Discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridines as potent and selective SST5 agonists for the treatment of congenital hyperinsulinism.

SST5 receptor activation potently inhibits insulin secretion from pancreatic β-cells, and an orally available nonpeptide selective SST5 agonist may be used to effectively manage the blood glucose levels of congenital HI patients to avoid severe hypoglycemia. Our medicinal chemistry efforts have led to the discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridine analogs as potent SST5 agonists. This class of molecules exhibits excellent human SST5 potency and selectivity against SST1, SST2, SST3 and SST4 receptors.

Mineral and Amino Acid Profiling of Different Hematopoietic Populations from the Mouse Bone Marrow.

Steady hematopoiesis is essential for lifelong production of all mature blood cells. Hematopoietic stem and progenitor cells (HSPCs) found in the bone marrow ensure hematopoietic homeostasis in an organism. Failure of this complex process, which involves a fine balance of self-renewal and differentiation fates, often result in severe hematological conditions such as leukemia and lymphoma.

Publisher Correction: Menstrual cycle rhythmicity: metabolic patterns in healthy women.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Association between lay perception of morbidity and appropriateness of specialized health care use in adolescent idiopathic scoliosis.

In absence of school scoliosis screening programs (SSSP) in Canada, this study examined the relationships between the lay person's perception of morbidity and the appropriateness of referral in orthopedics. A cross-sectional study was conducted with all children consecutively referred in orthopedics for suspected scoliosis. The 831 participants were classified as Appropriate, Late, or Inappropriate referrals for the orthopedic setting.

Sex-Specific Associations of Blood-Based Nutrient Profiling With Body Composition in the Elderly.

The intake of adequate amounts and types of nutrients is key for sustaining health and a good quality of life, particularly in the elderly population. There is considerable evidence suggesting that physiological changes related to age and sex modify nutritional needs, and this may be related to age-associated changes in body composition (BC), specifically in lean and fat body mass. However, there is a clear lack of understanding about the association of nutrients in blood and BC parameters in the elderly.

Menstrual cycle rhythmicity: metabolic patterns in healthy women.

The menstrual cycle is an essential life rhythm governed by interacting levels of progesterone, estradiol, follicular stimulating, and luteinizing hormones. To study metabolic changes, biofluids were collected at four timepoints in the menstrual cycle from 34 healthy, premenopausal women. Serum hormones, urinary luteinizing hormone and self-reported menstrual cycle timing were used for a 5-phase cycle classification.

Validation of the Brazilian Healthy Eating Index-Revised Using Biomarkers in Children and Adolescents.

The Brazilian Healthy Eating Index-Revised (BHEI-R) can be used to determine overall dietary patterns. We assessed the BHEI-R scores in children and adolescents, aged from 9 to 13 years old, and associated its component scores with biomarkers of health and dietary exposure. Three 24-h recalls were used to generate BHEI-R.

Vitamin B12 deficiency and impaired expression of amnionless during aging.

Background: Physical frailty and loss of mobility in elderly individuals lead to reduced independence, quality of life, and increased mortality. Vitamin B12 deficiency has been linked to several age-related chronic diseases, including in the musculo-skeletal system, where vitamin B12 deficiency is generally believed to be linked to poor nutritional intake. In the present study, we asked whether aging and frailty associate with altered vitamin B12 homeostasis in humans and investigated the underlying molecular mechanisms using preclinical models.

Identification of 4-(Aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine Derivatives as Potent, Selective, and Orally Efficacious Inhibitors of the Copper-Dependent Amine Oxidase, Lysyl Oxidase-Like 2 (LOXL2).

LOXL2 catalyzes the oxidative deamination of ε-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (allysine). Condensation with other allysines or lysines drives the formation of inter- and intramolecular cross-linkages, a process critical for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue.

Monoacylglycerol-enriched oil increases EPA/DHA delivery to circulatory system in humans with induced lipid malabsorption conditions.

It was hypothesized that under induced lipid malabsorption/maldigestion conditions, an enriched sn-1(3)-monoacylglycerol (MAG) oil may be a better carrier for n-3 long-chain PUFAs (LC-PUFAs) compared with triacylglycerol (TAG) from fish oil. This monocentric double blinded clinical trial examined the accretion of EPA (500 mg/day) and DHA (300 mg/day) when consumed as TAG or MAG, into the erythrocytes, plasma, and chylomicrons of 45 obese (BMI ≥30 kg/m and ≤40 kg/m) volunteers who were and were not administered Orlistat, an inhibitor of pancreatic lipases. Intake of MAG-enriched oil resulted in higher accretion of LC-PUFAs than with TAG, the concentrations of EPA and DHA in erythrocytes being, respectively, 72 and 24% higher at 21 days (P < 0.

Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis.

Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial.

An Autotaxin/Lysophosphatidic Acid/Interleukin-6 Amplification Loop Drives Scleroderma Fibrosis.

Objective: We previously implicated the lipid mediator lysophosphatidic acid (LPA) as having a role in dermal fibrosis in systemic sclerosis (SSc). The aim of this study was to identify the role of the LPA-producing enzyme autotaxin (ATX), and to connect the ATX/LPA and interleukin-6 (IL-6) pathways in SSc.

Methods: We evaluated the effect of a novel ATX inhibitor, PAT-048, on fibrosis and IL-6 expression in the mouse model of bleomycin-induced dermal fibrosis.

[Preventive withdrawal from work, psychosocial work demands and major depressive symptoms].

Aim: Our study objectives were as follows: assess exposure to psychosocial work demands among working pregnant women and women on preventive withdrawal from work; and measure the association between psychosocial work demands and major depressive symptoms, according to time of withdrawal from work.

Methodology: Karasek's abbreviated scale was used to measure psychosocial work demands (Job strain and "Iso-strain") and CES-D scale (Center for Epidemiological Studies Depression Scale) was used to measure major depressive symptoms (CES-D score≥23), at 24-26 weeks of pregnancy, among 3043 pregnant women in Montreal (Quebec) who worked at paid jobs at least 15 h/week and at least four consecutive weeks since the beginning of their pregnancy. Multivariate logistic regression models were built.

Pathways of healthcare utilisation in patients with suspected adolescent idiopathic scoliosis: a cross-sectional study.

Background: School screening programs for adolescent idiopathic scoliosis (AIS) have been discontinued in Canada and elsewhere because they were not considered cost-effective. In communities lacking such programs, we expect a significant variety of healthcare pathways and timeframes for patient referrals to orthopaedics. The objectives of this study were: 1) to characterise the healthcare pathways of young children with suspected AIS in a population without school screening; and 2) to investigate the relationships between these healthcare pathways and the appropriateness of referrals to specialised orthopaedic clinics.

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding.

Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain.

Maternal prenatal felt security and infant health at birth interact to predict infant fussing and crying at 12 months postpartum.

Infants born with medical problems are at risk for less optimal developmental outcomes. This may be, in part, because neonatal medical problems are associated with maternal distress, which may adversely impact infants. However, the reserve capacity model suggests that an individual's bank of psychosocial resources buffers the adverse effects of later-encountered stressors.

Importance of a Regular Source of Primary Care in Adolescents: The Case of Adolescent Idiopathic Scoliosis.

Aim: Primary care practitioners should screen young adolescent patients for idiopathic scoliosis and refer those who could benefit from bracing to prevent curve progression and the need for surgery. Adolescents without a regular source of primary care may be at higher risk for not having their scoliosis diagnosed in time to benefit from bracing. We sought to determine whether adolescents with idiopathic scoliosis and a regular source of primary care are at lower risk of scoliosis surgery.

Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects.

1. Crizotinib (XALKORI®), an oral inhibitor of anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor kinase (c-Met), is currently approved for the treatment of patients with non-small cell lung cancer that is ALK-positive. 2.

Identification of novel HSP90α/β isoform selective inhibitors using structure-based drug design. demonstration of potential utility in treating CNS disorders such as Huntington's disease.

A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/β inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/β inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90α/β selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD).

Perception of humanization of birth in a highly specialized hospital: let's think differently.

Our goal for this article was to identify the perceptions of health care professionals, administrators, and women concerning the humanization of childbirth care in a tertiary hospital. A single-case study design and a qualitative approach were used. We collected data through semistructured interviews, participant observation, field notes, and a questionnaire.

Understanding childbirth practices as an organizational cultural phenomenon: a conceptual framework.

Understanding the main values and beliefs that might promote humanized birth practices in the specialized hospitals requires articulating the theoretical knowledge of the social and cultural characteristics of the childbirth field and the relations between these and the institution. This paper aims to provide a conceptual framework allowing examination of childbirth practices through the lens of an organizational culture theory. A literature review performed to extrapolate the social and cultural factors contribute to birth practices and the factors likely overlap and mutually reinforce one another, instead of complying with the organizational culture of the birth place.

The effectiveness of scoliosis screening programs: methods for systematic review and expert panel recommendations formulation.

Background: Literature on scoliosis screening is vast, however because of the observational nature of available data and methodological flaws, data interpretation is often complex, leading to incomplete and sometimes, somewhat misleading conclusions. The need to propose a set of methods for critical appraisal of the literature about scoliosis screening, a comprehensive summary and rating of the available evidence appeared essential.

Methods: To address these gaps, the study aims were: i) To propose a framework for the assessment of published studies on scoliosis screening effectiveness; ii) To suggest specific questions to be answered on screening effectiveness instead of trying to reach a global position for or against the programs; iii) To contextualize the knowledge through expert panel consultation and meaningful recommendations.