Ontogenetic De Novo Copy Number Variations (CNVs) as a Source of Genetic Individuality: Studies on Two Families with MZD Twins for Schizophrenia

Genetic individuality is the foundation of personalized medicine, yet its determinants are currently poorly understood. One issue is the difference between monozygotic twins that are assumed identical and have been extensively used in genetic studies for decades [1]. Here, we report genome-wide alterations in two nuclear families each with a pair of monozygotic twins discordant for schizophrenia evaluated by the Affymetrix 6.0 human SNP array. The data analysis includes characterization of copy number variations (CNVs) and single nucleotide polymorphism (SNPs). The results have identified genomic differences between twin pairs and a set of new provisional schizophrenia genes. Samples were found to have between 35 and 65 CNVs per individual. The majority of CNVs (∼80%) represented gains. In addition, ∼10% of the CNVs were de novo (not present in parents), of these, 30% arose during parental meiosis and 70% arose during developmental mitosis. We also observed SNPs in the twins that were absent from both parents. These constituted 0.12% of all SNPs seen in the twins. In 65% of cases these SNPs arose during meiosis compared to 35% during mitosis. The developmental mitotic origin of most CNVs that may lead to MZ twin discordance may also cause tissue differences within individuals during a single pregnancy and generate a high frequency of mosaics in the population. The results argue for enduring genome-wide changes during cellular transmission, often ignored in most genetic analyses

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Computational Biology Methods and Their Application to the Comparative Genomics of Endocellular Symbiotic Bacteria of Insects

Comparative genomics has become a real tantalizing challenge in the postgenomic era. This fact has been mostly magnified by the plethora of new genomes becoming available in a daily bases. The overwhelming list of new genomes to compare has pushed the field of bioinformatics and computational biology forward toward the design and development of methods capable of identifying patterns in a sea of swamping data noise. Despite many advances made in such endeavor, the ever-lasting annoying exceptions to the general patterns remain to pose difficulties in generalizing methods for comparative genomics. In this review, we discuss the different tools devised to undertake the challenge of comparative genomics and some of the exceptions that compromise the generality of such methods. We focus on endosymbiotic bacteria of insects because of their genomic dynamics peculiarities when compared to free-living organisms

Balkan: od geografije do fantazije, Katarina Luketić

BACKGROUND: Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. METHODS: We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15-20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15-20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0.05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186). FINDINGS: Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1.78; 95% CI 1.22-2.58, p=0.003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3-5 adverse events, with similar proportions in each arm. INTERPRETATION: A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. FUNDING: The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC)

Culture Enriched Molecular Profiling of the Cystic Fibrosis Airway Microbiome

The microbiome of the respiratory tract, including the nasopharyngeal and oropharyngeal microbiota, is a dynamic community of microorganisms that is highly diverse. The cystic fibrosis (CF) airway microbiome refers to the polymicrobial communities present in the lower airways of CF patients. It is comprised of chronic opportunistic pathogens (such as Pseudomonas aeruginosa) and a variety of organisms derived mostly from the normal microbiota of the upper respiratory tract. The complexity of these communities has been inferred primarily from culture independent molecular profiling. As with most microbial communities it is generally assumed that most of the organisms present are not readily cultured. Our culture collection generated using more extensive cultivation approaches, reveals a more complex microbial community than that obtained by conventional CF culture methods. To directly evaluate the cultivability of the airway microbiome, we examined six samples in depth using culture-enriched molecular profiling which combines culture-based methods with the molecular profiling methods of terminal restriction fragment length polymorphisms and 16S rRNA gene sequencing. We demonstrate that combining culture-dependent and culture-independent approaches enhances the sensitivity of either approach alone. Our techniques were able to cultivate 43 of the 48 families detected by deep sequencing; the five families recovered solely by culture-independent approaches were all present at very low abundance (<0.002% total reads). 46% of the molecular signatures detected by culture from the six patients were only identified in an anaerobic environment, suggesting that a large proportion of the cultured airway community is composed of obligate anaerobes. Most significantly, using 20 growth conditions per specimen, half of which included anaerobic cultivation and extended incubation times we demonstrate that the majority of bacteria present can be cultured

Physical inactivity is the major determinant of obesity in black women in the North West Province, South Africa: the THUSA study. Transition and Health During Urbanisation of South Africa

Objective: we investigated the association between measures and determinants of obesity in African women.Methods: for a cross-sectional study of adult black women in the North West Province, South Africa, we used a stratified sample of 1040 volunteers from 37 randomly selected sites in the province according to the level of urbanization. We analyzed the association between measures of obesity, namely body mass index (BMI), waist circumference, waist-to-hip ratio, triceps and subscapular skinfolds, and socioeconomic factors, dietary intakes, and physical activity.Results: the rate of obesity (BMI &gt; 30) in the sample was 28.6%. We found a significant positive association between household income and measures of obesity. After exclusion of underreporters and adjustments for age, smoking, and household income, we found significant positive correlations between total energy intake, fat intake, and BMI. Physical activity index (derived from a subset of 530 subjects) correlated negatively with BMI and waist circumference. Subjects in the highest third of physical activity were less likely to be obese (odds ratio-0.38, 95% confidence interval-0.22–0.66).Conclusions: women with higher incomes and lower physical activity were at the greatest risk of increased BMI. Physical inactivity showed the strongest association with measures of obesity in this study

Physical Inactivity Is the Major Determinant of Obesity in Black Women in the North West Province, South Africa: The THUSA Study

OBJECTIVE: We investigated the association between measures and determinants of obesity in African women. METHODS: For a cross-sectional study of adult black women in the North West Province, South Africa, we used a stratified sample of 1040 volunteers from 37 randomly selected sites in the province according to the level of urbanization. We analyzed the association between measures of obesity, namely body mass index (BMI), waist circumference, waist-to-hip ratio, triceps and subscapular skinfolds, and socioeconomic factors, dietary intakes, and physical activity. RESULTS: The rate of obesity (BMI Ͼ 30) in the sample was 28.6%. We found a significant positive association between household income and measures of obesity. After exclusion of underreporters and adjustments for age, smoking, and household income, we found significant positive correlations between total energy intake, fat intake, and BMI. Physical activity index (derived from a subset of 530 subjects) correlated negatively with BMI and waist circumference. Subjects in the highest third of physical activity were less likely to be obese (odds ratio-0.38, 95% confidence interval-0.22-0.66). CONCLUSIONS: Women with higher incomes and lower physical activity were at the greatest risk of increased BMI. Physical inactivity showed the strongest association with measures of obesity in this study

The nutrition and health transition in the North West Province of South Africa: a review of the THUSA (Transition and Health during Urbanisation of South Africans) study

Objective: To describe how urbanisation influences the nutrition and health transition in South Africa by using data from the THUSA (Transition and Health during Urbanisation of South Africans) study.Design: The THUSA study was a cross-sectional, comparative, population-based survey.Setting: The North West Province of South Africa.Subjects: In total, 1854 apparently healthy volunteers, men and women aged 15 years and older, from 37 randomly selected sites. Pregnant and lactating women, those with diagnosed chronic diseases and taking medication, with acute infections or inebriated were excluded but screened for hypertension and diabetes mellitus. Subjects were stratified into five groups representing different levels of urbanisation in rural and urban areas: namely, deep rural, farms, squatter camps, townships and towns/cities.Outcome measures and methods: Socio-economic and education profiles, dietary patterns, nutrient intakes, anthropometric and biochemical nutrition status, physical and mental health indicators, and risk factors for non-communicable diseases (NCDs) were measured using questionnaires developed or adapted and validated for this population, as well as appropriate, standardised methods for the biochemical analyses of biological samples.Results: Subjects from the rural groups had lower household incomes, less formal education, were shorter and had lower body mass indices than those in the urban groups. Urban subjects consumed less maize porridge but more fruits, vegetables, animal-derived foods and fats and oils than rural subjects. Comparing women from rural group 1 with the urban group 5, the following shifts in nutrient intakes were observed: % energy from carbohydrates, 67.4 to 57.3; from fats, 23.6 to 31.8; from protein, 11.4 to 13.4 (with an increase in animal protein from 22.2 to 42.6 g day-1); dietary fibre, 15.8 to 17.7 g day-1; calcium, 348 to 512 mg day-1; iron from 8.4 to 10.4 mg day-1; vitamin A from 573 to 1246 g retinol equivalents day-1; and ascorbic acid from 30 to 83 mg day-1. Serum total cholesterol, low-density lipoprotein cholesterol and plasma fibrinogen increased significantly across groups; systolic blood pressure &gt;140 mmHg was observed in 10.4–34.8% of subjects in different groups and diabetes mellitus in 0.8–6.0% of subjects. Women in groups 1 to 5 had overweight plus obesity rates of 48, 53, 47, 61 and 61%, showing an increase with urbanisation. Subjects from group 2 (farm dwellers) showed the highest scores of psychopathology and the lowest scores of psychological well-being. The same subjects consistently showed the lowest nutrition status.Conclusions: Urbanisation of Africans in the North West Province is accompanied by an improvement in micronutrient intakes and status, but also by increases in overweight, obesity and several risk factors for NCDs. It is recommended that intervention programmes to promote nutritional health should aim to improve micronutrient status further without leading to obesity. The role of psychological strengths in preventing the adverse effects of urbanisation on health needs to be examined in more detail