The alpha+-thalassaemias are the commonest known human genetic disorders, affecting up to 80 per cent of some populations. Although there is good evidence from both epidemiological and clinical studies that these gene frequencies reflect selection by, and protection from, malaria, the mechanism is unknown. We have studied the epidemiology of malaria in childhood on the southwestern Pacific island of Espiritu Santo in Vanuatu and here we report that, paradoxically, both the incidence of uncomplicated malaria and the prevalence of splenomegaly, an index of malaria infection, are significantly higher in young children with alpha+-thalassaemia than in normal children. Furthermore, this effect is most marked in the youngest children and for the non-lethal parasite Plasmodium vivax. The alpha+-thalassaemias may have been selected for their ability beneficially to increase susceptibility to P. vivax, which, by acting as a natural vaccine in this community, induces limited cross-species protection against subsequent severe P. falciparum malaria.

Animals↗

PubMed1996

A trial of artemether or quinine in children with cerebral malaria.

BACKGROUND: Cerebral malaria has a mortality rate of 10 to 30 percent despite treatment with parenteral quinine, a situation that may worsen with the spread of quinine resistance. Artemether is a new antimalarial agent that clears parasites from the circulation more rapidly than quinine, but its effect on mortality is unclear. METHODS: We conducted a randomized, unblinded comparison of intramuscular artemether and intramuscular quinine in 576 Gambian children with cerebral malaria. The primary end points of the study were mortality and residual neurologic sequelae. RESULTS: Fifty-nine of the 288 children treated with artemether died in the hospital (20.5 percent), as compared with 62 of the 288 treated with quinine (21.5 percent). Among the 418 children analyzed at approximately five months for neurologic disease, residual neurologic sequelae were detected in 7 of 209 survivors treated with artemether (3.3 percent) and 11 of 209 survivors treated with quinine (5.3 percent, P = 0.5). After adjustment for potential confounders, the odds ratio for death was 0.84 (95 percent confidence interval, 0.53 to 1.32) in the artemether group, and for residual neurologic sequelae, 0.51 (95 percent confidence interval, 0.17 to 1.47). There were fewer local reactions at the injection site with artemether than with quinine (0.7 percent vs. 5.9 percent, P = 0.001). CONCLUSIONS: Artemether is as effective as quinine in the treatment of cerebral malaria in children.

Antimalarials↗

PubMed1996

Meiotic pachytene arrest in MLH1-deficient mice.

Germ line mutations in DNA mismatch repair genes including MLH1 cause hereditary nonpolyposis colon cancer. To understand the role of MLH1 in normal growth and development, we generated mice that have a null mutation of this gene. Mice homozygous for this mutation show a replication error phenotype, and extracts of these cells are deficient in mismatch repair activity. Homozygous mutant males show normal mating behavior but have no detectable mature sperm. Examination of meiosis in these males reveals that the cells enter meiotic prophase and arrest at pachytene. Homozygous mutant females have normal estrous cycles and reproductive and mating behavior but are infertile. The phenotypes of the mlh1 mutant mice are distinct from those deficient in msh2 and pms2. The different phenotypes of the three types of mutant mice suggest that these three genes may have independent functions in mammalian meiosis.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Bioproduction of human enzymes in transgenic tobacco.

Transgenic plants have significant potential in the bioproduction of complex human therapeutic proteins due to ease of genetic manipulation, lack of potential contamination with human pathogens, conservation of eukaryotic cell machinery mediating protein modification, and low cost of biomass production. Tobacco has been used as our initial transgenic system because Agrobacterium-mediated transformation is highly efficient, prolific seed production greatly facilitates biomass scale-up, and development of new "health-positive" uses for tobacco has significant regional support. We have targeted bioproduction of complex recombinant human proteins with commercial potential as human pharmaceuticals. Human protein C (hPC), a highly processed serum protease of the coagulation/anticoagulation cascade, was produced at low levels in transgenic tobacco leaves. Analogous to its processing in mammalian systems, tobacco-synthesized hPC appears to undergo multiple proteolytic cleavages, disulfide bond formation, and N-linked glycosylation. Although tobacco-derived hPC has not yet been tested for all posttranslational modifications or for enzymatic (anticlotting) activity, these results are promising and suggest considerable conservation of protein processing machinery between plants and animals. CropTech researchers have also produced the human lysosomal enzyme glucocerebrosidase (hGC) in transgenic tobacco. This glycoprotein has significant commercial potential as replacement therapy in patients with Gaucher's disease. Regular intravenous administration of modified glucocerebrosidase, derived from human placentae or CHO cells, has proven highly effective in reducing disease manifestations in patients with Gaucher's disease. However, the enzyme is expensive (dubbed the "world's most expensive drug" by the media), making it a dramatic model for evaluating the potential of plants to provide a safe, low-cost source of bioactive human enzymes. Transgenic tobacco plants were generated that contained the human glucocerebrosidase cDNA under the control of an inducible plant promoter. hGC expression was demonstrated in plant extracts by enzyme activity assay and immunologic cross-reactivity with anti-hGC antibodies. Tobacco-synthesized hGC comigrates with human placental-derived hGC during electrophoretic separations, is glycosylated, and, most significantly, is enzymatically active. Although expression levels vary depending on transformant and induction protocol, hGC production of > 1 mg/g fresh weight of leaf tissue has been attained in crude extracts. Our studies provide strong support for the utilization of tobacco for high-level production of active hGC for purification and eventual therapeutic use at potentially much reduced costs. Furthermore, this technology should be directly adaptable to the production of a variety of other complex human proteins of biologic and pharmaceutical interest.

Enzymes↗

PubMed1996

Synthesis and biological evaluation of N-acetylneuraminic acid-based rotavirus inhibitors.

Rotavirus can cause severe gastrointestinal disease, especially in infants and young children, and is particularly prevalent in Third-World countries. Therefore, the development of potential inhibitors of this virus is of great interest. The present study describes the synthesis and in vitro biological evaluation of a number of N-acetylneuraminic acid-based compounds as potential rotavirus inhibitors. Our data suggests that it is indeed possible to inhibit adhesion of the virus, and hence in vitro replication, with carbohydrate-based molecules, although this inhibition does appear to be strain dependent.

Animals↗

PubMed1996

Geographical perspectives on bednet use and malaria transmission in The Gambia, West Africa.

Insecticide-impregnated bednets are now widely accepted as an important tool in reducing malaria-related deaths in children in Africa. Defining the circumstances in which net treatment programmes are likely to be effective is essential to a rational development of this control strategy. In The Gambia a National Impregnated Bednet Programme was introduced into the primary health care system in 1992. Prior to its introduction baseline epidemiological and entomological studies were conducted throughout the country. These studies showed that in areas where mosquito biting nuisance was high, people protected themselves with bednets and that where mosquito densities (and therefore bednet usage) was low malaria prevalence rates were relatively high. Since the national programme is designed to assist only those people who already own a bednet (by providing the insecticide) an understanding of the factors which determine bednet ownership is needed to help evaluate the programme's effectiveness and provide guidelines for increasing bednet usage. Village scale bednet usage rates and malaria prevalence rates obtained from the baseline survey were correlated with certain geographical variables: dominant ethnic group, area, habitat, distance from the River Gambia and distance from the 'bluffline' (the interface between the sandstone soils and alluvial soils which border the river system). In a multiple regression analysis, bednet usage was independently associated with area (P < 0.001), ethnic group (P = 0.010), habitat (P = 0.006) and distance from the river (P = 0.013). A negative association of bednet usage with malaria prevalence persisted after allowing for the other variables. Malaria prevalence was not independently associated with area, ethnic group, habitat or distance from the river. Our analysis showed that the impregnated bednet programme is likely to be most effective in villages which are sited near to or on the alluvial soils in the middle and lower river zones. These villages, which were originally settled for easy access to the river (for transport) and its swampy margins (for rice production) are within the flight distance of mosquitoes that have their breeding sites on the poorly drained alluvial soils. Variation in malaria prevalence rates (after bednet usage has been taken into account) may be related to factors such as poverty and access to health care, and/or to localized differences in the ecology of The Gambia, which determine the duration and intensity of transmission. If the National Bednet Programme is to be effective throughout The Gambia it is vital to develop promotional activities which will encourage bednet usage in areas where nuisance biting by mosquitoes is low.

Animals↗

PubMed1996

Initial biocompatibility studies of a novel degradable polymeric bone substitute that hardens in situ.

Clinical management of osseous defects often requires bone grafts. The standard for treatment is autogenous bone harvested from sites such as either the iliac crest or the outer table of the calvaria. In addition to the problem of donor site morbidity and the limited supply of graft material, there is the additional operating time associated with harvesting procedures. A synthetic, bone graft substitute that can match the clinical performance of autogenous bone could alleviate these deficiencies. Therefore, a polymeric bone substitute was developed that consists of a four-armed star polymer of poly(dioxanone-co-glycolide) endcapped at each termini with a biocompatible lysine-based diisocyanate crosslinker. The polymer can be mixed with inorganic fillers such as either hydroxyapatite or tricalcium phosphate to form either injectable or moldable putty. The addition of a catalyst (for example, diethylaminoethanol and water) to the polymer produces a crosslinking reaction causing the combination to harden. This reaction is nontoxic, normo-thermic and can be performed in situ. During the course of the polymerization, carbon dioxide is liberated, producing an interconnected porous network within the implant, suitable for bone ingrowth. This paper will describe a preliminary biocompatibility assay of the bone substitute.

Animals↗

PubMed1996

Both in vitro and in vivo irradiation are associated with induction of macrophage-derived fibroblast growth factors.

Fibrosis in the lung directly underlying the field of irradiation is an almost universal long term sequelae of thoracic irradiation. It is assumed to represent the consequence of direct damage to local tissues and/or vascular endothelium by ionizing radiation. This view, however, is not in keeping with our current understanding of fibrotic processes, which suggest that growth factors for fibroblasts (including platelet-derived growth factor (PDGF), insulin-like growth factor I (IGF-I)) and cytokines stimulating collagen synthesis (notably transforming growth factor-beta) are largely responsible for this process. Since a major source of these factors is the macrophage, present in large numbers within the lung, it appeared possible that radiation-induced fibrosis might be mediated by similar mechanisms. Therefore, a study was designed to determine, first, whether in vitro irradiation of mononuclear phagocytes could induce the release of growth factors for fibroblasts. Second, we wished to ascertain whether these same growth factors might also be secreted by bronchoalveolar cells from humans who had undergone in vivo thoracic irradiation. The results of this study indicate that irradiation of a number of different types of mononuclear phagocytes resulted in the dose-dependent synthesis and release of several growth factors for fibroblasts, including PDGF, tumour factor-alpha (TNF-alpha) and IGF-I. Further, cells obtained by bronchoalveolar lavage from patients undergoing thoracic radiation spontaneously released PDGF following irradiation. These findings strongly support the contention that synthesis and release of macrophage-derived growth factors for fibroblasts (particularly PDGF and IGF-I) occur after thoracic irradiation and play a significant role in the pathogenesis of irradiation-induced pulmonary fibrosis in humans.

Breast Neoplasms↗

PubMed1996

Implementing a nationwide insecticide-impregnated bednet programme in The Gambia.

Earlier studies in The Gambia suggested that the use of impregnated bednets might prove to be a useful malaria control strategy. Based on the results of these studies, in 1992 the Government of The Gambia was encouraged to initiate a National Impregnated Bednet Programme (NIBP) as part of the National Malaria Control Programme Strategy. This paper describes the implementation process/procedure of the NIBP. Evaluation results showed that, overall, 83% of the bednets surveyed has been impregnated, and 77% of children under the age of five years and 78% of women of childbearing age were reported to be sleeping under impregnated bednets.

Adolescent↗

PubMed1996

Socioeconomic inequalities in coronary heart disease and stroke mortality among Australian men, 1979-1993.

BACKGROUND: During the 1970s in Australia, mortality from coronary heart disease (CHD) and stroke was higher among lower socioeconomic groups and inequalities were widening. This analysis examines subsequent trends in socioeconomic inequalities, with reference to socioeconomic patterns in major cardiovascular risk factors. METHODS: Socioeconomic status was defined by occupation. Age-standardized mortality rates were calculated for men aged 25-64, using death registration data and labour force estimates for 1979-1993. Risk factor data were taken from three cross-sectional population surveys conducted in 1980, 1983 and 1989. RESULTS: Men in manual occupations were at least 35 percent more likely to die from CHD than men in professional occupations and 60 percent more likely to die from stroke. Their 5-year population risk of a coronary event was 30 percent higher. Since 1979, both groups experienced reductions in coronary risk and mortality. CONCLUSIONS: Socioeconomic inequalities in CHD mortality continued to widen during the early 1980s, stabilized thereafter and persisted into the 1990s. Decreases in blood pressure and smoking prevalence contributed most to declines in coronary risk and to socioeconomic differentials.

Adult↗

PubMed1996

The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria.

Tumor necrosis factor (TNF) is thought to play a key role in the pathogenesis of cerebral malaria. A double-blind, placebo-controlled trial of an anti-TNF monoclonal antibody (B-C7) comprised 610 Gambian children with cerebral malaria, with mortality and residual neurologic sequelae as primary study end points. Sixty (19.9%) of 302 children who received B-C7 died compared with 64 (20.8%) of 308 children who received placebo (adjusted odds ratio [OR], 0.90; 95% confidence interval [CI], 0.57-1.42). Residual neurologic sequelae were detected in 15 (6.8%) of 221 survivors from the B-C7 group and in 5 (2.2%) of 225 survivors of the placebo group (adjusted OR, 3.35; 95% CI, 1.08-10.4). The monoclonal antibody used in this study did not improve survival in cerebral malaria and was associated with a significant increase in neurologic sequelae. A possible explanation of the latter observation is that the antibody acts to retain TNF within the circulation and thereby prolongs its effects on vascular endothelium.

Antibodies, Monoclonal↗

PubMed1996

Chloroquine resistance of Plasmodium falciparum malaria in Ethiopia and Eritrea.

We report on the first 2 years of operation of a new strategy for treatment for P. falciparum malaria patients who were not cured by a standard course of chloroquine. Any such patient who returned to a malaria treatment and detection post within 2 weeks was treated daily under supervision with chloroquine. Patients whose parasitaemia had not decreased below 25% of the initial level by day 3 or cleared completely by day 7 were given sulphadoxine/pyrimethamine (Fansidar). Of 39824 patients treated initially with chloroquine, 4% returned to the malaria post within 2 weeks of treatment; 87% of these were chloroquine resistant and treated with Fansidar and 28% of the returning patients were RIII resistant. Resistance was associated with geographical area, initial parasite density and age. Earlier studies had shown resistance to be confined to border areas, but we found that it was highest in the centre of the region, notably in the lowlands of the Shewa and Arsi provinces, and lowest in the west. Although imported cases have been held responsible for the development of resistance in border areas, other factors are likely to be important in the middle of the region. The implications of these findings for a treatment policy of P. falciparum malaria in the region are discussed.

Adolescent↗

PubMed1996

Report of the Fifth International Workshop on Human Chromosome 11 Mapping 1996.

Explore the source record for details and available documents.

Chromosome Mapping↗

PubMed1996

Providing care for elderly patients. A survey of Hamilton-Wentworth dentists' perceptions of their educational needs.

Explore the source record for details and available documents.

Aged↗