Localization of the gene for X-linked recessive type of retinitis pigmentosa (XLRP) to Xp21 by linkage analysis

The X-linked recessive type of retinitis pigmentosa (XLRP) causes progressive night blindness, visual field constriction, and eventual blindness in affected males by the third or fourth decade of life. The biochemical basis of the disease is unknown, and prenatal diagnosis and definitive carrier diagnosis remain elusive. Heterogeneity in XLRP has been suggested by linkage studies of families affected with XLRP and by phenotypic differences observed in female carriers. Localization of XLRP near Xp11.3 has been suggested by close linkage to an RFLP at the locus DXS7 (Xp11.3) detected by probe L1.28. In other studies a locus for XLRP with metallic sheen has been linked to the ornithine transcarbamylase (OTC) locus mapping to the Xp21 region. In this study, by linkage analysis using seven RFLP markers between Xp21 and Xcen, we examined four families with multiple affected individuals. Close linkage was found between XLRP and polymorphic sites OTC (θ = .06 with lod 5.69), DXS84 (θ = .05 with lod 4.08), and DXS206 (θ = .06 with lod 2.56), defined by probes OTC, 754, and XJ, respectively. The close linkage of OTC, 754, and XJ to XLRP localizes the XLRP locus to the Xp21 region. Data from recombinations in three of four families place the locus above L1.28 and below the Duchenne muscular dystrophy (DMD) gene, consistent with an Xp21 localization. In one family, however, one affected male revealed a crossover between XLRP and all DNA markers, except for the more distal DXS28 (C7), while his brother is recombined for this marker (C7) and not other, more proximal markers. This suggests that in this family the XLRP mutation maps near DXS28 and above the DMD locus.published_or_final_versio

Case-based review and olinical guidance on the use of genomic assays for early-stage breast cancer: Breast Cancer Therapy Expert Group (BCTEG)

In addition to classical clinicopathologic factors, such as hormone receptor positivity, human epidermal growth factor receptor 2 (HER2) status, and tumor size, grade, and lymph node status, a number of commercially available genomic tests may be used to help inform treatment decisions for early breast cancer patients. Although these tests improve our understanding of breast cancer and help to individualize treatment decisions, clinicians face challenges when deciding on the most appropriate test to order, and the advantages, if any, of one test over another. The Breast Cancer Therapy Expert Group (BCTEG) recently convened a roundtable meeting to discuss issues surrounding the use of genomic testing in early breast cancer, with the goal of providing practical guidance on the use of these tests by the community oncologist, for whom breast cancer may be only one of many tumor types they treat. The group recognizes that genomic testing can provide important prognostic (eg, risk for recurrence), and in some cases predictive, information (eg, benefit of chemotherapy, or extended adjuvant endocrine therapy), which can be used to help guide treatment decisions in breast cancer. The available tests differ in the types of information they provide, and in the patient populations and clinical trials that were conducted to validate them. We summarize the discussion of the BCTEG on this topic, and we also consider several patient cases and clinical scenarios in which genomic testing may, or may not, be useful to guide treatment decisions for the practicing community oncologist

Heterozygosity increases microsatellite mutation rate, linking it to demographic history

<p>Abstract</p> <p>Background</p> <p>Biochemical experiments in yeast suggest a possible mechanism that would cause heterozygous sites to mutate faster than equivalent homozygous sites. If such a process operates, it could undermine a key assumption at the core of population genetic theory, namely that mutation rate and population size are indpendent, because population expansion would increase heterozygosity that in turn would increase mutation rate. Here we test this hypothesis using both direct counting of microsatellite mutations in human pedigrees and an analysis of the relationship between microsatellite length and patterns of demographically-induced variation in heterozygosity.</p> <p>Results</p> <p>We find that microsatellite alleles of any given length are more likely to mutate when their homologue is unusually different in length. Furthermore, microsatellite lengths in human populations do not vary randomly, but instead exhibit highly predictable trends with both distance from Africa, a surrogate measure of genome-wide heterozygosity, and modern population size. This predictability remains even after statistically controlling for non-independence due to shared ancestry among populations.</p> <p>Conclusion</p> <p>Our results reveal patterns that are unexpected under classical population genetic theory, where no mechanism exists capable of linking allele length to extrinsic variables such as geography or population size. However, the predictability of microsatellite length is consistent with heterozygote instability and suggest that this has an important impact on microsatellite evolution. Whether similar processes impact on single nucleotide polymorphisms remains unclear.</p

Open-label randomised pragmatic trial (CONTACT) comparing naproxen and low-dose colchicine for the treatment of gout flares in primary care

OBJECTIVES: To compare the effectiveness and safety of naproxen and low-dose colchicine for treating gout flares in primary care. METHODS: This was a multicentre open-label randomised trial. Adults with a gout flare recruited from 100 general practices were randomised equally to naproxen 750 mg immediately then 250 mg every 8 hours for 7 days or low-dose colchicine 500 mcg three times per day for 4 days. The primary outcome was change in worst pain intensity in the last 24 hours (0-10 Numeric Rating Scale) from baseline measured daily over the first 7 days: mean change from baseline was compared between groups over days 1-7 by intention to treat. RESULTS: Between 29 January 2014 and 31 December 2015, we recruited 399 participants (naproxen n=200, colchicine n=199), of whom 349 (87.5%) completed primary outcome data at day 7. There was no significant between-group difference in average pain-change scores over days 1-7 (colchicine vs naproxen: mean difference -0.18; 95% CI -0.53 to 0.17; p=0.32). During days 1-7, diarrhoea (45.9% vs 20.0%; OR 3.31; 2.01 to 5.44) and headache (20.5% vs 10.7%; 1.92; 1.03 to 3.55) were more common in the colchicine group than the naproxen group but constipation was less common (4.8% vs 19.3%; 0.24; 0.11 to 0.54). CONCLUSION: We found no difference in pain intensity over 7 days between people with a gout flare randomised to either naproxen or low-dose colchicine. Naproxen caused fewer side effects supporting naproxen as first-line treatment for gout flares in primary care in the absence of contraindications. TRIAL REGISTRATION NUMBER: ISRCTN (69836939), clinicaltrials.gov (NCT01994226), EudraCT (2013-001354-95)

Widespread Gene Conversion in Centromere Cores

Data from maize show that centromeres strongly suppress crossing over and instead undergo frequent genetic exchange in the form of gene conversion

What Lies behind the Wish to Hasten Death? A Systematic Review and Meta-Ethnography from the Perspective of Patients

BACKGROUND: There is a need for an in-depth approach to the meaning of the wish to hasten death (WTHD). This study aims to understand the experience of patients with serious or incurable illness who express such a wish. METHODS AND FINDINGS: Systematic review and meta-ethnography of qualitative studies from the patient's perspective. Studies were identified through six databases (ISI, PubMed, PsycINFO, CINAHL, CUIDEN and the Cochrane Register of Controlled Trials), together with citation searches and consultation with experts. Finally, seven studies reporting the experiences of 155 patients were included. The seven-stage Noblit and Hare approach was applied, using reciprocal translation and line-of-argument synthesis. Six main themes emerged giving meaning to the WTHD: WTHD in response to physical/psychological/spiritual suffering, loss of self, fear of dying, the desire to live but not in this way, WTHD as a way of ending suffering, and WTHD as a kind of control over one's life ('having an ace up one's sleeve just in case'). An explanatory model was developed which showed the WTHD to be a reactive phenomenon: a response to multidimensional suffering, rather than only one aspect of the despair that may accompany this suffering. According to this model the factors that lead to the emergence of WTHD are total suffering, loss of self and fear, which together produce an overwhelming emotional distress that generates the WTHD as a way out, i.e. to cease living in this way and to put an end to suffering while maintaining some control over the situation. CONCLUSIONS: The expression of the WTHD in these patients is a response to overwhelming emotional distress and has different meanings, which do not necessarily imply a genuine wish to hasten one's death. These meanings, which have a causal relationship to the phenomenon, should be taken into account when drawing up care plans

ZFP36L1 Negatively Regulates Erythroid Differentiation of CD34+ Hematopoietic Stem Cells by Interfering with the Stat5b Pathway

ZFP36L1 negatively regulates erythroid differentiation of human hematopoietic progenitors by directly binding the 3′ UTR of Stat5b mRNA, thereby triggering its degradation. This study shows that posttranscriptional regulation is involved in the control of hematopoietic differentiation

How do pharmacists in English general practices identify their impact? An exploratory qualitative study of measurement problems

Background: In England, there is an ongoing national pilot to expand pharmacists’ presence in general practice. Evaluation of the pilot includes numerical and survey-based Key Performance Indicators (KPIs) and requires pharmacists to electronically record their activities, possibly by using activity codes. At the time of the study (2016), no national evaluation of pharmacists’ impact in this environment had been formally announced. The aim of this qualitative study was to identify problems that English pharmacists face when measuring and recording their impact in general practice. Methods: All pharmacists, general practitioners (GPs) and practice managers working across two West London pilot sites were invited, via e-mail, to participate in a focus group study. Appropriately trained facilitators conducted two audio-recorded, semi-structured focus groups, each lasting approximately one hour, to explore experiences and perceptions associated with the KPIs. Audio-recordings were transcribed verbatim and the data analysed thematically. Results: In total, 13 pharmacists, one GP and one practice manager took part in the study. Four major themes were discerned: inappropriateness of the numerical national KPIs (“whether or not we actually have positive impact on KPIs is beyond our control”); depth and breadth of pharmacists’ activity (“we see a huge plethora of different patients and go through this holistic approach - everything is looked at”); awareness of practice based pharmacists’ roles (“I think the really important [thing] is that everyone knows what pharmacists in general practice are doing”); and central evaluation versus local initiatives (“the KPIs will be measured by National Health Service England regardless of what we think” versus “what I think is more pertinent, are there some local things we’re going to measure?”). Conclusions: Measures that will effectively capture pharmacists’ impact in general practice should be developed, along with a set of codes reflecting the whole spectrum of pharmacists’ activities. Our study also points out the significance of a transparent, robust national evaluation, including exploring the needs/expectations of practice staff and patients regarding pharmacists’ presence in general practice

Using population admixture to help complete maps of the human genome

Tens of millions of base pairs of euchromatic human genome sequence, including many protein-coding genes, have no known location in the human genome. We describe an approach for localizing the human genome's missing pieces by utilizing the patterns of genome sequence variation created by population admixture. We mapped the locations of 70 scaffolds spanning four million base pairs of the human genome's unplaced euchromatic sequence, including more than a dozen protein-coding genes, and identified eight large novel inter-chromosomal segmental duplications. We find that most of these sequences are hidden in the genome's heterochromatin, particularly its pericentromeric regions. Many cryptic, pericentromeric genes are expressed in RNA and have been maintained intact for millions of years while their expression patterns diverged from those of paralogous genes elsewhere in the genome. We describe how knowledge of the locations of these sequences can inform disease association and genome biology studies