Persistent Long-Term Structural, Functional, and Metabolic Changes After Stress-Induced (Takotsubo) Cardiomyopathy

The HEROIC study was funded by the British Heart Foundation Project Grant no. PG/15/108/31928 (D.K.D.), the Josephine Lansdell British Medical Association 2015 Award (D.K.D.), and the Chief Scientist Office CGA-16-4 Catalytic Grant (D.K.D). D.E.N. is supported by the British Heart Foundation (CH/09/002) and a Wellcome Trust Senior Investigator Award (WT103782AIA).Peer reviewedPublisher PD

Long-term treatment with egg oral immunotherapy enhances sustained unresponsiveness that persists after cessation of therapy

We previously reported results of a randomized, placebo-controlled study of egg oral immunotherapy (eOIT), in which 27.5% of subjects achieved sustained unresponsiveness (SU) after 2 years. Here we report results of treatment through 4 years and long-term follow-up

The natural history of milk allergy in an observational cohort

There are few studies on the natural history of milk allergy. Most are single-site and not longitudinal, and these have not identified a means for early prediction of outcomes

GRAPPA-OMERACT consensus-based recommendations and research agenda for use of composite measures and treatment targets in PsA

BACKGROUND: Many composite disease activity measures and targets have been developed for psoriatic arthritis (PsA). This GRAPPA-OMERACT work stream aimed to further the development of consensus among physicians and patients.METHODS: Prior to the meeting, physicians and patients were surveyed on outcome measures. A consensus meeting (26 rheumatologists, dermatologists, and patient representatives) reviewed evidence on composite measures and potential treatment targets, plus survey results. After discussions, participants voted on proposals for use and consensus was established in a second survey.RESULTS: Survey results from 128 HCPS and 139 patients were analysed alongside a SLR summarising evidence. A weighted vote was cast for composite measures (for RCTs, most popular measures were PASDAS [40 votes] and GRACE [28 votes]; for clinical practice, most popular were 3-VAS [45 votes], DAPSA [26 votes]). After discussion there was no consensus on a composite measure. The group agreed that several composite measures could be used. Future studies should allow further validation and comparison. The group unanimously agreed that remission should be the ideal target with minimal/low disease activity a feasible alternative. The target should include assessment of musculoskeletal disease, skin and health related quality of life. The group recommended a target of treatment as VLDA, or MDA.CONCLUSIONS: Consensus was not reached on a continuous measure of disease activity. In the interim the group recommends several composites. Consensus was reached on a treatment target of VLDA/MDA. An extensive research agenda was composed and recommends that data on all PsA clinical domains be collected in ongoing studies. This article is protected by copyright. All rights reserved.</p

Sublingual immunotherapy for peanut allergy: Long-term follow-up of a randomized multicenter trial

We previously reported initial results of the first multi-center randomized, double blind, placebo controlled clinical trial of peanut sublingual immunotherapy (SLIT), observing a favorable safety profile associated with modest clinical and immunologic effects in the first year

Sublingual immunotherapy for peanut allergy: A randomized, double-blind, placebo-controlled multicenter trial

There are presently no available therapeutic options for peanut-allergic patients

Oral Immunotherapy for Treatment of Egg Allergy in Children

For egg allergy, dietary avoidance is the only currently approved treatment. We evaluated oral immunotherapy using egg-white powder for the treatment of children with egg allergy

An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility

Ras homologous guanosine triphosphatases (RhoGTPases) control several cellular functions, including cytoskeletal actin remodeling and cell migration. Their activities are downregulated by GTPase-activating proteins (GAPs). Although RhoGTPases are implicated in bone remodeling and osteoclast and osteoblast function, their significance in human bone health and disease remains elusive. Here, we report defective RhoGTPase regulation as a cause of severe, early-onset, autosomal-dominant skeletal fragility in a three-generation Finnish family. Affected individuals (n = 13) presented with multiple low-energy peripheral and vertebral fractures despite normal bone mineral density (BMD). Bone histomorphometry suggested reduced bone volume, low surface area covered by osteoblasts and osteoclasts, and low bone turnover. Exome sequencing identified a novel heterozygous missense variant c.652G>A (p.G218R) in ARHGAP25, encoding a GAP for Rho-family GTPase Rac1. Variants in the ARHGAP25 5′ untranslated region (UTR) also associated with BMD and fracture risk in the general population, across multiple genomewide association study (GWAS) meta-analyses (lead variant rs10048745). ARHGAP25 messenger RNA (mRNA) was expressed in macrophage colony-stimulating factor (M-CSF)–stimulated human monocytes and mouse osteoblasts, indicating a possible role for ARHGAP25 in osteoclast and osteoblast differentiation and activity. Studies on subject-derived osteoclasts from peripheral blood mononuclear cells did not reveal robust defects in mature osteoclast formation or resorptive activity. However, analysis of osteosarcoma cells overexpressing the ARHGAP25 G218R-mutant, combined with structural modeling, confirmed that the mutant protein had decreased GAP-activity against Rac1, resulting in elevated Rac1 activity, increased cell spreading, and membrane ruffling. Our findings indicate that mutated ARHGAP25 causes aberrant Rac1 function and consequently abnormal bone metabolism, highlighting the importance of RhoGAP signaling in bone metabolism in familial forms of skeletal fragility and in the general population, and expanding our understanding of the molecular pathways underlying skeletal fragility.</p

A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10−109); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10−9) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number