D.W. Makawiti

Reduced immune complex binding capacity and increased complement susceptibility of red cells from children with severe malaria-associated anemia.

Plasmodium falciparum malaria causes 1–2 million deaths per year. Most deaths occur as a result of complications such as severe anemia and cerebral malaria (CM) (coma). Red cells of children with severe malaria-associated anemia (SMA) have acquired deficiencies in the complement regulatory proteins complement receptor 1 (CR1, CD35) and decay accelerating factor (DAF, CD55). We investigated whether these deficiencies affect the ability of erythrocytes to bind immune complexes (ICs) and regulate complement activation. We recruited 75 children with SMA (Hb ≤ 6 g/dL) from the holoendemic malaria region of the Lake Victoria basin, western Kenya, and 74 age- and gender-matched uncomplicated malaria controls. In addition, we recruited 32 children with CM and 52 age- and gender-matched controls. Deficiencies in red cell CR1 and CD55 in children with SMA were accompanied by a marked decline in IC binding capacity and increased C3b deposition in vivo and ex vivo. Importantly, these changes were specific because they were not seen in red cells of children with CM or their controls. These data suggest that the declines in red cell CR1 and CD55 seen in children with SMA are of physiologic significance and may predispose erythrocytes to complement-mediated damage and phagocytosis in vivo.

Interaction of benzoquinones with mitochondria interferes with oxidative phosphorylation characteristics

Studies with four benzoquinones, viz. juglone, embelin, maesaquinone and maesanin, on rat liver mitochondria oxidative phosphorylation have been carried out. Three of the benzoquinones are uncouplers in the order juglone > maesoquinone > embelin, while maesanin is an inhibitor of electron transport and oxidative phosphorylation.

IN VIVO AND IN VITRO EFFECTS OF GRADED DOSES OF THE PESTICIDE HEPTACHLOR ON FEMALE SEX STEROID HORMONE PRODUCTION IN RATS

Adult female Sprague-Dawley rats were injected with corn oil or 5 mg, 20 mg, 25 mg or 30 mg per kg body weight of heptachlor solution every other day for up to 18 days. The rats were killed at the end of the experimental period, and blood samples were assayed for progesterone and oestrogen by radioimmunoassay. Ovarian cells from the rats were isolated and incubated either on their own, or in the presence of LH or FSH, and production of progesterone and oestrogen determined. Control incubations consisted of cells from corn oil-treated rats. The latter were also incubated on their own or in the presence of LH or FSH. Heptachlor significantly suppressed blood progesterone and oestradiol levels (P < 0.05 to P < 0.001), the degree of suppression depending on the dose and the stage of the oestrous cycle in which samples were obtained. Production of oestradiol by ovarian cells from heptachlor-treated rats was lower than for corn oil-treated controls. Cells from rats treated with low doses of heptachlor (5 mg per kg body weight) showed an increased production of progesterone, while high doses (> 20 mg per kg body weight) suppressed production.

Changes in the concentrations of testosterone, luteinising hormone and progesterone associated with administration of embelin

The mode of action of embelin, a naturally occurring plant benzoquinone with male fertility regulating potential, was investigated. Sexually mature white New Zealand male rabbits were injected intra-muscularly with embelin (30 mg/kg body wt) on alternate days for 14 days (7 injections). Blood was collected on alternate days over 27-day period from the beginning of embelin administration. Testosterone and progesterone levels were measured by radioimmunoassay and luteinising hormone (LH) by mouse interstitial cell testosterone bioassay. There was a marked reduction of testosterone concentrations within two days of embelin administration and up to 90% reduction by the 6th day. LH showed a corresponding rise with the falling testosterone levels. Similarly, there was rapid increase in progesterone levels with the administration of embelin. Both the concentrations of progesterone and LH declined when embelin dosage was stopped. Evidence from the observed changes in the levels of the three hormones suggest that embelin disrupts production of testosterone at the testicular level.

Effects of graded doses of the pesticide heptachlor on body weight, mating success, oestrous cycle, gestation length and litter size in laboratory rats

Adult female Sprague-Dawley rats were injected with 5 or 20 mg/kg body weight heptachlor solution every other day for up to 18 days. They were weighed every day and the stage of oestrus determined by vaginal smears. One experimental group was mated and pregnancy characteristics studied. Heptachlor affected body weights, cycle patterns, length of gestation period and litter sizes in a dose-related manner. At a dose of 20 mg/kg body weight, heptachlor caused a significant decrease in average body weight (P < 0.01), disrupted and/or prolonged oestrous cycles, decreased mating success (P < 0.001), slightly increased gestation length (P < 0.05) and decreased litter size (P < 0.01).

The effect of Trypanosoma vivax infection on late pregnancy and postpartum return to cyclicity in Boran cattle.

A study was designed to examine the effect of infection with Trypanosoma vivax KETRI 2501 on the maintenance of pregnancy and postpartum return to reproductive function in susceptible Galana (n = 6) and trypano-tolerant Orma Boran (n = 6) heifers during the third trimester of pregnancy. Of the 12 study animals, 3 Galana and 3 Orma Boran heifers served as controls. One of 3 Galana heifers calved prematurely with subsequent perinatal loss. Of the 2 heifers that produced live calves, 1 calf died shortly after birth, while the other survived. Two of 3 Orma heifers calved prematurely and all 3 calves died shortly after birth. The 6 control heifers produced live calves at term, all of which survived. Infection with T. vivax during the third trimester of pregnancy delayed the resumption of ovarian activity after calving, with the Ormas taking a significantly (P < 0.05) shorter time from calving to ovulation. There was no clear evidence that premature birth was associated with pathological changes in reproductive organs. Results from this study demonstrated that infection with pathogenic T. vivax during late pregnancy influenced the outcome of pregnancy in both susceptible Galana and trypano-tolerant Orma Boran heifers, resulting in premature births, perinatal loss, retained placentae, low birth weights and a prolonged period to the onset of postpartum ovarian activity.

The effect of experimental infection of Boran cattle in early and mid-pregnancy with Trypanosoma vivax.

Six susceptible Galana and five trypanotolerant Orma Boran (Bos indicus) cattle were infected experimentally with Trypanosoma vivax KETRI 2501 by cyclical transmission using Glossina morsitans during early and mid-pregnancy. Four pregnant animals, two of each Boran type were used as controls and remained uninfected throughout the study period. Three out of the six infected susceptible Galana Borans aborted, whilst one had a stillborn calf. None of the trypanotolerant Orma Boran cattle aborted and all carried their pregnancies to term. All control animals produced live calves at term. The mechanisms leading to disruption of reproductive function in susceptible Boran cattle were not clear but could involve a number of factors, including anaemia, weight loss and post-infection decline of plasma progesterone levels. It is concluded that infection with T. vivax disrupts maintenance of pregnancy in susceptible Galana Borans but does not affect maintenance of pregnancy in the Orma Boran, demonstrating their tolerance to infection with T. vivax.

Effect of different doses and routes of administration of embelin on plasma testosterone levels

Embelin has been shown to have potential for fertility regulation in male mammals. To further investigate this the effect of varying doses of embelin administered through different routes on plasma testosterone levels in sexually mature male white New Zealand rabbits was studied. An intramuscular injection of 5 mg/kg body weight of embelin caused a 54% declined in testosterone levels from 8.35±0.4 nmol (pre‐treatment) to 3.8±0.15 nmol/L (post‐treatment); mean±SEM. When orally administered as a suspension of 10 mg/kg body weight embelin caused a significant (p <0.001) lowering in the hormone levels from 12.2±0.70 nmol/L (pre‐treatment) to 4.55±0.35 nmol/L after treatment. But when administered orally as a 50 mg base tablet, a decline of 40% in testosterone levels was observed. Subcutaneous administration of 20 mg/kg body weight of embelin caused a 12.4% decline in the hormone levels from 26.6±1.30 nmol/L (pre‐treatment) to 18.9±1.30 nmol/L after treatment. The decline in the testosterone levels when embelin was administered either intramuscularly or as a suspension orally was rapid, while a tablet or subcutaneous injection caused a gradual decline. From the study it was concluded that oral administration offered the most effective and convenient route of delivery of embelin.

Sehistosoma 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.

Delayed recovery of adrenocortical and testicular function after chemotherapy of human trypanosomiasis

The following indicators of pituitary, adreno-cortical and testicular function were measured in 58 male African trypanosomiasis patients from Western Kenya; plasma cortisol, luteinizing hormone (LH) and testosterone levels. The measurements were carried out by specific radioimmunoassay methods in early and late stage infected patients on admission to hospital and in both groups of patients after one month of chemotherapy. Packed cell volume (PCV) and hemoglobin levels were also measured in all the patients to determine the extent of their anaemia and success of recovery. High parasitaemia, anaemia and clinical symptoms of human trypanosomiasis were found in the infected patients and were eliminated with chemotherapy in the infected/treated patients. Increased levels of cortisol and decreased concentrations of testosterone without significant changes in LH levels were evident in the infected patients; this condition remained unchanged even after one month of chemotherapy. Evidence is thus provided of persistent hormonal perturbations which probably indicate residual endocrine organ damage.