Shmuel Kivity

Randomised crossover trial of naltrexone in uraemic pruritus

BACKGROUND Most dialysis patients develop pruritus, for which current treatment is unsatisfactory. Endogenous opioids may be involved in this pruritus. We studied the effect of the opioid antagonist naltrexone on the pruritus of haemodialysis patients. METHODS Naltrexone 50 mg per day by mouth was given to 15 haemodialysis patients with severe resistant pruritus in a randomised, double-blind, placebo-controlled crossover trial. The naltrexone or placebo periods lasted 7 days each with a 7-day washout between the two periods. Pruritus was assessed by the patients on a visual analogue scale from 0 (no pruritus) to 10 (maximum), and mean daily scores were calculated. Plasma histamine and beta-endorphin levels were measured, and spontaneous and stimulated basophil histamine-release were determined. FINDINGS The median pruritus scores at the end of the naltrexone treatment were 2.1 (interquartile range 1.5-2.15) for the naltrexone-placebo sequence and 1.0 (0.4-1.15) for the placebo-naltrexone sequence. The respective values before naltrexone was given were 9.9 (9.85-9.95) and 9.9 (9.3-10.0). Plasma beta-endorphin levels were normal and remained unchanged during the study. Plasma histamine levels were high (mean 2.32 [SD 0.11] ng/mL, normal < 1.0) and decreased after naltrexone (to 1.8 [0.09], p < 0.01). Basophils from haemodialysis patients stimulated by interleukin-3 plus IgE antibodies released high amounts of histamine. The increase was 78.3 (19.3)% compared with 26.6 (16.3)% for five normal controls (p < 0.01). Incubation of the basophils with naloxone, another opioid antagonist, prevented this effect. INTERPRETATION Our data suggest short-term efficacy with few side-effects for the amelioration of uraemic pruritus with naltrexone.

A clinical and immunologic study of colchicine in asthma.

A double-blind, randomized, crossover chronic study was done to determine the efficacy of colchicine in 10 atopic patients with asthma. A constant dose of sustained-release theophylline and albuterol by inhalation, as needed, was administered. Compared to placebo, colchicine, 0.5 mg twice daily, significantly reduced the mean (+/- SEM) daily clinical score from 2.18 +/- 0.34 to 1.64 +/- 0.32 (p less than 0.05), and the daily number of inhalations of albuterol from 5.89 +/- 1.48 to 4.01 +/- 1.26 (p less than 0.02). Colchicine significantly (p less than 0.05) increased the concanavalin A-induced suppressor cell function from 16.2 +/- 4.6% to 39.0 +/- 10.7%, which was similar to healthy volunteers (41.1 +/- 3.5%). Furthermore, colchicine significantly (p less than 0.05) decreased serum IgE from 248 +/- 63 to 188 +/- 46 IU/ml. Colchicine had no significant effect on pulmonary function tests, the early phase reaction of antigen-induced bronchial inhalation challenge, and immediate skin test responses. Thus, colchicine has immunomodulatory effects that may perhaps have a mild benefit in the treatment of asthma.

The effect of food and exercise on the skin response to compound 48/80 in patients with food-associated exercise-induced urticaria-angioedema.

Food-associated, exercise-induced urticaria-angioedema is increasingly being recognized. We studied five atopic individuals in whom ingestion of food was followed by exercise-induced urticaria-angioedema. The combined effect of food and exercise on skin wheal response to compound 48/80 and histamine was studied. Symptoms could be reproduced in only four of the patients who performed strenuous exercise after ingestion of food to which they were skin sensitive. When symptoms appeared, that is, after a combination of food and exercise challenge, there was a marked increase in the wheal response to compound 48/80 (greater than 200%) and not to histamine. Food or exercise challenge alone did not induce any significant change in the skin reactivity to compound 48/80 or to histamine. It was concluded that mast cell releasability could be increased when the patient was subjected to combined factors.

Mite asthma in childhood: A study of the relationship between exposure to house dust mites and disease activity

BACKGROUND Children with asthma are commonly sensitized to the house dust mite. METHODS We took monthly measurements from July to December of the amount of mites in the mattresses of asthmatic children and correlated them with symptom score, pulmonary function, and airway hyperreactivity to methacholine. RESULTS In spite of the high number of Dermatophagoides pteronyssinus throughout this period, symptom and treatment scores, as well as PC20 to methacholine, worsened during the months of September and October. CONCLUSIONS It is concluded that when asthmatic children allergic to mites are exposed to high levels of mite allergen, the number of mites in the mattress dust no longer correlate with increased symptoms, and that other factors are more likely to be associated with exacerbation.

Expression of Th17 and Treg Lymphocyte Subsets in Hypertrophied Adenoids of Children and its Clinical Significance

Adenoid hypertrophy is the most common cause of upper airway obstruction and sleep-disordered breathing in children, yet its pathogenesis remains unclear. The identification of the novel helper T cell subsets, Th17 cells and regulatory T cells (Tregs) could provide new insight into our understanding of the mechanisms involved in the development of this condition. The purpose of this study is to evaluate the adenoidal lymphocyte subsets to describe the percentage of various lymphocyte subsets in hypertrophied adenoids and correlate them with symptom severity. Twenty consecutive children undergoing adenoidectomy were included, and lymphocytes were isolated from their adenoids. T cell subpopulations were detected by flow cytometry using a fluoresceinated monoclonal antibody directed against a number of cell markers (CD4+, CD8+, CD25+, FOXP3 IL17+, and others). We found a significant negative linear correlation between the Th17/Treg ratio and the patients’ clinical scores (R = −0.71 p < 0.005). The correlation was independent of age and gender. Decreased ratios of Th17/Treg subpopulations may play a role in the pathogenesis of adenoid hypertrophy.

Omalizumab for severe chronic spontaneous urticaria: Real-life experiences of 280 patients

Omalizumab for severe chronic spontaneous urticaria: Real-life experiences of 280 patients Zahava Vadasz, MD, PhD, Yuval Tal, MD, Menachem Rotem, MD, Vered Shichter-Confino, MD, Keren Mahlab-Guri, MD, Yael Graif, MD, Aharon Kessel, MD, Nancy Agmon-Levin, MD, Ramit Maoz-Segal, MD, Shmuel Kivity, MD, Shira Benor, MD, Idit Lachover-Roth, MD, Yuri Zeldin, MD, Migel Stein, MD, Ori Toker, MD, Gamal Hassoun, MD, Shira Bezalel-Rosenberg, MD, Elias Toubi, MD, Ilan Asher, MD*, and Zev Sthoeger, MD*; for The Israeli Forum for investigating and treating Chronic Spontaneous Urticaria (CSU)

Phospholipase A2-dependent release of inflammatory cytokines by superantigen-stimulated nasal polyps of patients with chronic rhinosinusitis.

Background Chronic rhinosinusitis (CRS) is an inflammatory/allergic disease with unclear pathophysiology, but it has been linked to an imbalance in the production of eicosanoids, which are metabolites of arachidonic acid, and results from phospholipids hydrolysis by phospholipase A2 (PLA2). As of yet, the role of PLA2 in CRS has hardly been studied, except for a report that group II PLA2 expression is elevated in interleukin (IL) 1β or tumor necrosis factor α-stimulated CRS nasal tissues with and without polyps. The PLA2 families include extracellular (secretory) and intracellular isoforms, which are involved in the regulation of inflammatory processes in different ways. Here we comprehensively investigated the expression of PLA2s, particularly those reported to be involved in respiratory disorders, in superantigen (SAE)-stimulated nasal polyps from patients with CRS with polyps, and determined their role in inflammatory cytokine production by inhibition of PLA2 expression. Methods The release of IL-5, IL-13, IL-17, and interferon γ by nasal polyps dispersed cells (NPDC) was determined concomitantly with PLA2 messenger RNA expression, under SAE stimulation, with or without dexamethasone, as a regulator of PLA2 expression. Results Stimulation of NPDCs by SAE-induced cytokine secretion with enhanced expression of several secretory PLA2 and Ca2+-independent PLA2, while suppressing cytosolic PLA2 expression. All these were reverted to the level of unstimulated NPDCs on treatment with dexamethasone. Conclusion This study further supports the key role of secretory PLA2 in the pathophysiology of respiratory disorders and presents secretory PLA2 inhibition as a therapeutic strategy for the treatment of CRS and airway pathologies in general.

Differential Proliferative Characteristics of Alveolar Fibroblastsin Interstitial Lung Diseases: Regulative Role of IL-1 and PGE2

Fibroblasts (Fb) from patients with sarcoidosis (SA) and hypersensitivity pneumonitis (HP) exhibited a lower proliferative capacity compared with Fb obtained from control (CO) and diffuse interstitial fibrosis patients (DIF). Proliferation of Fb from SA or lip patients was suppressed by autologous LPS-stimulated alveolar macrophages (AM) supernatants but not by those from CO patients. Similarly, alveolar macrophages (AM) derived supernatant, obtained from CO, did not suppress the proliferation of SA and HP Fb. AM from SA and HP patients secreted higher amounts of IL-1α and β compared with controls and compared with Fb from SA and HP patients. Steady levels of IL-1α and βmRNA were expressed in unstimulated and stimulated cultures. Fb from SA and HP patients could be stimulated by LPS to secrete significantly higher levels of PGE2 than those detected in supernatants from LPS stimulated Fb of DIF patients. Only the proliferation of Fb from SA and HP patients was sensitive to amounts of IL-1 equivalent to those detected in the lung of these diseases. As SA and HP are two diseases where irreversible deterioration occurs in only 20% of the patients, we hypothesize that mediators in the lung may modulate Fb proliferation. IL-1 of AM origin and PGE2 of Fb origin secreted at high levels, may be candidates for this suppression because it was abrogated by anti IL-1β and indomethacin.