Borderline--tuberculoid leprosy: clinical and immunological heterogeneity

The authors analysed some immunological criteria in leprosy patients diagnosed as borderline tuberculoid by the presentation of different grades of skin lesions as well as different grades of nerve involvement. Only 50% of the patients presented a single skin lesion and 58% had none or only one affected nerve. Nineteen patients (39.6%) showed a positive lepromin reaction (induration > or = 5 mm). Patients with a positive skin test had a greater number of skin lesions when compared with patients with a negative lepromin test. Fifty-seven percent of the patients were found to be positive using a lymphoproliferation test (LTT) in response to Mycobacterium leprae antigens. Positive LTT results did not correlate with the number of skin lesions, but patients unresponsive to LTT had a lesser extent of nerve involvement. Four out of 18 patients (22%) released high IFN gamma levels in PBMC culture stimulated by M. leprae. (mean U/ml +/- SD = 142 +/- 72). All of these 4 patients presented only one skin lesion, although three of them had more than one affected nerve. Nineteen out of 21 patients (90.5%) showed no anti-PGL-1 antibodies in their serum. The low levels of anti-PGL-1 antibodies among these patients confirmed their tuberculoid background even in those with multiple skin lesions. These findings seem to attribute an important role to IFN gamma in restraining the spreading of the infection in the skin, but IFN gamma may have an opposite effect on the nerves. The potential pathological effects of IFN gamma during the delayed type of hypersensitivity can be related to its ability to synergise with other inflammatory cytokines such as TNF alpha, IL-1 beta, and others.     

The interaction of GABA-A receptors with the serotoninergic system of the brain in regulating the testosterone level by the negative feedback mechanism

A unilateral hemicastration decreased the serotonin and 5-hydroxyindolacetic acid levels in the Wistar rat mediobasal hypothalamus, but not in the midbrain. These neurotransmitters were shown to interact in the process of androgen restoration after the hemicastration. The maximal contribution of GABAergic mechanisms in the testosterone feedback regulation involves the GABA effect via the central GABA-A receptors of the mediobasal hypothalamus' serotoninergic neurons, thus activating the hormone level restoration. The GABA seems to induce a serotonin-independent inhibition of the testosterone level stabilising after hemicastration.     

Maintenance of cardiovascular risk factor changes among middle-aged women in a lifestyle intervention trial

This paper proposes and defends the small worlds hypothesis, which states that expert physicians organize diagnostic knowledge on the basis of similarities between disease categories, forming 'small worlds' consisting of small subsets of diseases and their distinguishing features. Examining existing data from several previous studies, the authors provide support for the small worlds hypothesis and for a characterization of the process of expert medical diagnostic reasoning as a succession of limited comparisons involving related diagnostic hypotheses. In one study, subjects were presented clinical endocrine cases one statement at a time and were prompted to think aloud after presentation of each statement. A combination of discourse and protocol analysis techniques were used to investigate hypothesis generation and evaluation. In another study, dialogues from doctor-patient interviews were examined. It was found that expert subjects rapidly select relatively small sets of plausible diagnostic hypotheses (small worlds) and focus on the most relevant medical findings that distinguish among the diseases in such small worlds. Results from both studies indicate that expert physicians use efficient strategies for discriminating among these alternative hypotheses in a stepwise process. In contrast, non-experts often generate large numbers of possible diagnostic hypotheses, belonging to widely differing disease categories. The results provide empirical support for the theoretical basis of small worlds. The implications of these results for the study of medical expertise and knowledge engineering are discussed, as well as considerations for the development of decision support systems.     

Structural homologies with ATP- and folate-binding enzymes in the crystal structure of folylpolyglutamate synthetase

Folylpolyglutamate synthetase, which is responsible for the addition of a polyglutamate tail to folate and folate derivatives, is an ATP-dependent enzyme isolated from eukaryotic and bacterial sources, where it plays a key role in the retention of the intracellular folate pool. Here, we report the 2.4-A resolution crystal structure of the MgATP complex of the enzyme from Lactobacillus casei. The structural analysis reveals that folylpolyglutamate synthetase is a modular protein consisting of two domains, one with a typical mononucleotide-binding fold and the other strikingly similar to the folate-binding enzyme dihydrofolate reductase. We have located the active site of the enzyme in a large interdomain cleft adjacent to an ATP-binding P-loop motif. Opposite this site, in the C domain, a cavity likely to be the folate binding site has been identified, and inspection of this cavity and the surrounding protein structure suggests that the glutamate tail of the substrate may project into the active site. A further feature of the structure is a well defined Omega loop, which contributes both to the active site and to interdomain interactions. The determination of the structure of this enzyme represents the first step toward the elucidation of the molecular mechanism of polyglutamylation of folates and antifolates.     

Endolymphatic therapy and current detoxication methods in the treatment of peritonitis

An original method of endolymphatic therapy with the stimulation of the lymph outflow was developed and used in 108 patients with peritonitis. The dynamics of intoxication parameters was studied during the endolymphatic therapy, indirect electrochemical oxidation of blood, photochemotherapy and traditional treatment. The method proposed has been found to be most efficient. The method of endolymphatic therapy with the lymph stimulation allowed lethality from peritonitis to be decreased to 7.4%.     

Influence of the physicochemical state of impurities on the strength of silica fibers

The size distribution of compositional microinhomogeneities in silica glasses prepared by different methods is investigated by electron microscopy. The formation of these defects is caused by the presence of impurities introduced into the glass upon phase separation and segregation. The surface of millimeter-sized segments of silica optical fibers 125 μm in diameter always contains inhomogeneities up to 1 μm in size. This explains the growth of cracks to a critical size in microregions containing impurities in the course of strength tests of glass fibers.     

Membrane potential generation coupled to oxidation of external NADH in liver mitochondria

Oxidation of added NADH by rat liver mitochondria has been studied. It is found that exogenous NADH, when oxidized by rat liver mitochondria in sucrose hypotonic medium supplemented with Mg2+ and EGTA, generates a membrane potential (delta psi) even in the absence of added cytochrome c. ADP and phosphate decrease delta psi, the effect being reversed by oligomycin. Rotenone and myxothiazol do not inhibit delta psi generated by oxidation of exogenous NADH. Added cytochrome c increases the rate of the exogenous NADH oxidation and coupled delta psi formation. In sucrose isotonic medium, or in hypotonic medium without Mg2+, exogenous NADH fails to stimulate respiration and to form a membrane potential. In the presence of Mg2+, exogenous NADH appears to be effective in delta psi generation in isotonic sucrose medium if mitochondria were treated with digitonin. In isotonic KCl without Mg2+, oxidation of exogenous NADH is coupled to the delta psi formation and MgCl2 addition before mitochondria prevents this effect. In hypotonic (but not in isotonic) sucrose medium, Mg2+ makes a portion of the cytochrome c pool reducible by exogenous NADH or ascorbate. It is assumed that (i) hypotonic treatment or digitonin causes disruption of the outer mitochondrial membrane, and, as a consequence, desorption of the membrane-bound cytochrome c in a Mg2+-dependent fashion; (ii) incubation in isotonic KCI without Mg2+ results in swelling of mitochondrial matrix, disruption of the outer membrane and cytochrome c desorption whereas Mg2+ lowers the K+ permeability of the inner membrane and, hence, prevents swelling; (iii) desorbed cytochrome c is reduced by added NADH via NADH-cytochrome b5 reductase and cytochrome b5 or by ascorbate and is oxidized by cytochrome oxidase. The role of desorbed cytochrome c in oxidation of superoxide and cytoplasmic NADH as well as possible relations of these events to apoptosis are discussed.     

Integrins inhibit angiotensin II-induced contraction in rat aortic rings

Many extracellular matrix proteins contain the tripeptide sequence arginine-glycine-aspartate (RGD). This RGD motif is recognized by integrins, a family of adhesion receptors present on vascular smooth muscle cells. In the present study, we examined the ability of different RGD-containing peptides to affect the contraction of rat aortic rings in response to different agonists. We found that the peptide RGDS inhibited angiotensin-induced contraction in a dose dependent manner. In contrast, the peptides RGDW and RGES had no effect on angiotensin-induced contractility. We show that function-blocking antibodies to the integrins alphavbeta3 and alpha5beta1 also inhibit angiotensin-induced contraction. These effects were observed in the absence of an intact endothelium. In contrast, neither an antibody directed against the beta1 subunit nor the peptide RGDS had an effect on phenylephrine or 5-hydroxytryptamine-induced contraction. These data suggest that interactions of vascular smooth muscle with components of the surrounding extracellular matrix may influence the response of smooth muscle to agonists.