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Experiments were conducted on male, Sprague-Dawley rats of the same age fed a standard laboratory diet to determine the comparative effects of single and concurrent subclinical infections by coccidia (Eimeria nieschulzi) and roundworms (Nippostrongylus brasiliensis) on nutritional status and metabolism. All infections produced anorexia, but it was more prolonged and intense with the concurrent ones. Feed:gain ratios were increased only by infections by nematodes alone, but average daily gains were reduced beyond the effect of anorexia (i.e., "specifically") only with the double infections. Infections by coccidia only, but not by nematodes only, specifically reduced the apparent digestibility of dry matter, organic matter and N; whereas only the apparent N digestibility was specifically reduced by the double infections. Balances of N were reduced in infected rats and pair-fed controls during anoretic periods, but significant differences between the daily means for infected and pair-fed rats occurred only erratically. Specific increases in urinary N loss did not occur with the single infections, but occurred on 2 d with the double ones. Increased losses of fecal N occurred with both coccidial and double infections, but they were much more pronounced in the latter. No effects of infection on the balances or carcass contents of Ca and P occurred. The only significant differences between mean empty carcass densities occurred with the double-infected and free-fed uninfected groups, with the mean for the uninfected group being the higher.

Brains of growth hormone (GH)- and prolactin (PRL)-deficient Ames (df/df) and Snell (dw/dw) dwarf mice and normal mice of the same strains were examined for catecholamine (CA) histofluorescence, with particular emphasis upon the hypothalamic tuberoinfundibular (A12) (arcuate nucleus/median eminence) region, which plays a role in the regulation of both GH and PRL. Dwarfs and normal animals of both types also were treated with a drug regimen to deplete sequentially neuronal CA stores (reserpine), inhibit CA oxidation (nialamide) and load dopaminergic A12 cells with exogenous transmitter (norepinephrine), in order to test viability and axonal transport capacity of A12 neurons. In both types of dwarfs, compared with normals, fluorescence was markedly reduced in the zona externa of the median eminence, which is normally rich in terminals from A12 neurons. Fluorescence in the median eminence was particularly weak in Ames dwarfs, and A12 perikarya were difficult to discern in this group. Snell dwarfs showed reduced fluorescence of A12 perikarya when compared with the brightly fluorescent perikarya seen in normal mice. In supraoptic and paraventricular nuclei, and in the zona interna of the median eminence, CA fluorescence attributable to NE was comparable among dwarfs and normals; fluorescence of dopaminergic perikarya in substantia nigra was also unaffected in dwarfs. Exogenously administered NE effected enhanced fluorescence of A12 perikarya in normal mice and in Snell dwarfs; NE treatment in the Ames dwarf, however, failed to increase significantly the faint fluorescence of A12 cell bodies. The results indicate that dopaminergic A12 neurons in Snell dwarf mice are present and viable.(ABSTRACT TRUNCATED AT 250 WORDS)

The separate steps in the formation of aldosterone from cholesterol were studied in a strain of spontaneously hypertensive rats in which phenotypic obesity is inherited as a recessive trait (Koletsky rats). The obese and hypertensive state had little or no effect on side-chain cleavage of cholesterol, formation of progesterone from pregnenolone or 21-hydroxylation. Mitochondrial 18-hydroxylation of endogenous and exogenous corticosterone, however, as well as 18- and 11 beta-hydroxylation of deoxycorticosterone, were increased in obese hypertensive rats, both when compared with non-obese hypertensive siblings and when compared with healthy Sprague-Dawley rats. 18-Hydroxylation of corticosterone was increased more than 18-hydroxylation of deoxycorticosterone. In non-obese hypertensive rats, the adrenal content of mitochondrial cytochrome P-450 was lower than that in obese hypertensive rats but higher than that in rats of the conventional Sprague-Dawley strain. The results are discussed with respect to possible heterogeneity of adrenal cytochrome P-450 and to possible explanations for the changes observed.

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) acts through postsynaptic receptor sites which regulate membrane chloride ion channels. The GABA receptor-ionophore complex also contains modulatory receptor sites for two classes of centrally acting drugs, one for the benzodiazepines, and a second for both barbiturates and related depressants and for picrotoxin and related convulsants. The presence of these drug modulatory sites, directly on the GABA receptor protein, is consistent with other experimental observations; blocking GABA function can cause seizures, and augmenting GABA function can afford protection against seizures. This, and other circumstantial evidence, has suggested the possibility that a functional GABA deficit may be involved in some kinds of human epilepsy. Some neurochemical markers for GABA synapses have been reported to be altered in certain animal models as well as in human temporal lobe epilepsy. We have examined the postsynaptic GABA receptor complex using receptor binding assays for GABA, benzodiazepine (BZ), and barbiturate receptor sites in the seizure-susceptible gerbil, a genetic model of generalized epilepsy. A 30% deficit in BZ receptor binding was observed in the midbrain of seizure-sensitive animals relative to normal controls. This was shown by quantitative brain-slice binding autoradiography to involve a decrease in the number of binding sites in the substantia nigra (SN) and periaqueductal gray regions. A deficit in membrane receptors for BZs (which are linked to a subtype of postsynaptic GABA receptors) in a crucial region of brain might therefore contribute to seizure susceptibility in some kinds of epilepsy.

Light and electron microscopic observations on the structure of epiphyseal cartilages in the cmd/cmd mice, which had genetically failed to synthesize cartilage-characteristic proteoglycan but were normal in type II collagen synthesis, showed apparent abnormalities of collagen fibrils: e.g. increase in the diameter, appearance of periodic banding patterns and bundle-formation of collagen fibrils. These findings suggest that cartilage-characteristic proteoglycan normally limits the lateral growth of collagen fibrils and affects collagen fibrillogenesis in vivo.

Total hepatic water content, dry weight, protein, lipid, carbohydrate, RNA, DNA, and electrolyte concentrations were determined in control and Streptococcus pneumoniae-infected rats. During infection, there was a significant (P = 0.001) increase in total liver weight. This increase was the result of increased total liver water content and increased total liver dry weight. Intracellular water content, diameter of hepatocytes, and all measured constituents of hepatic dry weight, excluding DNA, increased significantly (P varied from 0.05-0.001) during infection. Concentrations of liver Na+ and Cl- increased significantly (P varied from 0.05-0.005), whereas the concentration of liver K+ decreased significantly (P = 0.01). Seemingly, there is an enlargement of hepatocytes due to increased intracellular water and increased dry weight during pneumococcal infection in the rat. The mechanism of these liver changes may be due, in part, to a shift of Na+ and K+ across liver cell plasma membranes.

Quaking mutants and jimpy mutants of mice have known deficiencies of myelination of the central nervous system, as well as lesser involvement of the peripheral nervous system. Both mutants also have altered polyamine synthesis and accumulation, particularly in the hindbrain and spinal column. The ratio of spermidine/spermine, which generally is higher in tissues with high rates of biosynthetic activity, was significantly lower in the mutants as compared to their normal siblings. In quaking mutants, 5 months of age, the spermidine concentration of hindbrain and spinal column was 60% that of controls. In contrast, the decreased spermidine/spermine ratio in jimpy mutants resulted from a marked increase in the spermine concentration in both forebrain and hindbrain. Alterations in the spermidine/spermine ratio could lead to reductions in the biosynthetic potential of the brain during development.

The growth and development of total body water, fat, ash and protein were examined in lean and obese Zucker rats (fa/fa) from 13 to 31 days of age. The obese rats began depositing significantly more fat compared to the lean controls by day 13. At this time the obese had 3.8% more carcass fat than the lean, with this difference increasing to almost 13% by day 31. Per cent ash and protein were significantly lower in the obese rats throughout the 18 day experimental study. However, when the absolute grams of these two parameters were expressed on a fat-free weight basis, no differences were recorded between the genotypes. There were also no differences when the slopes of the linear log-log growth equations for fat-free weight versus ash and protein were compared. These data do not lend support to the contentions that skeletal stunting and decreased protein deposition are present early in the development of the obese rat. A technique to identify obese rats at an early age without the necessity of killing them, by determining total body water with injected tritiated water was also examined. The method correctly identified obese and lean rats at 2 weeks of age. Further refinement of this technique is necessary before it may be used to precisely predict the genotype of a rat.

The subacute toxic effects of dietary T-2 toxin (20 ppm) incorporated in semipurified diets of 8%, 12% or 16% protein, were examined in young Swiss mice after one, two, three and four weeks. Dietary T-2 toxin caused substantial reductions in growth and food consumptaion, the degrees of which were greatest in mice fed the diets of reduced protein content. T-2 toxin consistently caused similar degrees of nonregenerative anemia, lymphopenia, thymic atrophy and gastric hyperkeratosis irrespective of the dietary protein level. However, erythroid hypoplasia was temporary in mice fed T-2 toxin in the 16%-protein diet such that erythroid precursors regenerated in splenic and bone marrow and were hyperplastic after four weeks. Liver to body weight ratios of mice fed T-2 toxin in the 16%-and 12%-protein diets increased during the four week trial in comparison to control mice fed at a similar rate. These observations indicated that suppression of erythropoiesis in mice by dietary T-2 toxin was temporarty and that the interval before regeneration was prolonged by diets of reduced protein content.

Lethal-milk (lm), a recessive mutation, occurred in the C57BL/6J inbred strain of mice. Lactating lm dams produce a zinc-deficient milk that is lethal to all nursing pups. If foster-nursed on normal dams, lm pups survive and become reproductively mature. Injection of zinc-glycinate into the pups or zinc supplementation of the water of the lactating dams reduces lethality. Other pleiotropic effects in lm mice include congenital otolith defects with delayed righting, "tail-spinning," and abnormal swimming. These effects are diagnostic criteria for segregation of lm mice among backcross progeny. About 40 percent of the expected number of lm pups survive to weaning. Zinc supplementation of the dam improves development of saccular but not of utricular otoliths; zinc does not improve survival of the lm pups among backcross progenies. The lm mice over eight months of age also exhibit extensive hair loss, dermatitis, and skin lesions. Possible roles of metallothionein in zinc and copper metabolism are discussed in regard to the pleiotropic effects of the lethal-milk mutation.

In induced amyloidosis the amyloid was first deposited in the portal areas, then in the centre of the lobule and disseminated through it in the spaces of Disse. No intracellular amyloid was found in the predeposit phase. In the hepatic lobule both mononuclear phagocytes and hepatocytes showed a topographic relationship to the first deposits of amyloid. Some macrophages showed invaginations or vacuoles containing amyloid fibrils. Between the microvilli of hepatocytes, parallel amyloid fibrils occurred. Between the amyloid fibrils were 30-50 nm membrane-bounded spherical particles which may have been lipoprotein aggregates. There was no large-scale phagocytosis of amyloid during the induction period or after survival without casein treatment up to 18 weeks. Lysosomal enzyme activity was seen in the deposits of extracellular amyloid.

Primary hypersecretion of insulin has been suggested as one possibility for the genetic fault of ob/ob mice. To test this hypothesis, streptozotocin (SZO) was used to reduce permanently insulin secretion in young lean and obese mice. After establishment of hyperglycaemia and weight reduction in treated obese mice (obese-SZO), daily insulin replacment was begun in some (obese-SZO-Ins). Obese-SZO mice maintained insulin levels and body weights similar to lean controls, though they were shorter and fatter, while food intake and blood sugar levels exceeded lean values. Obese-SZO-Ins mice with reduced islet hyperplasia, but great insulin resistance, gained more weight than obese-SZO mice; had high serum insulin and controlled blood glucose; and exhibited hyperphagia. These results suggest that primary hypersecretion of insulin cannot be the genetic defect, as ob/ob mice are hyperphagic, hyperglycaemic, insulin resistant, and "obese" even when insulin levels are restricted.

Histopathological observations were made on the spontaneous age-related kidney lesion in relation to some biochemical measurements for renal function using male SD rats from 82 to 560 days of age. Although all the rats examined were appearently healthy and had no gross lesions in the kidneys, several renal changes were detected histopathologically in the kidneys. The lesions occurred initially in renal tubules and then in glomerulus and in interstitial tissues successively increasing in severity with age. There was a correlation between the degree of the histopatholigical changes and the excreted amount of protein and sodium in the urine. The urinary protein was first detected at 34 days of age increasing with age. For rats of over 395 days of age, the urinary protein was greatly variable in amount among individuals. The negative correlation between urinary protein levels and those of serum albumin and urinary potassium was significant.

Spontaneous cardiac neoplasms were diagnosed in one Sprague-Dawley and seven Fischer 344 rats ranging in age from eight months to two years. All eight neoplasms were diagnosed as neurilemmomas. One neoplasm was composed of dense Antoni type A tissue with Verocay body formation, while seven others were composed principally of loose Antoni type B tissue. No specific site predilection was found.

Based upon studies on Ni deficiency with marked changes in intermediary metabolism, the recent investigation examined the extent to which deficient Ni supply affects the content of calcium, magnesium and phosphorus in rat femurs. In Ni deficiency the content of calcium and phosphorus was reduced, in the case of calcium even more so than accounted for by the decrease in bone weight. The result was Ca : P ratio of 1.8 : 1 in Ni deficiency compared with 2.0 : 1 in control animals. In the case of magnesium, however, the Mg concentration was increased by 45% in the bone fresh matter of the deficient animals. The reduced Ca retention in the bone is accordingly contrasted by an enhanced deposition of magnesium.

Kidney infection by Klossiella muris in highland house mice from Peru was associated with lowered metabolic capability (57%) and endurance time (25%) at maximum metabolic rate. Administration of coccidiostatic preparations improved the metabolic capability from 7.8 to 10.5 cc 0-2 g hr and the endurance from 2.8 to longer than 10 min. Their colony-reared offspring, which were free from parasites, sustained maximum metabolic rates of 13.8 cc 0-2/g hr also for longer than 10 min. This rate was slightly higher than the values found in both healthy lowland controls: feral house mice from Arkansas and laboratory white mice [lab: HA(ICR)]. Although clinically inapparent under oridinary conditions, the effects of K muris infection were easily demonstrated at high metabolic loads stimulated by cold. Thus emphasizing the importance of such performance tests in assessing the status of experimental subjects.

Hepatoblastomas from B6C3F1 and BALB/c mice were examined by light and electron microscopy and by immunohistochemical reactions for alpha-fetoprotein, keratin, and vimentin. Tumors occurred in one group of a chronic bioassay for the interaction of diet, genetic strain, and the carcinogen, 2-acetylaminofluorene. Tumors had several populations (including epithelial and mesenchymal cells) in various stages of differentiation. Neoplastic epithelial cells had features of embryonal hepatocytes, such as sparse cytoplasmic organelles, absence of glycogen, abundant free ribosomes, occasional bile canaliculi, and peroxisome-like dense bodies. Embryonal fibroblast-like cells had pleomorphic and folded nuclei with prominent perinuclear chromatin and dispersed cytoplasmic organelles. Fibroblast-like cells were surrounded by bundles of collagen fibrils. Intermediate or transitional types of cells were seen. No tumor cells were immunoreactive for mouse alpha-fetoprotein (AFP) antibody, unlike those in hepatocellular adenomas or carcinomas. Epithelial and mesenchymal tumor cells contained intermediate filaments throughout the cytoplasm; some of these cells stained for keratin but not for vimentin. These findings suggest that mouse hepatoblastomas are derived from bipotential liver blastema cells and are composed of a mixture of several cell populations.

The complete structure of the single-copy alpha A-crystallin gene of the blind mole rat (Spalax ehrenbergi) has been determined in order to elucidate the evolutionary effects of the loss of vision on a lens-specific protein and its gene. The alpha A-crystallin gene appears to have all the necessary transcriptional and translational signal sequences to be expressed in the rudimentary lens of the mole rat and gives rise to probably two protein products by means of alternative splicing, as in rodents with normal vision. Comparisons of the blind mole rat alpha A-crystallin sequence with alpha A sequences from other rodents reveal a considerable acceleration of the substitution rate at nonsynonymous positions in the mole rate lineage, which reflects a relaxation of selective constraints, but the acceleration is not to the extent that might be expected if the gene were now without any function. The remaining evolutionary constraints still imposed upon the mole rat alpha A-crystallin gene may possibly reflect the need for alpha-crystallin expression as an indispensable component in the developmental program of the atrophied eye.

Renin activity in peripheral plasma (PRA), renal cortex and brain tissue (cortex, stem, medulla oblongata) homogenates was studied in a bioassay after Serebrovskaya's modification of the method of Pickens. Fourty-nine spontaneously hypertensive rats (SHR) and 26 normotensive Wistar rats (NWR) were used. The results show that: 1) In spite of very high systolic blood pressure, PRA in SHR is in normal ranges; 2) Renin activity exists not only in the brain of NWR, but in the brain of SHR as well. 3) Renin activity in the different parts of the brain is not equal both in NWR and in SHR. 4) Renin activity in the cortex, the stem and the medulla oblongata of SHR is in normal ranges. 5) Renin activity in the medulla is higher than in other areas of the brain, both in NWR and in SHR, the difference being statistically significant in the latter. 6) No perceptible interrelation between arterial blood pressure, PRA, renal renin activity and renin activity in the cortex, and in the stem of the brain was established. It is suggested that higher renin activity in the medulla oblongata might be considered as an indication of the importance of the brain renin-angiotensin system, and its function in the cerebral (neural) regulation of the cardiovascular system. A causal connection between the renal and the brain renin-angiotensin systems, and the onset and maintenance of hypertension is assumed.

In the search for abnormalities in hypertensive vessels Ca kinetics was studied in the aorta of spontaneously hypertensive rats (SHR). The uptake of 45Ca was significantly less in hypertensive animals but the uptake of 'Lanthanum resistant' 45Ca was not. The efflux of 45Ca from aorta of SHR was different (P less than 0.01) from that of control rats because of faster initial efflux. The half-life of the first 2 components of efflux curves was significantly shorter in SHR. Results are interpreted as consequences of decreased Ca binding by smooth muscle membrane in hypertensive vessels.

The inferior oblique muscles of pigmented and albino guinea pigs were compared with respect to contractile and histochemical properties. No differences were found between the 2 kinds of animal in twitch and tetanic response or in fatigue properties. They also had the same fiber composition and fiber and capillary densities of their inferior obliques. These findings indicate that differences in eye muscle previously demonstrated and Siamese (albino) cats are related to the state of binocular vision and not to genetic variations between pigmented and albino animals.

Hypogonadal (hpg/hpg) mice deficient in gonadotropin-releasing hormone were used to study gonadotropin involvement in ovarian tumorigenesis following gamma irradiation. In the first experiment, 30-day-old hpg/hpg and normal (+/-) littermate mice were irradiated. The same mice were killed 10-15 mo later, and autopsies were performed. Ovaries of irradiated hpg/hpg mice were devoid of oocytes, but retained follicular structures. Neither mesothelial adenomas nor granulosa cell tumors were observed. In contrast, all irradiated +/- mice formed mesothelial adenomas or granulosa cell tumors, or both. Therefore, oocyte death in the absence of gonadotropins did not initiate ovarian tumorigenesis. In the second experiment, irradiated and nonirradiated hpg/hpg and +/- mice were injected 3 times weekly for 180 days with either low or high doses of pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) in combination. Irradiation reduced ovarian mass and markedly reduced ovarian weight increase in response to exogenous gonadotropins. Follicular dissolution and stromal cell hypertrophy were observed in saline-treated and gonadotropin-treated +/- mice that had been irradiated, and in hpg/hpg mice given the high gonadotropin dose. Mesothelial adenoma formation was observed in 100% of saline-treated, 14% of low dose-treated, and 11% of high dose-treated +/- mice. No mesothelial adenomas developed in any hpg/hpg or nonirradiated +/- mice, despite gonadotropin-induced stromal luteinization. These results indicate that, in the absence of gonadotropins, irradiation leads only to the loss of oocytes. The presence of gonadotropins was necessary to promote follicular dissolution and stromal luteinization, but was insufficient to stimulate mesothelial adenoma formation.

Intracellular pH was determined (DMO method) in European hamsters, in the spontaneously-occurring respiratory acidosis of hibernation, in hypercapnia due to breathing 12% CO2 in air in euthermy in spring, and in euthermicnormocapnic controls. From euthermy to hibernation, the temperature coefficient of pH was lowest in blood plasma and brain, intermediate in striated muscles (thigh muscles and diaphragm), and highest in heart and liver (Fig. 1). Correspondingly, the estimated dissociation ratio of the protein imidazole buffer groups, alpha Im, decreased markedly in plasma and brain, denoting an acid titration, but varied little in liver and heart. Striated muscles were intermediate (Fig. 2). Like in other mammals, intracellular responses to short-term euthermic respiratory acidosis were characterized by a partial metabolic compensation in the brain and a small metabolic acidification in striated muscles. In hibernation, a powerful metabolic compensation took place in liver and heart, nearly restoring alpha Im, but none occurred in brain (Figs. 3 to 5). The existence of an intracellular acidosis in brain and striated muscles during hibernation is in keeping with an inhibitory role of acidosis, whereas the homeostasis of intracellular alpha Im in liver and heart would subserve the eurythermal functioning of metabolic regulations in these organs, like in most organs of ectotherms.

In ob/ob mice, we showed previously that brown adipose tissue (BAT) has an abnormally low manganese (Mn) content associated with low Mn-superoxide dismutase (MnSOD) and succinate dehydrogenase (SDH) activities. These anomalies can be corrected partially by supplementing the diet with Mn. The present work was designed to find out whether the hypercorticism of the obese mouse plays a role in this anomalous Mn metabolism in BAT. Mn content and MnSOD and SDH activities were determined in BAT from control and adrenalectomized (ADX) obese mice and from control and corticosterone-supplemented lean mice. Adrenalectomy of the obese mouse restored BAT Mn content, SDH activity and lipid peroxidative activity to normal but had little effect on MnSOD activity. Corticosteroid supplementation in the lean mouse did not reproduce the anomalies of Mn metabolism found in the untreated obese mouse. These results show that hypercorticism alone is not responsible for the anomalies of Mn metabolism. It is possible that the hyperinsulinemia of the obese mouse is involved in this process since adrenalectomy corrected hyperinsulinemia in the obese mouse, but corticosteroid supplementation of the lean mouse did not reproduce the high plasma insulin levels or the anomalies in body composition typical of the untreated obese mouse.

Basal and hormone-stimulated lipolysis of adipose tissue was measured at successive stages during the development of fish oil-induced yellow fat disease in rats. Changes of lipolytic activity at an early stage of yellow fat disease were not seen. There was a significant increase of basal lipolysis and a decrease of stimulated lipolysis when many fat cells were affected (stage E). Since the increased basal lipolysis probably originates from degenerated fat cells, the mechanism of enzyme activation is not clear. The decreased stimulated lipolysis was proportional to the number of affected fat cells and resulted from membrane damage of these cells. Increased 5-nucleotidase activity, seen in affected fat cells, may be important, to this reduced stimulated lipolysis.