Receptor blocking, cholera, and Escherichia coli toxins.
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Biomedical subjects
Publications and source records attributed to M R Khan.
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We conducted a randomized trial among persons in rural Bangladesh to evaluate the side effects and immunogenicity of orally administered B subunit-killed whole cell (BS-WC) and killed whole cell-only (WC) cholera vaccines and a killed Escherichia coli strain K12 placebo proposed for field testing. Three doses of BS-WC, WC, E. coli, or a control agent were given with antacid to 1,257 women (aged greater than 15 years) and children (aged to to 15 years). The four groups exhibited no statistically significant differences in occurrence of symptoms after each dose, and rises in titers of vibriocidal (VC) antibodies to Inaba and Ogawa were twofold higher for vaccinees than for controls (P less than .001). Half of the persons with fourfold or greater VC responses to WC responded after the first dose; many additional patients, particularly young children, responded after subsequent doses. In contrast, 89% of persons who responded to BS-WC with twofold or greater rises in titer of IgG antibodies to cholera toxin did so after the first dose. After the third dose, vaccinees exhibited a fivefold higher rise in titer than did controls (P less than .001); a dose-to-dose booster effect was most evident in young children.
The role of muscle function in the aetiology of recurrent dislocation of the patella has been examined. Eleven of the 12 patients we studied had joint hypermobility. Muscle biopsies from eight of nine patients treated by surgery had a predominance of abnormal Type 2C fibres, and three of six patients whose quadriceps muscles were studied by electromyography also had abnormal results. Our preliminary findings suggest that there may be a primary muscular defect in many cases of recurrent dislocation of the patella.
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The protective efficacy of oral B subunit killed whole-cell (BS-WC) and killed whole-cell (WC) cholera vaccines was assessed in 63 498 Bangladeshi children aged 2-15 years and women aged over 15 years. Each received three doses of BS-WC, WC, or placebo in a randomised, double-blinded fashion. Surveillance for cases seeking medical care up to six months after the third dose revealed 26 cases of confirmed cholera in the placebo group, 4 cases in the BS-WC group (protective efficacy 85%; p less than 0.0001), and 11 cases in the WC group (protective efficacy 58%; p less than 0.01). For each vaccine protective efficacy was consistent in different age-groups (2-10 years versus greater than 10 years) and for different severities of cholera.
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In rural Bangladesh, family contacts of patients with cholera were studied prospectively to examine whether protection against colonization and disease due to Vibrio cholerae O1 was associated with circulating antibodies to V. cholerae. Family contacts (1,071) of 370 patients with cholera were visited daily for 10 days, cultured for V. cholerae, and queried about diarrhea. Sera collected on days 1 and 21 were assayed for vibriocidal antibodies, IgG and IgA antibodies to cholera toxin, and IgG antibodies to lipopolysaccharide (LPS). Vibriocidal titers of greater than or equal to 20 present in 50% of contacts by 20 years of age were associated with protection against both colonization and disease. An elevated level of IgG antitoxin was not associated with protection against colonization or disease but was the most sensitive indicator of recent symptomatic cholera and of immune response to the oral immunogen B subunit. IgG antibody to LPS and IgA antitoxin were of little value in predicting colonization or disease.
At the Matlab Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh, the authors examined the blood groups of patients hospitalized between January and September 1979 for diarrheal disease due to a variety of bacterial and viral agents. A significant association was identified only for cholera, in which cholera patients were twice as likely to have blood group O and one-ninth as likely to have blood group AB as community controls. A follow-up study of family contacts of cholera patients, carried out between September 1980 and July 1982, indicated that blood group did not affect an individual's risk of having a culture-proven infection with V. cholerae 01 but was directly related to the severity of disease. Individuals with the most severe diarrhea compared with those with asymptomatic infection were more often of blood group O (68% versus 36%, p less than 0.01) and less often of AB (0% versus 7%, p less than 0.01). It was not possible to identify the molecular basis for this genetically related protection using biologic models of cholera that are currently available. The constant selective pressure of cholera against people of O blood group may account in part for the extremely low prevalence of O group genes and the high prevalence of B group genes found among the people living in the Gangetic Delta.
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The prevalence of visual defects, especially from causes associated with nutritional deficiencies, and their relation to diarrhoea in rural Bangladesh have been studied. A trained physician and a team of health workers examined visual defects in 149 villages, with a total population of 182 976. According to WHO classification, night blindness (XN) was found in only 0.03 persons/1000 population and 0.04 were found to have conjunctival xerosis (XIA) and Bitot's spot (XIB). Corneal xerosis (X2, X3A, X3B) also was found in 0.04 persons/1000. Night blindness combined with conjunctival xerosis and Bitot's spot (XN + XIA + XIB) was present in 1.69 persons/1000 and all combined stages of active xerophthalmia were seen in 0.06 persons/1000. Xerophthalmia prevailed up to age 19 years. Males had a significantly higher (2.9) incidence/1000 than did females (1.2). The total rate of keratomalacial scar for all ages was 0.31 persons/1000, while corneal opacity from other causes was seen in 2.25 persons/1000 population. More than 2.06 persons/1000 had ocular manifestations of one or more vitamin A deficiencies, while 4.47 persons/1000 had other ocular diseases, except for cataracts. Only 12.0% of all the corneal scars (XS) were due to keratomalacia. History of night blindness is a good indicator of vitamin A deficiency. In 96% of cases, night blindness was associated with conjunctival xerosis and Bitot's spot (XN + XIA + XIB). The onset of approximately 86% of cases of corneal xerosis (X2, X3A, X3B) and night blindness associated with conjunctival xerosis and Bitot's spot (XN + XIA + XIB) was related to diarrhoea.
A randomized, controlled field trial was performed to test the ability of B subunit, the nontoxic, binding portion of cholera toxin, to block the toxin receptors (GM1 ganglioside) in the small intestine and thereby prevent diarrhea in individuals infected with Vibrio cholerae O1. Of 1,922 family contacts of 370 index patients selected randomly to receive orally on two successive days either B subunit (low dose, 1.0 mg; high dose, 5.0 mg) or placebo, 190 were asymptomatically infected on day 1 or day 2 of the study and within 24 hr of receiving B subunit. During the first 24-hr period of follow-up, the relative risk of disease among contacts receiving B subunit versus placebo was 0.18 for the low dose (P = .08) and 0.50 for the high dose (P = .22). Subsequently the relative risk increased toward 1.0 and was at no single point significantly reduced, although in five of the six follow-up periods the risk of disease was less in the B subunit group.
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We performed a prospective study to examine whether the IgA antibodies against cholera that are present in breast milk protect breast-fed infants and children against colonization with Vibrio cholerae 01 and disease. Among families of patients with cholera, we collected breast milk from mothers who had not had diarrhea in the previous week and monitored them and their breast-fed children for cholera colonization and diarrhea for 10 days. Breast milk was assayed for IgA antibodies to cholera toxin and lipopolysaccharide. Ninety-three mother--child pairs were studied; 30 infants became colonized with V. cholerae 01 and disease developed in 19. There were no differences between the antibody levels in milk fed to children who became colonized and in milk fed to children who did not. However, among the children who became colonized, those who had diarrhea drank breast milk containing significantly lower levels of both kinds of cholera antibodies than were present in the milk consumed by children who had no symptoms. We conclude that breast-milk antibodies against cholera do not appear to protect children from colonization with V. cholerae 01 but do protect against disease in those who are colonized.