Priority areas for current research on malaria during pregnancy.
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Female↗
Biomedical subjects
C Menendez
Publications and source records attributed to C Menendez.
Presence of acetyl coenzyme A (CoA) carboxylase and propionyl-CoA carboxylase in autotrophic Crenarchaeota and indication for operation of a 3-hydroxypropionate cycle in autotrophic carbon fixation.
The pathway of autotrophic CO2 fixation was studied in the phototrophic bacterium Chloroflexus aurantiacus and in the aerobic thermoacidophilic archaeon Metallosphaera sedula. In both organisms, none of the key enzymes of the reductive pentose phosphate cycle, the reductive citric acid cycle, and the reductive acetyl coenzyme A (acetyl-CoA) pathway were detectable. However, cells contained the biotin-dependent acetyl-CoA carboxylase and propionyl-CoA carboxylase as well as phosphoenolpyruvate carboxylase. The specific enzyme activities of the carboxylases were high enough to explain the autotrophic growth rate via the 3-hydroxypropionate cycle. Extracts catalyzed the CO2-, MgATP-, and NADPH-dependent conversion of acetyl-CoA to 3-hydroxypropionate via malonyl-CoA and the conversion of this intermediate to succinate via propionyl-CoA. The labelled intermediates were detected in vitro with either 14CO2 or [14C]acetyl-CoA as precursor. These reactions are part of the 3-hydroxypropionate cycle, the autotrophic pathway proposed for C. aurantiacus. The investigation was extended to the autotrophic archaea Sulfolobus metallicus and Acidianus infernus, which showed acetyl-CoA and propionyl-CoA carboxylase activities in extracts of autotrophically grown cells. Acetyl-CoA carboxylase activity is unexpected in archaea since they do not contain fatty acids in their membranes. These aerobic archaea, as well as C. aurantiacus, were screened for biotin-containing proteins by the avidin-peroxidase test. They contained large amounts of a small biotin-carrying protein, which is most likely part of the acetyl-CoA and propionyl-CoA carboxylases. Other archaea reported to use one of the other known autotrophic pathways lacked such small biotin-containing proteins. These findings suggest that the aerobic autotrophic archaea M. sedula, S. metallicus, and A. infernus use a yet-to-be-defined 3-hydroxypropionate cycle for their autotrophic growth. Acetyl-CoA carboxylase and propionyl-CoA carboxylase are proposed to be the main CO2 fixation enzymes, and phosphoenolpyruvate carboxylase may have an anaplerotic function. The results also provide further support for the occurrence of the 3-hydroxypropionate cycle in C. aurantiacus.
Acetyl Coenzyme A↗
Dihydrotestosterone, stanozolol, androstenedione and dehydroepiandrosterone sulphate inhibit leptin secretion in female but not in male samples of omental adipose tissue in vitro: lack of effect of testosterone.
Leptin, the product of the Ob gene, is a polypeptide hormone expressed in adipocytes which acts as a signalling factor from the adipose tissue to the central nervous system, regulating food intake and energy expenditure. It has been reported that circulating leptin levels are higher in women than in men, even after correction for body fat. This gender-based difference may be conditioned by differences in the levels of androgenic hormones. To explore this possibility, a systematic in vitro study with organ cultures from human omental adipose tissue, either stimulated or not with androgens (1 microM), was undertaken in samples obtained from surgery on 44 non-obese donors (21 women and 23 men). The assay was standardized in periods of 24 h, ending at 96 h, with no apparent tissue damage. Leptin results are expressed as the mean+/-s.e.m. of the integrated secretion into the medium, expressed as ng leptin/g tissue per 48 h. Spontaneous leptin secretion in samples from female donors (4149+/-301) was significantly higher (P<0.01) than that from male donors (2456+/-428). Testosterone did not exert any significant effect on in vitro leptin secretion in either gender (4856+/-366 in women, 3322+/-505 in men). Coincubation of adipose tissue with dihydrotestosterone (DHT) induced a significant (P<0.05) leptin decrease in samples taken from women (3119+/-322) but not in those taken from men (2042+/-430). Stanozolol, a non-aromatizable androgen, decreased (P<0.05) leptin secretion in female samples (2809+/-383) but not in male (1553+/-671). Dehydroepiandrosterone sulphate (DHEA-S) induced a significant (P<0.01) leptin decrease in female samples (2996+/-473), with no modifications in samples derived from males (1596+/-528). Exposure to androstenedione also resulted in a significant reduction (P<0.01) of leptin secretion in samples taken from women (2231+/-264), with no effect on male adipose tissue (1605+/-544). In conclusion, DHT, stanozolol, DHEA-S and androstenedione induced a significant inhibition of in vitro leptin secretion in samples from female donors, without affecting the secretion in samples from men. Testosterone was devoid of activity in either gender.
Adipose Tissue↗
African children with malaria in an area of intense Plasmodium falciparum transmission: features on admission to the hospital and risk factors for death.
Malaria remains the most important parasitic cause of mortality in humans. Its presentation is thought to vary according to the intensity of Plasmodium falciparum transmission. However, detailed descriptions of presenting features and risk factors for death are only available from moderate transmission settings. Such descriptions help to improve case management and identify priority research areas. Standardized systematic procedures were used to collect clinical and laboratory data on 6,624 children admitted to hospital over a 1-year period in an intensely malarious part of Tanzania. Frequencies of signs and symptoms were calculated and their association with a fatal outcome was assessed using multivariate logistic regression. There were 72 deaths among 2,432 malaria cases (case fatality rate [CFR] = 3.0%); 44% of the cases and 54% of the deaths were in individuals less than 1 year of age. There was no association between level of parasitemia and CFR. Increased risk of dying was independently found in all children with hypoglycemia (odds ratio [OR] = 6.7, 95% confidence interval [CI] = 3.9-11.7), in children 1-7 months of age with tachypnea (OR = 8.8, 95% CI = 2.6-30.5) and dehydration (OR = 5.0, 95% CI = 1.9-14.2), and in children 8 months to 4 years of age with chest indrawing (OR = 4.7, 95% CI = 2.0-11.2) and inability to localize a painful stimulus (OR = 6.9, 95% CI = 2.9-16.5). Children in the bottom quartile of weight-for-age were more likely to die (OR = 2.1, 95% CI = 1.3-3.5). Eight percent of the malaria cases had severe anemia (packed cell volume < 15%) but 24% received a blood transfusion. The epidemiology of malaria disease may be more complex than previously thought. Improved case management in a wide variety of health facilities may result from adequate identification and treatment of dehydration and hypoglycemia. Transfusion-requiring anemia is a major problem and sustainable, effective preventive measures are urgently needed.
Adolescent↗
Infection, oxford general practice series 40.
edited by L. Southgate, C. Lockie, S. Heard and M. Wood, Oxford University Press, 1997. pound27.50 (476 pages) ISBN 0 919 262092 4.
Journal Article↗
Theoretical considerations in estimating the growth hormone axis in adults.
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Adipose Tissue↗
Massive chronic intervillositis of the placenta associated with malaria infection.
Massive chronic intervillositis (MCI) is an infrequently recognized placental lesion thought to be of immunologic origin that has been associated with poor fetal outcome. It is characterized by a prominent inflammatory infiltrate in the intervillous space, composed mainly of monocytes and macrophages that can simulate a maternal malignant disorder involving the placenta. The villi are characteristically spared. We report 74 cases of placental malarial infection with morphologic features of MCI. In all cases, the massive inflammatory infiltrate was limited to the intervillous space, which appeared largely obliterated. Increased fibrin deposition and prominent syncytial knots were frequent associated findings. Inflammatory cells were CD45 and CD68 positive, consistent with a monocyte-macrophage population. Some polymorphonuclear leukocytes and scattered T and B lymphocytes were also present. Villi were not inflamed. Malarial pigment was present in all cases, and parasitized maternal erythrocytes were evident in 73 of 74 patients. The histologic pattern of MCI was observed in 17.6% of placentas with malarial parasites. Malarial MCI affected predominantly primigravida women (77%) and was associated with a reduced birth weight, which in 39 (53%) of the infants was less than 2500 g, and a low gestational age. None of the infants with placentas with MCI died in the early neonatal period. Morphologic changes of MCI are seen in a significant percentage of placentas with malarial infection, especially in primigravida women, and are associated with a low birth weight. Malarial infection should therefore be considered in the differential diagnosis of massive intervillous infiltrates.
Chorionic Villi↗
Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants.
BACKGROUND: Malaria and anaemia, especially that due to iron deficiency, are two leading causes of morbidity worldwide. Little is known about the relative contribution of Plasmodium falciparum infection and iron deficiency to the aetiology of anaemia in malaria-endemic areas. We undertook a randomised comparison of different strategies for control of anaemia and malaria in infants, including an assessment of the effect of iron supplementation on malaria susceptibility. METHODS: 832 infants born at one hospital in a malaria-hyperendemic area of Tanzania between January and October, 1995, were randomly assigned to group DI, receiving daily oral iron (2 mg/kg daily) plus weekly Deltaprim (3.125 mg pyrimethamine plus 25 mg dapsone); group IP, receiving iron plus weekly placebo; group DP, receiving daily placebo plus weekly Deltaprim; or group PP. supplementation was given from 8 to 24 weeks of age, and the weekly chemoprophylaxis from 8 to 48 weeks. The frequency of severe anaemia (packed-cell volume < 25%) and malaria episodes was assessed through a combination of passive case detection and cross-sectional surveys. FINDINGS: The groups that received iron supplementation had a lower frequency of severe anaemia than those that did not receive iron (0.62 vs 0.87 cases per person-year; protective efficacy 28.8% [95% CI 6.3-45.8). Iron supplementation had no effect on the frequency of malaria (0.87 vs 1.00 cases per person-year; protective efficacy 12.8% [-12.8 to 32.5]). The groups that received malaria prophylaxis had lower frequencies of both severe anaemia (0.45 vs 1.04 episodes per person-year; protective efficacy 57.3% [43.0-67.9]) and malaria (0.53 vs 1.34 episodes per person-year; protective efficacy 60.5% [48.2-69.9]) than the groups that did not receive prophylaxis. After the end of the intervention period, children who had received malaria chemoprophylaxis had higher rates of severe anaemia and malaria than non-chemoprophylaxis groups (relative risks 2.2 [1.3-3.7] and 1.8 [1.3-2.6]). INTERPRETATION: Malaria chemoprophylaxis during the first year of life was effective in prevention of malaria and anaemia but apparently impaired the development of natural immunity. Iron supplementation was effective in preventing severe anaemia without increasing susceptibility to malaria. Our findings support iron supplementation of infants to prevent iron-deficiency anaemia, even in malaria-endemic areas.
Adult↗
Plasmodium falciparum malaria in the first year of life in an area of intense and perennial transmission.
A longitudinal study of Plasmodium falciparum malaria in infants in Idete village, south-eastern Tanzania, was conducted over a period of 14 months in order to determine the incidence of P. falciparum infection and clinical malaria in the first year of life. Of 1356 blood slides from cross-sectional surveys, 52.1% were positive for asexual stages of P. falciparum. There were marked increases in P. falciparum prevalence, parasite densities, overall fever incidence and the incidence of malaria fevers with age for the first 6 months of life. The average attack rate, estimated from a reversible catalytic model, was 0.029 per day with a slight increase with age but there was no initial period of protection against infection in neonates. Estimated average duration of infections was 64 days, with infections in older infants lasting much longer than those contracted during the first 2 months of life. These results support the hypotheses that the main effect of passively transferred maternal immunity to malaria is in the control of asexual stage parasites, and that the level of clinical immunity depends upon the extent of recent exposure to parasites. Infants as young as 4 months of age are at high risk of clinical attacks. Intervention programmes against malaria in areas of the highest transmission should therefore be designed to include this group.
Cohort Studies↗
Duration of protection and age-dependence of the effects of the SPf66 malaria vaccine in African children exposed to intense transmission of Plasmodium falciparum.
The SPf66 synthetic vaccine is safe and partly efficacious against Plasmodium falciparum malaria among children 1-5 years old. The estimated vaccine efficacy [VE] for all clinical episodes over a period of 18 months after the third dose is 25% (95% confidence interval [CI], 1%-44%; P = .044). The observed temporal variations in efficacy could have been due to chance (likelihood ratio chi 2 = 13.8, 8 df; P = .086). Efficacy against clinical malaria did not vary significantly with age (chi 2 = 1.07, 4 df; P = .90). Overall parasite density was 21% lower in vaccine recipients than in the placebo group (95% CI, 0%-38%; P = .044). Further development of SPf66 may require trials to evaluate safety, immunogenicity, and efficacy when administered in the first year of life, together with other vaccines contained in the Expanded Programme of Immunization schedule.
Age Factors↗
A comparative study of the efficacies of chloroquine and a pyrimethamine-dapsone combination in clearing Plasmodium falciparum parasitaemia in school children in Tanzania.
A randomized study on the in vivo efficacies of chloroquine and a pyrimethamine-dapsone combination (Maloprim) in clearing P. falciparum parasitaemia was carried out in 77 asymptomatic semi-immune schoolchildren in the Kilombero District of Tanzania. Children were randomized to receive either chloroquine at a dose of 25 mg/kg over three days, or Maloprim (6.25 mg pyrimethamine + 50 mg dapsone for children under 10 years, and 12.5 mg pyrimethamine + 100 mg dapsone for children 10 or more years old) as a single dose. Children were followed-up for malaria parasitaemia at days 2, 7 and 14 after screening, randomization and treatment. The slide positivity rate was lower in the Maloprim group at all cross-sectional surveys (23 vs 37% at day 2; 9 vs 20% at day 7; 21 vs 32% at day 14) but none of these differences reached statistical significance. No cases in the Maloprim group showed RII resistance, whereas in the chloroquine group, 2 cases showed RII resistance and a further 2 cases RIII resistance (6%). No major side-effects were reported. The combination of pyrimethamine-dapsone appears to be a better choice than chloroquine as a chemoprophylactic regimen for malaria in this area. Although they need to be confirmed in a larger study, these results may be of interest to the policy-makers as well as researchers.
Antimalarials↗
Isolation and enzymic properties of levansucrase secreted by Acetobacter diazotrophicus SRT4, a bacterium associated with sugar cane.
Acetobacter diazotrophicus, a nitrogen-fixing bacterium associated with sugar cane, secretes a levansucrase (sucrose-2,6-beta-D-fructan 6-beta-D-fructosyltransferase; EC 2.4.1.10). This enzyme is constitutively expressed and represents more than 70% of the total proteins secreted by strain SRT4. The purified protein consists of a single 58 kDa polypeptide with an isoelectric point of 5.5. Its activity is optimal at pH 5.0. It catalyses transfructosylation from sucrose to a variety of acceptors including water (sucrose hydrolysis), glucose (exchange reaction), fructan (polymerase reaction) and sucrose (oligofructoside synthesis). In vivo the polymerase activity leads to synthesis of a high-molecular-mass fructan of the levan type. A. diazotrophicus levansucrase catalyses transfructosylation via a Ping Pong mechanism involving the formation of a transient fructosyl-enzyme intermediate. The catalytic mechanism is very similar to that of Bacillus subtilis levansucrase. The kinetic parameters of the two enzymes are of the same order of magnitude. The main difference between the two enzyme specificities is the high yield of oligofructoside, particularly 1-kestotriose and kestotetraose, accumulated by A. diazotrophicus levansucrase during sucrose transformation. We discuss the hypothesis that these catalytic features may serve the different biological functions of each enzyme.
Acetobacter↗
Malaria during pregnancy: a priority area of malaria research and control.
More than 2000 million people live in areas where malaria transmission occurs and are therefore at risk of being infected. It follows that 1000 million people are exposed to the risks of malaria when pregnant. Although the special features of malaria during pregnancy have been recognized for nearly a century(1), it is only recently that it is being considered as a priority for malaria research and control, as discussed here by Clara Menendez.
Journal Article↗
Changes in sex behaviour after menopause: effects of tibolone.
In order to analyse both sexual desire after menopause and its response to treatment with tibolone, a randomized placebo/tibolone trial has been designed with 28 postmenopausal patients. They were asked to answer a questionnaire designed by us to obtain quantitative measurements to describe changes in sexual desire. After selection, the patients were randomly assigned to two groups as follows: 14 in the group treated with 2.5 mg/day of tibolone and 14 in the placebo group treated with 500 mg/day of calcium. The patients were monitored after 3, 6 and 12 months. Before joining this study, they had signed a written consent. It was observed that the sexual desire after menopause underwent a significant fall, with decline in arousability and intercourse. The comparative results show that the patients treated with tibolone experience an improvement after the third month of treatment and this improvement was maintained until the end of treatment. We conclude that the questionnaire proposed here is a useful non-parametric method to diagnose a patient's sexuality status at the baseline assessment and a valuable tool for monitoring various therapies. Furthermore, tibolone proved to be effective in managing reduced sexual desire which appears in postmenopausal patients.
Anabolic Agents↗
Randomised trial of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania.
Malaria, especially that due to Plasmodium falciparum, is one of the most important parasitic disease in man. It causes more than 400 million cases per year and between 1 to 3 million deaths, mainly among young children and pregnant women in sub-Saharan Africa. The current malaria control strategies using rapid diagnosis and treatment as well as methods to reduce the man-vector contact have had limited success. In Kilombero district (Southern Tanzania), malaria transmission is perennial (parasite prevalence > or = 80% all year) and intense (approximatively 300 infectious bites per year). At the household level, each under-5 child suffers on average 3 clinical fever episodes per year. Minimum estimated community rates for serious malaria (cerebral malaria or malaria and anaemia) affect approximatively 5% of all children. Under conditions of a field experiment, the annual incidence of a febrile illness (axillary temperature > or = 37.5 degrees C) reported to the curative primary health services in each child was 0.86 of which 0,35 can be attributed to Plasmodium falciparum malaria. The best estimate of the SPf66 vaccine protective efficacy in the Kilombero was 31% (95% CI : 0.52).
Child, Preschool↗
Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania.
Effective, safe antimalarial vaccines have proved elusive. The synthetic polypeptide SPf66 vaccine is based on preerythrocytic and asexual blood-stage proteins of Plasmodium falciparum. We report here a randomised double-blind placebo-controlled trial of the efficacy of the SPf66 vaccine against clinical P falciparum malaria in idete, southern Tanzania, an area of intense perennial malaria transmission. 586 children aged 1-5 years received three doses of vaccine (n = 274) or placebo (n = 312). The incidence and density of parasitaemia were assessed through repeated cross-sectional surveys on subgroups of children. Morbidity was monitored over a 1 year period through passive case detection in all children plus active case detection in a subgroup of 191. An episode of clinical malaria was defined as measured fever (> or = 37.5 degrees C) and parasite density > 20,000/microL. No severe side-effects were seen and the frequency of mild side-effects after the third dose was less than 6%. The vaccine was highly immunogenic and after three doses all vaccine recipients had detectable anti-SPf66 antibodies: the geometric mean index of response was 8.3 in the vaccine group and 0.7 in the placebo group. The incidence of parasitaemia was similar in both groups. 123 children had at least one episode of clinical malaria during the follow-up period after the third dose and annual incidence rates were 0.25 in the vaccine group and 0.35 in the placebo group. Estimated vaccine efficacy was 31% (95% confidence interval 0-52%; p = 0.046). After the third dose there were 6 deaths among the study cohort (1 vaccine, 5 placebo). This study confirms that SPf66 is safe, immunogenic and reduces the risk of clinical malaria among children exposed to intense P falciparum transmission.
Child, Preschool↗
Vitamin A and iron supplementation in pregnancy.
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Anemia, Hypochromic↗
A trial of the synthetic malaria vaccine SPf66 in Tanzania: rationale and design.
The development of a safe, affordable and effective malaria vaccine to form part of control schemes in malaria endemic countries is a priority for researchers and public health officials. SPf66 is the first malaria vaccine to have shown partial protection against natural challenge in a phase III trial carried out in a hypoendemic area of Colombia. This paper describes the rationale and design of the first field trial of SPf66 outside South America, and the first to be conducted in an area of high perennial transmission.
Adult↗