Biomedical subjects
Publications and source records attributed to R H Gilman.
Serum samples from children and adults from several countries were tested by radioimmunoassay for antibody to the Norwalk virus. Antibody was commonly found in adults from all the countries tested. Antibody appears to be acquired more rapidly in children from underdeveloped countries than in children from the United States.
To investigate three possible causes of the acute hemolysis in the hemolytic-uremic syndrome, we studied prospectively 207 children and 34 adults with shigellosis in Bangladesh. Nineteen children showed acute hemolytic anemia, a leukemoid reaction, thrombocytopenia and oliguria; nine other had, in addition, a serum urea nitrogen level of over 100 mg per diciliter. Eight of the nine had pseudomembranous colitis, and six of the nine died. The frequency of bacteremia was similar in all grades of shigellosis. Circulating immune complexes were found in 10 of 20 patients with uncomplicated shigellosis and in four of six with severe hemolytic-uremic syndrome. Limulus assay for endotoxemia was positive in nine of 18 patients with hemolysis (50 per cent) and three of 61 with uncomplicated shigellosis (5 per cent) (P less than 0.001). These data support the hypothesis that severe colitis in shigellosis is associated with circulating endotoxin from the colon producing coagulopathy, renal microangiopathy and hemolytic anemia.
As an ancillary part of a typhoid fever vaccine study, 10 healthy adult male volunteers (nonimmunized controls) were serially bled 6 days before to 30 days after ingesting 10(5)Salmonella typhi organisms. Five persons developed typhoid fever 6-10 days after challenge, while five remained well. During the febrile illness, significant changes (P < 0.05) in the following hematological parameters were measured: a rise in alpha(1)-antitrypsin antigen concentration and high molecular weight kininogen clotting activity; a progressive decrease of platelet count (to 60% of the predisease state), functional prekallikrein (55%) and kallikrein inhibitor (47%) with a nadir reached on day 5 of the fever and a subsequent overshoot during convalescence. Despite the drop in functional prekallikrein and kallikrein inhibitor, there was no change in factor XII clotting activity or antigenic concentrations of prekallikrein and the kallikrein inhibitors, C1 esterase inhibitor (C1-INH) and alpha(2)-macroglobulin. Plasma from febrile patients subjected to immunoelectrophoresis and crossed immunoelectrophoresis contained a new complex displaying antigenic characteristics of both prekallikrein and C1-INH; the alpha(2)-macroglobulin, antithrombin III, and alpha(1)-antitrypsin immunoprecipitates were unchanged. Plasma drawn from infected-well subjects showed no significant change in these components of the kinin generating system. The finding of a reduction in functional prekallikrein and kallikrein inhibitor (C1-INH) and the formation of a kallikrein C1-INH complex is consistent with prekallikrein activation in typhoid fever. The correlation of these changes with the drop in platelet count suggests that a common mechanism may be responsible.
The usefulness of a single Widal test to diagnose typhoid fever in endemic areas was investigated. Reciprocal Salmonella typhi O and H titers greater than or equal to 40 and greater than or equal to 80, respectively, occurred in approximately 90% of 42 Mexican patients with bacteriologically-confirmed typhoid fever at the time of presentation to hospital and, by day 4 to 5 of clinical illness, in 70% of U.S. adult volunteers who developed typhoid fever in the course of vaccine efficacy trials but in only 0.7% (O) to 3% (H) of 275 healthy individuals from a non-endemic area. Healthy Peruvians from areas endemic for typhoid fever commonly had antibody which was age-related. Peak prevalence was found in 15- to 19-yr-olds in whom 29% had O titers greater than or equal to 40 and 76% had H titers greater than or equal to 80. A single Widal test in an unvaccinated individual showing elevated O and H titers is strongly suggestive of typhoid fever if the person comes from a non-endemic area or is a child less than 10 yr of age in an endemic area. Because of the high prevalence of antibody amongst healthy invididuals over 10 yr of age in endemic, areas, a single Widal test offers virtually no diagnostic assistance in adolescents and adults.
A mutant (Ty21a) of Salmonella typhi, which lacks the enzyme uridine 5'-diphosphate-glucose-4-epimerase, was evaluated in volunteers for use as a live attenuated oral typhoid vaccine. Five to eight doses of vaccine (containing 3-10(10) viable organisms per dose) were given to 155 men without significant side effects. The rate of excretion of the vaccine strain in stools was low, and the majority of isolations occurred on day 1 after vaccination. Revertants able to fement galactose were not found in any of 958 stool isolates tested. The mutant, strain Ty21a, grown in brain-heart infusion broth (BHIB) with 0.1% galactose, produces more O side chain than the same vaccine strain cultivated without galactose. Volunteers vaccinated with strain Ty21a grown in galactose and then challenged with 10(5) virulen S. typhi were significantly protected from disease and also had decreased stool carriage of S. typhi as compared with controls. Strain Ty21a grown without galactose did not provide vaccinees significant protection nor decrease fecal excretion of S. typhi as compared with controls. Strain Ty21a, when grown in BHIB with 0.1% galactose, results in a safe, stable and protective oral vaccine that warrants further study in field trials.
Children with heavy Trichuris infestation were compared with paediatric amoebic dysentery patients and normal children. Heavy Trichuris infestation was diagnosed by visualization of worms on anoscopy. Patients with heavy Trichuris infection had a longer duration of disease, more frequent hospitalization and a higher rate of rectal prolapse than did patients with amoebiasis. Five Trichuris children also had clubbing. Trichuris patients had lower mean haematrocrits (27%) and serum albumin (3-3 gm%) than did patients with amoebiasis (32% and 3-7 gm% respectively). Coinfection with Shigella and Salmonella was significantly increased in patients with heavy Trichuris infection compared to both amoebic and control group children. Trichuris patients were infected with Entamoeba histolytica more frequently (46%) than normal children. Heavy Trichuris infection is the probable cause of symptoms and signs seen in these patients.
Four studies were done with streptomycin-dependent Salmonella typhi as an oral, attenuated vaccine. Studies 1 and 3 employed freshly harvested vaccine, whereas studies 2 and 4 involved lyophilized vaccine. Five to eight doses (3 x 10(10)-10(11) organisms/dose) were given; oral streptomycin (1.0 g) was administered concomitantly in studies 2 and 3, with only two of the doses of vaccine in study 1, and was not given in study 4. No adverse reactions were encountered in 179 vaccinated men, and 94% of the men excreted the vaccine. In challenge studies (which included the control groups) with 10(5) virulent S. typhi organisms (Quailes strain), the fresh vaccine was highly protective (66%-78% efficacy), while lyophilized vaccine gave no clinical protection. Fresh vaccine also interfered significantly with intestinal proliferation of virulent S. typhi; only 17% of the vaccinees excreted organisms as compared with 75% of the controls. Studies of protection in mice showed no difference between immunogen content of the fresh and the lyophilized vaccines. Field trials with streptomycin-dependent, oral typhoid vaccine must await development of a lyophilized product that will retain the protective properties of the vaccine.
Three of seven volunteers with acute typhoid fever had Salmonella typhi isolated from the duodenum using a string capsule device. The string capsule device provides a simple method for culturing S. typhi from the duodenal contents. Its possible use in typhoid carriers is discussed.
The indirect hemagglutination test was used to study antibody titers to Entamoeba histolytica in different Malaysian populations. Eighty-seven percent of Orang Asli (western Malaysian aborigines) adults and 79% of Orang Asli children with acute amebic dysentery were seropositive. However, significantly fewer children (39%) with amebic dysentery had high titer responses (titer greater than or equal to 1:1,280) than did adults with amebic dysentery (76%). No correlation between proctoscopic severity and amebic titer was found. Forty-four percent of asymptomatic family members were seroresponders. Satak, an Orang Asli village located near towns, had significantly more seroresponders (32%) than did the isolated, deep jungle village, Belatim (4%).
A live attenuated oral cholera vaccine has been given to volunteers with complete safety. The vaccine strain appeared to multiply significantly in intestinal contents and to result in appreciable vibriocidal antibody response. Subsequent challenge with virulent Inaba vibrios demonstrated substantial protection from clinical illness and from vibrio shedding. The possibility of reversion to toxin production is discussed.
A live oral attenuated vaccine, lacking the enzyme epimerase, has been given with complete safety to 173 men. Two preparations of the vaccine, one with and one without galactose in the initial culture media, led to somewhat differing results. Vaccine A, prepared with galactose, was more readily identified in the stool specimens of its recipients and was more likely to provoke an O antibody response than was vaccine B. Furthermore, the clinical protection from typhoid fever was significant in the vaccine A group, whereas not so with the vaccine B counterpart. The protection afforded by vaccine A exceeds that of any of our previous candidate strains. It is perhaps not presumptuous to imagine that such a vaccine would be equally effective in an area endemic for typhoid fever, where the vaccine might act as a booster effect in a previously exposed population. Remaining questions to be answered include the duration of the protection, and the efficacy of a lyophilized preparation.
The recovery of Salmonella typhi from blood, rectal swab, urine, bone-marrow, and rose spots was compared in 62 patients with typhoid fever, most of whom had received some antibiotic therapy before presentation. S. typhi was isolated from culture of bone-marrow in 56 patients (90%); in contrast, S. typhi was recovered from blood in only 25 (40%), from stool in 23 (37%), and urine in 4 (7%). S. typhi was isolated from 24 (63%) of 38 patients who had rose-spot cultures. If culture sites had been limited to blood, stool, and urine, the bacteriological diagnosis would have been missed in 24 patients.
The efficacy of orally administered trimethoprim-sulfamethoxazole was compared with that of oral amoxicillin in therapy of typhoid fever due to both epidemic chloramphenicol-resistant and endemic chloramphenicol-sensitive Salmonella typhi. Both drug regimens were effective and of comparable value in treatment of chloramphenicol-resistant infections, as measured by duration of fever (124 hr and 115 hr, respectively) and duration of bacteremia (1.0 and 0.4 days, respectively). Trimethoprim-sulfamethoxazole therapy of infections due to chloramphenicol-sensitive S. typhi resulted in more rapid lysis of fever than did amoxicillin therapy. Trimethoprim and sulfamethoxazole were not synergistic in vitro against the chloramphenicol-resistant strain of S. typhi, and the role of sulfamethoxazole in treatment of such infections appears to be minimal. Oral administration of trimethoprim-sulfamethoxazole is effective therapy of chloramphenicol-resistant, and probably of ampicillin-amoxicillin-resistant, typhoid fever.
Clindamycin 450 mg every 8 hours for 3 days cured three non-immune patients of falciparum malaria, although the response was slow. The addition of quinine to this regimen provided an accelerated response and cured 3 of 5 other patients. Single doses of clindamycin given daily for 3 days, with or without quinine, cured 1 of 3 patients. Gastric intolerance to the drugs, probably accentuated by the clinical condition, was pronounced in some cases, the course of treatment being interrupted in three patients for this reason. Chesson strain Plasmodium vivax relapses in man were not inhibited by ingestion of 450 mg of clindamycin every 6 hours for 14 days.
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