A Phase 2 Randomized Controlled Multisite Study Using Omalizumab-facilitated Rapid Desensitization to Test Continued Discontinued Dosing in Multifood Allergic Individuals.

Background: As there is limited data on the sustainability of desensitization of multifood-oral immunotherapy (multifood-OIT), we conducted a multisite multifood-OIT study to compare the efficacy of successful desensitization with sustained dosing discontinued dosing after multifood-OIT.

Methods: We enrolled 70 participants, aged 5-22 years with multiple food allergies confirmed by double-blind placebo-controlled food challenges (DBPCFCs). In the open-label phase of the study, all participants received omalizumab (weeks 1-16) and multi-OIT (2-5 allergens; weeks 8-30) and eligible participants (on maintenance dose of each allergen by weeks 28-29) were randomized 1:1:1 to 1 g, 300 mg, or 0 mg arms (blinded, weeks 30-36) and then tested by food challenge at week 36.

Food allergy and omics.

Food allergy (FA) prevalence has been increasing over the last few decades and is now a global health concern. Current diagnostic methods for FA result in a high number of false-positive results, and the standard of care is either allergen avoidance or use of epinephrine on accidental exposure, although currently with no other approved treatments. The increasing prevalence of FA, lack of robust biomarkers, and inadequate treatments warrants further research into the mechanism underlying food allergies.

Allergen Immunotherapy.

Allergies affect a large proportion of the population. Allergies can adversely affect productivity, sleep, and quality of life and can lead to life-threatening reactions. Allergies can spread to affect multiple organ systems.

Treatment with rituximab and brentuximab vedotin in a patient of common variable immune deficiency-associated classic Hodgkin lymphoma.

Background: Patients with common variable immunodeficiency (CVID) have an increased risk of developing lymphoproliferative diseases, including non-Hodgkins lymphoma (Blood 116:1228-1234, 2010; Blood 119:1650-7, 2012). The incidence and prognosis of Hodgkin lymphoma in this population is not clear, with only a few case reports in the literature. Conventional cytotoxic chemotherapy, although highly efficacious in treating Hodgkin lymphoma in immune competent patients, is problematic in patients with CVID due to the increased risk of infectious complications (Ther Umsch 69:687-91, 2012; Pediatr Hematol Oncol 24:337-42, 2012).

Snake Venom Cytotoxins, Phospholipase As, and Zn-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance.

Snake venom toxins are responsible for causing severe pathology and toxicity following envenomation including necrosis, apoptosis, neurotoxicity, myotoxicity, cardiotoxicity, profuse hemorrhage, and disruption of blood homeostasis. Clinically, snake venom toxins therefore represent a significant hazard to snakebite victims which underscores the need to produce more efficient anti-venom. Some snake venom toxins, however, have great potential as drugs for treating human diseases.

Molecular models of the Mojave rattlesnake (Crotalus scutulatus scutulatus) venom metalloproteinases reveal a structural basis for differences in hemorrhagic activities.

Rattlesnake venom can differ in composition and in metalloproteinase-associated activities. The molecular basis for this intra-species variation in Crotalus scutulatus scutulatus (Mojave rattlesnake) remains an enigma. To understand the molecular basis for intra-species variation of metalloproteinase-associated activities, we modeled the three-dimensional structures of four metalloproteinases based on the amino acid sequence of four variations of the proteinase domain of the C.

Genetic Basis for Variation of Metalloproteinase-Associated Biochemical Activity in Venom of the Mojave Rattlesnake (Crotalus scutulatus scutulatus).

The metalloproteinase composition and biochemical profiles of rattlesnake venom can be highly variable among rattlesnakes of the same species. We have previously shown that the neurotoxic properties of the Mojave rattlesnake (Crotalus scutulatus scutulatus) are associated with the presence of the Mojave toxin A subunit suggesting the existence of a genetic basis for rattlesnake venom composition. In this report, we hypothesized the existence of a genetic basis for intraspecies variation in metalloproteinase-associated biochemical properties of rattlesnake venom of the Mojave rattlesnake.

The Hyper-IgE Syndromes: Lessons in Nature, From Bench to Bedside.

: Hyper-IgE syndrome is a primary immunodeficiency marked by abnormalities in the coordination of cell-cell signaling with the potential to affect TH17 cell, B cell, and neutrophil responses. Clinical manifestations include recurrent skin and lung infections, serum IgE elevation, connective tissue repair and development alterations, and the propensity for vascular abnormalities and tumor development. Signal transducer and activator of transcription 3 (STAT3) signaling, dedicator of cytokinesis 8 (DOCK8) signaling, and tyrosine kinase 2 (TYK2) signaling alterations have been implicated in 3 forms of hyper-IgE syndrome.

Interleukin-13 signaling and its role in asthma.

Asthma affects nearly 300 million people worldwide. The majority respond to inhaled corticosteroid treatment with or without beta-adrenergic agonists. However, a subset of 5 to 10% with severe asthma do not respond optimally to these medications.

Complement inactivating proteins and intraspecies venom variation in Crotalus oreganus helleri.

Complement inactivating properties were detected in venom from the southern California distribution of Crotalus oreganus helleri (Southern Pacific Rattlesnake). This activity showed strong geographic bias to the San Bernardino Mountain range, and venom from this area reacted strongly with Fraction 5 antiserum (AF5). However, venoms from the San Jacinto Mountain range, which have been previously shown to contain Mojave toxin, did not inhibit complement and did not react with AF5.

Mojave toxin in venom of Crotalus helleri (Southern Pacific Rattlesnake): molecular and geographic characterization.

Mojave toxin (MT) was detected in five of 25 Crotalus helleri (Southern Pacific rattlesnake) sampled using anti-MT antibodies and nucleotide sequence analysis. All of the venoms that were positive for MT were collected from Mt San Jacinto in Riverside Co., California.

Mojave rattlesnakes (Crotalus scutulatus scutulatus) lacking the acidic subunit DNA sequence lack Mojave toxin in their venom.

The venom composition of Mojave rattlesnakes (Crotalus scutulatus scutulatus) differs in that some individuals have Mojave toxin and others do not. In order to understand the genetic basis for this difference, genomic DNA samples from Mojave rattlesnakes collected in Arizona, New Mexico, and Texas were analyzed for the presence of DNA sequences that relate to the acidic (Mta) and basic (Mtb) subunits of this toxin. DNA samples were subjected to PCR to amplify nucleotide sequences from second to fourth exons of the acidic and basic subunits.

The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression.

A gene family of small membrane proteins, represented by phospholemman and the gamma subunit of Na,K-ATPase, was defined and characterized by the analysis of more than 1000 related ESTs (expressed sequence tags). In addition to new and more complete cDNA sequence for known family members (including MAT-8, CHIF, and RIC), the findings included two new family members and new splicing variants. A large number of EST replicates made it possible to derive curated DNA sequence with higher confidence and accuracy than from the sequencing of individual clones.

Purification of M5, a fibrinolytic proteinase from Crotalus molossus molossus venom that attacks complement.

Crotalus molossus molossus (northern blacktailed rattlesnake) venom contains agents that affect blood coagulation. A fibrin(ogen)olytic proteinase, called M5, was isolated and purified from this venom by ion exchange chromatography in a two-step procedure. M5 consists of a single non-glycosylated polypeptide chain with a molecular weight of 25 kDa and an isoelectric point of 7.

Differences in fibrinolysis and complement inactivation by venom from different northern blacktailed rattlesnakes (Crotalus molossus molossus).

Venom from 72 different Crotalus molossus molossus rattlesnakes was examined for fibrinolysis and for their ability to inactivate human complement. The fibrinolytic activity of the venoms was variable, but smaller (younger) snakes had less fibrinolytic activity than larger (older) snakes. Major differences between the venoms was detected by isoelectric focusing, and reflected in the number and pI of the proteins with fibrinolytic activity.

Cobra venom cytotoxin free of phospholipase A2 and its effect on model membranes and T leukemia cells.

Membrane-active toxins from snake venom have been used previously to study protein-lipid interactions and to probe the physical and biochemical states of biomembranes. To extend these studies, we have isolated from Naja naja kaowthia (cobra) venom a cytotoxin free of detectable phospholipase A2 (PLA2). The amino acid composition, pI (10.

Social support and psychiatric sickness absence: a prospective study of British civil servants.

Background: Studies on the direct and buffering effects of social support have not examined psychiatric sickness absence and few studies have considered support both at home and at work. This study addresses prospectively the effects of chronic stressors and social supports, at home and at work, on psychiatric sickness absence rates.

Methods: Sociodemographic factors, health and social support were measured at baseline, and short and long spells of sickness absence were measured prospectively over a 5-year period.

Using Labour Force Survey and census data to generate denominators for occupational injury rates: an application and expansion of Haggar-Guénette's method.

The calculation of rates of occupational injury claims is essential to identify groups at high risk, yet limitations of denominator data have often restricted our capacity to do this. Haggar-Guénette's method of using Statistics Canada's data on paid workers from the Labour Force Survey as denominators has been expanded by incorporating information from the Census. The method is illustrated by calculating denominators for male construction industry workers within the province of Ontario.

Sickness absence in the Whitehall II study, London: the role of social support and material problems.

Study Objective: To investigate the role of social supports, social networks, and chronic stressors: (i) as predictors of sickness absence; and (ii) as potential explanations for the socioeconomic gradient in sickness absence.

Design: A prospective cohort study (Whitehall II study) with sociodemographic factors, health and social support measured at baseline, and spells of sickness absence measured prospectively.

Setting: Twenty London based non-industrial departments of the British civil service.

In vitro evaluation of Pyrularia thionin-anti-CD5 immunotoxin.

The membrane-active peptide, Pyrularia thionin, purified from Pyrularia pubera, was covalently conjugated to an anti-CD5 monoclonal antibody. The membrane-active properties of thionin were not affected by the conjugation. The immunotoxin killed CD5+ lymphocytes in vitro at a concentration of 0.

Phospholipase A2 and cobra venom cytotoxin Vc5 interactions and membrane structure.

The hydrolytic activity and interaction of acidic and neutral phospholipase A2 (PLA2) with large unilamellar liposomes treated with cobra venom cytotoxin Vc5 (CT Vc5) were studied to more fully understand the modulating effects of cationic membrane-active peptides on PLA2. Studies were done by fluorescence displacement, EPR spin probes, and 31P-NMR. The results showed that CT Vc5 inhibits PLA2 activity on phosphatidylcholine liposomes.