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Biomedical subjects

I O Farah

Publications and source records attributed to I O Farah.

At least 19 recordsLinked to original sources
PubMed2001

An overview of animal models in experimental schistosomiasis and refinements in the use of non-human primates.

The complex nature of the schistosome parasite and its interaction with the mammalian host necessitates the continued use of live intact animal models in schistosomiasis research. This review acknowledges this necessity and highlights some of the important insights into the pathogenesis of the disease that have been gained from using various animal models. The use of non-human primates as more relevant models of human schistosomiasis is stated. In addition, the importance of animal welfare consideration when using primates for research is emphasized. Finally, some guidelines for the refined capture, handling and early humane endpoints for non-human primates to be used in experimental schistosomiasis are suggested.

Animal Welfare↗
PubMed2000

Repeated exposure induces periportal fibrosis in Schistosoma mansoni-infected baboons: role of TGF-beta and IL-4.

Recently, we observed that repeated Schistosoma mansoni infection and treatment boost Th2-associated cytokines and TGF-beta production in baboons. Other studies have shown that some chronically infected baboons develop hepatic fibrosis. Because TGF-beta, IL-2, and IL-4 have been shown to participate in development of fibrosis in murine schistosomiasis, the present study examined whether repeated exposure stimulates hepatic fibrosis in olive baboons. To test this hypothesis, animals were exposed to similar numbers of S. mansoni cercariae given once or repeatedly. After 19 wk of infection, animals were cured with praziquantel and reinfected once or multiple times. Hepatic granulomatous inflammation and fibrosis were assessed from serial liver biopsies taken at weeks 6, 9, and 16 after reinfection and egg Ag (schistosome egg Ag)-specific cytokine production by PBMC were measured simultaneously. Periportal fibroblast infiltration and extracellular matrix deposition (fibrosis), angiogenesis, and biliary duct hyperplasia developed in some animals. The presence and amount of fibrosis directly correlated with the frequency of exposure. Fibrosis was not associated with adult worm or tissue egg burden. The amount of fibrosis correlated with increased schistosome egg Ag-driven TGF-beta at 6, 9, and 16 wk postinfection (rs = 0.9, 0.8, and 0.54, respectively, all p < 0.01) and IL-4 production (p = 0.02) at 16 wk postinfection and not IFN-gamma, IL-2, IL-5, or IL-10. These data suggest that repeated exposure is a risk factor for periportal fibrosis by a mechanism that primes lymphocytes to produce increased levels of profibrotic molecules that include TGF-beta and IL-4.

Animals↗
PubMed2000

Adrenal cortex and stomach lesions associated with stress in wild male African green monkeys (Cercopithecus aethiops) in the post-capture period.

The objective of this study was to look for early pathological changes in stress target organs, adrenal glands, and stomachs in captured wild African green monkeys (AGMs). Three wild-caught male AGMs and seven singly housed wild AGMs were euthanized on day 1 and day 45 post-capture, respectively, and compared with four wild males euthanized with a rifle as controls. Morphometric analyses of the adrenal cortices and the cortical zones were done using an image analyzer. By day 45, the confined animals were clinically healthy, but had lost 47% mean body weight despite ad libitum feeding. The width of zona fasciculata in the controls was significantly smaller compared with that of 45-day monkeys (P < 0.05). Numerous acidophilic, hyperplastic and hypertrophic cells were present in the zona fasciculata of the 1-day confined AGMs. In the 45-day monkeys, there was glandular hyperplasia in the zona glomerulosa and the acini were distended and vacuous; yellow, granular pigmentation was distributed in the zona fasciculata. Acute stomach lesions represented by petechiation were seen in one monkey on day 1. Deep, circular, mucosal erosions, one to five in number and measuring from 0.5 to 1 mm in diameter, were present in three monkeys on day 45 post-capture. There were no adrenal cortex or stomach lesions in the rifle-shot monkeys. In conclusion, pathological lesions in the adrenal glands, and stomachs of the wild AGMs and weight loss occurred within the initial 45-day period following capture and confinement.

Adrenal Glands↗
PubMed2000

Schistosoma mansoni in mice: the pattern of primary cercarial exposure determines whether a secondary infection post-chemotherapy elicits a T helper 1- or a T helper 2-associated immune response.

Reinfection with Schistosoma mansoni following chemotherapy often results in an ameliorated granulomatous reaction and hence a mild disease. This study examined some of the immunological mechanisms that could be associated with this residual protection. BALB/c mice were infected with either a single dose (group A) of 100 S. mansoni cercariae or with 10 doses of 10 cercariae each (group B) given at 3-day intervals. The mice were treated with praziquantel 8 weeks postinfection and, 2 weeks later, together with another group of naive mice (group C), they were infected with a single dose of 100 cercariae each. All the animals were killed 8 weeks later and schistosome egg antigen (SEA)- and soluble adult worm antigen preparation (SWAP)-induced cytokine recall responses in splenocytes, as well as serum immunoglobulin levels, were quantified and hepatic granuloma sizes measured. Group A animals had higher levels of SEA-induced interferon-gamma (IFN-gamma) but lower levels of interleukin (IL)-5 than groups B and C (P < 0.01). Group B animals had low SEA-induced IFN-gamma levels and elevated IL-5 levels, although these were lower than group C. SEA-induced IL-10 was low in both groups A and B as compared to group C (P < 0.01). SWAP was less effective as an inducer of splenocyte cytokine production than SEA but both SWAP-induced IFN-gamma and IL-5 were detected in groups A and C. SEA- and SWAP-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) titres were not significantly different between the three groups. Granuloma diameters were larger in group C (mean 297 +/- 51.3 microm) as compared to groups A (174 +/- 49 microm, P < 0.01) and B (247.5 +/- 44 microm, P < 0.05). Taken together, these results demonstrate that granuloma size is reduced during a reinfection exposure compared with a primary infection. This reduction is associated with a T helper 1 response in mice exposed to a single large dose of cercariae in the primary infection and with a predominantly T helper 2 response in those infected with multiple small doses.

Animals↗
PubMed2000

Hepatic granulomatous response to Schistosoma mansoni eggs in BALB/c mice and olive baboons (Papio cynocephalus anubis).

Hepatic granulomatous inflammation is one of the key pathological lesions of a patent Schistosoma mansoni infection. This study was concerned with the sequential induction, formation and eventual modulation of the schistosome egg granuloma in the mouse, which develops schistosome-induced hepatic fibrosis, and the olive baboon, which usually does not. Six baboons were each infected with 1500 S. mansoni cercariae and liver biopsies were collected at weeks 6, 9, 13 and 17 post-infection (p.i.). The mice (n=25) were each infected with 100 cercariae and killed in groups of five at weeks 6, 9, 12, 18 and 21 p.i. Peak granuloma size was observed at week 6 p.i. in baboons (mean 355 +/- 65.6 microm) but at week 12 p.i. in mice (299 +/- 40.5 microm). Eosinophils were more abundant in the baboon (60.6 +/- 8.9%) than in the mouse (41.2 +/- 8.4%) at the time of maximal granuloma size (P < 0.01). Neutrophils formed 21.1 +/- 6.3% of peak mouse granulomata but were virtually absent in baboon granulomata. A feature of the modulating baboon granulomata was the emergence of multinucleated giant cells (MGCs); modulating mouse granulomata, on the other hand, were characterized by infiltration of fibroblasts and collagen deposition. Thus, by week 21 p.i. mouse granulomata were 92 +/- 16.0 microm in diameter and well delineated by concentric layers of fibrous tissue. Granulomata, however, were present in only two of the baboons at week 17 p.i. (44 +/- 61.2 microm in diameter). The other four had peri-portal cellular infiltration without granuloma formation, implying that baboon granulomata resolve spontaneously. These data suggest that high tissue eosinophilia and MGC formation are particularly efficient in bringing about the destruction of schistosome eggs and subsequent resolution of the egg granuloma without fibrosis. In conclusion, the baboon model more closely mimics the pathogenesis observed in man than does the mouse model.

Acute Disease↗
PubMed1999

The baboon as a non-human primate model of human schistosome infection.

Over the past three decades, intensive studies of murine schistosomiasis have provided important clues to the understanding of the human disease, but growing evidence suggests that these results derived from highly inbred strains of mice might not have direct applicability to the human infection. Recent data based on the baboon indicate that infection in this non-human primate might mirror the human situation. In this review, Mramba Nyindo and Idle Farah demonstrate that baboons provide an excellent non-human primate model that produces pathology and disease closely resembling that observed in humans, and address how studies in baboons can provide insights into mechanisms regulating schistosomiasis mansoni pathology and immunity. They also address, in a general way, issues related to the use of non-human primates in biomedical research.

Animal Welfare↗
PubMed1999

Cytokine control of the granulomatous response in Schistosoma mansoni-infected baboons: role of exposure and treatment.

Variations in exposure and treatment may contribute to heterogeneity in immunity and granuloma-induced pathology in human schistosomiasis. To examine this hypothesis, olive baboons were either repeatedly infected with Schistosoma mansoni cercariae or received an equivalent dose in a single infection. They were then cured with praziquantel and reinfected with a single exposure. Serial liver biopsies were obtained throughout the course of the experiment, and cytokine responses by peripheral blood mononuclear cells were measured every 2 to 3 weeks. Reinfection after treatment resulted in a twofold-smaller granuloma size at 6 and 9 weeks after infection compared to the size for the same period after primary infection (P < 0.001) but had no effect at 16 or 19 weeks postinfection. The pattern of exposure did not influence granuloma size. During primary infection schistosome-soluble egg antigen (SEA)-induced cytokine production correlated with granulomatous inflammation. Cytokine levels peaked during the acute infection, declined with chronic infection, and became undetectable after treatment. Reinfection after treatment stimulated a two- to three-fold increase in SEA-specific interleukin-4 (IL-4), IL-5, IL-10, IL-2, and transforming growth factor beta (TGF-beta) production and a marked rise in SEA-specific immunoglobulin E (IgE) and IgG regardless of the type of exposure. Cytokine production was significantly greater in repeatedly exposed animals (P < 0.001). SEA-induced gamma interferon production, however, did not increase with reinfection after treatment. SEA-induced TGF-beta was the only cytokine that remained elevated as the infection become chronic and correlated with diminished hepatic granuloma size, implying its participation in down-modulation. These studies demonstrate that baboons partially retain their ability to down-modulate the granulomatous response after treatment.

Animals↗
PubMed1999

Role of adult worm antigen-specific immunoglobulin E in acquired immunity to Schistosoma mansoni infection in baboons.

Allergic-type immune responses, particularly immunoglobulin E (IgE), correlate with protective immunity in human schistosomiasis. To better understand the mechanisms of parasite elimination we examined the immune correlates of protection in baboons (Papio cynocephalus anubis), which are natural hosts for Schistosoma mansoni and also develop allergic-type immunity with infection. In one experiment, animals were exposed to a single infection (1,000 cercariae) or were exposed multiple times (100 cercariae per week for 10 weeks) and subsequently were cured with praziquantel prior to challenge with 1, 000 cercariae. Singly and multiply infected animals mounted 59 and 80% reductions in worm burden, respectively (P < 0.01). In a second experiment, animals were inoculated with S. mansoni ova and recombinant human interleukin 12 (IL-12). This produced a 37 to 39% reduction in adult worm burden after challenge (P < 0.05). Parasite-specific IgG, IgE, IgM, and peripheral blood cytokine production were evaluated. The only immune correlate of protection in both experiments was levels of soluble adult worm antigen (SWAP)-specific IgE in serum at the time of challenge infection and/or 6 weeks later. Baboons repeatedly infected with cercariae or immunized with ova and IL-12 developed two- to sixfold-greater levels of SWAP-specific IgE in serum than did controls, and this correlated with reductions in worm burden (r2, -0.40 to -0.64; P, <0. 01). Thus, in baboons and unlike mice, adult worm-specific IgE is uniquely associated with acquired immunity to S. mansoni infection. This similar association of parasite-specific IgE and protection among primates infected with schistosomiasis, along with similar pathology, anatomy, and genetic make-up, indicates that baboons provide an excellent permissive experimental model for better understanding the mechanisms of innate and acquired immunity to schistosomiasis in humans.

Animals↗
PubMed1998

Peri-portal fibrosis of the liver due to natural or experimental infection with Schistosoma mansoni occurs in the Kenyan baboon.

The chronic granulomatous inflammation that occurs during schistosomiasis mansoni and its reparative healing lead to hepatic fibrosis, with subsequent portal hypertension (a life-threatening sequela). In the murine model, granuloma modulation invariably leads to formation of fibrous tissue and disposition of extracellular matrix. Typically, < 10% of patients infected with Schistosoma mansoni progress to clay-pipe-stem fibrosis. Similar fibrosis occurs in chimpanzees during experimental infections. Although previous studies of schistosomiasis mansoni in Kenyan baboons have failed to demonstrate appreciable liver fibrosis, classical peri-portal fibrosis has now been observed in the livers of three yellow baboons (Papio cynocephalus cynocephalus) with natural S. mansoni infections and three olive baboons (P. c. anubis) with experimental infections after each was challenged with 1000 S mansoni cercariae. The peri-portal fibrosis was indicated by marked fibroblast accumulation, increased collagen deposition, bile-duct hyperplasia and blood-vessel proliferation. The lesions were more severe in the naturally infected baboons than in those experimentally infected. No accompanying portal hypertension, ascites or portocaval anastomosis was noted in any of the animals. The development of the baboon as a model for chronic human schistosomiasis mansoni may be feasible.

Animals↗
PubMed1997

Schistosoma mansoni: development and modulation of the granuloma after or multiple exposures in the baboon (Papio cynocephalus anubis).

The ability of the host to modulate the granulomatous response around ova trapped in tissues determines the severity of disease to schistosome infections. Multiple factors may affect this modulation such as age, prior sensitization, history of treatment, and exposure. The present study examines the effect of different patterns of exposure on the sequential development and modulation of granuloma in juvenile Kenyan baboons (Papio cynocephalus anubis) after receiving either a single infection (SI) of 1500 Schistosoma mansoni cercariae or multiple infections (MI) of 150 cercariae, once a week for 10 weeks. Prior to sacrifice at 17 weeks postinfection (p.i.), liver biopsies were obtained at Weeks 0, 6, 9, and 13. SI animals experienced more prolonged dysentery and greater weight loss compared to MI animals. Peak hepatic granuloma size (mean 355 +/- 65.5 microns diameter), the maximum percentage of eosinophils in the granuloma (61%), and severity of disease occurred at 6 weeks in SI animals. Peak granuloma size and pathology did not appear until Week 9 in the MI animals (mean 317.7 +/- 67.3 microns diameter). Granuloma size, tissue eosinophilia, and gross pathology diminished by Week 13 p.i. and were virtually absent in both groups by Week 17. The decrease in granuloma size, pathology, and clinical illness resolved more rapidly in the MI baboons. Singly infected baboons were more susceptible to infection (83 +/- 12% of cercariae developed into adult worms) compared to MI baboons (67 +/- 7%, P < 0.01). Eggs recovered from tissues at necropsy were primarily confined to the large intestine (85% of total egg recovered), followed by liver (10%) and small intestine (5%). Significantly more eggs were recovered from MI compared to SI animals, indicating a higher fecundity of female worms in the MI baboons. These date demonstrate that granulomatous responses develop more slowly and modulate more rapidly with repeated infection compared to a single heavy infection and suggest the type of exposure may affect the pathologic response to infection.

Animals↗
PubMed1997

Acute schistosomiasis mansoni in the baboon Papio anubis gives rise to goblet-cell hyperplasia and villus atrophy that are modulated by an irradiated cercarial vaccine.

A histopathology study of the intestines of four Kenyan baboons (Papio anubis) infected by 800 cercariae of Schistosoma mansoni and euthanized at 10 weeks postinfection was done. The pathology was compared with that of four baboons first vaccinated with 10,000 irradiated cercariae and then challenged 8-10 weeks later with the same number of cercariae. Two baboons that were neither vaccinated nor challenged were used as controls. On postmortem examination, multifocal to coalescing granulomatous inflammatory responses to the eggs in the submucosa of the terminal ileum and colon were seen in all baboons exposed to the parasite. The mean numbers of goblet cells detected per villus at 20 cm from the pylorus were 12.8 +/- 2.6, 30.4 +/- 6.6, and 20.2 +/- 3.7 in the two uninfected baboons, the infected unvaccinated baboons, and the vaccinated and challenged baboons, respectively. Mild to total villus atrophy was present in all eight baboons exposed to the parasite. These lesions, which were less marked in infected but vaccinated baboons, may contribute to the clinical signs seen in acute simian schistosomiasis mansoni.

Acute Disease↗
PubMed1997

The presence of Cryptosporidium oocysts in stools of clinically diarrhoeic and normal nonhuman primates in Kenya.

A total of 114 nonhuman primates comprising 51 vervet monkeys (Cercopithecus aethiops) and 63 olive baboons (Papio anubis) were examined for Cryptosporidium oocysts using the modified Kinyoun's acid-fast staining technique. About 51.7% (59/114) of all the specimens examined, representing 78.4% (40/51) of the vervet monkeys and 30.1% (19/63) of the olive baboons were positive. Bright red, refractile Cryptosporidium oocysts were observed in the stained faecal smears against a blue background. Up to 4/6 (66.7%) of the diarrhoeic vervets and 2/3 (66.7%) baboons, respectively, were positive while the rest were negative. To the best of our knowledge, this report is the first on cryptosporidiosis in old world nonhuman primates in Kenya and probably the first report of the infection in olive baboons. Given the high frequency of oocysts in diarrhoeal specimens, the parasite may have been associated with clinical diarrhoea in the sampled animals. Cryptosporidium, which has been reported in humans in Kenya, is also suspected to occur in livestock. Its isolation from clinically ill, normal colony-borne and newly caught feral nonhuman primates has significant implications for both public health and animal agriculture in Kenya.

Animals↗
PubMed1996

Schistosoma mansoni induces in the Kenyan baboon a novel intestinal pathology that is manifestly modulated by an irradiated cercarial vaccine.

Light and scanning electron microscopic study of intestines of 5 baboons (Papio anubis) in a state of acute schistosomiasis mansoni after exposure to 800 cercariae was made. In addition to overt granulomatous inflammation in the mucosa of the colon and ileum, more subtle microscopic lesions consisting of smooth muscle hypertrophy and villous atrophy were present. The intensity and distribution of these lesions were less marked in 5 baboons previously vaccinated with 40,000 30-krad-attenuated cercariae and presenting a 39% mean protection level measured as a percent reduction in adult worms recovered from mesenteric vasculature at perfusion. No similar lesions were observed in 2 normal uninfected and nonvaccinated baboons. These results are comparable to what has been reported in mice infected by Schistosoma mansoni. The data indicate that villous atrophy, hypertrophy of muscularis mucosa, nd goblet cell hyperplasia are important pathological changes to be included in the evaluation of the efficacy of schistosomiasis vaccines in the baboon model, together with the routine adult worm recovery from mesenteric blood vessels and the overt liver and bowel pathology.

Acute Disease↗
PubMed1995

Schistosoma mansoni in the baboon: modulation of pathology after vaccination with polyclonal anti-idiotypic antibodies.

Vaccination of five baboons with an anti-idiotypic vaccine to irradiated Schistosoma mansoni cercariae resulted in nearly 19% protection compared to 39% protection conferred to five baboons vaccinated with an irradiated vaccine. Vaccination with the anti-idiotypic antibodies resulted in a significant reduction of pathology and granuloma size following challenge with live unattenuated cercariae. Results presented in this work are considered highly significant because the anti-idiotypic vaccine markedly influenced schistosomiasis morbidity which is the main consideration in this disease.

Animals↗
PubMed1993

Protective immunity in baboons vaccinated with a recombinant antigen or radiation-attenuated cercariae of Schistosoma mansoni is antibody-dependent.

Mice vaccinated with radiation-attenuated cercariae of Schistosoma mansoni exhibit high levels of resistance to challenge infection. We have previously shown that sera from these mice recognize polypeptides that are expressed on the surface of newly transformed schistosomula. We have cloned and sequenced a cDNA that encodes a 62-kDa portion of one of these polypeptides. Vaccination of mice with this 62-kDa polypeptide (designated rlrV-5) elicits high antibody titers and significant resistance to challenge infection. We report here the results of a vaccination trial in baboons with the rlrV-5 or radiation-attenuated cercariae. rlrV-5 was presented either in the form of protein micelles or complexed with the outer membrane protein of meningococcus to form proteosomes. The level of protection achieved in these groups ranged from 0 to 54%, with a mean of 27.7%. In baboons exposed to radiation-attenuated cercariae the level of protection was very high, with a mean of 84%. The resistance observed after vaccination with rlrV-5 or radiation-attenuated cercariae was reflected in the overall histopathology. Vaccination of baboons with rlrV-5 or radiation-attenuated cercariae elicited an antibody response against epitopes exposed on the surface of newly transformed schistosomula. In the case of baboons vaccinated with radiation-attenuated cercariae, this response was not limited to epitopes encompassed by rlrV-5. Analysis of individual baboon sera by ELISA demonstrated that there was a direct correlation between the anti-rlrV-5 titer and resistance to challenge worm burden, suggesting that the immunoprotective mechanism is antibody-dependent.

Animals↗
PubMed1993

High intraabdominal pressure: effects on clinical parameters and lung pathology in baboons (Papio cynocephalus and Papio anubis).

OBJECTIVE: The risks of a high intraabdominal pressure during laparoscopy are poorly documented. These aspects were studied in a relevant nonhuman primate model, the baboon (Papio anubis, Papio cynocephalus). STUDY DESIGN: The animals used were to be killed at the completion of a vaccine project. They were anesthetized and intubated but allowed to breathe spontaneously. In group 1 (n = 10) a fixed intraabdominal pressure (between 10 and 35 cm H2O [7 and 26 mm Hg]) was applied over 30 minutes. In group 2 (n = 7) the intraabdominal pressure was increased up to a maximum of 105 cm H2O (77 mm Hg). Blood vessels of the parietal peritoneum and omentum were systematically opened from 30 cm H2O (22 mm Hg) onward. Respiration and pulse rate were measured regularly, and the degree of respiratory distress was assessed. After death of the baboons a necropsy was carried out immediately to study the degree of lung atelectasis. RESULTS: In group 1 the respiration rate increased and the heart rate decreased. At an intraabdominal pressure of > or = 30 cm H2O (22 mm Hg) moderate respiratory distress was seen after 20 minutes. In group 2 one animal had a bilateral pneumothorax at a pressure of 60 cm H2O (44 mm Hg) and died at 90 cm H2O (66 mm Hg). Severe respiratory distress was observed in the other six animals. Severe lung atelectasis was present in only one of the five primates with moderate respiratory distress of group 1 and in all baboons of group 2. CONCLUSION: An increase of intraabdominal pressure up to 105 cm H2O (77 mm Hg) combined with intraabdominal blood vessel injury is not lethal in most baboons.

Abdomen↗
PubMed1988

Detection of parvoviruses in wolf feces by electron microscopy.

One hundred fifteen wolf (Canis lupus) feces were collected between 1980 and 1984 from northeastern Minnesota and were examined for canine parvovirus by negative contrast electron microscopy. Of these, seven (6%) samples revealed the presence of parvovirus. Some of these viruses were able to grow in cell cultures forming intranuclear inclusion bodies and giant cells.

Animals↗