rhIGF-I administration reduces insulin requirements, decreases growth hormone secretion, and improves the lipid profile in adults with IDDM.

IDDM is associated with elevated circulating levels of growth hormone (GH) and reduced insulin-like growth factor I (IGF-I). GH antagonizes the action of insulin-increasing insulin requirements in IDDM. The effects of subcutaneously administered rhIGF-I on glycemic control, insulin requirements, and GH secretion were studied in eight adults with IDDM. Patients received either placebo or rhIGF-I (50 microg/kg b.i.d.) for 19 days in a randomized, double-blind, parallel-design, placebo-controlled trial. Overnight GH, plasma glucose, free insulin, IGF-I, fructosamine, and lipid profiles were assessed during this period. rhIGF-I therapy increased IGF-I concentration from 117.1 +/- 14.2 (mean +/- SE) ng/ml (baseline) to 310.5 +/- 40.6 and 257.1 +/- 41.2 ng/ml on day 5 (P < 0.01 vs. baseline) and day 20 (P < 0.01 vs. baseline), respectively. After 19 days of rhIGF-I treatment, fructosamine concentrations were unchanged compared with baseline (439 +/- 32 vs. 429 +/- 35 micromol/l, day -1 vs. day 20, respectively), yet insulin requirements were decreased by approximately 45% (0.67 +/- 0.08 vs. 0.36 +/- 0.07 U x kg(-1) x day(-1), day -1 vs. day 19, respectively, P < 0.005). After 4 days of rhIGF-I therapy, there was a decrease in free insulin levels (8.38 +/- 1.47 vs. 4.98 +/- 0.84 mU/l, P < 0.05), mean overnight GH concentration (12.6 +/- 3.3 vs. 3.8 +/- 2.1 mU/l, P = 0.05), and total cholesterol and triglycerides (4.68 +/- 0.31 vs. 4.25 +/- 0.35 mmol/l, P < 0.05, 1.27 +/- 0.19 vs. 0.95 +/- 0.21 mmol/l, P < 0.001, respectively). There was no change in any variable in the placebo-treated patients. This study demonstrates that subcutaneous administration of rhIGF-I decreases insulin requirements and improves the plasma lipid profile while maintaining glycemic control in adults with IDDM. The excess nocturnal release of GH, characteristic of IDDM, is also decreased by rhIGF-I therapy.

Seroepizootiology of Helicobacter pylori gastric infection in nonhuman primates housed in social environments.

We determined the seroepizootiology of Helicobacter pylori infection in rhesus monkeys. Plasma was obtained from 196 animals (age range, 1 to 22 years) that were housed in social environments, either in indoor gang cages, in outdoor corrals, or in free-ranging forested conditions. Plasma immunoglobulin G levels were determined with a specific enzyme-linked immunosorbent assay, and the cutoff immunoglobulin G value for H. pylori seropositivity was determined from a study of 25 monkeys whose infection status was assessed by light microscopy and culture. One-year-old animals of both genders in all housing conditions had the lowest rate of positivity (60% in monkeys 1 year old versus 81% in monkeys 2 to 10 years old, P = 0.026). In addition, females tended to have higher rates of positivity than males. Seroconversion during a 1-year observation period occurred in 7 (28%) of 25 seronegative animals. Seroreversion occurred in 3 (4%) of the 78 positive animals; all 3 of these animals had received antimicrobial agents during the year. These observations demonstrate that the epizootiology of H. pylori infection in rhesus monkeys may serve as a model for human infection.

Normal serum biochemical and hematological values of the Sulawesi macaques.

Sulawesi macaque (SM) species are currently of interest to primatologists for genetic and behavioral studies world wide. However, there are no published reference hematological and serum biochemical profile values for several of the seven SM species. Twenty-five clinically healthy, outdoor housed, ketamine sedated Macaca tonkeana and Macaca maurus were serially sampled (two to four times) over a 16-month period (N = 68). Normal ranges were defined to include two standard deviations and 2.5-97.5 percentile. Significant differences in single sample data comparisons (P < 0.05) of species (serum Ca, MCHC), age (BUN, BUN/creatinine, alkaline phosphatase, phosphorus), gender (total protein, RBC, hemoglobin, HCT) and pregnancy (phosphorus and neutrophil count) groups were found. This normative data facilitates clinical evaluation of SM species and allows comparison to other macaque species.

Factors affecting the school placement of children with spina bifida.

Integrating children with disabilities into mainstream schools has been an active policy in Britain since the 1981 Education Act. 26 children with spina bifida, 13 of whom were educated in mainstream schools, and 13 in special schools were assessed to clarify the relative importance of the following factors 1) IQ, 2) Mobility, 3) Hand function, 4) Bladder and bowel function, and 5) Behaviour. A marked difference was found between those attending mainstream and special schools. 11/13 of the former attained scores within the normal range as compared to only 2/13 of the latter. Neither mobility nor hand function alone were found to influence school placement and a marked correlation was found between the two. Whilst those educated in special schools had more marked problems, all children functioned poorly compared with the norms for able-bodied peers. Neither bladder nor bowel incontinence hindered attendance at mainstream school, but faecal soiling was considered the more serious problem. The frequency of behavioural problems showed a similar distribution amongst the two groups. Comments from parents highlighted their reservations about both special and mainstream schooling which indicates the policy for integration needs considerably more commitment from Government and Education Authorities in order to succeed.

B virus (Herpesvirus simiae) infection in humans: epidemiologic investigation of a cluster.

A cluster of four cases of symptomatic B virus infection in humans occurred in Pensacola, Florida, in March 1987. Three cases occurred in persons who worked with monkeys at a research facility, and the fourth resulted from apparent autoinoculation through use of a nonprescription skin cream. Contact tracing identified 159 persons who may have been exposed to B virus (21 had been exposed to monkeys at the facility and 138 had been exposed to one or more of the case-patients), but no further cases were identified. Comparisons of restriction endonuclease patterns from B virus isolates linked two of the three cases in monkey handlers to one clinically ill monkey and the other to a second, healthy monkey. Three risk factors for human infection were identified: nonuse of mechanical or chemical restraints for monkeys before handling, nonuse of available protective gear, and direct viral inoculation through the application of a topical medication.

Reversible defect in cAMP metabolism in lymphocytes in malaria infection.

Peripheral blood lymphocytes were observed to have a defect in adenosine 3',5'-monophosphate (cAMP) metabolism during acute malaria infection which reversed once parasites were eliminated from the host circulation. The defect was characterized by decreased intracellular cAMP levels in lymphocytes and by hyporesponsiveness to adenosine or forskolin stimulation of cAMP production. These biochemical changes appeared to correlate functionally with a reduction in the proliferative response of lymphocytes to concanavalin A. A defect in the second messenger role of cAMP in immune effector cells may underlie immunosuppression in malaria infection.

Immunogenicity of liposomal malaria sporozoite antigen in monkeys: adjuvant effects of aluminium hydroxide and non-pyrogenic liposomal lipid A.

The immunogenicity of a recombinant protein (R32tet32) containing sequences from the tetrapeptide repeat region of the circumsporozoite protein of Plasmodium falciparum was enhanced by encapsulation in liposomes containing lipid A and adsorption of the liposomes with alum. The toxicities and efficacies of preparations containing different types and doses of lipid A were assessed by studying pyrogenicity in rabbits and adjuvanticity in monkeys. In each case liposomal lipid A was 25-fold to 200-fold less pyrogenic than free lipid A. Monophosphoryl lipid A, whether free or in liposomes, was the least pyrogenic of the three lipid A preparations tested. High antibody levels were obtained after immunization of rhesus monkeys with a formulation consisting of alum-adsorbed liposomes in which the liposomes contained R32tet32 and a strongly pyrogenic dose of native lipid A. Excellent antibody levels were also observed in monkeys immunized with a combination of R32tet32 encapsulated in alum-adsorbed liposomes containing non-pyrogenic doses of monophosphoryl lipid A and alum. The adjuvant effect was related to the dose of the lipid A in the liposomes, and the adjuvant effect was still strongly expressed despite suppression of the pyrogenic effect of lipid A. Antibody levels were considerably lower in monkeys immunized with liposomes lacking lipid A. It was concluded that a non-pyrogenic formulation of alum-adsorbed liposomes, in which the liposomes contained both lipid A and an encapsulated synthetic sporozoite antigen, shows considerable promise for inducing high titres of antibodies to sporozoites.

Epidemiology and characterization of leptospirosis at an urban and provincial site in Thailand.

Patients with FUOs at the Children's Hospital in Bangkok and the Chao Phya Abhai Bhu Bejhr Hospital in Prachinburi were screened for leptospirosis by blood and urine culture in addition to microagglutination testing of their serum. Animal populations in urban and periurban areas of Bangkok were surveyed for evidence of leptospira infection. Three rural sites near the Prachinburi Provincial Hospital were also surveyed. The rodents' and domestic animals' blood, urine, and/or kidney cell samples were cultured for leptospira. Sera from these animals were also tested for leptospira antibody. The bataviae serovar was the most commonly detected leptospiral agent in both man and animals. Presenting symptoms varied with age with children showing primarily fever, vomiting, headache, abdominal and generalized muscle pain and diarrhea whereas adults had fever, headache, anorexia, muscle pain and constipation. Blood samples from patients suspected of having leptospirosis were tested for antibody by the MAT and cultured in EMJH media. The following serogroups were identified: bataviae, autumanalis, javanica, hebdomadis, and pyrogens. Leptospirosis incidence in humans was much higher in the rainy/flooding year of 1983 compared to the relatively dry year of 1984. Results of our animal surveillance studies indicate that in addition to rats, which have previously been mentioned, dogs, bandicoots, cattle and pigs could be the source of human leptospirosis infection in both urban and provincial locations in Thailand.

An attempt to treat rabies encephalitis in monkeys with intrathecal live rabies virus RV 675. Brief report.

A highly attenuated rabies virus, RV 675, proved innocuous but immunogenic when injected intrathecally into monkeys by the lumbar route. Attempts to use this virus to modify the course of fatal rabies encephalitis in monkeys were inconclusive possibly because of the brief encephalitic illness. Further studies are indicated to investigate RV 675 as a candidate therapeutic agent for rabies encephalitis.

Anti-rabies virus IgM in serum and cerebrospinal fluid from rabid dogs.

An anti-rabies IgM antibody capture radio immunoassay was used to test serum and cerebrospinal fluid from 37 dogs held in quarantine for suspicion of rabies. Rabies was confirmed in dogs that died by mouse inoculation and subsequent examination of mouse brains by fluorescent antibody technique to detect rabies antigen. The mean counts per minute (CPM) of iodinated anti-rabies gamma globulin coupled IgM rabies antibody in CSF and serum from rabid dogs were significantly higher than in CSF and serum from non-rabid dogs. Mean CPM from rabid dogs was greater in CSF than in sera, in contrast with non-rabid dogs, from which mean cpm was higher in sera than CSF, suggesting that antibody may have been synthesized in the CSF. To evaluate this test further, a dog was infected by rabies virus, and serial serum and CSF specimens were collected until the time of death. IgM anti-rabies antibody developed in the CSF and serum 29 days following infection, and rose just before the dog died of rabies on day 34. The rabies MAC RIA is potentially useful as a diagnostic method in quarantined dogs with rabies-like illness. Perhaps more importantly, it may be applied to better understand the immunopathogenicity of rabies.

The neurovirulence of flaviviruses in crab-eating monkeys (Macaca fascicularis).

The neurovirulent properties of attenuated dengue-2 and yellow fever (YF) vaccines, dengue-2 (DEN-2) and Japanese encephalitis (JE) viruses were studied in crab-eating monkeys (Macaca fascicularis). Number of central nervous system sites (as proportion affected) with neurovirulence (NV) lesions were compared. The results indicate that these monkeys reliably developed NV-lesion when inoculated with either JE or YF vaccine viruses (87%). NV-lesions occurred in a minority when inoculated with DEN-2 vaccine virus, were of minimal severity (9%), were probably biologically insignificant, and were of equal or less severity than lesions produced by its parental virus (10%).

Serologic evidence of Hantaan-like virus in rodents and man in Thailand.

A serologic survey was conducted to determine the presence of antibody to Hantavirus in rodents in Thailand. Sera from over 300 rodents were tested by an immunofluorescent antibody method. Bandicota indica, a field rodent, was found to have a high incidence of infection (20-24%) in 2 locations. A Hantavirus was isolated from lung samples of B. indica. When sera were tested from humans living in Kanchanaburi and several locations in Bangkok, those people living in close proximity to the infected B. indica had greater than 30% prevalence of positive antibody titers.

Use of streptomycin and isoniazid during a tuberculosis epizootic in a rhesus and cynomolgus breeding colony.

An epizootic of tuberculosis occurred following the addition of new cynomolgus monkeys to a nonhuman primate breeding colony. A total of 5/47 cynomolgus and 51/148 rhesus became tuberculin positive (reactors). Mycobacterium tuberculosis was cultured from reactors which were euthanatized and monkeys which died spontaneously. The isolates were sensitive to the standard antitubercular agents. Rhesus reactors and their unweaned infants were quarantined and given streptomycin and isoniazid by intramuscular injection. Isoniazid was added to the drinking water quarantined and given streptomycin and isoniazid by intramuscular injection. Isoniazid was added to the drinking water of the remainder of the breeding colony to curtail the outbreak. Isoniazid toxicity was observed in both infants and adults with an overall incidence of 3%. Forty-eight rhesus reactors and their infants born before the outbreak were alive and healthy at the end of the treatment period. In addition, nine surviving infants were born during the 6 month treatment period. Tuberculin tests were still positive in many of the treated reactors following treatment. In this epizootic, the institution of quarantine and chemotherapy instead of euthanasia resulted in significant savings.

Intense transmission of Japanese encephalitis virus to pigs in a region free of epidemic encephalitis.

Epidemic Japanese encephalitis recurs annually in the northern provinces of Thailand, but in the southern provinces cases of human encephalitis are rare. We investigated transmission of Japanese encephalitis virus (JEV) to pigs in southern Thailand. Blood specimens from one hundred young pigs at abattoirs in three southern provinces were tested for JEV hemagglutination inhibiting (HAI) antibodies. Seventy-four percent were positive. Ten seronegative sentinel pigs were placed at five locations in one southern province. Seven of the ten pigs developed JEV HAI and JEV IgM ELISA antibodies within two weeks of placement. JEV was isolated from all seven seroconverting sentinel pigs from blood specimens collected 3 to 11 days after placement. Fifteen light-trap mosquito collections at the five locations all included known JEV vectors, some in large numbers. We conclude that there is intense transmission of JEV to pigs in southern Thailand despite the rare occurrence of human encephalitis in the same region.

Doxycycline prophylaxis for experimental leptospira infection in non-human primates and hamsters.

Doxycycline was effective as a chemoprophylactic agent for experimental Leptospira infection in non-human primates and hamsters. Monkeys injected intraperitoneally with Leptospira bataviae, and receiving only diluent as treatment developed a leptospiremia during the first week and later leptospires were cultured from the cerebrospinal fluid and urine. Monkeys treated daily with oral doxycycline for 10 days beginning one day before infection had a shortened period of detectable leptospiremia, and organisms were never detected in the cerebrospinal fluid or urine. Even an oral dose of doxycycline 2 hours before infection and on day 7 prevented the later infection of the cerebrospinal fluid and urine. In hamsters, doxycycline treatment prevented deaths from acute Leptospira infection and when hamsters were treated daily for 4 or more days, renal infection was prevented. The results of animal studies, the susceptibility of LC0475 and the five other isolates to doxycycline in vitro, and lack of evidence for antibiotic resistance in culture suggests this antibiotic may be useful as a prophylactic drug for high risk groups and an effective treatment for leptospirosis in Thailand.

Sporozoite-induced Plasmodium cynomolgi infections in captive born Macaca fascicularis.

Capability of captive born cynomolgus monkeys to substitute for rhesus in the Plasmodium cynomolgi radical curative antimalarial drug development model was examined. Eighteen monkeys divided into 3 groups were given standard or high doses of sporozoites intravenously. One group of 4 received 0.8 - 1.6 X 10(6) and a second group of 8 received 0.3 - 1.0 X 10(7) sporozoites. The third group of 6 was splenectomized and then received 3.0 - 4.0 X 10(6). The 2 groups of intact monkeys developed a persistent low level parasitemia; however, gametocyte production was poor. The splenectomized group developed a persistent parasitemia with a higher mean, which more closely resembled rhesus parasitemias. A high, post-patent leukocytosis consisting primarily of lymphocytes was observed in this group. Good gametocyte production resulted in the splenectomized group and oocysts were produced from all lots of Anopheles dirus which fed on them. Following clearance of blood forms, relapse potential was demonstrated in the 2 splenectomized monkeys tested. In this study the splenectomized captive born cynomolgus appeared to be capable of supplementing rhesus as an antimalarial drug testing model.