Carbon nanotube (CNT) reinforced (0.05–0.5% by wt) polycaprolactone (PCL)‐based composites were prepared by compression molding. Addition of 0.2% CNT caused a 131% improvement of tensile strength (TS) of PCL films. The tensile modulus (TM) and elongation at break (Eb) of PCL were also significantly improved with the addition of CNT. The water vapor permeability of PCL was 1.51 g·mm/m2·day but 0.2% CNT containing PCL films showed 1.08 g·mm/m2·day. Similarly, the oxygen transmission rate (OTR) of PCL films was found to decrease with the addition of CNT. But, carbon dioxide transmission rate (CO2TR) of PCL film was improved due to incorporation of CNT. Effect of gamma radiation on PCL films and CNT reinforced PCL‐based composites were also studied. The TS of the irradiated (10 kGy) PCL films gained to 75% higher than control sample. The TS of the 0.2% CNT reinforced composite film was reached to 41 MPa at 15 kGy dose. The barrier properties of non‐irradiated and irradiated (10 kGy) PCL films and composites (0.2% CNT reinforced) were also measured. Both PCL films and composites showed lower values of WVP upon irradiation and indicated better water vapor barrier. The OTR and CO2TR of the irradiated (10 kGy) PCL films and composites were decreased compared to their counterparts. Surface and interface morphologies of the composites were studied by scanning electron microscopy. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013

Objectives To validate the previously proposed classifi cation criteria for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). MethodsStep 1: retrospective/prospective webdata collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis ≤18 years.Step 2: blinded classifi cation by consensus panel of a representative sample of 280 cases.Step 3: statistical (sensitivity, specifi city, area under the curve and κ-agreement) and nominal group technique consensus evaluations. Results 827 patients with HSP, 150 with c-PAN, 60 with c-WG, 87 with c-TA and 52 with c-other were compared with each other. A patient was classifi ed as HSP in the presence of purpura or petechiae (mandatory) with lower limb predominance plus one of four criteria: (1) abdominal pain; (2) histopathology (IgA); (3) arthritis or arthralgia; (4) renal involvement. Classifi cation of c-PAN required a systemic infl ammatory disease with evidence of necrotising vasculitis OR angiographic abnormalities of medium-/small-sized arteries (mandatory criterion) plus one of fi ve criteria: (1) skin involvement; (2) myalgia/ muscle tenderness; (3) hypertension; (4) peripheral neuropathy; (5) renal involvement. Classifi cation of c-WG required three of six criteria: (1) histopathological evidence of granulomatous infl ammation; (2) upper airway involvement; (3) laryngo-tracheo-bronchial involvement; (4) pulmonary involvement (x-ray/CT); (5) antineutrophilic cytoplasmic antibody positivity; (6) renal involvement. Classifi cation of c-TA required typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of fi ve criteria: (1) pulse defi cit or claudication; (2) blood pressure discrepancy in any limb; (3) bruits; (4) hypertension; (5) Paediatric Rheumatology European Society propose validated classifi cation criteria for HSP, c-PAN, c-WG and c-TA with high sensitivity/specifi city. INTRODUCTIONIn 1990 the American College of Rheumatology (ACR) proposed classifi cation criteria for patients with vasculitides 1-5 by analysing 807 adults patients with different form of vasculitis: 85 with Henoch-Schönlein purpura (HSP), 118 with polyarteritis nodosa (PAN), 85 with Wegener granulomatosis (WG), 63 with Takayasu arteritis (TA) and 456 with other vasculitides (Churg-Strauss, hypersensitivity, giant cell arteritis and other unspecifi ed forms). 6 Patients with each specifi c vasculitis were compared with all the remaining diseases grouped into a single control category.The ACR criteria for HSP (sensitivity 87.1%, specifi city 87.7%) require the presence of at least two of the following: (1) age ≤20 years at disease onset; (2) palpable purpura; (3) acute abdominal pain; (4) biopsy showing granulocytes in the walls of small arterioles/venules. 1 The ACR criteria for PAN (sensitivity 82.2%, specifi city 86.6%) require at least three of the 10 following criteria: (1) granulocyte or mixed leucocyte infi ...

BACKGROUND We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. METHODS We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. RESULTS All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia — phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. CONCLUSIONS Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.)

Protein coding genes constitute only approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., ''whole exome'') have the potential to contribute to the understanding of rare and common human diseases. Here we report a method for whole-exome sequencing coupling Roche/NimbleGen whole exome arrays to the Illumina DNA sequencing platform. We demonstrate the ability to capture approximately 95% of the targeted coding sequences with high sensitivity and specificity for detection of homozygous and heterozygous variants. We illustrate the utility of this approach by making an unanticipated genetic diagnosis of congenital chloride diarrhea in a patient referred with a suspected diagnosis of Bartter syndrome, a renal salt-wasting disease. The molecular diagnosis was based on the finding of a homozygous missense D652N mutation at a position in SLC26A3 (the known congenital chloride diarrhea locus) that is virtually completely conserved in orthologues and paralogues from invertebrates to humans, and clinical follow-up confirmed the diagnosis. To our knowledge, whole-exome (or genome) sequencing has not previously been used to make a genetic diagnosis. Five additional patients suspected to have Bartter syndrome but who did not have mutations in known genes for this disease had homozygous deleterious mutations in SLC26A3. These results demonstrate the clinical utility of whole-exome sequencing and have implications for disease gene discovery and clinical diagnosis.Bartter syndrome ͉ congenital chloride diarrhea ͉ next-generation sequencing ͉ whole-exome sequencing ͉ personal genomes G enetic variation plays a major role in both Mendelian and non-Mendelian diseases. Among the approximately 2,600 Mendelian diseases that have been solved, the overwhelming majority are caused by rare mutations that affect the function of individual proteins; at individual Mendelian loci, approximately 85% of the disease-causing mutations can typically be found in the coding region or in canonical splice sites (1). For complex traits, genome-wide association studies have identified more than 250 common variants associated with risk alleles that contribute to a wide range of diseases (2, 3). To date, most of these impart small effects on disease risk (e.g., odds ratio of 1.2); moreover, even when extremely large studies have been performed, the vast majority of the genetic contribution to disease risk remain unexplained (4-6). These findings suggest that individually rare variants with relatively large effect may account for a large fraction of this missing trait variance. Indeed, studies addressing this question have documented the presence of individually rare variants with relatively large effect (7,8). Consistent with the Mendelian model, coding variants have proven to be prevalent sources of such rare variants.These considerations motivate implementation of robust approaches to sequencing complete c...

H+-ATPases are ubiquitous in nature; V-ATPases pump protons against an electrochemical gradient, whereas F-ATPases reverse the process, synthesizing ATP. We demonstrate here that mutations in ATP6B1, encoding the B-subunit of the apical proton pump mediating distal nephron acid secretion, cause distal renal tubular acidosis, a condition characterized by impaired renal acid secretion resulting in metabolic acidosis. Patients with ATP6B1 mutations also have sensorineural hearing loss; consistent with this finding, we demonstrate expression of ATP6B1 in cochlea and endolymphatic sac. Our data, together with the known requirement for active proton secretion to maintain proper endolymph pH, implicate ATP6B1 in endolymph pH homeostasis and in normal auditory function. ATP6B1 is the first member of the H+-ATPase gene family in which mutations are shown to cause human disease.