A possible role for granulocyte macrophage-colony stimulating factor in modulating teratogen-induced effects.

It was already shown that stimulation of the maternal immune system by allogeneic or xenogeneic leukocytes is capable of affecting embryonic responses to teratogenic insults and various cytokines, including granulocyte macrophage-colony stimulating factor (GM-CSF), were implicated as mediators of this effect. Therefore, in the present study we tried to assess the ability of GM-CSF to modulate teratogenic activity, along with possible changes in systemic as well as local maternal immune responses, that might be involved in the process. Thus, the percentage of cyclophosphamide (CP)-treated embryos exhibiting limb malformations was shown to decrease significantly following GM-CSF administration. This effect was found to be comparable to that demonstrated by intrauterine leukocytes administration. GM-CSF treatment resulted in a significant enhancement in maternal splenocytes Con-A-induced proliferation, as well as Interleukin-2 (IL-2) and IL-3 production. Examination of leukocyte cell surface antigens expressed by splenocytes revealed no statistically-significant changes in the level of the T lymphoid antigens Thy-1, CD5, CD4, CD8 and CD3, the macrophage antigen Mac-1, and the adhesion molecules LFA-1alpha, LFA-1beta and L-Selectin, following GM-CSF immunostimulation. In parallel, immunohistochemical analysis of the uteroplacental unit revealed Mac-1 and to a lesser extent LFA-1beta-positive cells localized to the myometrium and the placenta in both the control and the GM-CSF-treated groups, while no cells expressing Thy-1, CD3, CD4, CD8, or LFA-1alpha could be demonstrated. Our results suggest a possible role for GM-CSF in modulating teratogen-induced effects, a process in which maternal immune responses such as splenocytes proliferation and cytokine production might be involved.     

A possible role for lysozyme in determining acute exacerbation in chronic bronchitis.

The aggregation of non-serotypable Haemophilus influenzae (NTHI) by whole saliva from patients with chronic obstructive lung disease (COLD) was investigated. Significant differences were observed between salivary aggregating activity of a control and COLD population (P < 0.001). Saliva from patients less prone to acute exacerbations had a greater capacity to aggregate bacteria compared with saliva from patients with a predilection to infection. The mechanism of saliva-mediated aggregation of NTHI was investigated and shown to be related to lysozyme content. Lysozyme activity in saliva was measured by the turbidimetric technique and results showed that patients with chronic bronchitis had increased levels of salivary lysozyme, with a subpopulation within the non-infection-prone group having greater amounts. A significant difference was observed in salivary lysozyme between controls and non-infection-prone (P < 0.005) and infection-prone (P < 0.05) patients, respectively: the non-infection-prone patients having significantly (P < 0.005) more than the infection-prone patients. There was significant correlation (r = 0.742, P < 0.001) between salivary aggregation of NTHI and lysozyme activity. Chromatographically purified human lysozyme had a similar aggregation profile to that of saliva. There was no difference in serum and saliva lactoferrin concentrations between groups, but there was a significant increase (P < 0.05) in serum lysozyme concentration in the non-infection-prone group. This study suggests that the level of salivary lysozyme derived from macrophages may play an important role in determining resistance or susceptibility to acute bronchitis.     

Asthma and suicide: possible role of brain-derived neurotrophic factor

The suicide rates among asthmatic patients are higher than among the general population. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is strongly associated with suicide pathogenesis. BDNF also plays an important role in neuroimmune reactions in allergic diseases such as asthma. Therefore, we hypothesize that alterations of BDNF levels in the brain may explain the increased suicide rates among asthmatic patients.     

A possible role for phosphorylation of the acetylcholine receptor

The acetylcholine receptor (AChR) from Torpedo fuscomaculata can be phosphorylated. This reaction was fully characterised. In addition, the influence of factors with possible modulatory effects on the phosphorylation of this receptor were investigated. In order to suggest the possible role of phosphorylation in neurotransmission, the effects of this reaction on the binding of ligands to the AChR were investigated. It was found that phosphorylation enhanced the binding of the antagonist, alpha-bungarotoxin to the AChR. Due to experimental difficulties the effect on binding of the agonist, acetylcholine, to the receptor, could not be determined. However, a hypothesis is proposed regarding the role of phosphorylation of the AChR in neurotransmission.     

A possible role of estrogens in carcinogenesis of non-target tissues.

The mitogenic action of the estrogen-receptor complex is supposedly similar in both normal and malignant target tissues. As receptors are present in several types of non-target tissues, in the case of lesions at the nuclear acceptor sites, the complex in those might be able to cause successive mitoses. Estrogen-dependent tumors of non-target tissues have been reported by several investigators. In normal and malignant cells of the breast and some other types of non-endocrine cells, the ability to produce their own estrogens (from circulating precursors) has been shown. The locally formed estrogens might have a role in the initiation of some malignant transformations. Indications of this process are the switching to estrogen production of some neoplastic endocrine or undifferentiated cells, certain ectopic effects displayed by some cancerous tissues, and the possible roles of GH, PRL and cholesterol in the development of some malignancies. The present endocrine system for the synthesis of the sexual hormones might be a specialization of a system at the cellular level. Polypeptide hormones might evolve from regulatory parts of cyclases or phosphodiesterases. Traces of the original biological processes might still be maintained by several cell-types.     

Weight gain after cessation of cigarette smoking. A possible role for adipose-tissue lipoprotein lipase

Cigarette smokers weigh less than nonsmokers and gain weight when they stop smoking. Increased activity of lipoprotein lipase in adipose tissue in some smokers may represent a compensatory response to their reduced body weight. Consequently, we hypothesized that the enzyme's activity may be related to the rate at which smokers gain weight when they stop smoking. To test this hypothesis, we measured body weight and fasting lipoprotein lipase activity in adipose tissue in 15 cigarette smokers before they stopped smoking. The changes in body weight during the first two weeks of abstinence were correlated with the base-line lipase activity in these smokers (r = 0.82, P less than 0.0002). This relation remained significant in the 12 subjects who were still abstinent at three weeks (r = 0.63, P less than 0.03). These results suggest that lipoprotein lipase activity in adipose tissue has a counterregulatory role in the maintenance of body weight and adipose-tissue mass in smokers. The higher the level of lipase activity when the weight-reducing influences of cigarettes cease, the greater the rate at which weight is gained during the first three weeks of abstinence.     

A possible role for calcium in cyclic nucleotide mediated fluid secretion

This article suggests that calcium acts as an intermediate for intestinal fluid secretion mediated by adenosine-3':5'-cyclic monophosphoric acid (cAMP) and guanosine -3':5-'cyclic monophosphoric acid (cGMP). It is hypothesized that microbial enterotoxins disrupt the normal interrelationships between calcium and cyclic nucleotides, thereby leading to adverse biological effects. It is further proposed that the inhibitory effect of chlorpromazine on calmodulin accounts for the ability of this drug to inhibit enterotoxins which separately elevate cAMP or cGMP concentrations.     

Aborting solid tumours: A possible role for PGF2alpha

As well as being an efficacious abortifacient agent, PGF2alpha is known to be an endogenous mediator of parturition. It is the hypothesis of this paper that PGF2alpha may also be an effective macrophage tumouricidal activator; if correct, PGF2alpha may be said to ‘abort’ tumour cell mass. Indirect evidence for such a mechanism of action, as well as a theory as to the mode of action itself, is presented.     

A protective role for endogenous tumor necrosis factor in Toxoplasma gondii infection.

The involvement of tumor necrosis factor (TNF) in resistance to Toxoplasma gondii infection was examined by means of experiments in which mice were treated with anti-TNF antibodies prior to infection with ME49, a low-virulence Toxoplasma strain. In (BALB/cBy x C57BL/6J)F1 (CB6F1) mice, which are highly resistant to intraperitoneal (i.p.) infection with T. gondii ME49, 10(4) neutralizing units of anti-TNF caused a significant increase in trophozoite numbers in the peritoneal cavities of infected mice and transient signs of illness but no deaths. i.p. infection of anti-TNF-treated C57BL/6J (B6) mice, which are more susceptible to T. gondii and develop a chronic progressive toxoplasmosis, resulted in death for some of the mice. If the mice were infected perorally, however, and treated with anti-TNF, mortality was extensive in B6 mice but not in CB6F1 mice. Although it was not detected in their sera, TNF was found in the peritoneal fluids of i.p.-infected CB6F1 and B6 mice. Endogenously produced TNF thus appears to be an important mediator of resistance to T. gondii.     

Angiolymphoid hyperplasia with eosinophilia: possible aetiological role for immunisation.

Five young children (mean age 26.4 months) with angiolymphoid hyperplasia with eosinophilia (Kimura's disease) from either the upper arm or buttock were identified over 18 months. The unusual distribution of the lesions and the young age of the patients suggested a possible association with immunisation. The clinical and histopathological features in these cases were accordingly reviewed. The biopsy specimens showed the usual histological appearances of a prominent inflammatory component, fibrosis, and vascular proliferation associated with aggregates of eosinophils. The features were those of a reactive rather than neoplastic process. Immunohistochemical preparations showed positive staining of variable numbers of plasma cells with antibodies to IgG, IgM, IgA and IgE and a reticular staining of germinal centres with IgM and IgE antibodies. Immunisation histories obtained from the patients' general practitioners showed a remarkable correlation between the distribution of the lesions and the sites of injections and an aetiological role for immunisation in these cases seems likely.     

A protective role of platelet-activating factor in murine candidiasis.

Platelet-activating factor (PAF) is a potent phospholipid-derived modulator of immunological and inflammatory processes. In this study, the role of exogenous and endogenous PAF in resistance to infection with Candida albicans was investigated. Administration of PAF following a lethal challenge of C. albicans significantly protected mice from death and reduced the number of organisms in the kidneys. Neutralization of endogenous PAF with the PAF antagonist BN50739 shortened the mean survival time and increased the number of C. albicans cells per kidney. Shortly after infection of mice (30 min), significant levels of PAF were detected in the serum. PAF-induced protection appears to be mediated through the actions of tumor necrosis factor alpha (TNF-alpha), since pretreatment with anti-TNF-alpha before each injection of PAF abrogated the majority of PAF-induced enhanced resistance. Administration of PAF in vivo elevated serum TNF-alpha levels and TNF-alpha mRNA expression in the kidney. Production of TNF-alpha was markedly diminished by pretreatment with the PAF antagonist BN50739 prior to infection with C. albicans. We conclude that PAF, which is produced during infection with C. albicans, plays an important role in determining the level of resistance to this infectious microorganism. This effect of PAF appears to be mediated, at least in part, through the induction of TNF-alpha.     

Adenylate cyclase. A possible factor in the pathogenicity of Yersinia pestis]

Biological effect of homogenous preparation of Y. pestis adenylate cyclase on eucaryotic cells was studied. Adenylate cyclase, added (7.5 x 10(8) g/ml) to guinea pig macrophages lowers the level of chemiluminescence to 50-70%, has an appreciable cytotoxic effect on peritoneal macrophages and suppresses phosphorylation processes of leucocyte proteins from white mice. The experimental results obtained allow to suggest Y. pestis adenylate cyclase to be a pathogenic factor, contributing to the development of plague infection.     

A possible role for complement in the pathogenesis of chronic chagasic cardiomyopathy

The membrane attack complex (MAC) of complement participates in several inflammatory and proliferative processes by releasing pro-inflammatory cytokines and growth factors from target cells. Chronic Chagasic cardiomyopathy (CCH) is a parasitic dilated cardiopathy, characterized by severe fibrosis and inflammation, which differs from idiopathic dilated cardiomyopathy (DCM). Trypanosoma cruzi, the pathogenic organism of CCH, is a strong complement activator and can also induce alternative pathway activation by mammalian cells. This study explored whether the myocardium in CCH patients has increased MAC deposition, an expression of complement activation, compared to DCM patients. MAC was semi-quantified in endomyocardial human samples (29 CCH subjects, 18 DCM subjects, and four controls) by immunohistochemistry. MAC was present in the sarcolemma of 38% of CCH, 5.5% of DCM (p<0.02), and 0% of controls, and in interstitial inflammatory cells of CCH. No difference was observed in the expression of the complement regulatory protein CD59, indicating that increased MAC deposition is likely to be the result of complement activation rather than decreased protection. It is proposed that the increased MAC deposition found in CCH, but not in DCM or controls, may help to explain the diffuse myocardial fibrosis and inflammation characteristic of the disease.