The aim of this study was to determine crucial factors influencing the possibility of fascial closure after open abdomen. Between 2003 and 2013, 355 adult patients were treated with open abdomen in our institution. Their data were collected and retrospectively analyzed. They were divided into two groups depending on fascial closure or not (fascial closure, n = 137 (39%) vs. non-fascial closure, n = 218 (61%)). The patients who reached fascial closure had a significantly higher rate of initially performed open abdomen (97 patients (71%) vs. 118 (54%), p = 0.002) and the periods of time until a second and a third look operation were significantly shorter (2.7 ± 2.5 vs. 4.2 ± 6.6 days, p = 0.021 and 5.6 ± 3.7 vs. 8.5 ± 8.6 days, p = 0.006). Furthermore, the presence of peritonitis (64 patients (47%) vs. 83 patients (38%), p = 0.023) and large bowel resection (74 patients (54%) vs. 90 patients (41%), p = 0.022) were significantly higher in this group. Rates of in-hospital mortality (97 patients (44%) vs. 38 patients (28%), p = 0.002) and the presence of pancreatitis (19 patients (9%) vs. 3 patients (2%), p = 0.013) were significantly higher in the non-fascial closure group.

The probability to reach fascial closure after open abdomen seems to increase when open abdomen is performed initially and when early second and third look operations are performed. The presence of pancreatitis seems to be the only negative prognostic marker concerning fascial closure.

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Does mR imaging relaxometry allow noninvasive characterization of in vivo differentiation of muscle precursor cells?

To demonstrate the feasibility of in vivo monitoring of the myogenic differentiation process from human muscle precursor cells to mature skeletal muscle tissue by measuring characteristic magnetic resonance (MR) imaging relaxation and diffusion properties as a potential noninvasive diagnostic tool in muscle cell therapy. The study was approved by the ethics committee for studies in humans and the animal care committee. The hypothesis was tested by means of subcutaneous injection of human muscle precursor cells from the rectus abdominis muscle into nude mice (n = 18). Animals injected with human fibroblasts, prostate cancer cells, or collagen served as control animals (four in each group). T1, T2, T2*, and apparent diffusion coefficients (ADCs) were measured at 4.7-T MR imaging. MR imaging parameters were statistically evaluated by using analysis of variance with Bonferroni correction. The engineered muscle was characterized by means of immunofluorescence, Western blot, and contraction assays. Muscle tissue in the early stages of the differentiation process exhibited distinctly higher T1 (mean ± standard deviation, 2242 msec ± 116), T2 (224 msec ± 18), and T2* (33.3 msec ± 3.6) values and ADCs (1.53 × 10(-3) mm(2)/sec ± 0.03) compared with those of skeletal muscle. The muscle precursor cells exhibited a nonspecific pattern compared with that in control animals in the early stages. During differentiation, the relaxation and diffusion parameters decreased and approached the values for mature skeletal muscle tissue: T1, 1386 msec ± 88; T2, 32.0 msec ± 4.3; T2*, 10.8 msec ± 0.8; ADC, 1.39 × 10(-3) mm(2)/sec ± 0.02 (reference erector spinae muscle tissue: T1, 1417 msec ± 106; T2, 31.0 msec ± 2.4; T2*, 11.3 msec ± 1.7; and ADC, 1.40 × 10(-3) mm(2)/sec ± 0.03).

MR imaging relaxation and diffusion measurements can be used as potential biomarkers for noninvasive in vivo monitoring of the myogenic differentiation process from muscle precursor cells to mature skeletal muscle tissue in muscle cell therapy.

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Is higher fasting glucose next day after intravenous thrombolysis independently associated with poor outcome in acute ischemic stroke?

We aimed to test the outcome-predictive power of routine fasting glucose (FG) obtained at second day after onset in intravenous thrombolysis (IVT) acute ischemic stroke (AIS) patients. We identified AIS patients presenting to our institution between December 2011 and July 2013 within 4.5 hours of onset, who received admission glucose (AG) before IVT, FG, and glycated hemoglobin (HbA1c) the second day after admission, from our prospectively recorded stroke database. Multivariate logistic regression was used to assess the association of FG and 90-day modified Rankin Scale (mRS). Between December 2011 and July 2013, a total of 166 AIS patients received intravenous plasminogen activator. Of those, 119 patients who have AG before IVT, FG, and HbA1c the second day were included in the study. FG independently predicted 90-day clinical unfavorable outcome (mRS, 3-6 with an odds ratio of 1.576; 95% confidence interval [CI], 1.053-2.358; P = .027). This association was not significant in AG (P = .714), HbA1c (P = .655), and history of diabetes (P = .547). In receiver operating characteristic analysis, increased FG was associated with 90-day mRS (3-6) with an area under curve of .72, (95% CI, .65-.9; P = .001).

FG is a powerful predictor associated with the outcome in IVT-treated AIS patients independent of AG and HbA1c.

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Is a newly developed mouse monoclonal SOX10 antibody a highly sensitive and specific marker for malignant melanoma , including spindle cell and desmoplastic melanomas?

Recent immunohistochemical studies have demonstrated Sry-related HMG-Box gene 10 (SOX10) expression in malignant melanomas, malignant peripheral nerve sheath tumors, a subset of breast carcinomas, and gliomas. SOX10 has shown important clinical utility in its ability to detect desmoplastic and spindle cell melanomas. To date, most publications have employed a research use-only goat polyclonal SOX10 antibody for immunohistochemical staining. To describe the development of a new mouse monoclonal SOX10 antibody (BC34) and evaluate its immunohistochemical staining profile in a wide range of normal and neoplastic tissues, with an emphasis on melanoma. SOX10 antibody was optimized for staining using a polymer detection system and visualization with diaminobenzidine. In normal tissues, SOX10 was expressed in skin melanocytes and eccrine cells, breast myoepithelial and lobular epithelial cells, salivary gland myoepithelial cells, peripheral nerve Schwann cells, and central nervous system glial cells. SOX10 was expressed in 238 of 257 melanomas (92.6%), including 50 of 51 of both spindle cell and desmoplastic melanomas (98%). SOX10 was expressed in 100% of nevi (20 of 20) and schwannomas (28 of 28). In other neoplasms, SOX10 was expressed in 18 of 109 invasive ductal breast carcinomas (16.5%). All other carcinomas were negative for SOX10. SOX10 was identified in 25 of 52 central nervous system neoplasms, primarily in astrocytomas (22 of 41; 53.7%), and in 4 of 99 various sarcomas examined (4.0%).

The newly developed mouse monoclonal SOX10 antibody BC34 is highly sensitive and specific for malignant melanoma, including desmoplastic and spindle cell variants, and appears highly suitable for clinical use.

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Is abdominal aortic diameter increased in males with a family history of abdominal aortic aneurysms : results from the Danish VIVA-trial?

To investigate, at a population level, whether a family history of abdominal aortic aneurysm (AAA) is independently related to increased aortic diameter and prevalence of AAA in men, and to elucidate whether the mean aortic diameter and the prevalence of AAA are different between participants with male and female relatives with AAA. Observational population-based cross-sectional study. 18,614 male participants screened for AAA in the VIVA-trial 2008-2011 with information on both family history of AAA and maximal aortic diameter. Standardized ultrasound scan measurement of maximum antero-posterior aortic diameter. Family history obtained by questionnaire. Multivariate regression analysis was used to test for confounders: age, sex, smoking, comorbidity and medication. From the screened cohort, 569 participants had at least one first degree relative diagnosed with AAA, and 38 had AAA. Participants with a family history of AAA (+FH) had a significantly larger mean maximum aortic diameter (20.50 mm) compared with participants without family history of AAA (-FH) (19.07 mm, p < .0001), and +FH with female relatives with AAA had significantly larger mean maximum aortic diameter (21.8 mm) than +FH with male relatives (19.9 mm, p = .007). Furthermore the prevalence of AAA was significantly higher among +FH (6.7%) compared with -FH (3.0%) with an odds ratio (OR) of 2.2 (95% CI: 1.6 to 3.2, p < .001) and +FH with female relatives with AAA had a more than two and a half times increased prevalence of AAA compared with +FH with male relatives with AAA with an OR of 2.65.

First-degree male relatives of AAA patients have wider aortas and a twofold higher prevalence of AAA compared with the age adjusted background population. The prevalence of AAA was markedly higher in participants related to female, rather than male, patients with AAA.

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Does dual-specificity phosphatase 6 predict the sensitivity of progestin therapy for atypical endometrial hyperplasia?

We previously found that Dual-specificity phosphatase 6 (Dusp6) over-expression enhanced the growth-promoting effect of estrogen in endometrial adenocarcinoma cells. The aim of this study was to explore the correlation of Dusp6 expression with progestin sensitivity in atypical endometrial hyperplasia (AEH) and earlier endometrial carcinomas (EC). Using immunohistochemistry study, we analyzed the expression of Dusp6 protein in AEH. We found that progestin treatment was effective in 89% of AEH and 50% of EC. Before treatment, Dusp6 expression was significantly higher in progestin-sensitive AEH groups compared with progestin-resistant groups. After treatment, Dusp6 expression was significantly upregulated in progestin-sensitive groups, but not in progestin-resistant groups. Moreover, a high-dose of Dusp6 transfection significantly enhanced progestin-induced growth-inhibition in Ishikawa cells.

Dusp6 could be a predicting marker for deciding the effectiveness of progestin therapy in AEH.

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Does endoscopic transphenoidal surgery for acromegaly improve quality of life?

Acromegaly has important effects on quality of life (QOL). This is the first study to measure QOL in acromegalic patients after endoscopic transsphenoidal surgery (ETSS). We prospectively collected the RAND-36, Center for Epidemiologic Studies Depression (CES-D), and Pituitary QOL validated questionnaires and patients' demographics, clinical presentation, endocrine laboratory results, radiological studies, development of complications and remission rates from 20 consecutive acromegalic patients who had undergone endoscopic transphenoidal surgery. The eleven females and nine males had an average age of 42 years; 90 percent had macroadenomas and 70% had cavernous sinus invasion on their preoperative imaging. Ninety percent had improved symptoms post-operatively and 80% stated that treatment improved their QOL. Biochemically, 35% were cured, 35% had discordant results and 30% were not cured, while pan-hypopituitarism occurred in 4 patients. Physical health subscales and pituitary-related symptoms were similar to norms. "Social," "emotional health," and "energy levels" were significantly lower than norms. Seventy percent stated that their relationship with their physician "very much so" affected their quality of life. Pan hypopituitarism and adjuvant therapy were the most significant predictors of lower QOL subscale scores.

Transsphenoidal surgery improves QOL in acromegaly. Attempts to achieve a cure, avoidance of surgically induced pan-hypotpituitarism and adjuvant therapy, will improve quality of life. Our study demonstrates the important role of the patient-physician relationship to QOL and the need to measure QOL in addition to the traditional measures of outcome.

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Is smoking history , and not depression , related to deficits in detection of happy and sad faces?

Previous research has demonstrated that chronic cigarette smoking and major depressive disorder (MDD) are each associated with cognitive decrements. Further, these conditions co-occur commonly, though mechanisms in the comorbid condition are poorly understood. There may be distinct, additive, or overlapping factors underlying comorbid cigarette smoking and MDD. The present study investigated the impact of smoking and MDD on executive function and emotion processing. Participants (N=198) were grouped by diagnostic category (MDD and healthy controls, HC) and smoking status (ever-smokers, ES and never-smokers, NS). Participants completed the Facial Emotion Perception Test (FEPT), a measure of emotional processing, and the parametric Go/No-go task (PGNG), a measure of executive function. FEPT performance was analyzed using ANCOVA with accuracy and reaction time as separate dependent variables. Repeated measures MANCOVA was conducted for PGNG with performance measure and task level as dependent variables. Analyses for each task included diagnostic and smoking group as independent variables, and gender was controlled for. Results for FEPT reveal that lower overall accuracy was found for ES relative to NS, though MDD did not differ from HC. Post-hoc analyses revealed that ES were poorer at identifying happy and sad, but not fearful or angry, faces. For PGNG, poorer performance was observed in MDD relative to HC in response time to Go targets, but there were no differences for ES and NS. Interaction of diagnosis and smoking group was not observed for performance on either task.

The results of this study provide preliminary evidence for distinctive cognitive decrements in smokers and individuals with depression.

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Are fatty acid-amino acid conjugates essential for systemic activation of salicylic acid-induced protein kinase and accumulation of jasmonic acid in Nicotiana attenuata?

Herbivory induces the activation of mitogen-activated protein kinases (MAPKs), the accumulation of jasmonates and defensive metabolites in damaged leaves and in distal undamaged leaves. Previous studies mainly focused on individual responses and a limited number of systemic leaves, and more research is needed for a better understanding of how different plant parts respond to herbivory. In the wild tobacco Nicotiana attenuata, FACs (fatty acid-amino acid conjugates) in Manduca sexta oral secretions (OS) are the major elicitors that induce herbivory-specific signaling but their role in systemic signaling is largely unknown. Here, we show that simulated herbivory (adding M. sexta OS to fresh wounds) dramatically increased SIPK (salicylic acid-induced protein kinase) activity and jasmonic acid (JA) levels in damaged leaves and in certain (but not all) undamaged systemic leaves, whereas wounding alone had no detectable systemic effects; importantly, FACs and wounding are both required for activating these systemic responses. In contrast to the activation of SIPK and elevation of JA in specific systemic leaves, increases in the activity of an important anti-herbivore defense, trypsin proteinase inhibitor (TPI), were observed in all systemic leaves after simulated herbivory, suggesting that systemic TPI induction does not require SIPK activation and JA increases. Leaf ablation experiments demonstrated that within 10 minutes after simulated herbivory, a signal (or signals) was produced and transported out of the treated leaves, and subsequently activated systemic responses.

Our results reveal that N. attenuata specifically recognizes herbivore-derived FACs in damaged leaves and rapidly send out a long-distance signal to phylotactically connected leaves to activate MAPK and JA signaling, and we propose that FACs that penetrated into wounds rapidly induce the production of another long-distance signal(s) which travels to all systemic leaves and activates TPI defense.

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Does deficiency in Nrf2 transcription factor decrease adipose tissue mass and hepatic lipid accumulation in leptin-deficient mice?

To evaluate whether Nrf2 deficiency impacts insulin resistance and lipid accumulation in liver and white adipose tissue. Lep(ob/ob) mice (OB) with targeted Nrf2 deletion (OB-Nrf2KO) were generated. Pathogenesis of obesity and type 2 diabetes was measured in C57BL/6J, Nrf2KO, OB, and OB-Nrf2KO mice. Hepatic lipid content, lipid clearance, and very low-density lipoprotein (VLDL) secretion were determined between OB and OB-Nrf2KO mice. OB-Nrf2KO mice exhibited decreased white adipose tissue mass and decreased adipogenic and lipogenic gene expression compared with OB mice. Nrf2 deficiency prolonged hyperglycemia in response to glucose challenge, which was paralleled by reduced insulin-stimulated Akt phosphorylation. In OB mice, Nrf2 deficiency decreased hepatic lipid accumulation, decreased peroxisome proliferator-activated receptor γ expression and nicotinamide adenine dinucleotide phosphate (NADPH) content, and enhanced VLDL secretion. However, this observation was opposite in lean mice. Additionally, OB-Nrf2KO mice exhibited increased plasma triglyceride content, decreased HDL-cholesterol content, and enhanced apolipoprotein B expression, suggesting Nrf2 deficiency caused dyslipidemia in these mice.

Nrf2 deficiency in Lep(ob/ob) mice reduced white adipose tissue mass and prevented hepatic lipid accumulation but induced insulin resistance and dyslipidemia. This study indicates a dual role of Nrf2 during metabolic dysregulation-increasing lipid accumulation in liver and white adipose tissue but preventing lipid accumulation in obese mice.

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Do bone Marrow Stromal Cells Inhibit the Activation of Liver Cirrhotic Fat-Storing Cells via Adrenomedullin Secretion?

Cirrhosis, or liver fibrosis, which is mainly triggered by cirrhosis fat-storing cells (CFSCs) activation, has traditionally been considered an irreversible disease. However, recent observations indicate that even advanced fibrosis is still reversible by removing the causative agents. Anti-fibrotic effects of bone marrow-derived stromal cells (BMSCs) have been demonstrated by inhibiting CFSCs via cytokines secretion; however, the mechanisms are still unclear. The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated CFSCs. After the co-culture of CFSCs with BMSCs supernatants with or without the addition of recombinant rat adrenomedullin (AM)/AM-specific siRNA, western blot analysis was mainly used to detect the differences of relative protein expression on CFSCs. BMSC-secreted adrenomedullin (AM) effectively inhibited the proliferation and activation of CFSCs by suppressing the expression of Ang II and its binding receptor, AT1, which resulted in a reduction of p47-phox formation.

Our data suggested that BMSCs inhibited CFSC activation in vitro via the AM-Ang II-p47-phox signaling pathway, and since CFSC activation is an essential part of hepatic fibrosis process, this inhibition by BMSCs implies us new insights into the potential treatment of hepatic fibrosis via BMSCs.

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Does obesity increase risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage?

Not all patients with warfarin-related acute intracranial hemorrhage (ICH) achieve full reversal of international normalized ratio (INR) after the first dose of weight-based prothrombin complex concentrate (PCC). We sought to identify factors associated with anticoagulation reversal failure after the first dose of PCC. Consecutive patients who were hospitalized with warfarin-related acute ICH at a tertiary center between 1 January 2010 and 31 December 2012 were studied. Anticoagulation reversal failure was defined as INR ≥ 1.5 after the first dose of PCC. Logistic regression was performed to determine the predictors of anticoagulation reversal failure. Fifty-one patients with acute ICH received PCC for warfarin reversal using a weight-based protocol. Overall, 23 (45%) patients did not achieve full reversal of INR after the first dose. Those with anticoagulation reversal failure were obese (body mass index > 30 kg/m(2)) (41% vs. 14%, p = 0.03), had a higher initial INR (3.0 ± 1.4 vs. 2.0 ± 0.7, p = 0.001), and had a higher prevalence of initial INR >2.0 (22% vs. 67%, p = 0.001), compared with those who were successfully reversed. Multivariable logistic regression identified obesity (odds ratio 7.88, 95% CI 1.12 to 55.68) and initial INR >2.0 (odds ratio 12.49, 95% CI 2.27 to 68.87) as independent predictors of anticoagulation reversal failure.

Obesity and elevated initial INR are independently associated with anticoagulation reversal failure using the weight-based PCC protocol in patients with warfarin-related acute ICH. Further studies are needed to determine more effective dosing protocols and individualized strategies for anticoagulation reversal after acute ICH, especially among obese patients.

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Does rNA-seq analysis of the rat placentation site reveal maternal obesity-associated changes in placental and offspring thyroid hormone signaling?

In animal models, maternal obesity (OB) leads to augmented risk of offspring OB. While placental function is influenced by maternal habitus, the effect of maternal obesity on the interacting zones of the placenta [the labyrinth (LZ), junctional (JZ) and metrial gland (MG)] remains unknown. Using a rat maternal obesity model, we conducted transcriptomic profiling of the utero-placental compartments and fetal liver (FL) at dpc 18.5, in conjunction with analyses of mRNA expression of key thyroid hormone (TH) signaling genes in the placenta, fetus and weanling offspring.

Gene expression analysis of placenta and offspring revealed that each utero-placental compartment responds distinctly to maternal OB with changes in inflammatory signaling, lipid metabolism and hormone stimulus being the predominant effects. OB-induced alterations in 17 genes were confirmed by qPCR, including reductions in thyrotropin-releasing hormone (Trh) in JZ. We further characterized mRNA and protein expression of TH signaling regulators including deiodinases (Dio), TH receptors (Tr), and downstream targets (uncoupling proteins (Ucp)). A concerted down-regulation of multiple facets of thyroid hormone signaling in the JZ and FL was observed. JZ expression of thyroid hormone signaling components Trh, Dio2, Trα, and Ucp2 were negatively associated with maternal leptin. mRNA expression of TRH, TRβ and UCP1 were also decreased in term placenta from OB women. Finally, our studies identified persistent impairments in expression of TH related genes in tissues from offspring of obese dams.

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Is serum free 1,25-dihydroxy-vitamin D more closely associated with fibroblast growth factor 23 than other vitamin D forms in chronic dialysis patients?

Mineral bone disorder (MBD) is prevalent among chronic dialysis patients. However, relationship between different forms of vitamin D and fibroblast growth factor 23 (FGF-23) remains unclear in this population. A multicenter hemodialysis cohort was assembled. We evaluated 25-OH-D and 1,25-(OH)2-D, vitamin D-binding protein, and FGF-23, in this cohort. Multiple regression analyses were performed to investigate the relationship and stewardship between different vitamin D forms and FGF-23 concentrations. Chronic dialysis patients presented significantly higher FGF-23 concentrations. 25-OH-D concentrations of <20 ng/ml (deficiency), 20-30 ng/ml (insufficiency), and ≥30 ng/ml (sufficiency) were associated with progressively lower FGF-23 concentrations (p<0.01). Serum FGF-23 concentrations were significantly correlated with total (p=0.02), free (p<0.01) and bioavailable (p<0.01) 25-OH-D and total (p=0.04), free (p=0.02), and bioavailable (p=0.03) 1,25-(OH)2-D concentrations. With all 25-OH-D and 1,25-(OH)2-D forms in the regression model, we found that free 1,25-(OH)2-D outweighed all other vitamin D forms regarding its association with FGF-23 (p=0.03).

The relationship between FGF-23 and vitamin D is stronger using free forms of 25-OH-D and 1,25-(OH)2-D. Subsequent studies aiming at MBD should consider including free 25-OH-D and 1,25-(OH)2-D in the analysis.

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Is synovial T cell hyporesponsiveness to myeloid dendritic cells reversed by preventing PD-1/PD-L1 interactions?

The aim of this study was to investigate PD-1/PD-L1 involvement in the hyporesponsiveness of rheumatoid arthritis (RA) synovial fluid (SF) CD4 T cells upon stimulation by thymic stromal lymphopoietin (TSLP)-primed CD1c myeloid dendritic cells (mDCs). Expression of PD-1 on naïve (Tn), central memory (Tcm) and effector memory (Tem) CD4 T cell subsets was assessed by flow cytometry. PD-L1 expression and its regulation upon TSLP stimulation of mDCs from peripheral blood (PB) and SF of RA patients were investigated by quantitative RT-PCR and flow cytometry. The involvement of PD-1/PD-L1 interactions in SF T cell hyporesponsiveness upon (TSLP-primed) mDC activation was determined by cell culture in the presence of PD-1 blocking antibodies, with or without interleukin 7 (IL-7) as a recognized suppressor of PD-1 expression. PD-1 expression was increased on CD4 T cells derived from SF compared with PB of RA patients. TSLP increased PD-L1 mRNA expression in both PB and SF mDCs. PD-L1 protein expression was increased on SF mDCs compared with PB mDCs and was associated with T cell hyporesponsiveness. Blockade of PD-1, as well as IL-7 stimulation, during cocultures of memory T cells and (TSLP-primed) mDCs from RA patients significantly recovered T cell proliferation.

SF T cell hyporesponsiveness upon (TSLP-primed) mDC stimulation in RA joints is partially dependent on PD-1/PD-L1 interactions, as PD-1 and PD-L1 are both highly expressed on SF T cells and mDCs, respectively, and inhibiting PD-1 availability restores T cell proliferation. The potential of IL-7 to robustly reverse this hyporesponsiveness suggests that such proinflammatory cytokines in RA joints strongly contribute to memory T cell activation.

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Does microRNA-29b regulate migration in oral squamous cell carcinoma and its clinical significance?

MicroRNA (miRNA) machinery regulates cancer cell behavior, and has been implicated in patients' clinical status and prognosis. We found that microRNA-29b (miR-29b) increased significantly in advanced migratory cells. However, miR-29b controls the migration ability, and its regulatory mechanism in oral squamous cell carcinoma (OSCC) remains unknown. We triggered miR-29b expression in OSCC patients and cell lines by conducting real-time quantitative PCR. We determined the functions of miR-29b in the migration of OSCC cells by using gain- and loss-of-function approaches. We elevated the target genes of miR29b through software predictions and a luciferase report assay. We used an orthotopic OSCC animal model to investigate the effects of miR29b on OSCC cell metastasis in vivo. The clinical data revealed that miR-29b expression was correlated with lymph node metastasis and an advanced tumor stage in 98 OSCC patients. Furthermore, multivariate analysis revealed that miR-29b expression was significantly correlated with recurrence, and indicated poor survival. MiR-29b promoted OSCC cell migration and downregulated CX3CL1, a cell-cell adhesion regulator, which plays an essential role in miR-29b-regulated OSCC cell migration machinery. Furthermore, we found that CX3CL1 expression was correlated with lymph node metastasis and an early tumor stage in OSCC patients, and negatively correlated with miR-29b expression.

MiR-29b acts as an oncomir, promoting cell migration through CX3CL1 suppression, and could be a potential therapeutic target for preventing OSCC progression.

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Are pre-transplant impedance measures of reflux associated with early allograft injury after lung transplantation?

Acid reflux has been associated with poorer outcomes after lung transplantation. Standard pre-transplant reflux assessment has not been universally adopted. Non-acid reflux may also induce a pulmonary inflammatory cascade, leading to acute and chronic rejection. Esophageal multichannel intraluminal impedance and pH testing (MII-pH) may be valuable in standard pre-transplant evaluation. We assessed the association between pre-transplant MII-pH measures and early allograft injury in lung transplant patients. This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant MII-pH at a tertiary center from 2007 to 2012. Results from pre-transplant MII-pH, cardiopulmonary function testing, and results of biopsy specimen analysis of the transplanted lung were recorded. Time-to-event analyses were performed using Cox proportional hazards and Kaplan-Maier methods to assess the associations between MII-pH measures and development of acute rejection or lymphocytic bronchiolitis. Thirty patients (46.7% men; age, 54.2 years) met the inclusion criteria. Pre-transplant cardiopulmonary function and pulmonary diagnoses were similar between outcome groups. Prolonged bolus clearance (hazard ratio [HR], 4.11; 95% confidence interval [CI], 1.34-12.57; p = 0.01), increased total distal reflux episodes (HR, 4.80; 95% CI, 1.33-17.25; p = 0.02), and increased total proximal reflux episodes (HR, 4.43; 95% CI, 1.14-17.31; p = 0.03) were significantly associated with decreased time to early allograft injury. Kaplan-Meier curves also demonstrated differences in time to rejection by prolonged bolus clearance (p = 0.01) and increased total distal reflux episodes (p = 0.01). Sub-group analysis including only patients with MII-pH performed off proton pump inhibitors (n = 24) showed similar results.

Prolonged bolus clearance, increased total distal reflux episodes, and increased total proximal reflux episodes on pre-transplant MII-pH were associated with decreased time to early allograft injury after lung transplantation. Routine pre-transplant MII-pH may provide clinically relevant data regarding transplant outcomes and peri-transplant care.

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