Association of ovarian response with picoAMH in women undergoing controlled ovarian hyperstimulation.

OBJECTIVE: Our study aims to evaluate the diagnostic performance of a high-sensitivity picoAnti-Müllerian Hormone (picoAMH) for predicting ovarian response in women undergoing controlled ovarian hyperstimulation and occurrence of ovarian hyperstimulation syndrome. METHODS: Retrospective cohort study at a single academic fertility center including all patients with picoAMH ELISA who underwent controlled ovarian hyperstimulation. The primary outcome was the number of oocytes retrieved, and secondary outcomes included cycle cancellation and ovarian hyperstimulation syndrome. Patients were grouped into poor, normal, and hyper-responders based on number of oocytes retrieved. RESULTS: The mean AMH and antral follicle count (AFC) were significantly different between normal response vs. hyper response group (p < 0.0001). Only serum AMH and not AFC was significantly increased in patients diagnosed with ovarian hyperstimulation syndrome (OHSS). For prediction of OHSS, receiver operating characteristic (ROC) analysis revealed that AMH (area under the ROC curve [AUC] = 0.85) was significantly better than the AFC (AUC = 0.64). The serum AMH cut-off at sensitivity of 80% for predicting OHSS among hyper responders from ROC curve was 3.67 ng/ml. Serum AMH measured by picoAMH ELISA showed superior correlation to number of oocytes retrieved when compared to AFC in the age group over 40 years old (r2 = 0.74 and r2 = 0.4, respectively) CONCLUSION: This study shows great utility of picoAMH ELISA for predicting ovarian response to controlled ovarian hyperstimulation (COH). Diagnostic performance of picoAMH for prediction of OHSS is superior to the AFC in our cohort.

Metallization of Porous Polyethylene Using a Wire-Arc Spray Process for Heat Transfer Applications.

Metallization of polyethylene (PE) using thermal spray techniques has proved difficult due to its low melting point and softness. In this study, metallic coatings were applied on porous polyethylene substrates using a twin wire-arc spray process. Commercially available polyethylene sheets, 3 mm in thickness, were used as substrates. Copper (Cu), aluminum (Al), and zinc (Zn) were successfully deposited on the porous polymer, without prior surface preparation, to form coatings with thickness of about 400 µm. Coating surface morphology and cross-sections were examined using a scanning electron microscope. Individual metal splats on the porous and non-porous substrates were observed to study the differences in the bonding mechanisms. The adhesion strength and electrical resistivity of the coatings on porous PE were evaluated. It was found that the bond strength of all three metallic coatings was found to be higher than the ultimate fracture strength of the porous. These results suggest that porosity in the polymer helps to overcome the challenges of metallizing polyethylene and provides a significant reduction in the weight of the polymer. Therefore, all these properties aided in fabricating an extremely lightweight, composite material with potential use in thermal management applications.

Facile Synthesis of Mesoporous MnCO3 for Supercapacitor Applications.

We report a rapid and facile synthesis of MnCO3 with uniform mesopores for supercapacitor applications. Mesoporous MnCO3 was synthesised by a co-precipitation method using MnSO4 and (NH4)HCO3 as manganese and carbonate source, respectively. Powder X-ray diffraction study confirmed the formation of rhodochrosite phase of MnCO3. X-ray photoelectron spectroscopic study ascertained the oxidation state of Mn as 2+ in MnCO3. Scanning and Transmission electron microscopic studies revealed that nanograins of size less than 10 nm agglomerated into submicron sized spherical particles of MnCO3. N2 sorption studies displayed a typical type-IV isotherm with H2 hysteresis, demonstrating mesoporosity of as-prepared MnCO3. Furthermore, the mesoporous MnCO3 particles were evaluated for their capacitance properties by cyclic voltammetry and galvanostatic charge-discharge cycling in aqueous 0.1 M Mg(ClO4)2 electrolyte. The fabricated mesoporous MnCO3 electrodes delivered a specific capacitance of 144 F g-1 at a current density of 0.34 A g-1. It also exhibited good rate capability, high reversibility and cyclic stability over 1000 cycles.

Vitexin protects isoproterenol induced post myocardial injury by modulating hipposignaling and ER stress responses.

The molecular mechanisms involved in ER stress-induced post myocardial injury remain elusive. In this study, we have investigated the molecular mechanism of ER stress-mediated myocyte death in Isoproterenol (ISO) induced myocardial infarction and its inhibition by a potent anti oxidant and anti-apoptotic bioflavonoid, Vitexin. ISO mediated apoptosis was found to be associated with ER permeabilization and characterized by enhanced production of ROS, activation of caspase-3, modulation of Bcl2 family proteins and activation of bnip3. Moreover, post treatment with Vitexin inhibits the ISO induced translocation of CHOP to nucleus during MI. Further results have demonstrated that, activation of Mst1 through ER stress was diminished upon treatment with Vitexin. In addition to this, Vitexin treatment significantly downregulated the expression of p-Yap and p-Mst1 which were enhanced during post myocardial injury. Taken together, our data indicate that co-ordinated activation of ER stress and hipposignaling by ISO was ameliorated by the potent cardioprotective effects of Vitexin.

Optimization of oestradiol assays to improve utility in an in vitro fertilization setting.

Background The measurement of oestradiol is an integral component for the management of ovarian stimulation for in vitro fertilization. Automated immunoassays offer fast assay times and high throughput, with less sensitivity and specificity. The aim of this study is to optimize the oestradiol assay in patients undergoing ovarian stimulation for in vitro fertilization via comparison of oestradiol values obtained using two immunoassays compared with mass spectrometry. Methods Patients undergoing ovarian stimulation were prospectively recruited. Serum samples were analysed with ADVIA Centaur® CP Immunoassay, Abbott Architect i1000® immunoassay and AB Sciex 5500 liquid chromatography-tandem mass spectrometry (LC-MS/MS) systems. Per cent bias was determined for each system to report the average tendency of the values to be larger or smaller than the LC-MS/MS value. Linear regression of total follicular volume and oestradiol was computed. Results The ADVIA Centaur® CP assay had a positive bias of 20% compared with LC-MS/MS, while the Architect i1000® had a non-significant, negative bias of 0.3%. With regression fit, a clear, positive relationship was seen between follicular volume and oestradiol. The Architect i1000® assay had a greater correlation (R2 = 0.46) compared with Centaur® CP (R2 = 0.36), when oestradiol values were >1000 pg/mL (3670 pmol/L). Conclusions The Abbott Architect i1000® oestradiol assay exhibits greater agreement with LC-MS/MS and exhibited better correlation to follicular volume when oestradiol values are >1000 pg/mL (3670 pmol/L), prompting a change in the clinic's oestradiol platform. Attention to assay quality assurance via LC-MS/MS can improve the oestradiol accuracy and permit more informed clinical decisions for improved patient outcomes.

KAI1/CD82, Metastasis Suppressor Gene as a Therapeutic Target for Non-Small-Cell Lung Carcinoma.

Lung cancer is the most frequent malignancy and the leading cause of cancer-related death worldwide; it is the second most common cancer, comprising 1.69 million deaths worldwide per year. Among these, 85% of lung cancers are non-small-cell lung carcinoma (NSCLC). Metastasis is common in NSCLC patients and are responsible for most deaths. Kang-Ai 1 (KAI1), a tumor metastasis suppressor gene also known as Cluster of Differentiation 82 (CD82), is a member of the membrane tetraspanin protein family, which are capable of inhibiting the metastatic process in NSCLC. KAI1/CD82 suppresses metastasis via multiple mechanisms regulating inhibition of cell motility, adhesion, fusion, and proliferation. KAI1 may attenuate signaling to shut down metastatic colonization through attenuation of epidermal growth factor receptor (EGFR) signaling and inhibition of the Wnt signaling pathways. In this review, we focus on the differential expression of KAI1/CD82, a tumor metastasis suppressor gene that can inhibit cancer invasion and cell metastasis during NSCLC. The differential expression of KAI1/CD82 could prove to be of novel therapeutic significance in treating malignant tumors and in reducing their metastatic potential.

Targeting hepatocellular carcinoma with piperine by radical-mediated mitochondrial pathway of apoptosis: An in vitro and in vivo study.

Redox mediated cancer therapeutics are of immense interest in the recent decade due to their anticancer activity. Piperine is the principal alkaloid of black and long pepper. Although its anticancer activity has been reported in number of cancers , the precise molecular mechanism of action remains to be unravelled. Hence, in this study, for the first time, we delineated the mechanistic insight into the effect of piperine against hepatocellular carcinoma (HCC).MTT analysis determined the dose and time dependent cytotoxicity of piperine against Hep G2 cells. Further molecular studies evidenced the prooxidant property of piperine by inducing H2O2 driven mitochondria-mediated apoptosis in Hep G2 cells by inhibiting the peroxide detoxifying enzyme Catalase. Molecular docking and western blotting analysis uncovered the piperine mediated receptor tyrosine kinase inhibition and mitigation of HCC progression. In addition, histological investigations of piperine - treated, DEN-induced HCC rats showed significant prognosis with apoptotic cell death. Whereas,co-treatment of an antioxidant EUK-134 significantly abrogated its chemotherapeutic activity substantiating its radical-mediated anticancer property. Altogether, this study shows that the piperine may be a promising prooxidant drug for the amelioration of hepatocellular carcinoma.

Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells.

This corrects the article DOI: 10.1038/leu.2014.119.

Increased fibrosis and angiogenesis in subcutaneous gluteal adipose tissue in nascent metabolic syndrome.

AIMS: Metabolic syndrome (MetS) is globally a common disorder that predisposes to both diabetes and cardiovascular disease (CVD). There is a paucity of data on fibrosis and angiogenesis in adipose tissue (AT) in patients with nascent MetS uncomplicated by diabetes or CVD. Hence, we assayed various indices of fibrosis and angiogenesis in subcutaneous AT (SAT). METHODS: In both patients with MetS and matched controls, we determined fibrosis and the densities of CD31, VEGF and Angiopoietin (Angio) 2 and 1 by immunohistochemistry in gluteal SAT. RESULTS: The fibrosis score was significantly increased in SAT of Met S. Also, both CD31 and VEGF densities were significantly increased. Surprisingly, Angio-2 was not increased and the ratio of Angio2:1 was decreased. Both indices of fibrosis and angiogenesis correlated with biomediators of inflammation. CONCLUSIONS: In conclusion, we report increased fibrosis and paradoxical increased angiogenesis in gluteal SAT and speculate that the increased angiogenesis is a protective mechanism in mitigating further adipose tissue dysregulation in this depot.

A natural interomone 2-methyl-2-butenal stimulates feed intake and weight gain in weaned pigs.

A novel approach to potentially improve pig growth and welfare is to supplement environments with biologically meaningful odors that are deficient. The post-weaning environment lacks maternal odors that may contribute to the often-observed post-weaning lag in growth and health challenges. A recently reported rabbit maternal pheromone (2-methyl-2-butenal (2M2B)) may act as an interomone in the pig. The objective of this study was to determine if providing a maternal pheromone/interomone during transport and the post-weaning environment may enhance pig performance. A total of 40 replicated pens were used in a factorial arrangement of two transport olfactory experiences (Control v. 2M2B), two nursery olfactory experiences (Control v. 2M2B) and two sexes (barrow v. gilt). Pig body weight, average daily gain (ADG), average daily feed intake (ADFI) and gain : feed ratio (G : F) were measured and calculated over a 28-day post-weaning period. Pig sex and application of 2M2B during transport had no effect on pig performance. However, pigs that had 2M2B applied to their feeder at weaning had 15% greater feed intake (0.74 v. 0.64±0.03 kg/day, P<0.01) and 12% greater ADG (0.27 v. 0.24 kg/day, P<0.05) than control pigs. G : F ratio was not different between treatments. The interomone 2M2B is a novel, safe molecule that can improve pig post-weaning performance. This report highlights a new area of study and a natural class of compounds that can improve pig performance and potentially improve pig welfare.

The effect of the accessory proteins, soluble CD14 and lipopolysaccharide-binding protein on Toll-like receptor 4 activity in human monocytes and adipocytes.

BACKGROUND: There is a growinge body of evidence pointing towards an important role for Toll-like receptors (TLR) especially TLR4 in obesity and metabolic syndrome. OBJECTIVE: Owing to the paucity of data on the effect of the accessory proteins, lipopolysaccharide (LPS)-binding protein (LBP) and soluble CD14 (sCD14) on TLR4 activation, the present study was undertaken to examine the effect of sCD14 and LBP on TLR4 activation in pivotal cells of meta-inflammation, monocytes and adipocytes. METHODS: The dose-response effects of sCD14 and LBP on TLR4 protein abundance in monocytes obtained from normal human volunteers was determined by flow cytometry and in human-differentiated adipocytes by western blotting. Additionally, the nuclear factor-kappaB (NF-κB) p65 and downstream biomediators interleukin (IL)-1ß, IL-8, IL-6 and tumor necrosis factor (TNF)-α were measured in the cell culture supernatants by ELISA (enzyme-linked immunosorbent assay). RESULTS: In LPS-primed monocytes, sCD14 but not LBP, augments both TLR4 abundance and inflammatory biomediators (IL-1ß, IL-8, IL-6 and TNF-α).sCD14 also showed a similar effect in LPS-primed human adipocytes by augmenting TLR4 protein expression and activity in terms of NF-κB p65 and downstream biomediators (IL-1ß, IL-8, IL-6 and TNF-α). LBP at the highest concentration only promoted secretion of IL-8 and TNF-α. However in both monocytes and adipocytes, the effect of sCD14 was superior to LBP. CONCLUSIONS: In the present report, we make the novel observation that sCD14 compared with LBP, offers a preferred target to ameliorate TLR especially TLR4-induced inflammation and insulin resistance in human obesity and metabolic syndrome.

Dexamethasone promotes hypertrophy of H9C2 cardiomyocytes through calcineurin B pathway, independent of NFAT activation.

Metabolic syndrome-induced cardiac hypertrophy is a global concern leading to an increase in the morbidity and mortality of patients, with the signalling mechanism associated with them still unclear. The present study attempts to understand the metabolic syndrome-associated cardiac hypertrophy through an in vitro model using external stimuli well known for inducing metabolic disorders, i.e. dexamethasone (DEX), a synthetic glucocorticoid. DEX (0.1 and 1 µM) promoted cardiac hypertrophy in H9C2 cells at 4 days of treatment as evidenced through increased cell size and protein content. A significant induction in foetal gene reprogramming was observed, confirming the establishment of hypertrophy. Moreover, the hypertrophic response at 4 days was perceived to be physiological at 0.1 µM and pathological at 1 µM based on α-MHC and IGF1R expression, but complete inhibition in the PKB/AKT expression confirmed it to be pathological hypertrophy at both the concentrations (0.1 and 1 µM). The present study reports for the first time the mechanistic insights into DEX-mediated hypertrophy. It is hypothesized to be orchestrated through the activation of AT1R that is involved in the alteration of the cardiac isoform of SERCA2 expression perturbing the calcium homeostasis. This leads to the activation of calcineurin B, independent of NFAT involvement, which in coordination with ROS induces the activation of JNK of the MAPK signalling.

Anti-inflammatory Strategies to Prevent Diabetic Cardiovascular Disease.

Diabetes is a proinflammatory state and inflammation is crucial in the genesis of vascular complications. While there are many anti-inflammatory strategies, most of which have been shown to reduce inflammation in diabetes, there is sparse data on reduction in cardiovascular events (CVEs). To date, the only anti-inflammatory strategies that have been shown to reduce CVE in diabetes include statins, angiotensin receptor blockers, metformin, and pioglitazone. We also discuss the role of novel emerging therapies.

Pre-clinical efficacy of combined therapy with novel ß-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells.

The canonical wingless-type MMTV integration site (WNT)-ß-catenin pathway is essential for self-renewal, growth and survival of acute myeloid leukemia (AML) stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of ß-catenin, causing increased nuclear translocation and co-factor activity of ß-catenin with the transcriptional regulator T-cell factor (TCF) 4/lymphoid enhancer factor 1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate ß-catenin levels. BC treatment disrupted the binding of ß-catenin with the scaffold protein transducin ß-like 1 and proteasomal degradation and decline in the nuclear levels of ß-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-MYC and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs, exhibiting nuclear expression of ß-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD.

Serum adiposity-induced biomarkers in obese and lean children with recently diagnosed autoimmune type 1 diabetes.

BACKGROUND/OBJECTIVE: Obesity increases the risk of cardiovascular disease and diabetic complications in type 1 diabetes. Adipokines, which regulate obesity-induced inflammation, may contribute to this association. We compared serum adipokines and inflammatory cytokines in obese and lean children with new-onset autoimmune type 1 diabetes. SUBJECTS AND METHODS: We prospectively studied 32 lean and 18 obese children (age range: 2-18 yr) with new-onset autoimmune type 1 diabetes and followed them for up to 2 yr. Serum adipokines [leptin, total and high molecular weight (HMW) adiponectin, omentin, resistin, chemerin, visfatin], cytokines [interferon (IFN)-gamma, interleukin (IL)-10, IL-12, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha] and C-reactive protein (CRP) were measured at a median of 7 wk after diagnosis (range: 3-16 wk). RESULTS: Lean children were 71.9% non-Hispanic White, 21.9% Hispanic, and 6.3% African-American, compared with 27.8, 55.6, and 16.7%, respectively, for obese children (p = 0.01). Compared with lean children, obese children had significantly higher serum leptin, visfatin, chemerin, TNF-alpha and CRP, and lower total adiponectin and omentin after adjustment for race/ethnicity and Tanner stage. African-American race was independently associated with higher leptin among youth ≥10 yr (p = 0.007). Leptin levels at onset positively correlated with hemoglobin A1c after 1-2 yr (p = 0.0001) independently of body mass index, race/ethnicity, and diabetes duration. Higher TNF-alpha was associated with obesity and female gender, after adjustment for race/ethnicity (p = 0.0003). CONCLUSION: Obese children with new-onset autoimmune type 1 diabetes have a proinflammatory profile of circulating adipokines and cytokines that may contribute to the development of cardiovascular disease and diabetic complications.

Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells.

The histone demethylase LSD1 (KDM1A) demethylates mono- and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in acute myeloid leukemia (AML). Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the corepressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and CCAAT/enhancer binding protein α in cultured AML cells. In addition, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphological features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than mixed-lineage leukemia fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Co-treatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared with each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML.

Evaluation of the Nova StatStrip glucometer in a pediatric hospital setting.

CONTEXT: Routine point-of-care (POC) glucose monitoring in the pediatric setting has become increasingly important, both for assessing hypoglycemia as well as hyperglycemia. A reliable and precise system is required to monitor pediatric patients. OBJECTIVES: The aim of this study was to evaluate the Nova Biomedical StatStrip POC glucometer against the Roche ACCU-CHEK Inform in lieu of our currently used LifeScanSureStepFlexx POC glucose analyzer. DESIGN AND METHODS: Intra-assay and inter-assay precision, linearity, correlation and interference studies were performed as per the NCCLS criteria. An analysis of 37 pediatric samples across the linearity ranges of all the meters was used to assess concordance between the systems. RESULTS: The Nova StatStrip glucometer demonstrated an excellent coefficient of variation (<5%) for glucose across the entire analytical measurement range. The Nova StatStrip also had good concordance with the central laboratory (Bland-Altman plots r(2)=0.01), while Roche Inform had poorer correlation (Bland-Altman plots r(2)=0.46). We also evaluated the effect of hematocrit (20-60%) and maltose (100-500mg/dL) on the Nova StatStrip analyzer and demonstrated that there is little to no interference by either. CONCLUSIONS: The Nova StatStrip system gave the best performance with acceptable imprecision, good correlation, and minimal to no interference from hematocrit levels or maltose. The Nova StatStrip is a satisfactory replacement for our POC glucometer system and, additionally, provides results in less time (just 6 s) utilizing a lower amount of blood with the advantage of being immediately interfaced to our laboratory information systems.

Native valve Escherichia coli endocarditis following urosepsis.

Gram-negative organisms are a rare cause of infective endocarditis. Escherichia coli, the most common cause of urinary tract infection and gram-negative septicemia involves endocardium rarely. In this case report, we describe infection of native mitral valve by E. coli following septicemia of urinary tract origin in a diabetic male; subsequently, he required prosthetic tissue valve replacement indicated by persistent sepsis and congestive cardiac failure.

A novel peptide inhibitor attenuates C-reactive protein's pro-inflammatory effects in-vivo.

BACKGROUND: Higher levels of C-reactive protein (CRP) predict cardiovascular events and also portend a poorer prognosis in patients with acute coronary syndromes. Much in-vitro and in-vivo data support a role for CRP in atherogenesis. METHODS: Using the one-bead-one-compound (OBOC) combinatorial library method we have successfully identified peptides against human CRP that inhibit its biological effects in-vitro. Hence we tested the effect of the best characterized inhibitor (CRP-i2) on the effects of CRP in an appropriate animal model, Wistar rats. RESULTS: Treatment with CRP resulted in significant increase in superoxide anion, nuclear factor kappaB (NFκb) activity and the release of biomarkers of inflammation from macrophages compared to Wistar rats treated with human albumin (HuSA). Pre-treatment with the inhibitor, CRP-i2, resulted in a significant reduction in CRP induced superoxide anion, NFκb activity and biomarkers of inflammation. Also, there were no observed clinical or laboratory related adverse effects. CONCLUSIONS: We demonstrate that our novel peptide inhibitor attenuates the proinflammatory effects of CRP in-vivo. Future studies will examine the long-term effects of this inhibitor on vascular pathobiology.