Assessment of Ethylene Glycol Monobutyl and Monophenyl Ether Reproductive Toxicity Using a Continuous Breeding Protocol in Swiss CD-1 Mice

Assessment of Ethylene Glycol Monobutyl and Monophenyl EtherReproductive Toxicity Using a Continuous Breeding Protocol inSwiss CD-1 Mice. HEINDEL, J. J., GULATI, D. K., RUSSELL, V.S., REEL, J. R., LAWTON, A. D., AND LAMB, J. C., IV. (1990).Fundam. Appl Toxicol. 15,683–696. A continuous breedingreproduction study design was utilized to examine the reproductivetoxicity of ethylene glycol monobutyl ether (EGBE) and ethyleneglycol monophenyl ether (EGPE). Swiss CD-1 mice were administeredEGBE in drinking water (0, 0.5, 1.0, and 2.0%, i.e., 0.7, 1.3,and 2.1 g/kg body wt/day) and EGPE was administered via thefeed (0, 0.25, 1.25, and 2.5%, i.e., 0,0.4,2.0, and 4 g/kg bodywt/day). Both male and female mice were dosed for 7 days priorto and during a 98-day cohabitation period. EGBE was toxic atthe high (2%) and mid dose (1%) to adult F₀ female mice: 13out of 22 females at the high dose and 6 out of 20 at the middose died during the cohabitation period. Both the high- andmid-dose animals produced fewer litters/pair, fewer pups/litter,with decreased pup weight. These effects occurred in the presenceof decreased body weight, decreased water consumption, and increasedkidney weight. A crossover mating trial indicated that the reproductiveeffects could be attributed primarily to an effect on the female.This was substantiated at necropsy where testes and epididymisweights were normal as were sperm number and motility. Fertilityof the offspring of the 0.5% group was normal in the presenceof increased liver weights. With respect to EGPE, there wasno change in the ability to produce five litters during thecontinuous breeding period. There was, however, a significantbut small (10–15%) decrease in the number of pups/litterand in pup weight in the high-dose group. A crossover matingtrial suggested a female component of the reproductive toxicityof EGPE. While fertility was only minimally compromised, severeneonatal toxicity was observed. By Day 21 there were only 8out of 40 litters in the mid- and high-dose groups which hadat least one male and female/litter. Second generation reproductiveperformance of the mid-dose group (1.25%) was unaffected exceptfor a small decrease in live pup weight. In summary the reproductivetoxicity of EGBE and EGPE was only evident in the female andoccurred at doses which elicited general toxicity. EGBE wasparticularly toxic to adult female mice while EGPE was particularlytoxic to immature mice of both sexes.     

Reversal of the inhibitory effects of HIV-gp120 on CD4+ T cells by stimulation through the CD28 pathway

The effects of exposure to HIV-gp120 on proliferation and cytokine production by T cell lines were investigated. T cell lines were generated by stimulation of peripheral blood mononuclear cells from several healthy donors with cross-linked anti-CD3 antibodies and IL-2. These T cell lines exhibited the characteristics of Th1 cells, producing IL-2 and interferon-gamma (IFN-γ), but not IL-4, on stimulation with anti-CD3 antibodies. In the presence of gp120, stimulation with anti-CD3 antibodies was inhibited in terms of both proliferative responses and the secretion of IL-2 and IFN-γ. Similar effects were observed when a T cell line was stimulated in the presence of a synthetic peptide representing the CD4-binding region of gp120. Neither gp120 nor the CD4-binding region peptide had any effect on IL-4 production by the T cell lines. Stimulation through the CD28 pathway partially restored both the proliferative effect and cytokine production by T cell lines in response to anti-CD3 antibodies in the presence of gp120. Anti-CD28 antibodies also partially restored cytokine production when purified CD4⁺ T cells from a T cell line were stimulated with anti-CD3 antibodies in the presence of gp120. Anti-gp120 antibodies partially or completely reversed the inhibitory effects of gp120 on T cell proliferation. These results indicate that stimulation through the CD28 pathway may restore defective CD4⁺ T cell responses in HIV-infected individuals.     

THE PATTERN OF K-rasMUTATION IN PULMONARY ADENOCARCINOMA DEFINES A NEW PATHWAY OF TUMOUR DEVELOPMENT IN THE HUMAN LUNG

Codon 12 of the K-ras oncogene was screened for mutations in 65 surgically-resected primary pulmonary adenocarcinomas and in 32 tissue foci of alveolar atypical hyperplasia (AAH) by a polymerase chain reaction (PCR)-based method. Mutations in either position 1 or position 2 of codon 12 were detected in 16 tumours (25 per cent). When analysed by site of origin, mutations were seen in 9/26 (35 per cent) parenchymal and in 0/12 bronchial adenocarcinomas (P<0·02). K-ras mutations were seen in five AAH lesions from four patients. DNA sequencing showed that the great majority of mutations in both adenocarcinomas and AAH were G–T transversions. These findings provide support for the classification of pulmonary adenocarcinomas into bronchial and parenchymal subtypes and also provide molecular evidence to support the importance of AAH in the development of parenchymal cancers. © 1997 by John Wiley & Sons, Ltd.     

THE IMMUNOLOGICAL ARCHITECTURE OF B-LYMPHOCYTE AGGREGATES IN CRYPTOGENIC FIBROSING ALVEOLITIS

Cryptogenic fibrosing alveolitis (CFA) is believed to have a pathogenesis mediated by the cellular arm of the immune system. Previous studies have, however, indicated the presence of B-lymphocyte aggregates, as well as evidence of local immunoglobulin production and increased levels of B-cell growth factors. It has recently been shown that CFA is associated with the production of circulating IgG autoantibodies to antigen(s) associated with alveolar lining cells. This prompted an examination of the immunological architecture of the B-lymphocyte aggregates, in order to assess whether they might provide histological confirmation of a local humoral immune response in these patients. Thirty-eight consecutive open lung biopsy specimens were examined from patients with CFA and aggregates of B lymphocytes were identified in 37/38. In only five cases were germinal centres seen. The morphological appearances of the aggregates were reminiscent of those observed in mucosal associated lymphoid tissue (MALT). Using immunohistochemistry, despite the low frequency of true germinal centre formation, the B-lymphocyte aggregates were shown to contain the cellular micro-environment necessary for a humoral immune response. In addition, there was evidence of lymphocyte proliferation and activation within these aggregates. These results provide evidence of a local humoral immune response associated with B-lymphocyte aggregates in the lungs of patients with CFA.     

LOSS OF HETEROZYGOSITY AT 5q21 IN NON-SMALL CELL LUNG CANCER: A FREQUENT EVENT BUT WITHOUT EVIDENCE OF APC MUTATION

Four genetic polymorphisms in the APC and MCC genes at chromosome 5q21 were analysed for loss of heterozygosity (LOH) in 97 primary squamous carcinomas and adenocarcinomas of the lung. LOH was identified in at least two polymorphic loci in 41 percent of informative cases. There was no significant difference in the frequency of LOH between squamous carcinomas and adenocarcinomas. Within the adenocarcinoma group, however, LOH appeared to be more common in tumours having a bronchial origin (5/9; 56 per cent) than in parenchymal adenocarcinoma (6/21; 29 per cent). All 32 tumours showing LOH at one or more polymorphic sites were examined for mutations in the mutation cluster region (MCR) of APC by single-strand conformational polymorphism (SSCP) analysis. Mutations were not detected in any of these cases. We therefore propose that it is likely that a tumour suppressor gene on 5q other than APC is involved in the pathogenesis of lung cancer.     

OCULAR COMPLICATIONS IN HAEMODIALYSIS AND RENAL TRANSPLANT PATIENTS

Abstract
115 patients on haemodialysis and 160 renal transplant patients were examined over an eight year period. A high percentage in both groups were found to have ocular complications. These included disorders of the cornea, lens, retina, choroid, and optic nerve. In contrast to other studies on renal transplant patients a relatively large number had symptoms and even required surgery for cataract removal. 65 (40. 7%) had posterior sub-capsular cataracts. It is likely that nearly all were caused by the use of prednisone for immunosuppression. Of this number 25 (38.5%) had symptoms and 12 (18.5%) required cataract extraction. Pigmentary disturbances of the retinal pigment epithelium, together with vascular changes in the choroid were found in some. The implication of these relatively unknown complications, together with their possible aetiology, is discussed. The study emphasises the fact that all haemodialysis ana renal transplant patients should be monitored for ocular complications.     

Events of the excitation–contraction–relaxation (E–C–R) cycle in fast- and slow-twitch mammalian muscle fibres relevant to muscle fatigue

The excitation–contraction–relaxation cycle (E–C–R) in the mammalian twitch muscle comprises the following major events: (1) initiation and propagation of an action potential along the sarcolemma and transverse (T)-tubular system; (2) detection of the T-system depolarization signal and signal transmission from the T-tubule to the sarcoplasmic reticulum (SR) membrane; (3) Ca²⁺ release from the SR; (4) transient rise of myoplasmic [Ca²⁺]; (5) transient activation of the Ca²⁺-regulatory system and of the contractile apparatus; (6) Ca²⁺ reuptake by the SR Ca²⁺ pump and Ca²⁺ binding to myoplasmic sites. There are many steps in the E–C–R cycle which can be seen as potential sites for muscle fatigue and this review explores how structural and functional differences between the fast- and slow-twitch fibres with respect to the E–C–R cycle events can explain to a great extent differences in their fatiguability profiles.