Lack of airway response to nasal irritation in normal and asthmatic subjects

Abstract Twenty two subjects (10 normals, nine asthmatics and three who had suggestive histories for asthma but normal bronchial histamine challenges) underwent nasal challenges with logarithmic incremental doses of histamine or saline on alternate days. Nasal resistance (measured by posterior rhinometry), and forced expiratory volume in one second (FEV₁) were assessed after each dose of nasal histamine or placebo. After each nasal challenge (maximum nasal dose of 250 μg of histamine or doubling of nasal resistance) bronchial responsiveness was measured with a bronchial histamine challenge. Despite significant changes in nasal resistance with nasal histamine (p < 0.01) there was no significant change in the forced expiratory volume in one second, or in bronchial responsiveness. We were unable to demonstrate nasobronchial reflexes initiated by acute irritation of the nasal mucosa with histamine in either normal subjects or in those with mild to moderate asthma.     

MODES OF INACTIVATION OF NEUROHYPOPHYSIAL HORMONES: SIGNIFICANCE OF PLASMA DISAPPEARANCE RATE FOR THEIR PHYSIOLOGICAL RESPONSES

Analogues of oxytocin and deaminooxytocin with 4-glutamine replaced by 4-glutamic acid methyl ester readily lose their uterotonic activity when incubated with rat serum, presumably by hydrolysis to the much less active 4-glutamic acid derivatives. On the other hand, inactivation of the deaminooxytocin analogue in the rat uterus, as demonstrated by the 'oil-bath'technique, is only slightly more rapid than that of deaminooxytocin and distinctly slower than that of oxytocin. Its in situ/in vitro ratio of uterotonic activity is less than 0.1 whereas that for deaminooxytocin is about 3 and also the persistence of the uterotonic effect in situ is slightly less than that of deaminooxytocin. The results with these 'rapidly inactivated'analogues can be used as proof of some predictions of the three-compartment model for tissue distribution of neurohypophysial hormones and its influence upon the time course of a biological response published earlier. The potential use of analogues of neurohypophysial hormones as probes for inactivation mechanisms and the results thus far obtained are discussed.     

ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis

Estrogens can regulate germ cell function. Estrogen action is mediated via high affinity ERs; two subtypes (ERalpha and ERbeta) have been identified. We have shown previously that ERbeta is expressed in nuclei of multiple human testicular cells. A variant isoform of human (h) ERbeta (hERbetacx/2), formed by alternative splicing, has been identified in testicular cDNA libraries by two laboratories. The present study examined the expression of wild-type (ERbeta1) and variant (ERbeta2) beta receptors in human testes by 1) RT-PCR with isoform specific primers, and 2) single and double immunohistochemistry using monoclonal antibodies raised against peptides unique to the C termini of hERbeta1 and hERbeta2. PCR products specific for ERbeta1 and ERbeta2 were amplified from cDNA pools prepared from human testes and granulosa cells. On Western blots, the anti-ERbeta1 monoclonal antibody bound to recombinant ERbeta1 and the anti-ERbeta2 monoclonal to recombinant hERbeta2. Neither bound to the other ERbeta isoform nor to recombinant ERalpha. ERbeta1 and ERbeta2 proteins were both detected in human testis. Immunoexpression of ERbeta1 was most intense in pachytene spermatocytes and round spermatids, whereas low levels of expression were detected in Sertoli cells, spermatogonia, preleptotene, leptotene, zygotene, and diplotene spermatocytes. Highest levels of expression of ERbeta2 protein were detected in Sertoli cells and spermatogonia with low/variable expression in preleptotene, pachytene, and diplotene spermatocytes. No immunostaining was detected in elongating spermatids. Most interstitial cells expressed more ERbeta2 than ERbeta1. It is speculated that the cells most susceptible to modulation by estrogenic ligands are round spermatids in which levels of expression of ERbeta1 are high. In contrast, expression of ERbeta2, an isoform that may act as a dominant negative inhibitor of ER action, in Sertoli cells and spermatogonia, could protect these cells from adverse effects of estrogens.     

Response to 2'-deoxycoformycin after failure of interferon-alpha in nonsplenectomized patients with hairy cell leukemia

Two patients with hairy cell leukemia with massive splenomegaly and severe pancytopenia were treated with recombinant alpha-A interferon (IFN-alpha-2a). There was no significant response to a trial of IFN- alpha-2a (11 and 20 weeks) with respect to blood counts or spleen size. Subsequent treatment with 2'-deoxycoformycin (dCF) for 8 consecutive weeks (4 mg/m2/wk) resulted in normalization of spleen size and a normalization of peripheral blood counts and bone marrow in one patient. The second patient demonstrated a reduction in spleen size and improved blood counts following 9 weeks of dCF therapy but eventually became refractory. This demonstrates that dCF is non-cross-resistant with interferon and confirms the efficacy of dCF in nonsplenectomized patients.     

IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis

Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell–mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases.Disease conditions associated with pulmonary fibrosis are often progressive and have a poor long-term prognosis (1). In the context of developing new treatments for pulmonary fibrosis, the cytokines associated with the pathogenic milieu that can lead to aberrant extracellular matrix deposition are key targets, in particular interleukin (IL)-13, TGF-β, and, more recently, IL-17A (2). However, to develop more effective therapeutics for fibrotic lung diseases a greater understanding of the pathogenesis and the underlying mechanisms that lead to pulmonary fibrosis is needed (3, 4).The cytokine IL-13 was first implicated in fibrosis using profibrotic eggs from the type 2 cytokine-inducing pathogen Schistosoma mansoni, in the presence of a soluble IL-13Rα2-Fc fusion protein (5) and in Il13^−/− mice (6). IL-13 is now widely linked to a range of fibrotic conditions (7) including asthma, where IL-13 is being targeted as a therapy (8). In the context of the cellular source of IL-13 in the generation of fibrosis, CD4⁺ T helper (h) 2 cells are implicated (9). However, more recently innate lymphoid cells (ILC) are emerging as an important source of IL-13 (10, 11). In this context, the type 2 cytokine IL-25 is implicated in the generation of the recently identified IL-13–expressing ILC, termed ILC2 (11–14).Recent studies have implicated IL-25 and ILC2 in the pathogenesis of pulmonary conditions in both murine models and human conditions such as allergic asthma (12, 13, 15, 16). In murine studies intranasal administration of IL-25 results in evidence of pulmonary tissue remodeling including development of perivascular fibrosis, and intratracheal administration results in increased pulmonary Th2 cytokines and airways hyper-reactivity (AHR) (17, 18), whereas blocking IL-25 reduces AHR severity (19). Herein we describe a potential role for IL-25 in the generation of pulmonary fibrosis in experimental mouse models, via the activation of IL-13–producing ILC2. We also observe increases in both IL-25 and ILC2 in the lung of patients with idiopathic pulmonary fibrosis (IPF). These data suggest unique mechanisms for the generation of pulmonary fibrosis and identify an interesting area for further research on the role of IL-25 and ILC2 in the treatment of pulmonary fibrosis.     

Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: Pharmacokinetic characteristics

Treatment with 6-mercaptopurine (6MP) is associated with adverse gastrointestinal (GI) and hepatic effects. Four patients, ages 6.9 ± 2.6 (mean ± S.D.) years, with acute lymphocytic leukemia (ALL) on maintenance chemotherapy including 6MP, developed nausea, vomiting, abdominal pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 ± 1.0 (range 0.5–2) years. Liver biopsy in 1 patient was suggestive of drug-induced intrahepatic cholestatis. Symptoms resolved and liver function returned to normal after discontinuation of 6MP. Pharmacokinetic data of the symptomatic patients were compared with those of 25 ALL patients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabolites of 6MP in red blood cells of the patients with hepatotoxicity, were not significantly different when compared to patients without hepatotoxicity, suggesting similar absorption of 6MP in both groups. Time to achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak levels and standardized concentration versus time curve (AUC) per 1 mg of 6MP per m² of body surface area were significantly lower in the patients with hepatotoxicity (P = 0.016; P = 0.037, respectively). A significant correlation between peak 6MP levels and standardized AUC (r = 0.729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, leading to hepatotoxicity. © 1996 Wiley-Liss, Inc.     

On Turner's assessment of the personality assessment system

There are four principal flaws in the Turner, Willerman, and Horn (1976) assessment of the Personality Assessment System. (1) The methodologies employed are entirely linear and therefore fail to address the central innovative idea of the PAS, which is that personality can be accounted for through the interactions of abilities. (2) The specific hypotheses advanced, which are alleged to be deductions from the PAS, are based at best on an oversimplified understanding of the theory. (3) The sample employed is biased strongly toward overcompensation; this fact and its predictable consequences have gone unrecognized. (4) The MMPI clinical scales have been assumed to furnish reliable and valid measurement in an allegedly normal group. Viewed in the context of these problems, Turner's results are entirely consistent with the PAS. Indeed, strong support may be adduced from Turner's data for a global hypothesis of communality between the PAS and the 16PF.     

Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies

Arthrogryposis multiplex congenita affects approximately 1 in 3,000 individuals of different ethnic backgrounds and displays an equal incidence in males and females. The underlying mechanism for congenital contracture of the joints is decreased fetal movement during intrauterine development. This disorder is associated with over 400 medical conditions and 350 known genes that display considerable variability in phenotypic expression. In this report, four fetal or perinatal autopsy cases of arthrogryposis were studied by gross morphology, microscopic histopathologic examination, and whole genome sequencing of postmortem DNA. Two stillborn sibling fetuses with arthrogryposis, pterygia, and amyoplasia had compound heterozygous pathogenic variants in NEB. A neonate with a histopathologic diagnosis of nemaline myopathy had a heterozygous de novo pathogenic variant in ACTA1. Another stillborn infant with pterygia and arthrogryposis had a heterozygous de novo likely pathogenic variant in BICD2. These cases demonstrate the utility of whole genome sequencing as the principal diagnostic method of lethal forms of skeletal muscle disorders that present with arthrogryposis and muscle amyoplasia/hypoplasia. Molecular diagnosis provides an opportunity for studying patterns of inheritance and for family counseling concerning future pregnancies.