Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations

Molecular genetic assays for the detection of the JAK2 V617F (c.1849G>T) and other pathogenetic mutations within JAK2 exon 12 and MPL exon 10 are part of the routine diagnostic workup for patients presenting with erythrocytosis, thrombocytosis or otherwise suspected to have a myeloproliferative neoplasm. A wide choice of techniques are available for the detection of these mutations, leading to potential difficulties for clinical laboratories in deciding upon the most appropriate assay, which can lead to problems with inter-laboratory standardization. Here, we discuss the most important issues for a clinical diagnostic laboratory in choosing a technique, particularly for detection of the JAK2 V617F mutation at diagnosis. The JAK2 V617F detection assay should be both specific and sensitive enough to detect a mutant allele burden as low as 13%. Indeed, the use of sensitive assays increases the detection rate of the JAK2 V617F mutation within myeloproliferative neoplasms. Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2 V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays. Molecular results should be considered in the context of clinical findings and other haematological or laboratory results.

Group Trauma-Focused Cognitive-Behavioural Therapy with Former Child Soldiers and other War-affected Boys in the DR Congo: A Randomised Controlled Trial.

Background: The Democratic Republic of Congo (DRC) has been home to the world’s deadliest con?ict since World War II and is reported to have the largest number of child soldiers in the world. Despite evidence of the debilitating impact of war, no group-based mental health or psychosocial intervention has been evaluated in a randomised controlled trial for psychologically distressed former child soldiers.

Method: A randomised controlled trial involving 50 boys, aged 13–17, including former child soldiers (n = 39) and other war-affected boys (n = 11). They were randomly assigned to an intervention group, or wait-list control group. The intervention group received a 15-session, group-based, culturally adapted Trauma-Focused Cognitive–Behavioural Therapy (TF-CBT) intervention. Assessment interviews were completed at baseline, postintervention and 3-month follow-up (intervention group).

Results: Analysis of Covariance (ANCOVA) demonstrated that, in comparison to the wait-list control group, the TF-CBT intervention group had highly signi?cant reductions in posttraumatic stress symptoms, overall psychosocial distress, depression or anxiety-like symptoms, conduct problems and a signi?cant increase in prosocial behaviour (p < .001 for all). Effect sizes were higher when former child soldier scores were separated for sub-analysis. Three-month follow-up of the intervention group found that treatment gains were maintained.

Conclusions: A culturally modi?ed, group-based TF-CBT intervention was effective in reducing posttraumatic stress and psychosocial distress in former child soldiers and other war-affected boys.

Multiple Regulatory Pathways Associated with High-Level Ciprofloxacin and Multidrug Resistance in Salmonella enterica Serovar Enteritidis: Involvement of ramA and Other Global Regulators

Mechanisms of antibiotic resistance were examined in nalidixic acid-resistant Salmonella enterica serovar Enteritidis field isolates displaying decreased susceptibility to ciprofloxacin and in in vitro-derived ciprofloxacin-resistant mutants (104-cip and 5408-cip). All field isolates harbored a single gyrA mutation (D87Y). Deletion of acrB and complementation with wild-type gyrA increased quinolone susceptibility. Selection for ciprofloxacin resistance was associated with the development of an additional gyrA (S83F) mutation in 104-cip, novel gyrB (E466D) and parE (V461G) mutations in 5408-cip, overexpression of acrB and decreased susceptibility to nonquinolone antibiotics in both mutants, and decreased OmpF production and altered lipopoly- saccharide in 104-cip. Complementation of mutated gyrA and gyrB with wild-type alleles restored susceptibility to quinolones in 104-cip and significantly decreased the ciprofloxacin MIC in 5408-cip. Complementation of parE had no effect on quinolone MICs. Deletion of acrB restored susceptibility to ciprofloxacin and other antibiotics tested. Both soxS and marA were overexpressed in 104-cip, and ramA was overexpressed in 5408-cip. Inactivation of each of these global regulators lowered ciprofloxacin MICs, decreased expression of acrB, and restored susceptibility to other antibiotics. Mutations were found in soxR (R20H) and in soxS (E52K) in 104-cip and in ramR (G25A) in 5408-cip. In conclusion, both efflux activity and a single gyrA mutation contribute to nalidixic acid resistance and reduced ciprofloxacin sensitivity. Ciprofloxacin resistance and decreased susceptibility to multiple antibiotics can result from different genetic events leading to development of target gene mutations, increased efflux activity resulting from differential expression of global regulators associated with mutations in their regulatory genes, and possible altered membrane permeability.

Water Content Determinations for Peat and Other Organic Soils Using the Oven-Drying Method

There has been much debate in the literature over the past 60 years regarding an appropriate oven-drying temperature for water content determinations in peat and other organic soils. For inorganic soils, the water content is usually based on the equilibrium dry mass corresponding to drying temperatures in the range 100-110°C. However, for peat and other organic soils, several researchers have recommended lower drying temperatures in the range 60-90°C in an attempt to prevent possible charring, oxidation, and/or vaporization of substances other than pore water. However, all of the relevant water is not fully evaporated at too low a temperature, and because specimen dry mass is a function of drying temperature, the resulting water content values are lower than those determined for the temperature range 100-110°C. Experimental data reported in this article show that oven drying of peat and other organic soils at 100-110°C using either gravity-convection or forced-draft ovens is acceptable for routine water content determinations. Because a standardized oven temperature is desirable when correlating water content with other material properties, it is recommended that oven drying of peat and other organic soils be performed over temperature ranges of either 105-110°C or 105 ± 5°C, in line with standardized ranges for inorganic soils. © 2014 Copyright Taylor & Francis Group, LLC.

Total arsenic, inorganic arsenic, and other elements concentrations in Italian rice grain varies with origin and type

Rice is comparatively efficient at assimilating inorganic arsenic (As _i), a class-one, non-threshold carcinogen, into its grain, being the dominant source of this element to mankind. Here it was investigated how the total arsenic (As_t) and As_i content of Italian rice grain sourced from market outlets varied by geographical origin and type. Total Cr, Cd Se, Mg, K, Zn, Ni were also quantified. As_t concentration on a variety basis ranged from means of 0.18 mg kg^-1 to 0.28 mg kg ^-1, and from 0.11 mg kg^-1 to 0.28 mg kg^-1 by production region. For As_i concentration, means ranged from 0.08 mg kg^-1 to 0.11 mg kg^-1 by variety and 0.10 mg kg ^-1 to 0.06 mg kg^-1 by region. There was significant geographical variation for both As_t and As_i; total Se and Ni concentration; while the total concentration of Zn, Cr, Ni and K were strongly influenced by the type of rice.

Risk assessment of neonatal excipient exposure:Lessons from food safety and other areas

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: Development of a [3.3.0]-based series and other piperidine bioisosteres

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]​-​based series, e.g. I, displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was obsd., within this novel series and a no. of other piperidine bioisosteric cores.

Alcohol and the Risk of Barrett's Esophagus: A Pooled Analysis from the International BEACON Consortium

OBJECTIVES: Results from studies examining the association between alcohol consumption and the risk of Barrett's esophagus have been inconsistent. We assessed the risk of Barrett's esophagus associated with total and beverage-specific alcohol consumption by pooling individual participant data from five case–control studies participating in the international Barrett's and Esophageal Adenocarcinoma Consortium.
METHODS: For analysis, there were 1,282 population-based controls, 1,418 controls with gastroesophageal reflux disease (GERD), and 1,169 patients with Barrett's esophagus (cases). We estimated study-specific odds ratios (ORs) and 95% confidence intervals (95% CI) using multivariable logistic regression models adjusted for age, sex, body mass index (BMI), education, smoking status, and GERD symptoms. Summary risk estimates were obtained by random-effects models. We also examined potential effect modification by sex, BMI, GERD symptoms, and cigarette smoking.
RESULTS: For comparisons with population-based controls, although there was a borderline statistically significant inverse association between any alcohol consumption and the risk of Barrett's esophagus (any vs. none, summary OR=0.77, 95% CI=0.60–1.00), risk did not decrease in a dose-response manner (Ptrend=0.72). Among alcohol types, wine was associated with a moderately reduced risk of Barrett's esophagus (any vs. none, OR=0.71, 95% CI=0.52–0.98); however, there was no consistent dose–response relationship (Ptrend=0.21). We found no association with alcohol consumption when cases were compared with GERD controls. Similar associations were observed across all strata of BMI, GERD symptoms, and cigarette smoking.
CONCLUSIONS: Consistent with findings for esophageal adenocarcinoma, we found no evidence that alcohol consumption increases the risk of Barrett's esophagus.

Why are you tall while others are short? Agricultural production and other proximate determinants of global heights

We analyze the proximate determinants of the biological standard of living from a global perspective, namely high-quality nutrition and the disease environment during the nineteenth and twentieth centuries. Until the mid-twentieth century, the local availability of cattle, meat, and milk per capita and the local disease environment mainly determined the stature of the population – and, by implication, how long they lived and how healthy they were. During the late twentieth century, the trade of agricultural products and health-promoting technologies increased in relative importance; hence, the local availabilities became less decisive in explaining height differences.

A review of patents relating to therapeutic angiogenesis using endothelial progenitors and other vasculogenesis-related cell types

Stem and progenitor cells have generated considerable scientific and commercial interest in recent years due to their potential for novel cell therapy for a variety of medical conditions. A highly active research area in the field of regenerative medicine is vascular biology. Blood vessel repair and angiogenesis are key processes with endothelial progenitor cells (EPCs) playing a central role. Clinical trials for ischemic conditions, such as myocardial infarction and peripheral arterial disease, have suggested cell therapies to be feasible, safe, and potentially beneficial. Development of efficient methodologies to deliver EPC-based cytotherapies offers new hope for millions of patients with ischemic conditions. Evidence indicates that EPCs, depending on the subtype, mediate angiogenesis through different mechanisms. Differentiation into endothelium and complete integration into damaged vasculature was the first EPC mechanism to be proposed. However, many studies have demonstrated that vasoregulatory paracrine factor secretion by transplanted cells is also important. Many EPC subsets enhance angiogenesis and promote tissue repair by cytokine release without incorporating into the damaged vasculature. Whatever the mechanism, vascular repair and therapeutic angiogenesis using EPCs represent a realistic treatment option and also provides many commercialization opportunities. This review discusses recent advances in the EPC field whilst recounting relevant patents.