Naturally acquired antibodies to sporozoites do not prevent malaria: vaccine development implications.

The first human vaccines against the malaria parasite have been designed to elicit antibodies to the circumsporozoite protein of Plasmodium falciparum. However, it is not known whether any level of naturally acquired antibodies to the circumsporozoite protein can predict resistance to Plasmodium falciparum malaria. In this study, 83 adults in a malaria-endemic region of Kenya were tested for circumsporozoite antibodies and then treated for malaria. They were monitored for the development of new malaria infections for 98 days. Antibody levels, as determined by four assays in vitro, were indistinguishable between the 60 individuals who did and the 23 who did not develop parasitemia during follow-up, and there was no apparent relation between day of onset of parasitemia and level of antibodies to circumsporozoite protein. Unless immunization with sporozoite vaccines induces antibodies that are quantitatively or qualitatively superior to the circumsporozoite antibodies in these adults, it is unlikely that such antibodies will prevent infection in areas with as intense malaria transmission as western Kenya.

Blood pressure and associated factors in a rural Kenyan community.

Blood pressure (BP) and associated factors were determined in 1737 men in a remote Kenyan agricultural community. Systolic BP showed no significant rise with age until after 54 years; diastolic BP showed a small rise with age. Both systolic and diastolic BP correlated with weight independent of age. Systolic and diastolic BP correlated positively with casual urinary sodium/potassium and negatively with potassium/creatinine ratios. Both systolic and diastolic BP correlated significantly with the number of years of education, as did urinary sodium/potassium and sodium/creatinine ratios. Potassium/creatinine ratios were negatively correlated with the number of years of education. Blood pressure and urinary sodium/creatinine ratios were significantly lower in subsistence farmers compared with those in other occupations, and potassium/creatinine ratios were significantly higher. Two pilot studies of Luo tribesmen showed a strong correlation between casual urinary electrolyte ratios and those derived from 24-hour urine samples and a greater variance of sodium excretion between these people than that found within individuals. These results suggest that a relationship between BP and casual urine electrolyte estimations may be identifiable in communities where there is less day-to-day dietary variation. They also suggest that some of the changes in BP associated with urbanization could be mediated by changes in dietary electrolytes.

Electrocardiographic changes during treatment of leishmaniasis with pentavalent antimony (sodium stibogluconate).

Serial electrocardiograms (ECGs) were obtained during 65 courses of sodium stibogluconate treatment in 59 Kenyan patients with leishmaniasis (56 visceral and 3 cutaneous). ECG abnormalities developed during 54% of the treatment courses. The frequency with which abnormalities occurred was related to the total daily dose of antimony (Sb), increasing from 2/9 patients treated with 10 mg Sb/kg/d to 25/48 treated with 20-30 mg Sb/kg/d and 8/8 treated with 40-60 mg Sb/kg/d. The frequency with which ECG abnormalities developed was also related to the duration of treatment, increasing from 11/65 patients after 7 days to 18/44 after 15 days, 26/39 after 30 days and 11/12 after 60 days. ECG abnormalities were similar to those previously described during treatment with trivalent antimonial drugs, the most common being flattening and/or inversion of T waves. Prolongation of the corrected QT interval occurred in 13 patients, all of whom were treated for more than 30 days or with more than 20 mg Sb/kg/d. One patient died suddenly during the fourth week of treatment with 60 mg Sb/kg/d, and 2 patients died of measles after 9 or 10 days of treatment with 30 mg Sb/kg/d. QT prolongation and a concave ST segment developed in all 3 patients who died. We conclude that minor ECG abnormalities are common when sodium stibogluconate is used at doses above 20 mg Sb/kg/d for more than 15 days, and that life-threatening arrhythmias may occur if very high doses are used.

Field evaluation of an enzyme-linked immunosorbent assay (ELISA) for Plasmodium falciparum sporozoite detection in anopheline mosquitoes from Kenya.

An enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody that recognizes a repetitive epitope on the circumsporozoite protein of Plasmodium falciparum was used in Kenya to assess malaria infections in Anopheles gambiae s.l. and An. funestus. The ELISA confirmed that 88% of 44 sporozoite-positive gland dissections were P. falciparum. The ELISA infection rate of 18.6% (n = 736) for individually tested mosquitoes for both species was significantly higher than the 10.4% (n = 537) salivary gland sporozoite rate determined by dissection. This difference was due to ELISA detection of medium and large sized oocysts on the midguts of infected mosquitoes which did not contain salivary gland sporozoites. From a series of 379 Anopheles that were cut at the thorax, ELISA tests on "head" and "body" portions showed that 29.5% of 95 positive mosquitoes contained circumsporozoite antigen in the body portion in the absence of salivary gland infections. This field evaluation demonstrates that the ELISA can most accurately be used to estimate sporozoite rates by cutting mosquitoes at the thorax and testing anterior portions.

Blood pressure and its correlates in an African tribe in urban and rural environments.

As part of a longitudinal study of migrants who move from a subsistence farming rural society to Nairobi, blood pressures and associated factors were measured in cross sectional studies of members of the Luo tribe in their traditional rural environment and in the urban environment of Nairobi. Blood pressures in Nairobi correlated with duration of urban residence. In the rural area men showed a negligible rise in blood pressure with age, and both sexes showed a significantly smaller rise than in the urban area. Although mean weights of the rural group were smaller, this did not account for all the urban/rural differences in blood pressures. Nevertheless, mean urinary sodium concentration and sodium ratios (sodium/potassium and sodium/creatinine) were significantly higher in the urban group whereas mean urinary potassium concentration and potassium/creatinine ratio were significantly lower. Perhaps the ratio of sodium to potassium in the diet contributes to the different blood pressure profiles of these two populations.

Blood pressure patterns in relation to age, weight and urinary electrolytes in three Kenyan communities.

The blood pressure patterns of three Kenyan communities have been studied: 861 members of the Luo tribe in a rural community, 281 members of the Kamba tribe in a rural community and 310 "urban" Luo living in Nairobi. The slope of linear regression of blood pressure with age was significantly different in each population: rural Luo had the smallest rise with age and urban Luo had the largest rise with age, while the Kamba tribe were in between. The differences could not be accounted for by weight. Urinary electrolyte data showed rural Luo had the lowest sodium ratios (sodium/creatinine, sodium/potassium) and the highest potassium/creatinine ratio: urban Luo had the highest sodium and lowest potassium ratios and rural Kamba had values in between. The differences in blood pressures between the two groups of the same tribe in different environments (rural and urban Luo) were far greater than those between different genetic groups (Kamba and Luo) underlining the importance of environmental factor(s) in the determination of arterial pressure. Furthermore, these data support the theory that the dietary intake of sodium and potassium are the major influential environmental factors affecting blood pressure.

Immunity after treatment of human schistosomiasis mansoni. I. Study design, pretreatment observations and the results of treatment.

This paper describes the design of a study on immunity to reinfection after treatment of children with Schistosoma mansoni infections, the initial observations on transmission that led to the selection of the study population, the effects of treatment, and the results of immunological tests carried out before and at five weeks after treatment. Iietune village in Machakos District, Kenya, was selected on the basis of high prevalence and intensities of infection in a small preliminary survey, a stable population living in a small area amenable to detailed study, and a lack of previous intervention in the area. Subsequent observations over a pretreatment period of one year confirmed that prevalence and intensities of infection among children attending the local primary school were high. This was associated with extensive contact of members of the community with water-bodies shown to contain large numbers of infected snails. Analysis of pretreatment intensities of infection and water contact patterns in the schoolchildren allowed the selection of 129 children showing a broad scatter between: (a) high intensity, low water contact, and predicted to be non-immune, and (b) low intensity, high water contact, and predicted to be immune. These children were treated with oxamniquine, 30 mg/kg in divided doses. Five weeks after treatment, 70% of children showed apparent complete cure, and the over-all reduction in geometric mean egg output was 98.9%. Since these children represented only a small proportion of the whole community, there was no obvious reduction in transmission, as reflected by snail infection rates, during the following five-month period. Thus, we are in a position to determine whether successfully treated children do or do not become reinfected in a high transmission environment in which it will be possible to make direct estimates of exposure. Immunological tests carried out immediately before treatment were consistent with a pattern of high exposure leading to the early expression of immune responses in most infected children. Eosinophil levels were elevated in 61% of the children, all of whom showed detectable levels of antibodies against adult worm and egg antigens, as measured by ELISA. In addition, all patients showed antibodies capable of mediating eosinophil-dependent killing of schistosomula. At five weeks after treatment, eosinophil counts and anti-adult worm antibody levels had risen, whereas anti-egg antibodies remained grossly unchanged. The wide variation in the levels of responses shown by different individuals will allow us to test whether such responses are associated with resistance to reinfection during the follow-up period.

Eosinophilia and eosinophil helminthotoxicity in patients treated for Schistosoma mansoni infections.

The changes in eosinophil levels and in eosinophil-mediated antibody-dependent schistosomular cytotoxicity, following treatment for Schistosoma mansoni infections, have been investigated in 2 similar groups of patients aged 15-50 years. Patients in group 1 were treated with either hycanthone or oxamniquine, and those in group 2 with hycanthone or praziquantel. Eosinophil levels were significantly increased in both groups. In group 1 peripheral blood eosinophil counts rose from a mean of 175/microliters before treatment to 745/microliters 3 weeks after treatment, and in group 2 from 181/microliters to 1066/microliters. The increase in eosinophil levels was positively correlated with a rise in circulating anti-adult worm antibodies (r = -0.587, P less than 0.05), whereas a negative correlation was recorded with anti-egg antibodies (r = -0.727). Despite some enhanced eosinophil helminthotoxicity following treatment in some of the individuals in group 1 (7/15), the change overall was not significant. In group 2, in which a different standard anti-schistosomular antibody was used, the eosinophil killing capacity recorded at 3 weeks was lower than that before commencement of treatment (t = 2.89, P less than 0.01). The eosinophil stimulating activity, detected in cultured mononuclear cell supernatants (MCS) from individual patients, correlated with eosinophil levels (r = 0.582, P less than 0.02) but there was no association with eosinophil killing. MCS activity did not appear to be boosted by treatment. These studies showed that peripheral blood eosinophil counts were increased following treatment, but their ability to kill schistosome larvae is variable and may depend on the immune serum used as the source of anti-schistosomular antibody.

Antibodies against haemorrhagic fever viruses in Kenya populations.

Human sera from Lodwar (77 sera), Nzoia (841 sera), Masinga (251 sera), Laisamis (174 sera) and the Malindi/Kilifi area (556 sera) in Kenya were tested by indirect immunofluorescence for antibodies against Marburg, Ebola (Zaire and Sudan strains), Congo haemorrhagic fever, Rift Valley fever and Lassa viruses. Antibodies against Ebola virus, particularly the Zaire strain, were detected in all regions and were, over-all, more abundant than antibodies against the other antigens. Ebola and Marburg antibody prevalence rates were highest in the samples from Lodwar and Laisamis, both semi-desert areas. Antibodies against Rift Valley fever virus were also highest in the Lodwar sample followed by Malindi/Kilifi and Laisamis. Congo haemorrhagic fever virus antibodies were rare and no antibodies against Lassa virus were detected in the 1899 sera tested.

Visceral leishmaniasis unresponsive to antimonial drugs. II. Response to high dosage sodium stibogluconate or prolonged treatment with pentamidine.

Ten Kenyan patients with visceral leishmaniasis unresponsive to sodium stibogluconate, at a dose of 16 to 20 mg Sb/kg body-weight/day given for 30 to 98 days, were treated with 20 mg Sb/kg bw given every eight hours. This regimen was modified or abandoned in six patients because of suspected toxicity, although toxicity was difficult to assess because of intercurrent illness. Toxic effects included lethargy, anorexia, vomiting, electrocardiographic changes, fall in haemoglobin and rise in liver enzymes. One patient died, probably from a cardiac arrhythmia. Two patients were cured, four responded partially and four showed no response. Pentamidine, at a dose of 4 mg/kg body-weight given one to 3 times per week for 5 to 39 weeks, was given as initial treatment in one patient and after failure of sodium stibogluconate in seven. Toxic effects included nephritis, hepatitis, transient diabetes and subcutaneous abscesses. Two patients were cured, two responded partially, three showed no response and one, after apparent cure, relapsed and was unresponsive to additional pentamidine treatment. Low-frequency, long-duration pentamidine was often useful in maintaining any improvement made during treatment with the less well tolerated high-dose, high frequency sodium stibogluconate. We observed the step-wise development of resistance to both sodium stibogluconate and pentamidine. The problems of managing patients with visceral leishmaniasis which is unresponsive to conventional doses of pentavalent antimonials are discussed and some tentative suggestions put forward.

Immunity after treatment of human schistosomiasis mansoni. II. Identification of resistant individuals, and analysis of their immune responses.

Intensities of re-infection were monitored at three-monthly intervals after treatment of Schistosoma mansoni infections in a group of 119 Kenyan schoolchildren, whose levels of water contact were also observed. 22 children showed high reinfection intensities (greater than 100 eggs per gram of faeces) by 12 months after treatment, and were considered to be susceptible. Out of 70 children who showed low reinfection intensities during the same period (less than 30 eggs per gram), 35 showed high levels both of total water contact and of contact with sites containing infected snails. In these children, the relative lack of reinfection could not be attributed to a lack of exposure, and they were classified as resistant to reinfection. Comparison of the two groups, resistant and susceptible, revealed no difference in pretreatment intensities of infection. However, there was a marked difference in age, the mean age of the resistant group being two years greater than that of the susceptible group, within a restricted starting age range. These findings indicated that resistance was an acquired and age-dependent phenomenon, not obviously related to previous egg-induced pathology. Studies of immune responses revealed no clearcut correlate of resistance, but there were interesting differences between the two groups. Whereas anti-egg antigen responses declined after treatment to a greater extent in the resistant than in the susceptible group, antibodies mediating eosinophil-dependent killing of schistosomula rose markedly in both groups, strongly suggesting that the resistant children were being exposed to cercariae. Anti-adult worm antibodies rose sharply in both groups immediately after treatment, and thereafter declined to pretreatment levels. Although some individual children showed high levels of IgE anti-schistosomulum antibodies, there were no significant differences between the two groups. Since all children showed detectable levels of antibodies mediating eosinophil-dependent killing of schistosomula, the possibility was considered that such antibodies might be a necessary, but not a limiting, factor in immunity. Instead, the functional state of the effector cells mediating antibody-dependent killing might be limiting. Eosinophil levels, measured as an indirect estimate of eosinophil functional activity, did not differ between the two groups. There were, however, marked differences between different individuals in their capacity to produce eosinophil-stimulating monocyte mediators, and although this cannot yet be related to resistance, this aspect is worth further study.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunity after treatment of human schistosomiasis mansoni. III. Long-term effects of treatment and retreatment.

Group mean Schistosoma mansoni reinfection patterns are presented for 2 years after treatment with oxamniquine in 1981 of over 100 9- to 16-year-old Kenyan schoolchildren, and for one year after retreatment in 1983 with either oxamniquine or praziquantel when most (nearly 700) infected people in the whole community were treated. Quality control confirmed comparable Kato egg counts throughout the study. Continuing transmission after 1981 raised prevalence to nearly its original level within 6 months, but intensity remained suppressed throughout the 2 year follow-up and very few children reacquired heavy infections (greater than 400 eggs/g). Age and sex had significant effects: reinfection diminished with age, especially among boys--a pattern not apparently attributable to differential water contact. Children with heavy pretreatment infections tended to develop heavy reinfections but this trend was not statistically significant on a group basis, nor were similar trends during the period of less pronounced transmission following the 1983 community treatment. Oxamniquine was equally effective in children receiving it in both 1981 and 1983, and the efficacy of praziquantel resembled that of oxamniquine. In this area of Kenya, repeated chemotherapy will be needed to contain transmission, probably annually or biennially, unless supplemented with other, effective control measures. These findings confirm the beneficial effects of treating even a limited segment of a community at intervals of a year or more without necessarily stopping transmission. They are also compatible with recent findings on potential immune mechanisms in man.

Evidence for predisposition of individual patients to reinfection with Schistosoma mansoni after treatment.

Statistical analysis of the relationship between intensities of infection before treatment and during reinfection after treatment in a sample of 119 Kenyan schoolchildren demonstrated a positive association, indicating that the individuals differed consistently in their tendency to become infected. This association was stronger in young children but the trend was detectable in older individuals. Possible reasons for this variation and for its apparently greater influence in younger age groups are discussed.

Predisposition of humans to infection with Schistosoma mansoni: evidence from the reinfection of individuals following chemotherapy.

In a study of faecal egg counts of Schistosoma mansoni from 359 people of all ages from a rural Kenyan community, a positive association was demonstrated between infection intensity in individuals before treatment and reinfection intensity in the same individuals 9 months after treatment in certain age groups of the sampled population. Consequences and possible causes of these observations are discussed in terms of the epidemiology and control of schistosomiasis.

Production and nitrogen responses of the African dwarf shrub Indigofera spinosa to defoliation and water limitation.

The dwarf shrub Indigofera spinosa Forsk. (Papilionacea), a native forage species of arid Northwest Kenya, was propogated from seed, grown in a controlled environment, and subjected to three treatments of defoliation and watering frequencies in a factorial experimental design. Biomass production and nitrogen accumulation in tissue components were measured to determine defoliation responses in a water-limited environment. We hypothesized that plants would maintain biomass and nitrogen flows despite removal of aboveground meristems and tissues by defoliation. Principal experimental results included a slight reduction (11%; P=0.08) of total biomass production by clipping ca. 1/3 or 2/3 of new leaves and stems and all apical meristems every month. Total aboveground production was not affected by clipping, while final root biomass was reduced 17% by the 2/3 clipping. The least water stressed plants were affected most negatively by defoliation, and the unclipped plants responded more negatively to greater water limitation. Plants achieved partial biomass compensation through alterations in shoot activity and continued allocation of photosynthate to roots. A smaller fraction of leaf production was directed to litter in clipped plants although clipping only removed the youngest tissues, suggesting that clipping increased leaf longevity. In turn, each leaf probably contributed a greater total quantity of photosynthate. Photosynthetic rates were also likely to have been increased by clipping water-stressed plants. In contrast to biomass, plants overcompensated for nitrogen lost to defoliation. Total nitrogen uptake by individual plants was stimulated by defoliation, as there was more total nitrogen in leaves and stems. Increased nitrogen uptake was achieved by clipping stimulation of total uptake per unit of root rather than of total root mass.

The Kenyan Luo migration study: observations on the initiation of a rise in blood pressure.

OBJECTIVE: To demonstrate the magnitude, timing, and cause of changes in blood pressure that occur in migrants from a low blood pressure population on moving to an urban area. DESIGN: A controlled longitudinal observational study of migrants as soon after migration as possible and follow up at three, six, 12, 18, and 24 months after migration. A cohort of controls living in a rural area who were matched for age, sex, and locality were also observed at the same periods. SETTING: 35 Villages on the northern shores of Lake Victoria in western Kenya and Nairobi. PARTICIPANTS: 325 Members of the Luo tribe aged 15 to 34 years who had migrated to Nairobi and 267 controls living in villages. The numbers of both groups reduced during follow up such that only 63 migrants and 143 controls were followed up for two years. MAIN OUTCOME MEASURES: A medical questionnaire and three 24 hour diet histories were completed by migrants and controls. Height, weight, pulse, and blood pressure were measured. Three 12 hour overnight urine samples were collected from all participants and analysed for sodium, potassium, and creatinine concentrations. RESULTS: The mean systolic blood pressure of migrants was significantly higher than that of controls throughout the study, and the distribution of blood pressure was shifted to the right compared with controls. The mean diastolic blood pressure of the two groups diverged over time. Blood pressure differences were not due to selective migration. The migrants' mean urinary sodium:potassium ratio was higher than that of controls (p less than 0.001) throughout, and weight and pulse rate were also higher among migrants, although differences diminished with time. CONCLUSIONS: Urinary sodium:potassium ratio, pulse rate, and weight are important predictors of increased blood pressure among migrants from a low blood pressure community and may also be implicated in the initiation of essential hypertension.

Determinants of blood pressure changes due to urbanization: a longitudinal study.

Changes in blood pressure (BP) and associated factors which occur on migration from a rural to an urban environment are under observation in a longitudinal study. Blood pressures, heart rate (HR), urinary electrolytes, sociological and anthropometric data are recorded at 0, 3, 6, 12, 18 and 24 months following migration and compared with a cohort of age and sex-matched rural based controls. Data from the first 6 months' follow-up reveal that the migrants' BPs are higher and tend to rise compared with controls, in whom BP falls progressively with time. Changes in body weight and dietary electrolytes appear to explain some of the BP differences, while differences in pulse rates between groups suggest that a further mechanism operative through the autonomic nervous system is responsible for some of the elevation of systolic BP shown amongst migrants, particularly on arrival in the urban area.