The distribution of somatomedins in the nervous system of the cat and their release following neural stimulation

Recent evidence suggests a regulatory role in the nervous system for somatomedins. The present study, using a somatomedin radioreceptorassay which primarily detects insulin-like growth factors 1 and 2, shows that somatomedins are widely distributed throughout the nervous system of the cat. Whilst somatomedins were present in all CNS regions, the highest concentration occurred in the hypothalamus followed by cerebral cortex. In the spinal cord, the dorsal roots contained twice the concentration found in the ventral roots. Activity was also present in the sympathetic ganglia, vagus nerve and sciatic nerves. Following electrical stimulation of the brachial and sciatic nerves somatomedins were released into perfusates from extirpated cut limbs. These findings suggest that somatomedins may be neuroregulatory hormones.     

The role of testosterone in the feedback control of male FSH and LH secretion

Summary Intramuscular administration of 250 mg testosterone oenanthate per week over a period of 21 weeks treatment rapidly and sustainedly suppressed serum LH as well as FSH levels in seven normal males, while serum testosterone rose by a factor of approximately two. These together with other data provide increasing evidence for a feedback control of FSH secretion by gonadal steroids in the male in addition to the already described but as yet undefined tubular testicular factor.     

Pre-exposure of murine macrophages to lipopolysaccharide inhibits the induction of nitric oxide synthase and reduces leishmanicidal activity

Murine macrophages produce nitric oxide (NO) from L-arginine on stimulation with lipopolysaccharide (LPS), alone or with interferon-γ (IFN-γ). The effect of incubation of macrophages with low concentrations of LPS on NO synthesis on subsequent stimulation was investigated, using a murine macrophage cell line, J774, and peritoneal macrophages from CBA mice. Cells which had been incubated with LPS produced significantly lower amounts of NO, and expressed lower levels of NO synthase activity, following stimulation with IFN-γ and LPS, or with a high concentration of LPS. This effect was not reversed by tumor necrosis factor-α. The ability of CBA macrophages to kill the intracellular parasite Leishmania major was markedly reduced by pre-incubation with LPS. Reduced NO production by macrophages previously exposed to LPS is a manifestation of endotoxin tolerance, and may represent an important means of regulation of NO synthesis and thus a survival mechanism for intracellular parasites.     

Cell proliferation depends on mitochondrial Ca2+ uptake: inhibition by salicylate

Store-operated Ca²⁺ entry (SOCE) is a ubiquitous Ca²⁺ influx pathway involved in control of multiple cellular and physiological processes including cell proliferation. Recent evidence has shown that SOCE depends critically on mitochondrial sinking of entering Ca²⁺ to avoid Ca²⁺-dependent inactivation. Thus, a role of mitochondria in control of cell proliferation could be anticipated. We show here that activation of SOCE induces cytosolic high [Ca²⁺] domains that are large enough to be sensed and avidly taken up by a pool of nearby mitochondria. Prevention of mitochondrial clearance of the entering Ca²⁺ inhibited both SOCE and cell proliferation in several cell types including Jurkat and human colon cancer cells. In addition, we find that therapeutic concentrations of salicylate, the major metabolite of aspirin, depolarize partially mitochondria and inhibit mitochondrial Ca²⁺ uptake, as revealed by mitochondrial Ca²⁺ measurements with targeted aequorins. This salicylate-induced inhibition of mitochondrial Ca²⁺ sinking prevented SOCE and impaired cell growth of Jurkat and human colon cancer cells. Finally, direct blockade of SOCE by the pyrazole derivative BTP-2 was sufficient to arrest cell growth. Taken together, our results reveal that cell proliferation depends critically on mitochondrial Ca²⁺ uptake and suggest that inhibition of tumour cell proliferation by salicylate may be due to interference with mitochondrial Ca²⁺ uptake, which is essential for sustaining SOCE. This novel mechanism may contribute to explaining the reported anti-proliferative and anti-tumoral actions of aspirin and dietary salicylates.     

Effect of ageing of serum on consumption of antibody by B1C-globulin determinants; evidence for circulating breakdown products in glomerulonephritis

Changes in antibody consumption by the A and D determinants of β_1C-globulin were found to increase as serum aged in vitro. Consumption by the A determinant was 1·6 times and by the D determinant, 2·5–3 times greater in aged serum than in fresh EDTA plasma. The most likely explanation for the increased consumption with ageing is steric changes occurring as the β_1C molecule fragments into β_1A and α_2D, resulting in exposure of additional antibody combining sites. In specimens from patients with hypocomplementemic nephritis, the increase in consumption with ageing was less than in normal subjects. The data add to the evidence presented in earlier studies of the presence in vivo, in certain nephritics, of breakdown products of β_1C-globulin. The most abundant breakdown product would be α_2D-globulin.     

Murine model of pulmonary anthrax: kinetics of dissemination, histopathology, and mouse strain susceptibility

Bioweapons are most often designed for delivery to the lung, although this route is not the usual portal of entry for many of the pathogens in the natural environment. Vaccines and therapeutics that are efficacious for natural routes of infection may not be effective against the pulmonary route. Pulmonary models are needed to investigate the importance of specific bacterial genes in virulence, to identify components of the host immune system that are important in providing innate and acquired protection, and for testing diagnostic and therapeutic strategies. This report describes the characteristics of host and Bacillus anthracis interactions in a murine pulmonary-infection model. The infective dose varied depending on the route and method of inoculation. The germination process in the lung began within 1 h of inoculation into the lung, although growth within the lung was limited. B. anthracis was found in the lung-associated lymph nodes approximately 5 h after infection. Minimal pneumonitis was associated with the lung infection, but significant systemic pathology was noted after dissemination. Infected mice typically succumbed to infection approximately 3 to 4 days after inoculation. The 50% lethal doses differed among inbred strains of mice, but within a given mouse strain, neither the age nor the sex of the mice influenced susceptibility to B. anthracis.     

Candidate vaccine antigens identified by antibodies from mice vaccinated with 15- or 50-kilorad-irradiated cercariae of Schistosoma mansoni.

In murine schistosomiasis, the highest levels of resistance to cercarial challenge are obtained by vaccination with radiation-attenuated cercariae. To identify candidate vaccine antigens relevant to the vaccine model, we examined parasite antigens recognized by antibodies from mice vaccinated with irradiated cercariae of Schistosoma mansoni. To optimize recognition of a wide spectrum of antigens, several factors that influence the level of protection in this model were varied; specifically, we examined the effect of (i) single versus multiple vaccinations with irradiated cercariae, (ii) the dose of irradiation (15 or 50 kilorads) administered to the cercariae, and (iii) the genetic background of mouse strains, high-responder (C57BL/6J) versus moderate-responder (CBA/J) mice. We found that the number of vaccinations did not alter antibody specificity but modified the relative antibody titers against particular antigens. The dose of irradiation used to attenuate the immunizing cercariae had a similar effect on antibody titers but in addition influenced antibody specificity. Only mice that had been vaccinated with moderately irradiated cercariae recognized cathepsin B (Sm31) and Sm32. Interestingly, when vaccinated mice of the two strains, C57BL/6J and CBA/J, were compared, differences in antibody responses to particular antigens were observed. Both strains recognized the integral membrane protein Sm23, glutathione S-transferase, and cathepsin B, whereas Sm32 and paramyosin were recognized only by CBA/J mice, and heat shock protein 70 was recognized exclusively by C57BL/6J mice. In this study, we conclusively identified six distinct antigens that are specifically recognized by the humoral immune response of vaccinated mice.