Biomarkers of vitamin B-12 status in NHANES: a roundtable summary123456

A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B-12–related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES—serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy)—and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. The roundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12–related biomarkers. They agreed that problems with sensitivity and specificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA

Biomarkers of folate status in NHANES: a roundtable summary123456

A roundtable to discuss the measurement of folate status biomarkers in NHANES took place in July 2010. NHANES has measured serum folate since 1974 and red blood cell (RBC) folate since 1978 with the use of several different measurement procedures. Data on serum 5-methyltetrahydrofolate (5MTHF) and folic acid (FA) concentrations in persons aged ≥60 y are available in NHANES 1999–2002. The roundtable reviewed data that showed that folate concentrations from the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA; used in NHANES 1991–1994 and NHANES 1999–2006) were, on average, 29% lower for serum and 45% lower for RBC than were those from the microbiological assay (MA), which was used in NHANES 2007–2010. Roundtable experts agreed that these differences required a data adjustment for time-trend analyses. The roundtable reviewed the possible use of an isotope-dilution liquid chromatography–tandem mass spectrometry (LC-MS/MS) measurement procedure for future NHANES and agreed that the close agreement between the MA and LC-MS/MS results for serum folate supported conversion to the LC-MS/MS procedure. However, for RBC folate, the MA gave 25% higher concentrations than did the LC-MS/MS procedure. The roundtable agreed that the use of the LC-MS/MS procedure to measure RBC folate is premature at this time. The roundtable reviewed the reference materials available or under development at the National Institute of Standards and Technology and recognized the challenges related to, and the scientific need for, these materials. They noted the need for a commutability study for the available reference materials for serum 5MTHF and FA

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial

Purpose: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Methods: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. Results: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P < 0.01) versus TPC; median OS was 10.0 and 4.8 months, respectively. Improvement in OS was observed in both poorer and better GPA prognostic groups. Survival rates at 12 months were 44.4% for EP versus 19.4% for TPC. Consistent with the overall BEACON population, fewer patients on EP experienced grade ≥3 toxicity (50 vs. 70%). Conclusions: The significant improvement in survival in BCBM patients provides encouraging data for EP in this difficult-to-treat subgroup of patients. A phase three trial of EP in BCBM patients is underway (ClinicalTrials.gov NCT02915744)

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Vascularity and VEGF/VEGFR2 signaling in the dentine-pulp complex of immature and mature permanent teeth

To examine the microvessel density (MVD) and spatial distribution of endothelial cells and angiogenic activity in immature and mature permanent teeth using immunohistochemistry.Healthy third molars with immature and mature root development were formalin-fixed, decalcified in 10% ethylenediaminetetraacetic acid, and processed for routine immunohistochemistry with endothelial cell markers anti-CD34 and anti-CD146 and angiogenic markers anti-vascular endothelial growth factor (VEGF) and anti-VEGF receptor-2 (VEGFR2). Staining was visualized with diaminobenzidine and examined using light microscopy. The distribution of markers was analyzed qualitatively and quantitatively in the coronal, middle, and apical regions of the dentine-pulp complex.There were spatial differences in protein expression for immature and mature teeth. The pulps of immature teeth were more vascular, had a greater number of CD34+ and CD146+ cells, and a significantly higher MVD in the coronal region than those of mature teeth (P=0.03). The apical papilla contained few blood vessels. VEGF/VEGFR2 activity was significantly greater for immature teeth (P=0.001). VEGF was expressed throughout the pulp-dentine complex, but there was significantly more growth factor coronally (immature P=0.04 and mature P=0.02). VEGFR2 was expressed less than VEGF but was seen on the endothelial cells and single cells unrelated to a vessel lumen.The spatial distribution of vascular and angiogenic (VEGF/VEGFR2) markers indicates the potential for altered healing responses in the pulps of immature and mature teeth. Immature teeth have a greater MVD and VEGF/VEGFR2 expression than mature teeth, and the increased expression of these markers in the coronal region of both tooth types is important for pulp healing

Effect of a 12-Week Almond-Enriched Diet on Biomarkers of Cognitive Performance, Mood, and Cardiometabolic Health in Older Overweight Adults

Long term nut consumption is associated with reduced risk of coronary heart disease and better cognitive function. This study examined supplementing habitual diets with almonds or carbohydrate-rich snack foods (providing 15% energy) on biomarkers of cardiovascular and metabolic health, mood and cognitive performance. Participants (overweight/obese, 50&ndash;80 years) were randomised to an almond-enriched diet (AED) or isocaloric nut-free diet (NFD) for 12 weeks. Body weight, blood lipids, glucose, insulin, blood pressure (BP), arterial stiffness, cell adhesions molecules, C reactive protein (CRP), mood, and cognitive performance (working memory primary outcome), dietary profiles and energy intake/expenditure were measured at baseline and Week 12 in 128 participants (n = 63 AED, n = 65 NFD). Compared with NFD, AED was associated with altered macro and micronutrient profiles, but no differences in energy intake or expenditure. The AED significantly reduced triglycerides and SBP but there were no other changes in cardiometabolic biomarkers, mood, or cognitive performance. The inclusion of almonds in the diet improves aspects of cardiometabolic health without affecting cognitive performance or mood in overweight/obese adults

Comparison of two low-fat diets, differing in protein and carbohydrate, on psychological wellbeing in adults with obesity and type 2 diabetes: a randomised clinical trial

Abstract Background Although higher-protein diets (HP) can assist with weight loss and glycemic control, their effect on psychological wellbeing has not been established. The objective of this study was to compare the effects of a HP and a higher-carbohydrate diet (HC), combined with regular exercise, on psychological wellbeing both during weight loss (WL) and weight maintenance phases (WM). Methods In a parallel RCT, 61 adults with T2D (mean ± SD: BMI 34.3 ± 5.1 kg/m2, aged 55 ± 8 years) consumed a HP diet (29% protein, 34% carbohydrate, 31% fat) or an isocaloric HC diet (21%:48%:24%), with moderate intensity exercise, for 12 weeks of WL and 12 weeks of WM. Secondary data evaluating psychological wellbeing was assessed using: Problems Areas in Diabetes (PAID); Diabetes-39 Quality of Life (D-39); Short Form Health Survey (SF-36); Perceived Stress Scale-10 (PSS-10) and the Leeds Sleep Evaluation Questionnaire (LSEQ) at Weeks 0, 12 and 24 and evaluated with mixed models analysis. Results Independent of diet, improvements for PAID; D-39 diabetes control; D-39 severity of diabetes; SF-36 physical functioning and SF-36 general health were found following WL (d = 0.30 to 0.69, P ≤ 0.04 for all) which remained after 12 weeks of WM. SF-36 vitality improved more in the HP group (group x time interaction P = 0.03). Associations were seen between HbA1c and D-39 severity of diabetes rating (r = 0.30, P = 0.01) and SF-36 mental health (r = − 0.32, P = 0.003) and between weight loss and PAID (r = 0.30, P = 0.01). Conclusion Several improvements in diabetes-related and general psychological wellbeing were seen similarly for both diets following weight loss and a reduction in HbA1c with most of these improvements remaining when weight loss was sustained for 12 weeks. A HP diet may provide additional increases in vitality. Trial registration The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12613000008729) on 4 January 2013