Implementation of chemoprophylaxis of leprosy in the Southern Marquesas with a single dose of 25 mg per kg rifampin

Between 1967 and 1987 in the Southern Marquesas, a remote archipelago in French Polynesia, the detection rate of leprosy was 48.9 per 100,000 when it was 8.6 per 100,000 for French Polynesia as a whole. In 1988, a program of chemoprophylaxis of leprosy with a single dose of 25 mg/kg rifampin was implemented, and 2751 persons (98.7% of the population) were treated in the Southern Marquesas. In addition, 678 South Marquesans and 2466 members of their families living in the Northern Marquesas and in the Society Archipelago, received the same chemoprophylaxis. Among 2676 persons studied in the Southern Marquesas (97.4% of the treated population), 130 had elevated IgM anti-phenolic glycolipid-I antibodies by ELISA without any evidence of leprosy. The onset of a skin lesion of borderline leprosy in a boy 3 months after chemoprophylaxis raises the question of the nature of such a skin lesion and, indirectly, of the effectiveness of the chemoprophylaxis.     

T cell expression of MyD88 is required for resistance to Toxoplasma gondii

Resistance to Toxoplasma gondii depends on dendritic cells to recognize this pathogen and secrete IL-12, in turn promoting IFN-gamma production from responding T cells. The adaptor protein, myeloid differentiation primary-response gene 88 (MyD88), is important for most Toll-like receptor (TLR) signaling, as well as IL-1R/IL-18R signals. There is considerable evidence that MyD88 is required for the innate sensing of T. gondii and IL-12 responses. Although Myd88(-/-) mice challenged with T. gondii have defective IL-12 and Th1 effector responses and succumb to disease, administration of IL-12 to Myd88(-/-) mice partially restores the Th1 response and yet fails to prolong survival. This finding suggested that MyD88 may mediate signals within T cells important for resistance to this pathogen. To evaluate the role of MyD88 in T cells under noncompetitive conditions, bone marrow chimeras were generated, in which the T cells lacked MyD88, but MyD88-dependent innate immune responses were intact. Upon challenge with T. gondii, these chimeric mice were more susceptible to disease, developing severe toxoplasmic encephalitis and succumbing within 30 days. Splenocytes and brain mononuclear cells isolated from infected chimeric mice produced less IFN-gamma when cultured with a T. gondii-derived antigen. The increase in susceptibility observed was independent of signals via the IL-1R and IL-18R, suggesting a role for TLRs in MyD88-mediated T cell responses to T. gondii. These observations show that, in addition to a role for MyD88 in innate responses, T cell expression of MyD88 is necessary for prolonged resistance to a pathogen.     

Oxprenolol in the treatment of hypertension in the elderly

Controversy continues to surround the value of drug treatment of hypertension in the elderly. Epidemiologic evidence implicates hypertension as a major risk factor in the precocious development of stroke and coronary heart disease in the elderly subject as clearly as it is implicated in the younger person. The hemodynamic and neuroendocrine profiles of the older patient with essential hypertension are similar to those of younger patients in the stable phase of the disease. However, the arterial ravages induced by many years of sustained hypertension render the circulation of the elderly subject more sensitive to pharmacologic intervention. The benefit-risk ratio of most antihypertensive drugs appears to be inversely related to age. Diuretics reduce the blood pressure at rest but have no influence on the increases in systolic pressure during normal activity; in addition, they carry potentially serious metabolic hazards in the elderly hypertensive patient. Centrally acting drugs likewise lower the blood pressure at rest without influencing the high systolic pressures induced by exercise. They also enhance the tendency to endogenous depression. Adrenergic-neurone blocking drugs and alpha-adrenoceptor antagonists are contraindicated because of the frequency of impaired cardiovascular reflexes in the elderly. The beta-blocking drugs can reduce the risk of coronary and cerebrovascular disease in the older patient with hypertension. They appear to be well tolerated, but because of their impaired metabolic handling in many elderly patients they should probably be used in smaller doses than those prescribed in younger patients. The influence of antihypertensive treatment on cardiovascular morbidity and mortality in the elderly hypertensive patient is not known.     

Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease

A micromethod adapted for automated determinations was used to measure basal plasma levels of homocyst(e)ine [H(e)]. These levels included the sum of free and bound forms of homocysteine, its disulfide oxidation product, homocystine, and the homocysteine-cysteine-mixed disulfide. Two groups of subjects were studied: apparently healthy individuals (n = 103) and patients with peripheral arterial occlusive disease (PAOD) (n = 47). Because age in PAOD patients was higher than in control subjects, the control subjects were subdivided into younger and older groups (aged 60 years or less and more than 60 years, respectively). The H(e) levels in the younger groups were 11.18 +/- 3.58 (mean +/- SD, expressed as homocysteine) and 8.58 +/- 2.82 nmol/ml in men and women, respectively; in the older groups, the levels were 10.74 +/- 2.16 and 9.04 +/- 2.16 nmol/ml in men and women, respectively. There was a positive correlation of H(e) levels with age in the younger control women (r = 0.373; p less than 0.02); no significant correlations were present in the other three control groups. Levels of H(e) in PAOD patients (15.44 +/- 5.76 and 17.04 +/- 8.26 nmol/ml in men and women, respectively) were significantly higher than those indicated above in the older controls. Next, the PAOD patients were assigned to two subgroups: 1) those with normal levels of H(e) (within two standard deviations of the mean of the control values) and 2) those with elevated levels of H(e). Age, cholesterolemia, and the prevalence of smoking and diabetes were similar in both subgroups. These results suggest that elevated plasma H(e) is an independent risk factor for arterial occlusive disease.     

Studies on the expression of the TNFα receptors (p55 and p75) and their relative contributions to prostanoid production and glycolytic rate by rheumatoid synovial fibroblasts in vitro

Summary The effect of monoclonal antibodies against the 55-and 75-kDa (p 55 and p 75) tumour necrosis factor (TNF) receptors on two tumour necrosis factor alpha (TNF ) induced responses was studied in rheumatoid synovial fibroblasts (RSF) in vitro. This provided functional evidence for the expression of both receptor types, which was confirmed by substantial inhibition of ¹²⁵ITNF binding to RSF by both antibodies. TNF stimulation of prostanoid production was found to be a function of ligand binding to both receptor types, wheras the stimulation of cellular glycolysis was largely mediated via the p55 receptor. Thus, we showed that RSF express both types of TNF receptor and functional studies showed that stimulation of each receptor results in both similar and dissimilar cellular responses.     

Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation

The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes the formation of its own inhibitor in a highly selective fashion: only a single syn1-triazole regioisomer with defined substitution positions and linker distances is generated from a series of reagent combinations. Inhibition measurements revealed this syn1-triazole isomer to be the highest affinity reversible organic inhibitor of AChE with association rate constants near the diffusion limit. The corresponding anti1 isomer, not formed by the enzyme, proved to be a respectable but weaker inhibitor. The crystal structures of the syn1- and anti1-mouse AChE complexes at 2.45- to 2.65-A resolution reveal not only substantial binding contributions from the triazole moieties, but also that binding of the syn1 isomer induces large and unprecedented enzyme conformational changes not observed in the anti1 complex nor predicted from structures of the apoenzyme and complexes with the precursor reactants. Hence, the freeze-frame reaction offers both a strategically original approach for drug discovery and a means for kinetically controlled capture, as a high-affinity complex between the enzyme and its self-created inhibitor, of a highly reactive minor abundance conformer of a fluctuating protein template.     

Moderate alcohol consumption and diseases of the gastrointestinal system: a review of pathophysiological processes

BACKGROUND/AIMS: Alcohol drinking is responsible for a number of gastrointestinal diseases and cancers. Although heavy drinking episodes and chronic drinking are well linked to mechanisms of disease, moderate alcohol consumption and its effects are less well known. This review attempts to fill a gap in the literature surrounding moderate alcohol consumption. METHODS: A systematic review of the English literature using PubMed was used. RESULTS: A dose-response risk relationship exists between alcohol consumption and digestive disease risk. Acetaldehyde is the main factor in alcohol-related damage in moderate alcohol consumption and acts through numerous methods to exert damaging effects. CONCLUSION: Zero alcohol intake is recommended for lowest risk of alcohol-related digestive tract diseases and conditions. However, given the lowest overall mortality is associated with moderate drinking, moderate drinking with no bingeing episodes is recommended.     

Studies on the infectious etiology of human rheumatoid arthritis. II. Search for humoral and cell-bound antibodies against mycoplasmal antigens.

A total of 29 rheumatoid patients and 19 nonrheumatoid patients were tested for evidence of present or past infection by M pneumoniae, M hominis, M fermentans, M arthritidis, M pulmonis, and M hyorhinis. The techniques of lymphocye transformation, metabolic-inhibiting antibody test, and mycoplasmcidal antibody test indicated no significant difference in the response of rheumatoid as opposed to nonrheumatoid patients.