BRCA1 and BRCA2 mutations in a population-based study of male breast cancer

Background: The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear. Methods: We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk. Results: Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives. Conclusion: These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found

Factors predicting pain and early discontinuation of tumour necrosis factor-α-inhibitors in people with rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Register

Background: We examined pain levels in 2 cohorts assembled from the British Society for Rheumatology Biologics Register (BSRBR), and investigated which factors predicted Bodily Pain scores and discontinuation of TNFα-inhibitors. Method: Data were retrieved from BSRBR-RA databases for up to 1 year after commencing TNFα-inhibitors (n=11995) or being treated with non-biologic therapies (n=3632). Bodily Pain scores were derived from the Short Form-36 (SF36) questionnaire and norm-transformed to allow comparison with UK population averages. Discontinuation data were from physician reports. Other data, including 28-joint disease activity score (DAS28) measurements, were from clinical examination, interview, medical records and self-report questionnaires. DAS28-P was derived as the proportion of DAS28 attributed to patient-reported factors (tender joint count and visual analogue score). Missing baseline variables from both cohorts were imputed into 20 replicate datasets. Odds ratios (OR) and adjusted OR were calculated for higher than median pain within each cohort. Results: Participants reported moderate to severe pain at baseline, and pain scores remained >1SD worse than normal population standards at 1 year, even when disease activity responded to treatment. Baseline pain was associated with DAS28-P, worse physical function, worse mental health, and DAS28. After logistic regression, independent predictors of higher than median pain at follow up were baseline Bodily Pain score, higher DAS28-P, worse physical function or mental health and co-morbidities. Higher age, male gender, and higher BMI were additional independent predictors of higher pain in participants who received TNFα-inhibitors. Baseline pain was also one of the predictors of discontinuation of the first TNFα-inhibitor within 1 year, as were female gender, current smoking, co-morbidities, extra-articular manifestations and worse function. Conclusion: Pain persists in people with treated RA, even in those for whom inflammation responds to treatment. Worse pain outcomes are predicted by factors different to those typically found to predict inflammatory disease activity in other studies. Worse pain at baseline also predicts discontinuation of TNFα-inhibitors. Improved pain management should complement inflammatory disease suppression in RA

Amino Acid Requirements in Critically Ill Patients with Acute Kidney Injury Treated with Continuous Renal Replacement Therapy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90284/1/phco.28.5.600.pd

Comparison of PfHRP-2/pLDH ELISA, qPCR and microscopy for the detection of Plasmodium events and prediction of sick visits during a malaria vaccine study.

BACKGROUND: Compared to expert malaria microscopy, malaria biomarkers such as Plasmodium falciparum histidine rich protein-2 (PfHRP-2), and PCR provide superior analytical sensitivity and specificity for quantifying malaria parasites infections. This study reports on parasite prevalence, sick visits parasite density and species composition by different diagnostic methods during a phase-I malaria vaccine trial. METHODS: Blood samples for microscopy, PfHRP-2 and Plasmodium lactate dehydrogenase (pLDH) ELISAs and real time quantitative PCR (qPCR) were collected during scheduled (n = 298) or sick visits (n = 38) from 30 adults participating in a 112-day vaccine trial. The four methods were used to assess parasite prevalence, as well as parasite density over a 42-day period for patients with clinical episodes. RESULTS: During scheduled visits, qPCR (39.9%, N = 119) and PfHRP-2 ELISA (36.9%, N = 110) detected higher parasite prevalence than pLDH ELISA (16.8%, N = 50) and all methods were more sensitive than microscopy (13.4%, N = 40). All microscopically detected infections contained P. falciparum, as mono-infections (95%) or with P. malariae (5%). By qPCR, 102/119 infections were speciated. P. falciparum predominated either as monoinfections (71.6%), with P. malariae (8.8%), P. ovale (4.9%) or both (3.9%). P. malariae (6.9%) and P. ovale (1.0%) also occurred as co-infections (2.9%). As expected, higher prevalences were detected during sick visits, with prevalences of 65.8% (qPCR), 60.5% (PfHRP-2 ELISA), 21.1% (pLDH ELISA) and 31.6% (microscopy). PfHRP-2 showed biomass build-up that climaxed (1813±3410 ng/mL SD) at clinical episodes. CONCLUSION: PfHRP-2 ELISA and qPCR may be needed for accurately quantifying the malaria parasite burden. In addition, qPCR improves parasite speciation, whilst PfHRP-2 ELISA is a potential predictor for clinical disease caused by P. falciparum. TRIAL REGISTRATION: ClinicalTrials.gov NCT00666380

An intervention program with the aim to improve and maintain work productivity for workers with rheumatoid arthritis: design of a randomized controlled trial and cost-effectiveness study

<p>Abstract</p> <p>Background</p> <p>Workers with rheumatoid arthritis (RA) often experience restrictions in functioning at work and participation in employment. Strategies to maintain work productivity exist, but these interventions do not involve the actual workplace. Therefore the aim of this study is to investigate the (cost)effectiveness of an intervention program at the workplace on work productivity for workers with RA.</p> <p>Methods/design</p> <p>This study is a randomized controlled trial (RCT) in specialized rheumatology treatment centers in or near Amsterdam, the Netherlands. Randomisation to either the control or the intervention group is performed at patient level. Both groups will receive care as usual by the rheumatologist, and patients in the intervention group will also take part in the intervention program. The intervention program consists of two components; integrated care, including a participatory workplace intervention. Integrated care involves a clinical occupational physician, who will act as care manager, to coordinate the care. The care manager has an intermediate role between clinical and occupational care. The participatory workplace intervention will be guided by an occupational therapist, and involves problem solving by the patient and the patients’ supervisor. The aim of the workplace intervention is to achieve consensus between patient and supervisor concerning feasible solutions for the obstacles for functioning at work. Data collection will take place at baseline and after 6 and 12 months by means of a questionnaire. The primary outcome measure is work productivity, measured by hours lost from work due to presenteeism. Secondary outcome measures include sick leave, quality of life, pain and fatigue. Cost-effectiveness of the intervention program will be evaluated from the societal perspective.</p> <p>Discussion</p> <p>Usual care of primary and outpatient health services is not aimed at improving work productivity. Therefore it is desirable to develop interventions aimed at improving functioning at work. If the intervention program will be (cost)effective, substantial improvements in work productivity might be obtained among workers with RA at lower costs. Results are expected in 2015.</p> <p>Trial registration number</p> <p>NTR2886</p

A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors

Host proteins are essential for HIV entry and replication and can be important nonviral therapeutic targets. Large-scale RNA interference (RNAi)-based screens have identified nearly a thousand candidate host factors, but there is little agreement among studies and few factors have been validated. Here we demonstrate that a genome-wide CRISPR-based screen identifies host factors in a physiologically relevant cell system. We identify five factors, including the HIV co-receptors CD4 and CCR5, that are required for HIV infection yet are dispensable for cellular proliferation and viability. Tyrosylprotein sulfotransferase 2 (TPST2) and solute carrier family 35 member B2 (SLC35B2) function in a common pathway to sulfate CCR5 on extracellular tyrosine residues, facilitating CCR5 recognition by the HIV envelope. Activated leukocyte cell adhesion molecule (ALCAM) mediates cell aggregation, which is required for cell-to-cell HIV transmission. We validated these pathways in primary human CD4 + T cells through Cas9-mediated knockout and antibody blockade. Our findings indicate that HIV infection and replication rely on a limited set of host-dispensable genes and suggest that these pathways can be studied for therapeutic intervention

Genome analysis and physiological comparison of Alicycliphilus denitrificans strains BC and K601T

The genomes of the Betaproteobacteria Alicycliphilus denitrificans strains BC and K601T have been sequenced to get insight into the physiology of the two strains. Strain BC degrades benzene with chlorate as electron acceptor. The cyclohexanol-degrading denitrifying strain K601T is not able to use chlorate as electron acceptor, while strain BC cannot degrade cyclohexanol. The 16S rRNA sequences of strains BC and K601T are identical and the fatty acid methyl ester patterns of the strains are similar. Basic Local Alignment Search Tool (BLAST) analysis of predicted open reading frames of both strains showed most hits with Acidovorax sp. JS42, a bacterium that degrades nitro-aromatics. The genomes include strain-specific plasmids (pAlide201 in strain K601T and pAlide01 and pAlide02 in strain BC). Key genes of chlorate reduction in strain BC were located on a 120 kb megaplasmid (pAlide01), which was absent in strain K601T. Genes involved in cyclohexanol degradation were only found in strain K601T. Benzene and toluene are degraded via oxygenase-mediated pathways in both strains. Genes involved in the meta-cleavage pathway of catechol are present in the genomes of both strains. Strain BC also contains all genes of the ortho-cleavage pathway. The large number of mono- and dioxygenase genes in the genomes suggests that the two strains have a broader substrate range than known thus far.This research was supported by the Technology Foundation, the Applied Science Division (STW) of the Netherlands Organization for Scientific Research (NWO), project number 08053, the graduate school WIMEK (Wageningen Institute for Environment and Climate Research, which is part of SENSE Research School for Socio-Economic and Natural Sciences of the Environment, www.wimek-new.wur.nl and www.sense.nl), SKB (Dutch Centre for Soil Quality Management and Knowledge Transfer, www.skbodem.nl) and the Consolider project CSD-2007-00055. The research was incorporated in the TRIAS (TRIpartite Approaches 469 toward Soil systems processes) program (http://www.nwo.nl/en/research-and-results/programmes/alw/trias-tripartite-approach-to-soil-system-processes/index. html). Flávia Talarico Saia was supported by a FAPESP (the State of São Paulo Research Foundation) scholarship (2006-01997/5). The work conducted by the DOE JGI is supported by the Office of Science of the United States Department of Energy under contract number DE-AC02-05CH11231. Alfons Stams acknowledges support by an ERC (European Research Counsil) advanced grant (project 323009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The role of anti-malarial drugs in eliminating malaria

Abstract Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia and transmissibility coincides with peak asexual parasite densities. Mature Plasmodium falciparum gametocytes are more drug resistant and affected only by artemisinins and 8-aminoquinolines. The key operational question now is whether primaquine should be added to artemisinin combination treatments for the treatment of falciparum malaria to reduce further the transmissibility of the treated infection. Radical treatment with primaquine plays a key role in the eradication of vivax and ovale malaria. More evidence is needed on the safety of primaquine when administered without screening for G6PD deficiency to inform individual and mass treatment approaches in the context of malaria elimination programmes.</p

Unraveling infectious structures, strain variants and species barriers for the yeast prion [PSI+]

Prions are proteins that can access multiple conformations, at least one of which is beta-sheet rich, infectious and self-perpetuating in nature. These infectious proteins show several remarkable biological activities, including the ability to form multiple infectious prion conformations, also known as strains or variants, encoding unique biological phenotypes, and to establish and overcome prion species (transmission) barriers. In this Perspective, we highlight recent studies of the yeast prion [PSI+], using various biochemical and structural methods, that have begun to illuminate the molecular mechanisms by which self-perpetuating prions encipher such biological activities. We also discuss several aspects of prion conformational change and structure that remain either unknown or controversial, and we propose approaches to accelerate the understanding of these enigmatic, infectious conformers