Incidences of selected lesions in control female Harlan Sprague-Dawley rats from two-year studies performed by the National Toxicology Program

The NTP has a long history of using Fischer rats and has compiled a large database of incidences of lesions seen in control animals. Such a database is lacking for Harlan Sprague-Dawley (SD) rats. The intention of this paper is to report spontaneous lesions observed in female vehicle control Harlan SD rats, and to compare the incidence in 2 strains of rats (Fischer and Harlan SD) used in NTP studies. Female Harlan SD rats served as the test animals for a special series of 2-year studies. Male rats were not used in these studies. Complete histopathology was performed on all animals, and the pathology results underwent comprehensive NTP pathology peer review. The most commonly observed neoplasms in these female control Harlan SD rats were mammary gland fibroadenoma (71%), tumors of the pars distalis of the pituitary (41%) and thyroid gland C-cell tumors (30%). Female Fischer rats had incidences of 44% for mammary gland fibroadenomas, 34% for tumors of the pars distalis, and 16% for thyroid gland C-cell tumors. Fischer rats had a 15% incidence of clitoral gland tumors, while the Harlan SD rats had an incidence of < 1%. In contrast to Fischer F344 rats, the Harlan SD rats had a high incidence of squamous metaplasia of the uterus (44.2%). Squamous metaplasia is not a lesion commonly observed in NTP control Fischer rats. The Harlan SD rats had a very low incidence of mononuclear cell leukemia (0.5%), compared with an incidence of 24% in female Fischer rats.     

Redistribution of Na-K-ATPase in the dystrophic rat retinal pigment epithelium

Summary Our previous studies have shown that a breakdown in tight junctions in the dystrophic retinal pigment epithelium (RPE) of Royal College of Surgeons' rats is accompanied by changes in intramembrane structure which suggest a redistribution of intramembrane particles. We have now investigated, using thep-nitrophenyl phosphate technique, the possibility that a specific membrane protein, Na-K-ATPase, is redistributed as tight junctions break down in the dystrophic RPE. In the normal RPE, Na-K-ATPase activity is restricted to the apical membrane. Junctional membranes and membranes around phagosomes are free of enzyme activity, suggesting a segregation of the transport enzyme from the Junctional and phagocytic membrane. In the dystrophic RPE, prior to changes in tight junctions, enzyme activity is restricted to the apical membrane. During the initial stages of Junctional breakdown, Junctional membranes and membranes around cytoplasmic inclusions are also labelled. As the breakdown progresses, Na-K-ATPase activity is often present laterally and basolaterally and is sometimes absent apically. Enzyme activity is seen basally only where RPE cells have detached from Bruch's membrane and are superimposed over each other. These changes suggest that Na-K-ATPase redistributes during junctional breakdown, but that attachments between the RPE and Bruch's membrane may restrict the redistribution. The apparent reduction of enzyme activity apically suggests that active transport across the dystrophic RPE may be reduced as the tight junctions break down.     

Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons

Mast cells that are in close proximity to autonomic and enteric nerves release several mediators that cause neuronal hyperexcitability. This study examined whether mast cell tryptase evokes acute and long-term hyperexcitability in submucosal neurons from the guinea-pig ileum by activating proteinase-activated receptor 2 (PAR2) on these neurons. We detected the expression of PAR2 in the submucosal plexus using RT-PCR. Most submucosal neurons displayed PAR2 immunoreactivity, including those colocalizing VIP. Brief (minutes) application of selective PAR2 agonists, including trypsin, the activating peptide SL-NH₂ and mast cell tryptase, evoked depolarizations of the submucosal neurons, as measured with intracellular recording techniques. The membrane potential returned to resting values following washout of agonists, but most neurons were hyperexcitable for the duration of recordings (> 30 min–hours) and exhibited an increased input resistance and amplitude of fast EPSPs. Trypsin, in the presence of soybean trypsin inhibitor, and the reverse sequence of the activating peptide (LR-NH₂) had no effect on neuronal membrane potential or long-term excitability. Degranulation of mast cells in the presence of antagonists of established excitatory mast cell mediators (histamine, 5-HT, prostaglandins) also caused depolarization, and following washout of antigen, long-term excitation was observed. Mast cell degranulation resulted in the release of proteases, which desensitized neurons to other agonists of PAR2. Our results suggest that proteases from degranulated mast cells cleave PAR2 on submucosal neurons to cause acute and long-term hyperexcitability. This signalling pathway between immune cells and neurons is a previously unrecognized mechanism that could contribute to chronic alterations in visceral function.     

Immunologic mechanisms in hypersensitivity pneumonitis: I. Evidence for cell-mediated immunity and complement fixation in pigeon breeders' disease

Immunologic studies were performed on 5 patients with pigeon breeders' disease. Intradermal injection of pigeon serum produced an immediate wheal-and-flare reaction within 15 minutes and a secondary Arthus-type reaction within 4 to 8 hours. Immunofluorescent studies of the secondary reaction site showed IgG, C3, and C4 in 2 patients. Patients' sera produced multiple precipitin bands with pigeon serum when reacted by double diffusion in gel. IgG antibody isolated from each of the patients' serum formed precipitating immune complexes that fixed large amounts of complement (C4) when added to fresh human serum. Peripheral blood lymphocytes from 4 of the 5 patients produced macrophage migration inhibitory factor (MIF) when challenged with dilute pigeon serum. These studies are the first to show complement fixing antibodies and macrophage MIF production by lymphocytes from patients with hypersensitivity lung disease and suggest that both humoral and cellular immunity may be important in the pathogenesis of these disorders.     

Effects of supra-physiological changes in human ovarian hormone levels on maximum force production of the first dorsal interosseus muscle

The purpose of this study was to investigate the effects of supra-physiological changes in ovarian hormone levels on maximum force production in two conditions, one physiological (pregnancy) and one pseudo-physiological (in vitro fertilization (IVF) treatment). Forty IVF patients were tested at four distinct stages of treatment and 35 women were tested during each trimester of pregnancy and following parturition. Maximum voluntary isometric force per unit cross-sectional area of the first dorsal interosseus muscle was measured. Plasma concentrations of total and bioavailable oestradiol and testosterone were measured, in addition to the total concentrations of progesterone and human chorionic gonadotropin. Despite significant changes in the concentrations of total progesterone, 17beta-oestradiol, bioavailable oestradiol and testosterone between phases, strength did not change significantly throughout IVF treatment (1.30+/-0.29, 1.16+/-0.38, 1.20+/-0.29 and 1.26+/-0.34 N mm-2, respectively, in the 4 phases of IVF treatment). Force production was significantly higher during the second trimester of pregnancy than following childbirth (1.33+/-0.20 N mm-2 at week 12 of pregnancy, 1.51+/-0.42 N mm-2 at week 20, 1.15+/-0.26 N mm-2 at week 36 and 0.94+/-0.31 N mm-2 at week 6 postnatal) but was not significantly correlated with any of the hormones measured. These data suggest that extreme changes in the concentrations of reproductive hormones do not affect the maximum force-generating capacity of young women.