Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD).

BACKGROUND: Previous estimates of the prevalence of Menkes disease, a lethal X-linked recessive disorder of copper metabolism, were based on confirmed clinical cases ascertained from specific populations and varied from 1 in 40,000 to 1 in 354,507. With newly available population-based allelic frequencies of DNA sequence variants, the expected birth prevalence of Menkes disease and other ATP7A-related phenotypes can be reconsidered using Hardy-Weinberg theoretical principles. METHODS: We reviewed the canonical ATP7A transcript in the current version of gnomAD (v2.1.1) to evaluate frequency of complete loss-of-function alleles in a diverse normal control population. As a comparator, we used the DMD locus, associated with Duchenne and Becker Muscular Dystrophy, another X-linked recessive trait. We applied Hardy-Weinberg theory and PolyPhen-2 in silico plus REVEL and CADD ensemble analyses to calculate estimated frequencies of normal and predicted deleterious ATP7A alleles. RESULTS: We identified 1106 total ATP7A variants out of 205,523 alleles in gnomAD, with missense variants most common (43.4%). Complete loss-of-function variants were found in four ATP7A alleles (frequency = 0.0000194), including three frameshift/nonsense mutations and one canonical splice donor site defect. Assuming Harvey-Weinberg equilibrium, this frequency of pathogenic alleles predicts 1 in 34,810 live male births with Menkes disease or other ATP7A-related disorders each year in the US. The same analysis for DMD loss-of-function variants predicted 1 in 7246 newborn males with Duchenne (or Becker) muscular dystrophy. We also identified nine ATP7A missense variants in gnomAD predicted as deleterious by PolyPhen-2 and stringent REVEL/CADD criteria, comprising 12 more disease-causing alleles and raising the estimated birth prevalence to 1 in 8664 and predicting 225 newborns with Menkes disease or other ATP7A-related disorders per year in the US alone. CONCLUSIONS: Assuming Harvey-Weinberg equilibrium, the allelic frequency of deleterious ATP7A variants in a genomic database from a large diverse population predicts a birth prevalence of Menkes disease or ATP7A-related disorders as high as 1 in 8664 live male births. This genome-driven ascertainment of deleterious ATP7A alleles in the population implies a higher birth prevalence of Menkes disease and ATP7A-related conditions than previously appreciated. A population-based newborn screening pilot study for Menkes disease will be instrumental in confirming the prediction.

Aerothermoelastic-Acoustics Simulation of Flight Vehicles.

This paper describes a novel computational-fluid-dynamics-based numerical solution procedure for effective simulation of aerothermoacoustics problems with application to aerospace vehicles. A finite element idealization is employed for both fluid and structure domains, which fully accounts for thermal effects. The accuracies of both the fluid and structure capabilities are verified with flight- and ground-test data. A time integration of the structural equations of motion, with the governing flow equations, is conducted for the computation of the unsteady aerodynamic forces, which uses a transpiration boundary condition at the surface nodal points in lieu of the updating of the fluid mesh. Two example problems are presented herein to that effect. The first one relates to a cantilever wing with a NACA 0012 airfoil. The solution results demonstrate the effect of temperature loading that causes a significant increase in acoustic response. A second example, the hypersonic X-43 vehicle, is also analyzed; and relevant results are presented. The common finite element-based aerothermoelastic-acoustics simulation process, its applicability to the efficient and routine solution of complex practical problems, the employment of the effective transpiration boundary condition in the computational fluid dynamics solution, and the development and public domain distribution of an associated code are unique features of this paper.

Binding of HIV-1 gp120 to DC-SIGN promotes ASK-1-dependent activation-induced apoptosis of human dendritic cells.

During disease progression to AIDS, HIV-1 infected individuals become increasingly immunosuppressed and susceptible to opportunistic infections. It has also been demonstrated that multiple subsets of dendritic cells (DC), including DC-SIGN⁺ cells, become significantly depleted in the blood and lymphoid tissues of AIDS patients, which may contribute to the failure in initiating effective host immune responses. The mechanism for DC depletion, however, is unclear. It is also known that vast quantities of viral envelope protein gp120 are shed from maturing HIV-1 virions and form circulating immune complexes in the serum of HIV-1-infected individuals, but the pathological role of gp120 in HIV-1 pathogenesis remains elusive. Here we describe a previously unrecognized mechanism of DC death in chronic HIV-1 infection, in which ligation of DC-SIGN by gp120 sensitizes DC to undergo accelerated apoptosis in response to a variety of activation stimuli. The cultured monocyte-derived DC and also freshly-isolated DC-SIGN⁺ blood DC that were exposed to either cross-linked recombinant gp120 or immune-complex gp120 in HIV⁺ serum underwent considerable apoptosis after CD40 ligation or exposure to bacterial lipopolysaccharide (LPS) or pro-inflammatory cytokines such as TNFα and IL-1ß. Furthermore, circulating DC-SIGN⁺ DC that were isolated directly from HIV-1⁺ individuals had actually been pre-sensitized by serum gp120 for activation-induced exorbitant apoptosis. In all cases the DC apoptosis was substantially inhibited by DC-SIGN blockade. Finally, we showed that accelerated DC apoptosis was a direct consequence of excessive activation of the pro-apoptotic molecule ASK-1 and transfection of siRNA against ASK-1 significantly prevented the activation-induced excessive DC death. Our study discloses a previously unknown mechanism of immune modulation by envelope protein gp120, provides new insights into HIV immunopathogenesis, and suggests potential therapeutic approaches to prevent DC depletion in chronic HIV infection.

The discriminatory capacity of BMD measurements by DXA and dual X-ray and laser (DXL) at the calcaneus including clinical risk factors for detecting patients with vertebral fractures.

UNLABELLED: Osteoporotic fracture risk depends on bone mineral density (BMD) and clinical risk factors (CRF). Five hundred and eighty-eight untreated female and male outpatient subjects were evaluated, 160 with vertebral fractures. BMD was measured both by using calcaneal dual X-ray and laser (DXL) and dual-energy X-ray absorptiometry (DXA), and CRF were evaluated. Detection frequencies for different BMD methods with or without CRF are presented. INTRODUCTION: Osteoporotic fracture risk depends on bone mineral density and clinical risk factors. DXA of the spine/hip is considered a gold standard for BMD assessment, but due to degenerative conditions, particularly among the older population, assessment of BMD at the lumbar spine has been shown to be of limited significance. Portable calcaneal dual X-ray technology and laser can be an easily obtainable alternative. METHODS: Vertebral fractures were evaluated in a baseline analysis of 588 females and males (median age 64.4, range 17.6-93.1 years), comparing BMD measurements by using DXL and DXA and CRF with/without BMD. One hundred and sixty subjects had radiological verified vertebral fractures. Area under receiver-operating characteristic curves (AUROCC) and univariate and multiple logistic regressions were calculated. RESULTS: AUROCC for detection of vertebral fractures was comparable for DXL at calcaneus and DXA at femoral neck (DXL 0.665 and DXA 0.670). Odds ratio for prevalent vertebral fracture was generally weak for DXA femoral neck (0.613) and DXL (0.521). Univariate logistic regression among CRF without BMD revealed age, prevalent fragility fracture, and body mass index significantly associated with prevalent vertebral fracture (AUROCC = 0.805). Combining BMD and CRF, a prognostic improvement in case of DXA at femoral neck (AUROCC 0.869, p = 0.02), DXL at calcaneus (AUROCC 0.869, p = 0.059), and DXA at total hip (AUROCC 0.861, p = 0.06) was observed. CONCLUSIONS: DXL was similarly sensitive compared with DXA for identification of subjects with vertebral fragility fractures, and combination of CRF with BMD by DXL or DXA further increased the discriminatory capacity for detection of patients susceptible to vertebral fracture.

[Pneumatosis intestinalis in anorexia nervosa: a case report]. / Ein Fallbericht einer Pneumatosis intestinalis bei Anorexia nervosa.

Pneumatosis intestinalis (PI) is identified as the accumulation of gas within the wall of the small or large intestine. It was first described by Du Vernoi in 1783. The pathogenesis is supposed to be multifactorial. It is assumed that there are 3 paths of disease development: mechanical, bacterial and biochemical. Adult patients are mostly asymptomatic and PI is diagnosed frequently by different radiological methods. The treatment of patients depends on their clinical picture. Most patients can be treated only with antibiotics and elemental diet. In a small number of cases, surgical intervention is essential. We report about a 35-year-old female patient with anorexia nervosa who developed PI after an excessive use of chewing gum for 3 years.

Phosphogenesis in the 2460 and 2728 million-year-old banded iron formations as evidence for biological cycling of phosphate in the early biosphere.

The banded iron formation deposited during the first 2 billion years of Earth's history holds the key to understanding the interplay between the geosphere and the early biosphere at large geological timescales. The earliest ore-scale phosphorite depositions formed almost at ∼2.0-2.2 billion years ago bear evidence for the earliest bloom of aerobic life. The cycling of nutrient phosphorus and how it constrained primary productivity in the anaerobic world of Archean-Palaeoproterozoic eons are still open questions. The controversy centers about whether the precipitation of ultrafine ferric oxyhydroxide due to the microbial Fe(II) oxidation in oceans earlier than 1.9 billion years substantially sequestrated phosphate, and whether this process significantly limited the primary productivity of the early biosphere. In this study, we report apatite radial flowers of a few micrometers in the 2728 million-year-old Abitibi banded iron formation and the 2460 million-year-old Kuruman banded iron formation and their similarities to those in the 535 million-year-old Lower Cambrian phosphorite. The lithology of the 535 Million-year-old phosphorite as a biosignature bears abundant biomarkers that reveal the possible similar biogeochemical cycling of phosphorus in the Later Archean and Palaeoproterozoic oceans. These apatite radial flowers represent the primary precipitation of phosphate derived from the phytoplankton blooms in the euphotic zones of Neoarchean and Palaoeproterozoic oceans. The unbiased distributions of the apatite radial flowers within sub-millimeter bands do not support the idea of an Archean Crisis of Phosphate. This is the first report of the microbial mediated mineralization of phosphorus before the Great Oxidation Event when the whole biosphere was still dominated by anaerobic microorganisms.

Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection.

Severe acute respiratory syndrome (SARS) is caused by infection of a previously undescribed coronavirus (CoV). L-SIGN, encoded by CLEC4M (also known as CD209L), is a SARS-CoV binding receptor that has polymorphism in its extracellular neck region encoded by the tandem repeat domain in exon 4. Our genetic risk association study shows that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. L-SIGN is expressed in both non-SARS and SARS-CoV-infected lung. Compared with cells heterozygous for L-SIGN, cells homozygous for L-SIGN show higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation and a lower capacity for trans infection. Thus, homozygosity for L-SIGN plays a protective role during SARS infection.

Contribution of incense burning to indoor PM10 and particle-bound polycyclic aromatic hydrocarbons under two ventilation conditions.

Burning incense to worship Gods and ancestors is a traditional practice prevalent in Asian societies. This work investigated indoor PM10 concentrations resulting from incense burning in household environments under two conditions: closed and ventilated. The exposure concentrations of particle-bound polycyclic aromatic hydrocarbons (PAHs) were estimated. The factors of potential exposure were also evaluated. Under both conditions, samples were taken at three locations: 0.3, 3.5 and 7 m away from the altar during three periods: incense burning, the first 3 h, and the 4-6 h after cessation of combustion. PAH concentrations of incense smoke were assessed in the laboratory. Personal environment monitors were used as sampling instruments. The results showed a significant contribution of incense burning to indoor PM10 and particulate PAH concentrations. PM10 concentrations near the altar during incense burning were 723 and 178 microg/m3, more than nine and 1.6 times background levels, under closed and ventilated conditions, respectively. Exposure concentrations of particle-bound PAHs were 0.088-0.45 microg/m3 during incense burning. On average, PM10 and associated PAH concentrations were about 371 and 0.23 microg/m3 lower, respectively, in ventilated environments compared with closed conditions. Concentrations were elevated for at least 6 h under closed conditions.

Characteristics of sorption losses of polychlorinated biphenyl congeners onto glass surfaces.

Sorption losses to glass surfaces of five polychlorinated biphenyl (PCB) congeners in aqueous solutions were investigated. Adsorption/desorption experiments were conducted under conditions that simulated actual sample handling procedures for environmental samples. It was found that the adsorption loss is related to the degree of chlorination. PCB congener 180 lost the most onto glass surfaces, followed by congeners 138, 101/28, and 52, in decreasing order. More PCB adsorption occurred onto glass under conditions of agitation and higher temperature (22 degrees C) during the five-day experimental period. The salinity effect ("salting out effect") was also observed in this work. The efficiency of desorption (rinsing three times with solvent) was found to be ineffective in extracting adsorbed PCBs. It was necessary to use mechanical shaking for extraction. Storage of samples up to five days resulted in sorption losses as much as 30%, 17%, 30%, 40%, and 55% of PCB 28, 52, 101, 138, and 180, respectively. Sorption losses need to be considered when conducting water sampling or toxicological studies to avoid underestimation of the actual PCB concentrations and their toxic effects.

Coating effects on the glass adsorption of polychlorinated biphenyl (PCB) congeners.

The effects of coating materials on polychlorinated biphenyl (PCB) adsorption in aqueous solution were assessed in an attempt to minimize PCB sorption loss during sampling processes. A coating material, which enhances PCB adsorption and allows adsorbed PCBs to be readily extracted by solvents, can act as a sampling concentrator to reduce PCB losses from both adsorption and evaporation. Several coating materials were evaluated, including paraffin oil, silicone oil, dimethyldichlorosilane (Sylon-CT), Prosil 28 and polydimethylsiloxane (PDS) with viscosity 0.65, 50 (PDS 50), and 500 (PDS 500) cSt. PDS and silicone oil enhanced adsorption for all five congeners examined (IUPAC No. 28, 52, 101, 138, and 180). Sylon-CT, paraffin oil and Prosil 28 had inconsistent effects on adsorption of different congeners. Desorption of adsorbed PCBs onto all coating types was assessed. The recovery efficiency of extracting PCBs with solvents was enhanced greatly with all coatings as opposed to non-coated surfaces, with the exception of paraffin oil. Coating with silicon oil, PDS 50, and 500 resulted in virtually 100% recovery of adsorbed PCBs. It was also found that Teflon containers were poor substitutes for glass containers and failed to minimize PCB losses. Among the materials studied, the best coating that could be used as a sampling concentrator was PDS 500.