Miracle-dz/UniFAR-FTUs huggingface dataset:
The dual PPARα/γ agonist tesaglitazar blocks progression of pre‐existing atherosclerosis in APOE*3Leiden.CETP transgenic mice

Background and purpose: We have evaluated the effects of a peroxisome proliferator‐activated receptor (PPAR)α/γ agonist on the progression of pre‐existing atherosclerotic lesions in APOE*3Leiden.cholesteryl ester transfer protein (E3L.CETP) transgenic mice.
Therapeutically targeting protein–glycan interactions

Glycosylation is the most common form of post‐translational modifications by which oligosaccharide side chains are covalently attached to specific residues of the core protein. Especially O‐linked glycan structures like the glycosaminoglycans were found to contribute significantly to many (patho‐)biological processes like inflammation, coagulation, cancer and viral infections. Glycans exert their function by interacting with proteins thereby changing the structure of the interacting proteins and consequently modulating their function. Given the complex nature of cell‐surface and extracellular matrix glycan structures, this therapeutic site has been neglected for a long time, the only exception being the antithrombin III‐glycan interaction which has been sucessfully targeted by unfractionated and low‐molecular weight heparins for many decades. Due to the recent breakthrough in the ‘–ome’ sciences, among them proteomics and glycomics, protein–glycan interactions became more amenable for therapeutic approaches so that novel inhibitors of this interaction are currently in preclinical and clinical studies. An overview of current approaches, their advantages and disadvantages, is given and the promising potential of pharmacologically interfering with protein–glycan interactions is highlighted here.
A Case Series of Patients with Pancreatic Cancer and Cholangiocarcinoma Treated with nab-Paclitaxel at a Single Institution

Background: Locally advanced or metastatic pancreatic cancer patients have a poor prognosis with median survival less than 12 months. Nanoparticle albumin bound (nab)-paclitaxel is a novel agent that has demonstrated antitumor effects in cancers that overexpress the albumin binding protein SPARC (secreted protein acidic and rich in cysteine), which includes pancreatic cancer. A recent phase III trial comparing nab-paclitaxel and gemcitabine to gemcitabine alone demonstrated a survival advantage in patients with previously untreated metastatic pancreatic cancer. Here we present our local experience with this drug in patients with gastrointestinal malignancies. Methods: Patients treated with nab-paclitaxel for gastrointestinal malignancies at the Cross Cancer Institute in Edmonton, Alberta, Canada were identified and these patient’s medical records were interrogated for data. Results: Three patients with pancreatic cancer and two with cholangiocarcinoma have been treated with nab-paclitaxel at the Cross Cancer Institute. Three patients achieved stable disease, while one had a partial response, and one had progressive disease after the first assessment. Median time to progression was 3.7 months. Median overall survival (OS) was 32.5 months. Median OS from initiation of nab-paclitaxel was 7.2 months. Patients tolerated treatment with nab-paclitaxel well with only one patient requiring treatment modification due to neutropenia. Conclusion: The experience at this single center supports published evidence that nab-paclitaxel is a safe and effective therapy in pancreatic cancer, but also suggests that it may have activity in cholangiocarcinoma, which to our knowledge is the first published evidence of this in humans.
The Epidemiology, Clinical Manifestations, and Management of Chagas Heart Disease

Chagas disease results from infection by the protozoan parasite Trypanosoma cruzi and is endemic in Latin America. T cruzi is most commonly transmitted through the feces of an infected triatomine, but can also be congenital, via contaminated blood transfusion or through direct oral contact. In the acute phase, the disease can cause cardiac derangements such as myocarditis, conduction system abnormalities, and/or pericarditis. If left untreated, the disease advances to the chronic phase. Up to one‐half of these patients will develop a cardiomyopathy, which can lead to cardiac failure and/or ventricular arrhythmias, both of which are major causes of mortality. Diagnosis is confirmed by serologic testing for specific immunoglobulin G antibodies. Initial treatment consists of the antiparasitic agents benznidazole and nifurtimox. The treatment of Chagas cardiac disease comprises standard medical therapy for heart failure and amiodarone for ventricular arrhythmias, with consideration for implantable cardioverter‐defibrillator. Chagas disease causes the highest infectious burden of any parasitic disease in the Western Hemisphere, and increased awareness of this disease is essential to improve diagnosis, enhance management, and reduce spread.
Effects of Ranolazine in Patients With Chronic Angina in Patients With and Without Percutaneous Coronary Intervention for Acute Coronary Syndrome: Observations From the MERLIN‐TIMI 36 Trial

Ranolazine, a piperazine derivative with anti‐ischemic effects, reduces the frequency of angina and improves exercise performance in patients with chronic angina. The effects of ranolazine in patients with established ischemic heart disease and chronic angina undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) is not well described. We hypothesized that ranolazine would reduce ischemic events, regardless of revascularization.
Objectives and Design of the Russian Acute Coronary Syndrome Registry (RusACSR)

The Russian Acute Coronary Syndrome Registry (RusACSR) is a retrospective, continuous, nationwide, Web‐based registry of patients with acute coronary syndromes (ACS). The RusACSR is a database that uses a secure Web‐based interface for data entry by individual users. Participation in the RusACSR is voluntary. Any clinical center that provides health care to ACS patients can take part in the RusACSR. The RusACSR enrolls ACS patients who have undergone care in Russian hospitals from February 2008 to the present. Key data elements and methods of data analysis in the RusACSR are presented in this article. Up to 2015, 213 clinical centers from 36 regions of Russia had participated in the RusACSR. Currently, the database contains data on more than 250 000 ACS patients who underwent care from 2008 to 2015. Some current problems are highlighted in this article. The RusACSR is a perspective project for different epidemiologic studies in Russian ACS patients.
Analysis of binding site for the novel small‐molecule TLR4 signal transduction inhibitor TAK‐242 and its therapeutic effect on mouse sepsis model

Background and purpose: TAK‐242, a novel synthetic small‐molecule, suppresses production of multiple cytokines by inhibiting Toll‐like receptor (TLR) 4 signalling. In this study, we investigated the target molecule of TAK‐242 and examined its therapeutic effect in a mouse sepsis model.
Pharmacological and electrophysiological characterization of nine, single nucleotide polymorphisms of the hERG‐encoded potassium channel

Background and purpose: Potencies of compounds blocking KV11.1 [human ether‐ago‐go‐related gene (hERG)] are commonly assessed using cell lines expressing the Caucasian wild‐type (WT) variant. Here we tested whether such potencies would be different for hERG single nucleotide polymorphisms (SNPs).
Rapid psychosocial function screening test identified treatment failure in HIV+ African youth

Abstract Psychosocial dysfunction in older children and adolescents is common and may lead to nonadherence to HIV treatments. Poor adherence leads to HIV treatment failure and the development of resistant virus. In resource-limited settings where treatment options are typically limited to only one or two available lines of therapy, identification of individuals at highest risk of failure before failure occurs is of critical importance. Rapid screening tools for psychosocial dysfunction may allow for identification of those children and adolescents who are most likely to benefit from limited psychosocial support services targeted at preventing HIV treatment failure. The Pediatric Symptom Checklist (PSC) is used in high resource settings for rapid identification of at-risk youth. In 692 HIV-infected treated children (ages of 8–< 17 years) in Botswana, having a high score on the PSC was associated with having virologic failure (OR 1.7, 95% CI: 1.1–2.6). The PSC may be a useful screening tool in pediatric HIV.
Análisis de la Morfología del Raquis Torácico y Lumbar en Mujeres Trabajadoras de una Cooperativa Hortofrutícola

El objetivo del presente estudio fue analizar la disposicion angular del raquis toracico y lumbar en bipedestacion y sedentacion relajada en mujeres trabajadoras de una empresa hortofruticola. Un total de 50 mujeres (media de edad: 43,62±8,43 anos) fueron evaluadas mediante un Spinal Mouse en bipedestacion y en sedentacion relajada. Los valores angulares medios para el raquis toracico y lumbar fueron de 32,74±8,76 y -21,66±19,12 en bipedestacion y de 36,32±10,55 y -1,08±18,14, en sedentacion. En bipedestacion, un elevado porcentaje de casos (86% y 68,3%) presentaban una cifosis toracica y lordosis lumbar dentro de los valores de normalidad. En sedentacion, el 74% presentaban hipercifosis toracica y el 20% una inversion lumbar. En conclusion, aunque en bipedestacion la mayoria de las mujeres presentaban una morfologia del raquis dentro de los valores de normalidad, en sedentacion se observo un elevado porcentaje de casos con hipercifosis toracica y el raquis lumbar en inversion. Debido a las consecuencias negativas que se asocian a dichas desalineaciones raquideas, es recomendable aplicar programas de mejora de la actitud postural en estas trabajadoras, preferentemente en su contexto laboral.
The Understanding of Informed Consent Information—Definitions and Measurements in Empirical Studies

Participants’ understanding of consent information has been subject to rather intensive studies. This review was undertaken with the aim of exploring how understanding has been defined and measured in empirical studies of trial participants’ understanding of consent information. The databases Medline, Embase, ISI Web of Science, and PsycINFO were used to identify relevant literature published until October 2007. The following search terms were used: (informed consent OR consent forms) AND (clinical trials OR clinical research) AND (comprehension OR understanding). Thirty-five papers fulfilled the inclusion criteria and were reviewed in detail. Different terms were assigned to the variable: “understanding,” “comprehension,” “retention,” “awareness,” or “recognition. ” A definition of what these terms implied was seldom given. Most of the studies used questionnaires for measuring the subjects’ understanding. The instruments differed substantially with regard to time of measurement, number of questions and which topics were covered. Most of the instruments were developed specifically for each study. The variation in definitions and measurements hinders comparisons of findings and thus improvement of consent forms based upon empirical studies.
DNA mismatch repair (MMR)‐dependent 5‐fluorouracil cytotoxicity and the potential for new therapeutic targets

The metabolism and efficacy of 5‐fluorouracil (FUra) and other fluorinated pyrimidine (FP) derivatives have been intensively investigated for over fifty years. FUra and its antimetabolites can be incorporated at RNA‐ and DNA‐levels, with RNA level incorporation provoking toxic responses in human normal tissue, and DNA‐level antimetabolite formation and incorporation believed primarily responsible for tumour‐selective responses. Attempts to direct FUra into DNA‐level antimetabolites, based on mechanism‐of‐action studies, have led to gradual improvements in tumour therapy. These include the use of leukovorin to stabilize the inhibitory thymidylate synthase‐5‐fluoro‐2′‐deoxyuridine 5′ monophoshate (FdUMP)‐5,10‐methylene tetrahydrofolate (5,10‐CH2FH4) trimeric complex. FUra incorporated into DNA also contributes to antitumour activity in preclinical and clinical studies. This review examines our current state of knowledge regarding the mechanistic aspects of FUra:Gua lesion detection by DNA mismatch repair (MMR) machinery that ultimately results in lethality. MMR‐dependent direct cell death signalling or futile cycle responses will be discussed. As 10–30% of sporadic colon and endometrial tumours display MMR defects as a result of human MutL homologue‐1 (hMLH1) promoter hypermethylation, we discuss the use and manipulation of the hypomethylating agent, 5‐fluorodeoxycytidine (FdCyd), and our ability to manipulate its metabolism using the cytidine or deoxycytidylate (dCMP) deaminase inhibitors, tetrahydrouridine or deoxytetrahydrouridine, respectively, as a method for re‐expression of hMLH1 and re‐sensitization of tumours to FP therapy.
A Phase II Trial of Temozolomide and IFN-α in Patients with Advanced Renal Cell Carcinoma

The combination of temozolomide (TEM) and interferon-α (IFN-α) previously demonstrated a 30% response rate in metastatic melanoma. A single institution, phase II trial evaluating the efficacy of TEM/IFN in patients with advanced renal cell carcinoma (RCC) was conducted. Safety and tumor response were the main outcomes. Eligible patients received 200 mg/m2/day TEM orally on days 1-5 every 28 days, with IFN 2.5 million U/m2/day subcutaneously (s.c.) three alternate days/week for days 1-15 first cycle, then 5 million U/m2/day s.c. 3 alternate days/week throughout each 28-day cycle. Efficacy was evaluated every 8 weeks, and dose-limiting toxicities (DLTs) were treated with dose reductions of the culprit drug. Sixteen patients (ages 37-67) were initially enrolled. Of the 14 evaluable patients, there was one minor response. Best response was stable disease, with 7 patients remaining on study for ≥6 months. Five were alive for more than 2 years, and 2 remain alive at 45 and 50 months after enrollment. DLTs inclu.
Low‐flow/low‐gradient aortic stenosis—Still a diagnostic and therapeutic challenge

Aortic stenosis (AS) is the most frequently observed valvular heart disease. During the symptomatic stage, the rate of death increases dramatically, so that a precise diagnostic approach is taken to guide therapeutic options. Of patients with severe AS, 30% to 50% present with low‐flow/low‐gradient AS (LF/LGAS) status. This review focuses on LF/LGAS and the best diagnostic and therapeutic management in either classic LF/LGAS with reduced left ventricular ejection fraction (LVEF) or paradoxical LF/LGAS with preserved LVEF. Current literature demonstrates that in classic LF/LGAS it is crucial to rule out a pseudo‐severe AS, because reduced LVEF may result in an incomplete opening of the valve. This can be done by low‐dose dobutamine stress echocardiography. Classic LF/LGAS has poor clinical outcomes when managed conservatively; therefore, surgical or interventional aortic valve replacement should be performed. In paradoxical LF/LGAS, the LVEF is preserved (>50%), but impaired filling of the concentric hypertrophied ventricle leads to reduced stroke volume. Therefore, diagnostic and therapeutic decisions in paradoxical LF/LGAS are even more challenging. It is a heterogeneous disease entity, and it is crucial to rule out any diagnostic errors because numerous potential confounders might lead to misdiagnosis. As in classic stenosis, pseudo‐severe stenosis must be ruled out as well. Evaluation via multidetector computed tomography or transesophageal echocardiography can help to evaluate the morphologic alterations of the valve (eg, calcification). Further studies are necessary to understand this disease entity and to evaluate the optimal diagnostic and therapeutic approach for these patients.
Theoretical models of parental HIV disclosure: A critical review

Abstract This study critically examined three major theoretical models related to parental HIV disclosure (i.e., the Four-Phase Model [FPM], the Disclosure Decision Making Model [DDMM], and the Disclosure Process Model [DPM]), and the existing studies that could provide empirical support to these models or their components. For each model, we briefly reviewed its theoretical background, described its components and/or mechanisms, and discussed its strengths and limitations. The existing empirical studies supported most theoretical components in these models. However, hypotheses related to the mechanisms proposed in the models have not yet tested due to a lack of empirical evidence. This study also synthesized alternative theoretical perspectives and new issues in disclosure research and clinical practice that may challenge the existing models. The current study underscores the importance of including components related to social and cultural contexts in theoretical frameworks, and calls for more adequately designed empirical studies in order to test and refine existing theories and to develop new ones.
Determination of ideal target exercise heart rate for cardiac patients suitable for rehabilitation

Exercise prescription for patients with cardiovascular disease remains a challenge. The concept of exercising at an intensity equivalent to one's anaerobic threshold has been well studied and highly recommended in the fitness industry for other populations. For this concept to be applicable to patients with cardiovascular disease, the level and intensity of activity must not trigger myocardial ischemia.
The Psychiatry of Light

AbstractBright light therapy and the broader realm of chronotherapy remain underappreciated and underutilized, despite their empirical support. Efficacy extends beyond seasonal affective disorder and includes nonseasonal depression and sleep disorders, with emerging evidence for a role in treating attention-deficit/hyperactivity disorder, delirium, and dementia. A practical overview is offered, including key aspects of underlying biology, indications for treatment, parameters of treatment, adverse effects, and transformation of our relationship to light and darkness in contemporary life.
Shedding greater light on the natural history and prevalence of multiple sclerosis

This is the first in a series of articles giving a comprehensive and up-to-date review of the theory and practice of multiple sclerosis (MS). This article examines the natural history of multiple sclerosis. MS is an autoimmune, demyelinating disease of the central nervous system with a complex and uncertain aetiology. MS was first described clinically by Jean-Martin Charcot in 1863 although the first documented case is thought to date back to the 14th century with an account of the life of St Lidwina. The cause of MS is unclear although it is known that genetic susceptibility in combination with exposure to certain environmental factors in childhood is required for someone to develop MS. The various studies exploring the epidemiology of MS and the possible environmental factors which have been implicated will be reviewed.
Understanding the partial protection of male circumcision for HIV prevention among women in Iringa Region, Tanzania: An ethnomedical model

Communicating the partial efficacy of male circumcision for HIV prevention is challenging. Understanding how people conceptualize risk can help programs communicate messages in a way that is understandable to local communities. This article explores women's ethnomedical model of disease transmission related to male circumcision in Iringa Region, Tanzania. We conducted in-depth interviews (IDIs) with 32 female partners of male circumcision clients and focus group discussions (FGDs) with married (n=3) and unmarried (n=3) women from November 2011 to February 2012. Interviews were digitally recorded, transcribed, and translated into English, and codes were developed based on emerging themes. While women understand that circumcised men are still at risk of HIV, risk is perceived to be low as long as both partners avoid abrasions during sexual intercourse and the man's penis is kept clean. Women said that HIV transmission only occurs when both partners have abrasions on their genitalia and mixing of blood occurs. Abrasions are thought to be the result of friction from fast or dry sex and are more likely to occur with uncircumcised men; thus, HIV can be prevented if a man is circumcised and couples have gentle, lubricated sex. In addition, women reported that the foreskin traps particles of sexually transmitted infections (STIs) including HIV, which can easily be passed on to female partners. In contrast, circumcised men are viewed as being able to clean themselves of disease particles and, therefore, do not easily acquire diseases or transmit them to female partners. These findings align with the scientific understanding of increased HIV risk associated with abrasions or microflora in the foreskin; however, the ethnomedical model differs from scientific understanding in that disease transmission can in fact occur without either of these conditions. Programs can build upon these findings to better convey risks along with the benefits of male circumcision.
Sexual risk-taking behaviour among HIV outpatients in Argentina

HIV prevention strategies must be based on evidence of risk behaviours among people with HIV infection. This study aimed to determine the demographic, behavioural and self-reported disease/treatment variables that predict sexual risk behaviour, defined as unprotected intercourse with a partner of unknown or negative HIV status, among HIV-infected outpatients in Buenos Aires, Argentina. Two hundred consecutive outpatients (response rate 76.5%) participated in a self-complete cross sectional survey. The majority (49.5%) identified as heterosexual, and most were on antiretroviral therapy (ART) (75.5%). Undetectable viral load was currently achieved by 63%. Unprotected intercourse with a person of unknown or discordant status in the previous three months was reported by 20%. In multivariate analysis, risk was associated with lower distress from physical symptoms (p=0.012), greater distress from psychological symptoms (p=0.038) and being on treatment had borderline association with risk (p=0.058). The data reveal an important link between self-reported experience of disease, and treatment, with risk. Secondary prevention, care and treatment should not be conducted in isolation from each other if outcomes are to be optimised.
Activation of cardiac muscarinic M3 receptors induces delayed cardioprotection by preserving phosphorylated connexin43 and up‐regulating cyclooxygenase‐2 expression

Background and purpose: Activation of muscarinic M3 mucarinic acetylcholine receptors (M3‐mAChRs) has been previously shown to confer short‐term cardioprotection against ischaemic injuries. However, it is not known whether activation of these receptors can provide delayed cardioprotection. Consequently, the present study was undertaken to investigate whether stimulation of M3‐mAChRs can induce delayed preconditioning in rats, and to characterize the potential mechanism.
Caspase‐3 knock‐down reverses contractile dysfunction induced by sepsis in adult rat ventricular myocytes

Background and purpose: The present study tested the hypothesis that selective caspase‐3 (C‐3) knock‐out would regulate the contractile actions of noradrenaline (NA) in the dysfunction of adult rat ventricular myocytes (ARVMs) induced by sepsis. Here, we have studied the contractile response of ARVMs, transfected with C‐3 small interfering RNA (C‐3 siRNA), to NA.