Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Expression and Regulation of Osteoprotegerin in Adipose Tissue

PURPOSE: Osteoprotegerin (OPG), a potent inhibitor of osteoclastic bone resorption, has a variety of biological functions that include anti-inflammatory effects. Adipocytes and osteoblasts share a common origin, and the formation of new blood vessels often precedes adipogenesis in developing adipose tissue microvasculature. We examined whether OPG is secreted from adipocytes, therefore contributing to the prevention of neovascularization and protecting the vessels from intimal inflammation and medial calcification. MATERIALS AND METHODS: The mRNA expression of OPG and receptor activator of NF-kappaB ligand (RANKL) was measured in differentiated 3T3L1 adipocytes and adipose tissues. RESULTS: OPG mRNA expression increased with the differentiation of 3T3L1 adipocytes, while RANKL expression was not significantly altered. OPG mRNA was expressed at higher levels in white adipose tissue than in brown adipose tissue and was most abundant in the epididymal portion. In differentiated 3T3L1 adipocytes, Rosiglitazone and insulin reduced the OPG/RANKL expression ratio in a dose- and time- dependent manner. In contrast, tumor necrosis factor-alpha (TNF-alpha) increased the expression of both OPG and RANKL in a time-dependent manner. The OPG/RANKL ratio was at a maximum two hours after TNF-alpha treatment and then returned to control levels. Furthermore, OPG was abundantly secreted into the media after transfection of OPG cDNA with Phi C31 integrase into 3T3L1 cells. CONCLUSION: Our results indicate that OPG mRNA is expressed and regulated in the adipose tissue. Considering the role of OPG in obesity-associated inflammatory changes in adipose tissue and vessels, we speculate that OPG may have both a protective function against inflammation and anti-angiogenic effects on adipose tissue.ope

Quality of Life and Costs in Parkinson's Disease: A Cross Sectional Study in Hungary.

BACKGROUND: Patient reported outcomes and costs of illness are useful to capture some of the multiple effects of a disease and its treatments. Our aim was to assess quality of life (QoL) and costs of Parkinson's disease (PD) in Hungary, and to analyze their associations. METHODS: A cross-sectional questionnaire survey was conducted in one neurology university clinic. Clinical characteristics, PD related resource utilizations and productivity loss in the past 12 months were recorded; the Hoehn&Yahr (HY) scale, PDQ-39 and EQ-5D questionnaires were applied. Cost calculation was performed from the societal perspective. RESULTS: 110 patients (34.5% female) were involved with mean age of 63.3 (SD = 11.3) and disease duration of 8.2 (SD = 5.8) years. PDQ-39 summary score was 48.1 (SD = 13.4). The average EQ-5D score was 0.59 (SD = 0.28), and was significantly lower than the population norm in age-groups 45-74. The correlation was significant between EQ-5D and PDQ-39 (-0.47, p = 0.000), the HY scale and EQ-5D (-0.3416, p = 0.0008) and PDQ-39 (0.3419, p = 0.0006) scores. The total mean cost was euro6030.2 (SD = 6163.0)/patient/year (direct medical 35.7%, direct non-medical 29.4%, indirect cost 34.9%). A one year increase in disease duration and 0.1 decrease of the EQ-5D utility score increase the yearly costs by 8 to 10%, and 7.8%, respectively. The effect of the PDQ-39 score on total cost was not significant. CONCLUSIONS: Disease severity and public health importance of PD are clearly demonstrated by the magnitude of QoL loss. PD-related costs are substantial, but are much lower in Hungary than in Western European countries. Disease duration and EQ-5D score are significant proxy of costs

Recessive Antimorphic Alleles Overcome Functionally Redundant Loci to Reveal TSO1 Function in Arabidopsis Flowers and Meristems

Arabidopsis TSO1 encodes a protein with conserved CXC domains known to bind DNA and is homologous to animal proteins that function in chromatin complexes. tso1 mutants fall into two classes due to their distinct phenotypes. Class I, represented by two different missense mutations in the CXC domain, leads to failure in floral organ development, sterility, and fasciated inflorescence meristems. Class II, represented by a nonsense mutation and a T-DNA insertion line, develops wild-type–like flowers and inflorescences but shows severely reduced fertility. The phenotypic variability of tso1 alleles presents challenges in determining the true function of TSO1. In this study, we use artificial microRNA, double mutant analysis, and bimolecular fluorescence complementation assay to investigate the molecular basis underlying these two distinct classes of phenotypes. We show that the class I mutants could be converted into class II by artificial microRNA knockdown of the tso1 mutant transcript, suggesting that class I alleles produce antimorphic mutant proteins that interfere with functionally redundant loci. We identified one such redundant factor coded by the closely related TSO1 homolog SOL2. We show that the class I phenotype can be mimicked by knocking out both TSO1 and its homolog SOL2 in double mutants. Such antimorphic alleles targeting redundant factors are likely prevalent in Arabidopsis and maybe common in organisms with many sets of paralogous genes such as human. Our data challenge the conventional view that recessive alleles are always hypomorphic or null and that antimorphic alleles are always dominant. This study shows that recessive alleles can also be antimorphic and can produce a phenotype more severe than null by interfering with the function of related loci. This finding adds a new paradigm to classical genetic concepts, with important implications for future genetic studies both in basic research as well as in agriculture and medicine

Population distribution and burden of acute gastrointestinal illness in British Columbia, Canada

BACKGROUND: In developed countries, gastrointestinal illness (GI) is typically mild and self-limiting, however, it has considerable economic impact due to high morbidity. METHODS: The magnitude and distribution of acute GI in British Columbia (BC), Canada was evaluated via a cross-sectional telephone survey of 4,612 randomly selected residents, conducted from June 2002 to June 2003. Respondents were asked if they had experienced vomiting or diarrhoea in the 28 days prior to the interview. RESULTS: A response rate of 44.3% was achieved. A monthly prevalence of 9.2% (95%CI 8.4 – 10.0), an incidence rate of 1.3 (95% CI 1.1–1.4) episodes of acute GI per person-year, and an average probability that an individual developed illness in the year of 71.6% (95% CI 68.0–74.8), weighted by population size were observed. The average duration of illness was 3.7 days, translating into 19.2 million days annually of acute GI in BC. CONCLUSION: The results corroborate those from previous Canadian and international studies, highlighting the substantial burden of acute GI

The Lactobacillus flora in vagina and rectum of fertile and postmenopausal healthy Swedish women

<p>Abstract</p> <p>Background</p> <p><it>Lactobacillus </it>species are the most often found inhabitants of vaginal ecosystem of fertile women. In postmenopausal women with low oestrogen levels, <it>Lactobacillus </it>flora is diminishing or absent. However, no studies have been performed to investigate the correlation between oestrogen levels and the lactobacilli in the gut. The aim of the present study was to investigate the relation in healthy women between vaginal and rectal microbial flora as well as possible variations with hormone levels.</p> <p>Methods</p> <p>Vaginal and rectal smears were taken from 20 healthy fertile women, average 40 years (range 28-49 years), in two different phases of the menstrual cycle, and from 20 postmenopausal women, average 60 years (range 52-85 years). Serum sex hormone levels were analyzed. Bacteria from the smears isolated on Rogosa Agar were grouped by Randomly Amplified Polymorphic DNA and identified by multiplex PCR and partial 16S rRNA gene sequencing.</p> <p>Results</p> <p><it>Lactobacillus crispatus </it>was more often found in the vaginal flora of fertile women than in that of postmenopausal (p = 0.036). Fifteen of 20 fertile women had lactobacilli in their rectal smears compared to 10 postmenopausal women (p = 0.071). There was no correlation between the number of bacteria in vagina and rectum, or between the number of bacteria and hormonal levels. Neither could any association between the presence of rectal lactobacilli and hormonal levels be found.</p> <p>Conclusion</p> <p><it>Lactobacillus crispatus </it>was more prevalent in the vaginal flora of fertile women, whereas the <it>Lactobacillus </it>flora of rectum did not correlate to the vaginal flora nor to hormonal levels.</p

Whole genome sequencing reveals high clonal diversity of Escherichia coli isolated from patients in a tertiary care hospital in Moshi, Tanzania

Abstract Background Limited information regarding the clonality of circulating E. coli strains in tertiary care hospitals in low and middle-income countries is available. The purpose of this study was to determine the serotypes, antimicrobial resistance and virulence genes. Further, we carried out a phylogenetic tree reconstruction to determine relatedness of E. coli isolated from patients in a tertiary care hospital in Tanzania. Methods E. coli isolates from inpatients admitted at Kilimanjaro Christian Medical Centre between August 2013 and August 2015 were fully genome-sequenced at KCMC hospital. Sequence analysis was done for identification of resistance genes, Multi-Locus Sequence Typing, serotyping, and virulence genes. Phylogeny reconstruction using CSI Phylogeny was done to ascertain E. coli relatedness. Stata 13 (College Station, Texas 77,845 USA) was used to determine Cohen’s kappa coefficient of agreement between the phenotypically tested and whole genome sequence predicted antimicrobial resistance. Results Out of 38 E. coli isolates, 21 different sequence types (ST) were observed. Eight (21.1%) isolates belonged to ST131; of which 7 (87.5.%) were serotype O25:H4. Ten (18.4%) isolates belonged to ST10 clonal complex; of these, four (40.0%) were ST617 with serotype O89:H10. Twenty-eight (73.7%) isolates carried genes encoding beta-lactam resistance enzymes. On average, agreement across all drugs tested was 83.9%. Trimethoprim/sulphamethoxazole (co-trimoxazole) showed moderate agreement: 45.8%, kappa =15% and p = 0.08. Amoxicillin-clavulanate showed strongest agreement: 87.5%, kappa = 74% and p = 0.0001. Twenty-two (57.9%) isolates carried virulence factors for host cells adherence and 25 (65.7%) for factors that promote E. coli immune evasion by increasing survival in serum. The phylogeny analysis showed that ST131 clustering close together whereas ST10 clonal complex had a very clear segregation of the ST617 and a mix of the rest STs. Conclusion There is a high diversity of E. coli isolated from patients admitted to a tertiary care hospital in Tanzania. This underscores the necessity to routinely screen all bacterial isolates of clinical importance in tertiary health care facilities. WGS use for laboratory-based surveillance can be an effective early warning system for emerging pathogens and resistance mechanisms in LMICs

Exceptionally Preserved Cambrian Trilobite Digestive System Revealed in 3D by Synchrotron-Radiation X-Ray Tomographic Microscopy

The Cambrian ‘Orsten’ fauna comprises exceptionally preserved and phosphatised microscopic arthropods. The external morphology of these fossils is well known, but their internal soft-tissue anatomy has remained virtually unknown. Here, we report the first non-biomineralised tissues from a juvenile polymerid trilobite, represented by digestive structures, glands, and connective strands harboured in a hypostome from the Swedish ‘Orsten’ fauna. Synchrotron-radiation X-ray tomographic microscopy enabled three-dimensional internal recordings at sub-micrometre resolution. The specimen provides the first unambiguous evidence for a J-shaped anterior gut and the presence of a crop with a constricted alimentary tract in the Trilobita. Moreover, the gut is Y-shaped in cross section, probably due to a collapsed lumen of that shape, another feature which has not previously been observed in trilobites. The combination of anatomical features suggests that the trilobite hypostome is functionally analogous to the labrum of euarthropods and that it was a sophisticated element closely integrated with the digestive system. This study also briefly addresses the preservational bias of the ‘Orsten’ fauna, particularly the near-absence of polymerid trilobites, and the taphonomy of the soft-tissue-harbouring hypostome