Succinate in dystrophic white matter: A proton magnetic resonance spectroscopy finding characteristic for complex II deficiency

A deficiency of succinate dehydrogenase is a rare cause of mitochondrial encephalomyopathy. Three patients, 2 sisters and I boy from an unrelated family, presented with symptoms and magnetic resonance imaging signs of leukoencephalopathy. Localized proton magnetic resonance spectroscopy indicated a prominent singlet at 2.40ppm in cerebral and cerebellar white matter not present in gray matter or basal ganglia. The signal was also elevated in cerebrospinal fluid and could be identified as originating from the two equivalent methylene groups of succinate. Subsequently, an isolated deficiency of complex II (succinate:ubiquinone oxidoreductase) was demonstrated in 2 patients in muscle and fibroblasts. One of the sisters died at the age of 18 months. Postmortem examination showed the neuropathological characteristics of Leigh syndrome. Her younger sister, now 12 months old, is also severely affected; the boy, now 6 years old, follows a Milder, fluctuating clinical course. Magnetic resonance spectroscopy provides a characteristic pattern in succinate dehydrogenase deficiency

Design, Synthesis and Characterization of a Highly Effective Inhibitor for Analog-Sensitive (as) Kinases

Highly selective, cell-permeable and fast-acting inhibitors of individual kinases are sought-after as tools for studying the cellular function of kinases in real time. A combination of small molecule synthesis and protein mutagenesis, identified a highly potent inhibitor (1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) of a rationally engineered Hog1 serine/threonine kinase (Hog1T100G). This inhibitor has been successfully used to study various aspects of Hog1 signaling, including a transient cell cycle arrest and gene expression changes mediated by Hog1 in response to stress. This study also underscores that the general applicability of this approach depends, in part, on the selectivity of the designed the inhibitor with respect to activity versus the engineered and wild type kinases. To explore this specificity in detail, we used a validated chemogenetic assay to assess the effect of this inhibitor on all gene products in yeast in parallel. The results from this screen emphasize the need for caution and for case-by-case assessment when using the Analog-Sensitive Kinase Allele technology to assess the physiological roles of kinases

Migrant health in Italy: a better health status difficult to maintain-country of origin and assimilation effects studied from the Italian risk factor surveillance data

Many studies on migrant health have focused on aspects of morbidity and mortality, but very few approach the relevant issues of migrants' health considering behavioral risk factors. Previous studies have often been limited methodologically because of sample size or lack of information on migrant country of origin. Information about risk factors is fundamental to direct any intervention, particularly with regard to non-communicable diseases that are leading causes of death and disease. Thus, the main focus of our analysis is the influence of country of origin and the assimilation process

How are gender equality and human rights interventions included in sexual and reproductive health programmes and policies: A systematic review of existing research foci and gaps

The importance of promoting gender equality and human rights in sexual and reproductive health (SRH) programmes and policies has been affirmed in numerous international and regional agreements, most recently the 2030 Agenda for Sustainable Development. Given the critical role of research to determine what works, we aimed to identify research gaps as part of a broader priority setting exercise on integrating gender equality and human rights approaches in SRH programmes and policies. A systematic literature review of reviews was conducted to examine the question: what do we know about how research in the context of SRH programmes and policies has addressed gender equality and human rights and what are the current gaps in research. We searched three databases for reviews that addressed the research question, were published between 1994-2014, and met methodological standards for systematic reviews, qualitative meta-syntheses and other reviews of relevance to the research question. Additional grey literature was identified based on expert input. Articles were appraised by the primary author and examined by an expert panel. An abstraction and thematic analysis process was used to synthesize findings. Of the 3,073 abstracts identified, 56 articles were reviewed in full and 23 were included along with 10 from the grey literature. The majority focused on interventions addressing gender inequalities; very few reviews explicitly included human rights based interventions. Across both topics, weak study designs and use of intermediate outcome measures limited evidence quality. Further, there was limited evidence on interventions that addressed marginalized groups. Better quality studies, longer-term indicators, and measurement of unintended consequences are needed to better understand the impact of these types of interventions on SRH outcomes. Further efforts are needed to cover research on gender equality and human rights issues as they pertain to a broader set of SRH topics and populations.Scopu

Who Feels Disadvantaged? Reporting Discrimination in Surveys

In this chapter, we seek to shed light on the mechanisms of perceived discrimination: Who, among recent immigrants, is more likely to feel discriminated against and report it when asked in a survey? Social scientists typically define discrimination as an observable and unjust difference in the treatment of distinct groups. To personally feel discriminated against, people must be aware of the differential treatment and perceive it as unjust. We show that reporting discrimination when asked in a survey depends substantially upon individual traits, including aspects that shape whether discrimination is accepted and whether immigrants feel attached to the host society. Although respondents report less discrimination if their job situation has improved after migration, people more likely report discrimination when they originate from countries in which the national legislature represents ethnic minority groups relatively well. Earlier difficulties related to the migration process and the lack of supporting networks continue to affect the perception of unfair treatment. Moreover, we show that individuals distinguish to a surprising degree between discrimination in and outside the work environment. For instance, when they are proficient in the local language, respondents often report discrimination in the workplace but not in a public environment. This distinction between discrimination in the workplace and discrimination in public also depends strongly upon the immigrant's origin. We conclude that contemporary individual-level measures and policy recommendations merely approximate discriminatory patterns; we urge future research to consider factors that affect individual perception of discrimination

Risk factors and myocardial infarction in patients with obstructive sleep apnea: impact of β2-adrenergic receptor polymorphisms

BACKGROUND: The increased sympathetic nervous activity in patients with obstructive sleep apnea (OSA) is largely responsible for the high prevalence of arterial hypertension, and it is suggested to adversely affect triglyceride and high-density lipoprotein (HDL) cholesterol levels in these patients. The functionally relevant polymorphisms of the β2-adrenergic receptor (Arg-47Cys/Arg16Gly and Gln27Glu) have been shown to exert modifying effects on these risk factors in previous studies, but results are inconsistent. METHODS: We investigated a group of 429 patients (55 ± 10.7 years; 361 men, 68 women) with moderate to severe obstructive sleep apnea (apnea/hypopnea index (AHI) 29.1 ± 23.1/h) and, on average, a high cardiovascular risk profile (body mass index 31.1 ± 5.6, with hypertension in 60.1%, dyslipidemia in 49.2%, and diabetes in 17.2% of patients). We typed the β2-adrenergic receptor polymorphisms and investigated the five most frequent haplotypes for their modifying effects on OSA-induced changes in blood pressure, heart rate, and lipid levels. The prevalence of cardiovascular risk factors and coronary heart disease (n = 55, 12.8%) and survived myocardial infarction (n = 27, 6.3%) were compared between the genotypes and haplotypes. RESULTS: Multivariate linear/logistic regressions revealed a significant and independent (from BMI, age, sex, presence of diabetes, use of antidiabetic, lipid-lowering, and antihypertensive medication) influence of AHI on daytime systolic and diastolic blood pressure, heart rate, prevalence of hypertension, and triglyceride and HDL levels. The β2-adrenergic receptor genotypes and haplotypes showed no modifying effects on these relationships or on the prevalence of dyslipidemia, diabetes, and coronary heart disease, yet, for all three polymorphisms, heterozygous carriers had a significantly lower relative risk for myocardial infarction (Arg-47Cys: n = 195, odds ratio (OR) = 0.32, P = 0.012; Arg16Gly: n = 197, OR = 0.39, P = 0.031; Gln27Glu: OR = 0.37, P = 0.023). Carriers of the most frequent haplotype (n = 113) (haplotype 1; heterozygous for all three polymorphisms) showed a five-fold lower prevalence of survived myocardial infarction (OR = 0.21, P = 0.023). CONCLUSION: Our study showed no significant modifying effect of the functionally relevant β2-adrenergic receptor polymorphisms on OSA-induced blood pressure, heart rate, or lipid changes. Nevertheless, heterozygosity of these polymorphisms is associated with a lower prevalence of survived myocardial infarction in this group with, on average, a high cardiovascular risk profile

Metabolomics Reveals Reduction of Metabolic Oxidation in Women with Polycystic Ovary Syndrome after Pioglitazone-Flutamide-Metformin Polytherapy

Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients