Birt-Hogg-Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant predisposition to the development of follicular hamartomas (fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney ...neoplasms. Germline mutations in BHD are associated with the susceptibility for BHDS. We previously described 51 BHDS families with BHD germline mutations.
To characterise the BHD mutation spectrum, novel mutations and new clinical features of one previously reported and 50 new families with BHDS.
Direct bidirectional DNA sequencing was used to screen for mutations in the BHD gene, and insertion and deletion mutations were confirmed by subcloning. We analysed evolutionary conservation of folliculin by comparing human against the orthologous sequences.
The BHD mutation detection rate was 88% (51/58). Of the 23 different germline mutations identified, 13 were novel consisting of: four splice site, three deletions, two insertions, two nonsense, one deletion/insertion, and one missense mutation. We report the first germline missense mutation in BHD c.1978A>G (K508R) in a patient who presented with bilateral multifocal renal oncocytomas. This mutation occurs in a highly conserved amino acid in folliculin. 10% (5/51) of the families had individuals without histologically confirmed fibrofolliculomas. Of 44 families ascertained on the basis of skin lesions, 18 (41%) had kidney tumours. Patients with a germline BHD mutation and family history of kidney cancer had a statistically significantly increased probability of developing renal tumours compared to patients without a positive family history (p = 0.0032). Similarly, patients with a BHD germline mutation and family history of spontaneous pneumothorax had a significantly increased greater probability of having spontaneous pneumothorax than BHDS patients without a family history of spontaneous pneumothorax (p = 0.011). A comprehensive review of published reports of cases with BHD germline mutation is discussed.
BHDS is characterised by a spectrum of mutations, and clinical heterogeneity both among and within families.
Abstract Background Patients with atrial fibrillation receiving dialysis are at a high risk of ischemic stroke. The role of warfarin in mitigating this risk in patients with atrial fibrillation ...receiving dialysis is uncertain. Our objective was to examine the safety and efficacy of warfarin in patients who have atrial fibrillation and are receiving dialysis. Methods We used Medline, Embase, and the Cochrane Library to conduct a systematic review and meta-analysis of published and unpublished observational and interventional studies relating to the use of warfarin in patients with atrial fibrillation receiving dialysis, which provided data on the risk of stroke and/or bleeding outcomes relative to placebo or no anticoagulation therapy. A random effects model was used to calculate pooled adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for these outcomes. Results No randomized controlled trials met the criteria for inclusion. Fourteen observational studies (20,398 participants) were included in the analysis. The use of warfarin was not associated with ischemic stroke (14 studies; 20,398 participants, aHR 0.77, 95% CI 0.55 to 1.07), intracranial hemorrhage (hemorrhagic stroke) (4 studies; 15,726 participants, aHR 1.93, 95% CI 0.93-4.00), gastrointestinal bleeding (3 studies, 14,693 participants, aHR 1.19, 95% CI 0.8-1.76) or all-cause mortality (7 studies; 16,172 participants, aHR 0.89, 95% CI 0.72-1.11). Conclusion Observational studies suggest that warfarin was not associated with a clear benefit or harm among patients who have atrial fibrillation and are receiving dialysis. These estimates were limited by study heterogeneity including the inability to account for a number of important confounders such as the time in the therapeutic range. Given the high prevalence of atrial fibrillation, stroke, and bleeding complications in this population, well-designed clinical trials of warfarin and other anti-coagulants are urgently needed.
We explore star formation histories (SFHs) of galaxies based on the evolution of the star formation rate stellar mass relation (SFR-M). Using data from the FourStar Galaxy Evolution Survey (ZFOURGE) ...in combination with far-IR imaging from the Spitzer and Herschel observatories we measure the SFR-M relation at 0.5 < z <. Similar to recent works we find that the average infrared spectral energy distributions of galaxies are roughly consistent with a single infrared template across a broad range of redshifts and stellar masses, with evidence for only weak deviations. We find that these two estimates are in broad qualitative agreement, but that there is room for improvement at a more detailed level. At early times the SFHs suggest mass growth rates that are as much as 10 x higher than inferred from the SMF. However, at later times the SFHs under-predict the inferred evolution, as is expected in the case of additional growth due to mergers.
Finding massive galaxies that stopped forming stars in the early Universe presents an observational challenge because their rest-frame ultraviolet emission is negligible and they can only be reliably ...identified by extremely deep near-infrared surveys. These surveys have revealed the presence of massive, quiescent early-type galaxies appearing as early as redshift z ≈ 2, an epoch three billion years after the Big Bang. Their age and formation processes have now been explained by an improved generation of galaxy-formation models, in which they form rapidly at z ≈ 3-4, consistent with the typical masses and ages derived from their observations. Deeper surveys have reported evidence for populations of massive, quiescent galaxies at even higher redshifts and earlier times, using coarsely sampled photometry. However, these early, massive, quiescent galaxies are not predicted by the latest generation of theoretical models. Here we report the spectroscopic confirmation of one such galaxy at redshift z = 3.717, with a stellar mass of 1.7 × 10
solar masses. We derive its age to be nearly half the age of the Universe at this redshift and the absorption line spectrum shows no current star formation. These observations demonstrate that the galaxy must have formed the majority of its stars quickly, within the first billion years of cosmic history in a short, extreme starburst. This ancestral starburst appears similar to those being found by submillimetre-wavelength surveys. The early formation of such massive systems implies that our picture of early galaxy assembly requires substantial revision.
Summary Background Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In ...a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. Methods In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov , number NCT01495585. Findings Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were −0·73 log IU/mL in group 1 (95% CI 0·17–1·31; p=0·03) and −1·54 log IU/mL in group 2 (1·21–1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change ( r2 =0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days SE 0·24), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 SE 0·06 vs 0·739 0·05, p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Interpretation Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. Funding National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health , and Eiger Biopharmaceuticals Inc.
To estimate the incidence, size, and growth rate of geographic atrophy (GA) during 5 years of follow-up among participants in the Comparison of Age-Related Macular Degeneration Treatments Trials ...(CATT).
Cohort within a clinical trial.
Participants included in CATT.
A total of 1185 CATT participants were randomly assigned to ranibizumab or bevacizumab treatment and to 3 treatment regimens. Participants were released from protocol treatment at 2 years and examined at approximately 5 years (N = 647). Two masked graders assessed the presence and size of GA in digital color photographs (CPs) and fluorescein angiograms (FAs) taken at baseline and years 1, 2, and 5. Cox proportional hazard models were used to identify risk factors for incidence of GA. Annual change in the square root of the total area of GA was the measure of growth. Multivariate linear mixed models including baseline demographic, treatment, and ocular characteristics on CP/FA and optical coherence tomography (OCT) as candidate risk factors were used to estimate adjusted growth rates, standard errors (SEs), and 95% confidence intervals (CIs).
Geographic atrophy incidence and growth rate.
Among the 1011 participants who did not have GA at baseline and had follow-up images gradable for GA, the cumulative incidence was 12% at 1 year, 17% at 2 years, and 38% at 5 years. At baseline, older age, hypercholesterolemia, worse visual acuity, larger choroidal neovascularization (CNV) area, retinal angiomatous proliferation (RAP) lesion, GA in the fellow eye, and intraretinal fluid were associated with a higher risk of incident GA. Thicker subretinal tissue complex and presence of subretinal fluid were associated with less GA development. The overall GA growth rate was 0.33 mm/year (SE, 0.02 mm/year). Eyes treated with ranibizumab in the first 2 years of the clinical trial had a higher growth rate than eyes treated with bevacizumab (adjusted growth rate, 0.38 vs. 0.28 mm/year; P = 0.009). Geographic atrophy in the fellow eye, hemorrhage, and absence of sub-retinal pigment epithelium fluid at baseline were associated with a higher growth rate.
Development of GA is common 5 years after initiating therapy. Several risk factors identified at 2 years of follow-up persist at 5 years of follow-up.
Hurricane-intensity forecast improvements currently lag the progress achieved for hurricane tracks. Integrated ocean observations and simulations during hurricane Irene (2011) reveal that the ...wind-forced two-layer circulation of the stratified coastal ocean, and resultant shear-induced mixing, led to significant and rapid ahead-of-eye-centre cooling (at least 6 °C and up to 11 °C) over a wide swath of the continental shelf. Atmospheric simulations establish this cooling as the missing contribution required to reproduce Irene's accelerated intensity reduction. Historical buoys from 1985 to 2015 show that ahead-of-eye-centre cooling occurred beneath all 11 tropical cyclones that traversed the Mid-Atlantic Bight continental shelf during stratified summer conditions. A Yellow Sea buoy similarly revealed significant and rapid ahead-of-eye-centre cooling during Typhoon Muifa (2011). These findings establish that including realistic coastal baroclinic processes in forecasts of storm intensity and impacts will be increasingly critical to mid-latitude population centres as sea levels rise and tropical cyclone maximum intensities migrate poleward.
Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG). TRK fusions have a critical role in ...tumourigenesis in 40% of infant HGG. Here we report the first case of a TRK fusion-driven HGG treated with larotrectinib-the first selective pan-TRK inhibitor in clinical development. This 3-year-old girl had failed multiple therapies including chemotherapy and radiotherapy. Tumour profiling confirmed an ETV6-NTRK3 fusion. Treatment with larotrectinib led to rapid clinical improvement with near total resolution of primary and metastatic lesions on MRI imaging. This is the first report of a TRK fusion glioma successfully treated with a TRK inhibitor.
Background Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective ...contributions to heritability are unknown. Objective To quantify the risk associated with genes and environment on familial clustering of EoE. Methods Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree “Nuclear-Family” relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE “Twins” probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined. Results Analysis of the Nuclear-Family–based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P < .001) than in sisters, mothers, and females, respectively. The risk of EoE for other siblings was 2.4%. In the Nuclear-Family cohort, combined gene and common environment heritability was 72.0% ± 2.7% ( P < .001). In the Twins cohort, genetic heritability was 14.5% ± 4.0% ( P < .001), and common family environment contributed 81.0% ± 4% ( P < .001) to phenotypic variance. Probandwise concordance in monozygotic co-twins was 57.9% ± 9.5% compared with 36.4% ± 9.3% in dizygotic co-twins ( P = .11). Greater birth weight difference between twins ( P = .01), breast-feeding ( P = .15), and fall birth season ( P = .02) were associated with twin discordance in disease status. Conclusions EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).
We study the effects of galaxy environment on the evolution of the stellar mass function (SMF) over 0.2 < z < 2.0 using the FourStar Galaxy Evolution (ZFOURGE) Survey and NEWFIRM Medium-Band Survey ...(NMBS) down to the stellar mass completeness limit, (9.5) at z = 1.0 (2.0). We compare the SMFs for quiescent and star-forming galaxies in the highest and lowest environments using a density estimator based on the distance to the galaxies' third-nearest neighbors. For star-forming galaxies, at all redshifts there are only minor differences with environment in the shape of the SMF. For quiescent galaxies, the SMF in the lowest densities shows no evolution with redshift other than an overall increase in number density (φ*) with time. This suggests that the stellar mass dependence of quenching in relatively isolated galaxies both is universal and does not evolve strongly. While at , the SMF of quiescent galaxies is indistinguishable in the highest and lowest densities, at lower redshifts, it shows a rapidly increasing number density of lower-mass galaxies, , in the highest-density environments. We argue that this evolution can account for all the redshift evolution in the shape of the total quiescent galaxy SMF. This evolution in the quiescent galaxy SMF at higher redshift (z > 1) requires an environmental quenching efficiency that decreases with decreasing stellar mass at 0.5 < z < 1.5 or it would overproduce the number of lower-mass quiescent galaxies in denser environments. This requires a dominant environmental process such as starvation combined with rapid gas depletion and ejection at z > 0.5-1.0 for galaxies in our mass range. The efficiency of this process decreases with redshift, allowing other processes (such as galaxy interactions and ram-pressure stripping) to become more important at later times, z < 0.5.
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