Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that, in addition to motor, sensory, and cognitive symptoms, also causes constipation, which is poorly understood. Here, we characterize gastrointestinal (GI) dysmotility in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and evaluate whether autoantibodies target the enteric nervous system (ENS) and cause dysmotility. METHODS: EAE was induced in male SJL and B6 mice. GI motility was assessed in vivo and ex vivo in wild type (WT) and B cell-deficient mice. MS and EAE serum was used to survey potential targets in the ENS and changes in the ENS structure were characterized using immunohistochemistry. KEY RESULTS: EAE mice developed accelerated gastric emptying and delayed whole GI transit with reduced colonic motility. Fecal water content was reduced, and colonic migrating myoelectrical complexes (CMMC) and slow waves were less frequent. Colons from EAE mice exhibited decreased GFAP levels in glia. Sera from MS patients and from EAE mice targeted ENS neurons and glia. B-cell deficiency in EAE protected against colonic dysmotility. CONCLUSIONS & INFERENCES: Consistent with symptoms experienced in MS, we demonstrate that EAE mice widely exhibit features of GI dysmotility that persisted in the absence of extrinsic innervation, suggesting direct involvement of ENS neurocircuitry. The absence of GI dysmotility in B cell-deficient mice with EAE together with EAE and MS serum immunoreactivity against ENS targets suggests that MS could be classified among other diseases known to induce autoimmune GI dysmotility.

Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection.

We enrolled 427 consecutive patients with tuberculosis diagnosed in Cité Soleil, Haiti in a trial of short-course intermittent therapy. All patients received supervised therapy with isoniazid, rifampin, pyrazinamide, and ethambutol thrice weekly for 8 wk, followed by isoniazid and rifampin thrice weekly for 18 wk. At entry, the 177 human immunodeficiency virus (HIV)-infected patients (42%) were found significantly more likely to have extrapulmonary tuberculosis and negative tuberculin skin tests (p < 0.05). Treatment was well tolerated by both groups of patients, and adherence to the treatment regimen was over 90%. Among patients with pulmonary or intrathoracic tuberculosis, 9% of HIV-seropositive and 1% of HIV-seronegative patients died during therapy (p < 0.001), whereas 81% and 87%, respectively, of those in the two groups were cured. Relapses occurred in 5.4% of HIV-seropositive and 2.8% of HIV-seronegative patients who completed treatment (p = 0.36). Survival after tuberculosis was poorer in HIV-seropositive patients, whose probability of dying was 33% at 18 mo after diagnosis as compared with 3% for HIV-seronegative patients (p < 0.001). HIV-seropositive patients who died had significantly lower median CD4 lymphocyte counts than did HIV-seropositive patients who survived (p < 0.001). Treatment of tuberculosis with short-course, thrice-weekly, supervised therapy in the setting of a developing country is highly efficacious in both HIV-seropositive and -seronegative patients.

Pancreatitis associated with human immunodeficiency virus infection: a matched case-control study.

To determine the frequency of pancreatitis and to define risk factors for pancreatitis in patients with AIDS, we compared patients with pancreatitis to patients without pancreatitis in an urban infectious disease practice. Pancreatitis was defined as at least one clinical sign or symptom (nausea, vomiting, abdominal pain, or tenderness) accompanied by elevation of serum amylase or lipase. Twenty-four (22%) of 105 patients with AIDS, 2 (4%) of 46 patients with AIDS-related complex, 1 (3%) of 39 asymptomatic patients infected with HIV-1, and none of 9 uninfected patients at risk for HIV-1 developed pancreatitis as defined above. Fourteen patients experienced multiple episodes and three were symptomatic for more than 2 months. Pancreatitis was more likely to have occurred in patients with AIDS (P < .001), biliary tract disease (P = .013), and hypertriglyceridemia (P = .032). After matching for these factors and duration of current HIV disease, cryptosporidiosis, intravenous pentamidine, and isoniazid were each associated independently with pancreatitis (P < .05). Before didanosine (ddl) became available, 22% of the patients with AIDS in this practice had pancreatitis. Cryptosporidiosis, isoniazid, and intravenous pentamidine should be considered among the potential etiologies.

Percentile regression analysis of correlated antibody responses.

Antibody responses following vaccination usually are analysed by comparing geometric mean concentrations across levels of relevant covariates and by comparing the proportions of vaccinees responding. In the regression setting, the analyses are done on log-transformed concentrations, estimating geometric mean responses conditional on a vector of covariates. More detailed analyses examining the relationship of covariates to different parts of the response distribution may be performed through the application of asymmetric least squares estimation of regression percentiles. We present a method for accounting for correlation in percentile regression analyses of longitudinal antibody response data. We illustrate the procedures with measles antibody response data from Haitian children who participated in a randomized trial of high titre vaccines. The strongest dose and strain effects were seen in the low end of the antibody concentration distributions.

Differential mortality by measles vaccine titer and sex.

Mortality was evaluated in 1972 children who had received measles vaccines at 6-11 months of age that were 10-fold (medium titer) or 100-fold (high titer) greater than standard titer. Mortality among boys did not differ by vaccine titer and was similar to mortality in children who received standard-titer vaccine. Girl recipients of high-titer vaccine had somewhat greater mortality than girls who received medium-titer vaccine (risk ratio = 1.71, 95% confidence interval = 0.91-3.24). Increased mortality was associated with high-titer vaccine for girls but not for boys (P = .04). There was no evidence of selection bias or preferential health care by sex that might explain the differential mortality. This mortality pattern has been noted in two other populations with high background infant and childhood mortality. The biologic basis for this effect on mortality has not been determined. Data from this and other studies have resulted in discontinuation of the use of high-titer measles vaccines.

The utility of verbal autopsies for identifying HIV-1-related deaths in Haitian children.

OBJECTIVE: To determine whether deaths among Haitian infants born to HIV-1-seronegative women could be distinguished from deaths among children born to HIV-1-seropositive women using the verbal autopsy technique. METHODS: Mothers of 315 Haitian children who died were interviewed about events leading to the child's death. Three physicians independently reviewed interview data and determined the probable cause of death without knowledge of maternal HIV-1 status or hospital records. The underlying causes of death assigned to the infants were analyzed to determine whether maternal HIV status could be predicted. RESULTS: There was good agreement among the physicians (kappa = 0.62) and 90% agreement between hospital records and the verbal autopsy diagnosis. Compared with children born to HIV-1-seronegative women, deaths in children born to HIV-1-seropositive mothers were more likely to be ascribed to a presumptive diagnosis of AIDS (37 versus 21%; P = 0.01). The sensitivity and specificity of verbal autopsies for identifying deaths associated with maternal HIV-1 infection ranged from 37 to 59% and from 69 to 79%, respectively, depending on the classification system used. The predictive positive value of a death believed to be consistent with pediatric HIV-1 infection was 26-30% and the predictive negative value was 85-90%. CONCLUSION: Verbal autopsies may be useful for distinguishing certain causes of death, but have limited utility for distinguishing deaths associated with maternal HIV-1 infection from deaths among children born to HIV-1-seronegative women.

Childhood survival in Haiti: protective effect of measles vaccination.

To evaluate the impact of measles vaccination on survival of children residing in a periurban slum in Haiti, a total-population survey was conducted 2.5 years after completion of a one-time study of the serologic response to measles vaccine administered in the same population. Pregnancy histories from the 16,400 women in the population revealed that 1499 children had been born during a 7-month interval that would have made them eligible for participation in the measles vaccine program. Of these children, 1381 (92.1%) survived to 9 months of age, the median age that measles vaccine had been administered. Seventy-three infants had died between 9 and 39 months of age. Mortality of infants who were seronegative before receiving measles vaccine was significantly lower (P = .0013) than that of unvaccinated infants (3/235 vs 70/1056, respectively). Other factors positively associated with survival between 9 and 39 months of age included socioeconomic status (P = .0002), maternal literacy (P = .0020), maternal knowledge and use of oral rehydration solution (P = .0002), and an interval of greater than 24 months to the birth of the next younger sibling (P = .0012). Multivariate stepwise logistic regression analysis was used to evaluate the independent association of measles vaccination by adjusting for other factors that also correlated with survival and that might have been associated with maternal seeking of vaccinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Malabsorption of oral antibiotics in humans and rats with giardiasis.

We observed unexplained treatment failures in 13 patients with serious infections and apparent incidental giardiasis. Antibiotic concentrations were assayed in the serum from patients before initiating anti-Giardia therapy and again 2 to 3 weeks after therapy. The peak serum concentrations of antibiotics were higher after treatment for giardiasis. The rat model of giardiasis was used to examine the hypothesis that oral antibiotics are malabsorbed during Giardia lamblia infection. Twenty-eight-day-old Sprague-Dawley rats were fed amoxicillin (50 mg/kg/dose), ampicillin (50 mg/kg/dose), cefaclor (50 mg/kg/dose), cephalexin (50 mg/kg/dose), erythromycin (50 mg/kg/dose), penicillin V (50 mg/kg/dose) or sulfamethoxazole (20 mg/kg/dose) and sera were assayed for antibiotics at 1, 2, 4, 6 and 12 hours after therapy. The same rats were fed 10(5) G. lamblia cysts on 4 consecutive days. On Day 7 of infection the rats were fed the same antibiotic and sera were assayed for antibiotics at 1, 2, 4, 6 and 12 hours after therapy. The mean peak serum concentrations for all drugs except sulfamethoxazole were significantly higher in the rats before infection with G. lamblia. These data suggest that oral antibiotic therapy maybe compromised by decreased absorption in the presence of giardiasis.