Biomarker profiles of acute heart failure patients with a mid-range ejection fraction

OBJECTIVES: In this study, the authors used biomarker profiles to characterize differences between patients with acute heart failure with a midrange ejection fraction (HFmrEF) and compare them with patients with a reduced (heart failure with a reduced ejection fraction [HFrEF]) and preserved (heart failure with a preserved ejection fraction [HFpEF]) ejection fraction. BACKGROUND: Limited data are available on biomarker profiles in acute HFmrEF. METHODS: A panel of 37 biomarkers from different pathophysiological domains (e.g., myocardial stretch, inflammation, angiogenesis, oxidative stress, hematopoiesis) were measured at admission and after 24 h in 843 acute heart failure patients from the PROTECT trial. HFpEF was defined as left ventricular ejection fraction (LVEF) of ≥50% (n = 108), HFrEF as LVEF of <40% (n = 607), and HFmrEF as LVEF of 40% to 49% (n = 128). RESULTS: Hemoglobin and brain natriuretic peptide levels (300 pg/ml [HFpEF]; 397 pg/ml [HFmrEF]; 521 pg/ml [HFrEF]; ptrend <0.001) showed an upward trend with decreasing LVEF. Network analysis showed that in HFrEF interactions between biomarkers were mostly related to cardiac stretch, whereas in HFpEF, biomarker interactions were mostly related to inflammation. In HFmrEF, biomarker interactions were both related to inflammation and cardiac stretch. In HFpEF and HFmrEF (but not in HFrEF), remodeling markers at admission and changes in levels of inflammatory markers across the first 24 h were predictive for all-cause mortality and rehospitalization at 60 days (pinteraction <0.05). CONCLUSIONS: Biomarker profiles in patients with acute HFrEF were mainly related to cardiac stretch and in HFpEF related to inflammation. Patients with HFmrEF showed an intermediate biomarker profile with biomarker interactions between both cardiac stretch and inflammation markers. (PROTECT-1: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function; NCT00328692)

Cardiac circRNAs Arise Mainly From Constitutive Exons Rather Than Alternatively Spliced Exons

Circular RNAs (circRNAs) are a relatively new class of RNA molecules, and knowledge about their biogenesis and function is still in its infancy. It was recently shown that alternative splicing underlies the formation of circular RNAs (circRNA) arising from the Titin (TTN) gene. Since the main mechanism by which circRNAs are formed is still unclear, we hypothesized that alternative splicing, and in particular exon skipping, is a major driver of circRNA production. We performed RNA sequencing on human and mouse hearts, mapped alternative splicing events, and overlaid these with expressed circRNAs at exon-level resolution. In addition, we performed RNA sequencing on hearts of Rbm20 KO mice to address how important Rbm20-mediated alternative splicing is in the production of cardiac circRNAs. In human and mouse hearts, we show that cardiac circRNAs are mostly (~90%) produced from constitutive exons and less (~10%) from alternatively spliced exons. In Rbm20 KO hearts, we identified 38 differentially expressed circRNAs of which 12 were produced from the Ttn gene. Even though Ttn appeared the most prominent target of Rbm20 for circularization, we also detected Rbm20-dependent circRNAs arising from other genes including Fan1, Stk39, Xdh, Bcl2l13, and Sorbs1. Interestingly, only Ttn circRNAs seemed to arise from Rbm20-mediated skipped exons. In conclusion, cardiac circRNAs are mostly derived from constitutive exons, suggesting that these circRNAs are generated at the expense of their linear counterpart and that circRNA production impacts the accumulation of the linear mRNA

LXRα improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes

Aims/hypothesis Diabetic cardiomyopathy is a myocardial disease triggered by impaired insulin signalling, increased fatty acid uptake and diminished glucose utilisation. Liver X receptors (LXRs) are key transcriptional regulators of metabolic homeostasis. However, their effect in the diabetic heart is largely unknown. Methods We cloned murine Lxr alpha (also known as Nr1h3) behind the a-myosin heavy chain (alpha Mhc; also known as Myh6) promoter to create transgenic (Lxr alpha-Tg) mice and transgene-negative littermates (wild-type [WT]). A mouse model of type 2 diabetes was induced by a high-fat diet (HFD, 60% energy from fat) over 16 weeks and compared with a low-fat diet (10% energy from fat). A mouse model of type 1 diabetes was induced via streptozotocin injection over 12 weeks. Results HFD manifested comparable increases in body weight, plasma triacylglycerol and insulin resistance per OGTT in Lxr alpha-Tg and WT mice. HFD significantly increased left ventricular weight by 21% in WT hearts, but only by 5% in Lxr alpha-Tg. To elucidate metabolic effects in the heart, microPET (positron emission tomography) imaging revealed that cardiac glucose uptake was increased by 1.4-fold in WT mice on an HFD, but further augmented by 1.7-fold in Lxr alpha-Tg hearts, in part through 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and restoration of glucose transporter 4 (GLUT4). By contrast, streptozotocin-induced ablation of insulin signalling diminished cardiac glucose uptake levels and caused cardiac dysfunction, indicating that insulin may be important in Lxr alpha-mediated glucose uptake. Chromatin immunoprecipitation assays identified natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), as potential direct targets of cardiac Lxr alpha overexpression. Conclusions/interpretation Cardiac-specific Lxr alpha overexpression ameliorates the progression of HFD-induced left ventricular hypertrophy in association with increased glucose reliance and natriuretic peptide signalling during the early phase of diabetic cardiomyopathy. These findings implicate a potential protective role for LXR in targeting metabolic disturbances underlying diabetes

Use of biomarkers to establish potential role and function of circulating microRNAs in acute heart failure

Background: Circulating microRNAs (miRNAs) emerge as potential heart failure biomarkers. We aimed to identify associations between acute heart failure (AHF)-specific circulating miRNAs and well-known heart failure biomarkers.Methods: Associations between 16 biomarkers predictive for 180 day mortality and the levels of 12 AHF-specific miRNAs were determined in 100 hospitalized AHF patients, at baseline and 48 hours. Patients were divided in 4 pre-defined groups, based on clinical parameters during hospitalization. Correlation analyses between miRNAs and biomarkers were performed and complemented by miRNA target prediction and pathway analysis.Results: No significant correlations were found at hospital admission. However, after 48 hours, 7 miRNAs were significantly negatively correlated to biomarkers indicative for a worse clinical outcome in the patient group with the most unfavorable in-hospital course (n = 21); miR-16-5p was correlated to C-reactive protein (R = -0.66, p-value = 0.0027), miR-106a-5p to creatinine (R = -0.68, p-value = 0.002), miR-223-3p to growth differentiation factor 15 (R = -0.69, p-value = 0.0015), miR-652-3p to soluble ST-2 (R = -0.77, p-value &lt;0.001), miR-199a-3p to procalcitonin (R = -0.72, p-value &lt;0.001) and galectin-3 (R = -0.73, p-value &lt;0.001) and miR-18a-5p to procalcitonin (R = -0.68, p-value = 0.002). MiRNA target prediction and pathway analysis identified several pathways related to cardiac diseases, which could be linked to some of the miRNA-biomarker correlations.Conclusions: The majority of correlations between circulating AHF-specific miRNAs were related to biomarkers predictive for a worse clinical outcome in a subgroup of worsening heart failure patients at 48 hours of hospitalization. The selective findings suggest a time-dependent effect of circulating miRNAs and highlight the susceptibility to individual patient characteristics influencing potential relations between miRNAs and biomarkers. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.</p

HIV, STI prevalence and risk behaviours among women selling sex in Lahore, Pakistan

<p>Abstract</p> <p>Background</p> <p>More than 340 million cases of curable sexually transmitted infections (STIs) were estimated to have occurred worldwide in 1995. Previous studies have shown that the presence of other concomitant STIs increases the likelihood of HIV transmission. The first national study of STIs conducted in Pakistan in 2004 revealed a high burden of STIs among women selling sex. The HIV epidemic in Pakistan has thus far followed the "Asian epidemic model". Earlier studies among women selling sex have shown a low prevalence of HIV coupled with a low level of knowledge about AIDS. The aim of our study was to estimate the prevalence of HIV and STIs, and assess knowledge and risk behaviours related to HIV/STI, among women selling sex in Lahore, Pakistan.</p> <p>Methods</p> <p>A total of 730 participants were recruited through respondent-driven sampling. The participants were women selling sex in three areas (referred to as "A", "B", and "C") of Lahore. A structured questionnaire addressing demographic information, sexual life history, sexual contacts, and knowledge and practices related to HIV/STI prevention was administered by face-to-face interview. Biological samples were obtained from all participants and tested for HIV, <it>Treponema pallidum</it>, <it>Neisseria gonorrhoeae</it>, <it>Chlamydia trachomatis </it>and <it>Trichomonas vaginalis</it>. Pearson's chi-square and multivariable logistic regression analysis were performed to test associations between potential risk factors and specified diagnosed infections.</p> <p>Results</p> <p>The prevalence of HIV infection was 0.7%, <it>T pallidum </it>4.5%, <it>N gonorrhoeae </it>7.5%, <it>C trachomatis </it>7.7% and <it>T vaginalis </it>5.1%. The participants had been selling sex for a median period of seven years and had a median of three clients per day. Sixty five percent of the participants reported that they "Always use condom". The median fee per sexual contact was Rs. 250 (3 Euro). Compared to Areas A and C, women selling sex in Area B had a significantly higher risk of chlamydial infection, gonorrhoea and trichomoniasis. Among the participants, 37% had correct knowledge about HIV/AIDS transmission and its prevention.</p> <p>Conclusions</p> <p>The prevalence of HIV was <1%, and of any other STI 18.5% among participating women selling sex in Lahore, Pakistan. A reasonably high condom use, a relatively low number of sexual partners, and a relatively low prevalence of STIs might have contributed to the low HIV prevalence.</p

Validation of the Internet Addiction Test in Students at a Pakistani Medical and Dental School

Despite growing concerns over pathological internet usage, studies based on validated psychometric instruments are still lacking in Pakistan. This study aimed to examine the psychometric properties of the Internet Addiction Test (IAT) in a sample of Pakistani students. A total of 522 students of medicine and dentistry completed the questionnaire, which consisted of four sections: (a) demographics, (b) number of hours spent on the Internet per day, (c) English version of the IAT, and (d) the Defense Style Questionnaire-40. Maximum likelihood analysis and principal axis factoring were used to validate the factor structure of the IAT. Convergent and criterion validity were assessed by correlating IAT scores with number of hours spent online and defense styles. Exploratory and confirmatory factor analysis reflected the goodness of fit of a unidimensional structure of the IAT, with a high alpha coefficient. The IAT had good face and convergent validity and no floor and ceiling effects, and was judged easy to read by participants

A survey of Autism knowledge and attitudes among the healthcare professionals in Lahore, Pakistan

<p>Abstract</p> <p>Background</p> <p>The diagnosis and treatment of Autism in Pakistan occurs in multiple settings and is provided by variety of health professionals. Unfortunately, knowledge and awareness about Autism is low among Pakistani healthcare professionals & the presence of inaccurate and outdated beliefs regarding this disorder may compromise early detection and timely referral for interventions. The study assessed the baseline knowledge and misconceptions regarding autism among healthcare professionals in Pakistan which can impact future awareness campaigns.</p> <p>Methods</p> <p>Physicians (psychiatrists, pediatricians, neurologists and family physicians) and non-physicians (psychologists and speech therapists) participated in this study. Knowledge of DSM-IV TR criteria for Autistic Disorder, beliefs about social, emotional, cognitive, treatment and prognosis of the disorder were assessed. Demographic information regarding the participants of the survey was also gathered.</p> <p>Results</p> <p>Two hundred and forty seven respondents (154 Physicians & 93 Non-physicians) participated in the study. Mean age of respondents was 33.2 years (S.D 11.63) with 53% being females. Reasonably accurate familiarity with the DSM IV-TR diagnostic criteria of Autistic Disorder was observed. However, within the professional groups, differences were found regarding the utilization of the DSM-IV-TR criteria when diagnosing Autistic Disorder. Non-Physicians were comparatively more likely to correctly identify diagnostic features of autism compared with Physicians (P-value <0.001). Significant misunderstandings of some of the salient features of autism were present in both professional groups.</p> <p>Conclusion</p> <p>Results suggests that current professionals in the field have an unbalanced understanding of autism due to presence of several misconceptions regarding many of the salient features of autism including developmental, cognitive and emotional features. The study has clinical implications and calls for continued education for healthcare professionals across disciplines with regards to Autism in Pakistan.</p

A revision of the akysid catfish genus Acrochordonichthys Bleeker

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75446/1/j.1095-8649.2001.tb02260.x.pd

The associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma

BACKGROUND: Maspin, a member of the serpin family, is a suppressor of tumor growth, an inhibitor of angiogenesis and an inducer of apoptosis. Maspin induces apoptosis by increasing Bax, a member of the Bcl-2 family of apoptosis-regulating proteins. In this exploratory study, we investigated the associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma (IHCCA). METHODS: Twenty-two paraffin-embedded samples were analyzed by immunohistochemical methods using Maspin, Bax and CD34 antibodies. Maspin was scored semiquantitatively (HSCORE). Apoptosis was assessed using an antibody against cleaved caspase-3. RESULTS: The strong relationship observed between the expression of Maspin and Bax, indicates that Bax is likely to be the key effector of Maspin-mediated induction of apoptosis as indicated by the activation of cleaved caspase-3. We categorized Maspin HSCORE by calculating the optimal cutpoint. A Maspin HSCORE above the cutpoint was inversely related with tumor dimension, depth of tumor and vascular invasion. Uni/multivariate analysis suggests that a Maspin HSCORE below the cutpoint significantly worsens the patients' prognosis. Tumors with Maspin HSCORE below the cutpoint had a shorter survival (11+/-5 months) than did patients with Maspin HSCORE above the cutpoint (27+/-4 months), whereas Kaplan-Meier analysis and logrank test showed no significant difference in overall survival between the patients. CONCLUSION: The associated expression of Maspin and Bax might delay tumor progression in IHCCA. Maspin above the cutpoint might counteract tumor development by increasing cell apoptosis, and by decreasing tumor mass and cell invasion. The combined expression of Maspin and Bax appears to influence the susceptibility of tumor cholangiocytes to apoptosis and thus may be involved in delaying IHCCA progression

Distinct Steps of Neural Induction Revealed by Asterix, Obelix and TrkC, Genes Induced by Different Signals from the Organizer

The amniote organizer (Hensen's node) can induce a complete nervous system when grafted into a peripheral region of a host embryo. Although BMP inhibition has been implicated in neural induction, non-neural cells cannot respond to BMP antagonists unless previously exposed to a node graft for at least 5 hours before BMP inhibitors. To define signals and responses during the first 5 hours of node signals, a differential screen was conducted. Here we describe three early response genes: two of them, Asterix and Obelix, encode previously undescribed proteins of unknown function but Obelix appears to be a nuclear RNA-binding protein. The third is TrkC, a neurotrophin receptor. All three genes are induced by a node graft within 4–5 hours but they differ in the extent to which they are inducible by FGF: FGF is both necessary and sufficient to induce Asterix, sufficient but not necessary to induce Obelix and neither sufficient nor necessary for induction of TrkC. These genes are also not induced by retinoic acid, Noggin, Chordin, Dkk1, Cerberus, HGF/SF, Somatostatin or ionomycin-mediated Calcium entry. Comparison of the expression and regulation of these genes with other early neural markers reveals three distinct “epochs”, or temporal waves, of gene expression accompanying neural induction by a grafted organizer, which are mirrored by specific stages of normal neural plate development. The results are consistent with neural induction being a cascade of responses elicited by different signals, culminating in the formation of a patterned nervous system