LYSMD3: A mammalian pattern recognition receptor for chitin.

Chitin, a major component of fungal cell walls, has been associated with allergic disorders such as asthma. However, it is unclear how mammals recognize chitin and the principal receptor(s) on epithelial cells that sense chitin remain to be determined. In this study, we show that LYSMD3 is expressed on the surface of human airway epithelial cells and demonstrate that LYSMD3 is able to bind chitin, as well as β-glucan, on the cell walls of fungi.

Development and application of novel immunoassays for eosinophil granule major basic proteins to evaluate eosinophilia and myeloproliferative disorders.

Background: During eosinophil differentiation, the granule eosinophil major basic protein 1 (eMBP1) is synthesized as a 32-kDa precursor form, referred to as proMBP1, which is processed into the 14-kDa mature form of eMBP1. The prevalence of these two forms of MBP1 in most pathological conditions remains unknown.

Objective: To develop the immunoassays that differentiate mature eMBP1 and proMBP1 and apply them to analyze their levels in biological fluids from patients with eosinophilia and hematologic disorders.

Fungal allergen-induced IL-33 secretion involves cholesterol-dependent, VDAC-1-mediated ATP release from the airway epithelium.

Key Points: Alternaria aeroallergens induce the release of ATP from human bronchial epithelial (HBE) cells by activating a conductive pathway involving voltage-dependent anion channel-1 (VDAC-1) and by exocytosis of ATP localized within membrane vesicles. Inhibition of VDAC-1 blocked Alternaria-evoked Ca uptake across the plasma membrane of HBE cells and interleukin (IL)-33 release into the extracellular media. Reducing cholesterol content with a cholesterol scavenger (β-methylcyclodextrin) or statin compound (simvastatin) blocked ATP and IL-33 release by lowering the expression of VDAC-1 in the plasma membrane.

Early Life Represents a Vulnerable Time Window for IL-33-Induced Peripheral Lung Pathology.

IL-33, an IL-1 family cytokine, is constitutively expressed in mucosal tissues and other organs in healthy humans and animals, and expression levels increase in inflammatory conditions. Although IL-33-mediated promotion of type 2 immune responses has been well established, a gap in our knowledge regarding the functional diversity of this pleiotropic cytokine remains. To address this gap, we developed a new IL-33 transgenic mouse model in which overexpression of full-length IL-33 is induced in lung epithelial cells under conditional control.

Oxidative stress serves as a key checkpoint for IL-33 release by airway epithelium.

Background: Interleukin (IL)-33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL-33 release is controlled. The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a key role in antioxidant response regulation.

Unsupervised network mapping of commercially available immunoassay yields three distinct chronic rhinosinusitis endotypes.

Background: Endotyping chronic rhinosinusitis (CRS) through simplified cytokine assays may help direct individualized therapy such as corticosteroids, antibiotics, or biologics. We performed an unsupervised network analysis to endotype CRS and control subjects using a commercially available cytokine-chemokine immunoassay.

Methods: A 41-plex cytokine-chemokine array along with major basic protein (MBP) assay was performed on sinonasal surgical tissue of 32 adults.

An immunologic test for chronic rhinosinusitis based on free intranasal eosinophilic major basic protein.

Background: A histologic hallmark of chronic rhinosinusitis (CRS) is an eosinophilic inflammation, present with and without nasal polyposis and independent of atopy. Eosinophils migrate through nasal tissue including the epithelium into the nasal airway mucus, where they form clusters and degranulate, releasing granule proteins including the toxic major basic protein (MBP). Specific biomarkers for CRS, which could be used as a diagnostic test for CRS with a high sensitivity and specificity, are presently lacking.

Viral Inactivation of Human Osteochondral Grafts with Methylene Blue and Light.

Objective: Cartilage injury is one of the most common disorders of synovial joints. Fresh osteochondral allografts are becoming a standard treatment; however, they are supply constrained with a potential risk of disease transmission. There are no known virucidal processes available for osteochondral allografts and most methods presently available are detrimental to cartilage.

Regulation of TLR2 expression and function in human airway epithelial cells.

Toll-like receptor (TLR1-6) mRNAs are expressed in normal human bronchial epithelial cells with higher basal levels of TLR3. TLR2 mRNA and plasma membrane protein expression was enhanced by pretreatment with Poly IC, a synthetic double-stranded RNA (dsRNA) known to activate TLR3. Poly IC also enhanced mRNA expression of adaptor molecules (MyD88 and TIRAP) and coreceptors (Dectin-1 and CD14) involved in TLR2 signaling.

IL-33-activated dendritic cells induce an atypical TH2-type response.

Background: IL-33, a recently discovered IL-1 family cytokine, is implicated in the development of T(H)2-type responses in vivo. However, the cellular targets for IL-33 are poorly understood.

Objective: We tested the hypotheses that dendritic cells (DCs) respond to IL-33 and that IL-33-activated DCs prime naive CD4(+) T cells to produce T(H)2-type cytokines.

Pimecrolimus reduces eosinophil activation associated with calcium mobilization.

Background: Pimecrolimus is a calcineurin inhibitor that inhibits T cell and mast cell activation and effectively treats atopic dermatitis. However, its effects on eosinophils, a cell type implicated in allergic disease pathology, are unknown. Therefore, we examined the effects of pimecrolimus on eosinophil superoxide anion production, degranulation and survival.

Clinical correlates of serum pro-major basic protein in a spectrum of eosinophilic disorders and myelofibrosis.

Background/aims: Eosinophil cytoplasmic granules contain major basic protein (MBP), which is primarily translated from its precursor, proMBP. In this study, we evaluated the plasma level of proMBP in eosinophilic and chronic myeloproliferative disorders (MPN).

Methods: The levels of plasma proMBP were measured by radioimmunoassay in 25 healthy controls, 23 patients with systemic mastocytosis (SM), 11 patients with idiopathic eosinophilia (IE) and a cohort of 170 patients with MPN which included 76 patients with de novo myelofibrosis, 42 with polycythemia vera (PV), 17 with postpolycythemic myeloid metaplasia (Post-PV MF), 21 with essential thrombocythemia (ET) and 14 with postthrombocythemic myeloid metaplasia (Post-ET MF).

Single-dose pharmacokinetics of the DNA-binding bioreductive agent NLCQ-1 (NSC 709257) in CD2F1 mice.

NLCQ-1 (NSC 709257) is a weak DNA-binding bioreductive antiproliferative agent, with potent in vitro antiproliferative activity against rodent and human tumor cell lines under aerobic and anaerobic conditions. Interest in this quinoline analog is based in part on its in vivo synergistic antitumor effect with radiotherapy or chemotherapy against mouse tumors and human xenografts. A sensitive, specific HPLC method was developed to measure NLCQ-1 in biological fluids.

Rat and human liver cytochrome P-450 isoform metabolism of ecteinascidin 743 does not predict gender-dependent toxicity in humans.

Ecteinascidin 743 (ET743, NSC648766) is a marine natural product with potent in vivo activity in human xenograft models. Hepatotoxicity was the most prominent toxicity in preclinical studies and was greater in female rats than in male rats. To assess the potential implications for human toxicities, the in vitro metabolism of ET743 was characterized using rat and human preparations.

Mechanism of topical glucocorticoid treatment of hay fever: IL-5 and eosinophil activation during natural allergen exposure are suppressed, but IL-4, IL-6, and IgE antibody production are unaffected.

Background: Allergic rhinitis is traditionally defined as an IgE- and mast cell-mediated hypersensitivity reaction. Allergen challenge models suggest that cytokines and eosinophil mediators may also play roles. However, the causal relationship among inflammatory cells, their products, and patients' symptoms during natural allergen exposure has not been established.

Improved preservation of residual renal function in chronic hemodialysis patients using polysulfone dialyzers.

Our objective was to determine whether patients with chronic renal failure requiring maintenance hemodialysis retain intrinsic renal function longer when using reprocessed polysulfone (PS) membrane hemodialyzers or single-use cellulose acetate (CA) membrane hemodialyzers. Fifty consecutive patients with residual renal function (urea clearance > 2.0 mL/min) using PS dialyzers were compared with a retrospective, disease- and time-matched population of patients using CA dialyzers.

Occupational allergic rhinoconjunctivitis and asthma due to fennel seed.

Background: A patient with complaints of rhinitis and asthma occurring at work presented for consultation.

Objectives: To evaluate the role of the foods and spices with which he worked, in the causation of his complaints, and to evaluate his immune reactivity to these materials.

Methods: Allergy skin testing and in vitro RAST assays were carried out.

Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements.

Methods to examine sputum for indices of airway inflammation are evolving. We have examined the repeatability and the validity of an improved method to measure sputum cells and fluid-phase eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), albumin, fibrinogen, tryptase, and interleukin-5 (IL-5). Sputum was induced with hypertonic saline twice within 6 d in 10 healthy subjects, 19 stable asthmatics, and 10 smokers with nonobstructive bronchitis.

Clinical benefits of high and variable sodium concentration dialysate in hemodialysis patients.

Twenty-one hemodialysis patients were studied during 25 dialysis sessions with a dialysate sodium of 140 mEq/L and during 25 sessions with a high and variable sodium dialysate (145 mEq/L decreased to 140 mEq/L). Bicarbonate dialysate and ultrafiltration-controlled dialysis equipment were used. Neither the average interdialytic weight gain nor the predialysis and postdialysis blood pressures changed.

Anaphylaxis in a milk-allergic child after ingestion of milk-contaminated kosher-pareve-labeled "dairy-free" dessert.

Milk-allergic persons often rely on kosher labeling to select dairy-free foods. A 2-year-old boy experienced multiple generalized reactions after ingestion of milk or milk products; his serum contained elevated levels of milk-specific IgE antibodies, and his milk skin test was strongly positive. An identical reaction occurred after ingestion of "pareve"-labeled raspberry sorbet.

Narcotic-induced histamine release: a comparison of morphine, oxymorphone, and fentanyl infusions.

This study, using an improved histamine assay, repeated previous studies that demonstrated large doses of morphine for induction of anesthesia in patients undergoing coronary artery bypass grafting were associated with histamine release. Thirty randomized patients received infusions of either morphine, 1 mg/kg, oxymorphone, 0.2 mg/kg, or fentanyl, 50 micrograms/kg, over a 10-minute period for induction of anesthesia prior to surgery.

Laboratory investigation of deaths due to anaphylaxis.

To establish a useful laboratory protocol to investigate possible cases of fatal anaphylaxis, we measured mast-cell-derived tryptase levels and allergen-specific immunoglobulin E (IgE) antibody levels in sera obtained prior to or within 24 h after death from 19 anaphylaxis victims. Elevated serum tryptase levels (range = 12 ng/mL to 150 micrograms/mL) were found in nine of nine Hymenoptera sting fatalities, six of eight food-induced fatalities, and two of two reactions to diagnostic therapeutic agents. Tryptase levels were normal (less than 10 ng/mL) in 57 sequential sera obtained postmortem from six control patients.

Anaphylactoid reaction to ethanol.

We studied a 14-year-old boy who developed a pruritic rash and facial swelling after ingestion of beer or wine. A blinded challenge with purified ethanol was positive demonstrating ethanol itself to be the offending agent. An IgE-mediated reaction to ethanol or one of its metabolites as a hapten is possible, or the reaction may involve unusual metabolism of ethanol with accumulation of acetaldehyde and/or direct mast cell degranulation.