Neuroprotection by anaesthetics in rodent models of traumatic brain injury: a systematic review and network meta-analysis.

BACKGROUND: Anaesthetic neuroprotection in the setting of traumatic brain injury (TBI) remains unproved and is based upon the results in preclinical experiments. Here, we sought to synthesise the results in rodent models of TBI, and to evaluate the effects of publication bias, experimental manipulation, and poor study quality on the effect estimates. METHODS: After a systematic review, we used pairwise meta-analysis to estimate the effect of anaesthetics, opioids, and sedative-hypnotics on neurological outcome, and network meta-analysis to compare their relative efficacy. We sought evidence of bias related to selective publication, experimental manipulation, and study quality. RESULTS: Sixteen studies, involving 32 comparisons, were included (546 animals). The treatment improved the neurological outcomes by 35%; 95% confidence interval: 26-44%; P<0.001. The statistical heterogeneity was small (12%), but the 95% prediction interval for the estimate was wide (15-56%). The statistical power was low: 61% (90% confidence interval: 22-86%). The small sample size in the studies was a serious shortcoming reducing the statistical heterogeneity and obscuring differences in outcome between drugs and between experimental conditions. CONCLUSIONS: Anaesthetics do provide neuroprotection in rodent models of TBI. The effect-size estimates do not appear to be exaggerated by selective publication, experimental manipulation, or study design. The main shortcoming of the included studies were small sample sizes leading to low power and imprecision, which precluded the network meta-analysis from providing a meaningful ranking for efficacy amongst the drugs. Reliable preclinical investigations of neuroprotection by anaesthetics will require larger sample sizes.

Maternal exposure to carbon monoxide and fine particulate matter during pregnancy in an urban Tanzanian cohort.

Low birthweight contributes to as many as 60% of all neonatal deaths; exposure during pregnancy to household air pollution has been implicated as a risk factor. Between 2011 and 2013, we measured personal exposures to carbon monoxide (CO) and fine particulate matter (PM2.5 ) in 239 pregnant women in Dar es Salaam, Tanzania. CO and PM2.5 exposures during pregnancy were moderately high (geometric means 2.0 ppm and 40.5 µg/m3 ); 87% of PM2.5 measurements exceeded WHO air quality guidelines. Median and high (75th centile) CO exposures were increased for those cooking with charcoal and kerosene versus kerosene alone in quantile regression. High PM2.5 exposures were increased with charcoal use. Outdoor cooking reduced median PM2.5 exposures. For PM2.5 , we observed a 0.15 kg reduction in birthweight per interquartile increase in exposure (23.0 µg/m3 ) in multivariable linear regression; this finding was of borderline statistical significance (95% confidence interval 0.30, 0.00 kg; P = 0.05). PM2.5 was not significantly associated with birth length or head circumference nor were CO exposures associated with newborn anthropometrics. Our findings contribute to the evidence that exposure to household air pollution, and specifically fine particulate matter, may adversely affect birthweight.

Causes, magnitude and management of burns in under-fives in district hospitals in Dar es Salaam, Tanzania.

OBJECTIVES: To determine the causes, magnitude and management of burns in children under five years of age who were admitted in the district hospitals of Dar es Salaam City, Tanzania. METHODS: In this study, a total of 204 under fives were enrolled. Questionnaires were used to elicit if the parent/caretaker had the knowledge of the cause of the burns, what was done immediately after burn injury, first aid given immediately after burn, source of the knowledge of first aid and when the child was taken to the hospital. Also the questionnaire was cited with data on the management of burns in the hospitals through observation and checking the treatment files. RESULTS: Forty nine percent were males while 50.5% were females. Most of the children (54.9%) were aged between 1-2 years. 78.4% had scalds while 21.6% had flame burns. No children were found to have burns caused by chemicals or electricity. Most of the burns (97.5%) occurred accidentally, although some (2.5%) were intentional. 68.6% of these burn injuries occurred in the kitchen. Immediately after burn 87.3% of the children had first aid applied on their wounds while 12.7% didn't apply anything. Of the agents used, honey was the most used (32.8%) followed by cold water (16.7%). The source of knowledge on these agents was from relatives and friends (72.5%), schools (7%), media (6%) and medical personnel (14%). The study further revealed that analgesics, intravenous fluids, antiseptics and antibiotics were the drugs used for treatment of burns in the hospital and that there was no specialized unit for burns in the hospitals. CONCLUSIONS: Causes of childhood burns are largely preventable requiring active social/medical education and public enlighten campaigns on the various methods of prevention. The government to see to it that hospitals have specialized units for managing burn cases and also the socio-economic status of its people be improved.

[Conclusions and recommendations of a WHO expert consultation meeting on iron supplementation for infants and young children in malaria endemic areas]. / Conclusions et recommandations à l'issue de la consultation de l'OMS sur la lutte contre la carence martiale chez le nourrisson et le jeune enfant dans les pays d'endémie palustre.

This article presents the results of an expert consultation meeting aimed at evaluating the safety and public health implications of administering supplemental iron to infants and young children in malaria-endemic areas. Participants at this meeting that took place in Lyon, France on June 12-14, 2006 reached consensus on several important issues related to iron supplementation for infants and young children in malaria-endemic areas. The conclusions in this report apply specifically to regions where malaria is endemic.

Dhfr and dhps mutations in Plasmodium falciparum isolates in Mlandizi; Kibaha; Tanzania: association with clinical outcome

Sulfadoxine-pyrimethamine (SP); the current first line antimalarial drug in Tanzania; is compromised by evolution and spread of mutations in the parasite's dhfr and dhps genes. In the present study we established the baseline frequencies of Plasmodium falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) mutant genotypes and their potential for predicting the in vivo efficacy of SP in Mlandizi; Tanzania. The efficacy of SP treatment was by following 116 children with uncomplicated falciparum malaria for 14 days after treatment. Infected blood samples were collected on filter paper at days 0; 3; 7 and 14. Parasite genomic DNA was extracted and point mutations at positions 51; 59; 108 and 164 of the dhfr gene and at 581; 540 and 437 of the dhps gene were analysed by nested Polymerase Chain Reaction/ Restriction Fragment Length Polymorphism. Out of 116 children enrolled; 98 (86) of eligible children demonstrated an adequate clinical response by day 14. There were 7.3early and 6.7late therapeutic failures. At day 0; only 8.0(4/50) the parasites showed no mutation at the dhfr locus; for dhps this was 73. Triple mutant dhfr alleles (Ile 51; Arg 59; Asn 108) occurred in 47; double mutant dhps (Gly 437; Glu 540) alleles in 7.9. No mutation was detected at codon 164 of the dhfr gene. The presence of triple dhfr mutant alleles was related to clinical failure; but did not show significant association (Fisher exact test; P=0.166; OR 2.15 0.77OR6.20). The higher rates of mutation on the dhfr do not spell a bright future for SP treatment in Tanzania. It is rational to think of an alternative first line antimalarial drug; while retaining SP for malaria intermittent treatment in pregnancy

Higher IL-10 levels are associated with less effective clearance of Plasmodium falciparum parasites.

The implications of high levels of the immune regulatory cytokine IL-10 in Plasmodium falciparum malaria are unclear. IL-10 may down-regulate pro-inflammatory responses and also exacerbate disease by inhibiting anti-parasitic immune functions. To study possible inhibiting effects on parasite clearance, IL-10 plasma levels were determined in 104 Tanzanian children, 1 to 4 years old, with acute uncomplicated P. falciparum malaria, and analysed for association with parasite densities during 3 days of anti-malarial treatment. Higher baseline IL-10 plasma levels were associated with statistically significantly higher parasite densities after 24, 48 and 72 h of treatment. These associations could not be explained by differences in initial parasitaemia, temperature, age, sex or type of treatment. Induction of high IL-10 production might be a direct or indirect mechanism whereby the parasite evades the immune response.

Comparison of chlorproguanil-dapsone with sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in young African children: double-blind randomised controlled trial.

BACKGROUND: Increasing resistance to sulfadoxine-pyrimethamine is leading to a decline in its effectiveness. We aimed to assess the safety profile of chlorproguanil-dapsone (CD), and to compare the safety and efficacy of this drug with that of sulfadoxine-pyrimethamine (SP) as treatment for uncomplicated falciparum malaria. METHODS: We undertook a double-blind, randomised trial in 1850 consecutively recruited children with uncomplicated falciparum malaria, pooling data from five African countries. Analyses were based on all randomised patients with available data. FINDINGS: CD was significantly more efficacious than SP (odds ratio 3.1 [95% CI 2.0-4.8]); 1313 patients (96%) given CD and 306 (89%) given SP achieved acceptable clinical and parasitological response by day 14. Adverse events were reported in 46% and 50% of patients randomised to CD and SP, respectively (treatment difference -4.4%, [95% CI -10.1 to 1.3]). Haemoglobin in the CD group was significantly lower than in the SP group at day 7, a difference of -4 g/L (95% CI -6 to -2). Mean day 14 haemoglobin (measured only for the small number of patients whose day 7 data caused concern) was 94 g/L (92-96) and 97 g/L (92-102) after CD and SP, respectively. Glucose-6-phosphate dehydrogenase deficient patients on CD had greater odds than those on SP of having a fall of 20 g/dL or more in haemoglobin when baseline temperature was high. Methaemoglobinaemia was seen in the CD group (n=320, mean 0.4% [95% CI 0.4-0.4]) before treatment, 4.2% (95% CI 3.8-4.6) (n=301) at day 3, and 0.6% (0.6-0.7) (n=300) at day 7). INTERPRETATION: CD had greater efficacy than SP in Africa and was well tolerated. Haematological adverse effects were more common with CD than with SP and were reversible. CD is a useful alternative where SP is failing due to resistance.

Age, temperature, and parasitaemia predict chloroquine treatment failure and anaemia in children with uncomplicated Plasmodium falciparum malaria.

The prevalence of chloroquine-resistant Plasmodium falciparum malaria has been increasing in sub-Saharan Africa and parts of South America over the last 2 decades, and has been associated with increased anaemia-associated morbidity and higher mortality rates. Prospectively collected clinical and parasitological data from a multicentre study of 788 children aged 6-59 months with uncomplicated P. falciparum malaria were analysed in order to identify risk factors for chloroquine treatment failure and to assess its impact on anaemia after therapy. The proportion of chloroquine treatment failures (combined early and late treatment failures) was higher in the central-eastern African countries (Tanzania, 53%; Uganda, 80%; Zambia, 57%) and Ecuador (54%) than in Ghana (36%). Using logistic regression, predictors of early treatment failure included younger age, higher baseline temperature, and greater levels of parasitaemia. We conclude that younger age, higher initial temperature, and higher baseline parasitaemia predict early treatment failure and a higher probability of worsening anaemia between admission and days 7 or 14 post-treatment.

Acridine Orange for malaria diagnosis: its diagnostic performance, its promotion and implementation in Tanzania, and the implications for malaria control.

One hundred years ago, Giemsa's stain was employed for the first time for malaria diagnosis. Giemsa staining continues to be the method of choice in most malarious countries, although, in the recent past, several alternatives have been developed that exhibit some advantages. Considerable progress has been made with fluorescent dyes, particularly with Acridine Orange (AO). The literature on the discovery, development and validation of the AO method for malaria diagnosis is reviewed here. Compared with conventional Giemsa staining, AO shows a good diagnostic performance, with sensitivities of 81.3%-100% and specificities of 86.4%-100%. However, sensitivities decrease with lower parasite densities, and species differentiation may occasionally be difficult. The most notable advantage of the AO method over Giemsa staining is its promptness; results are readily available within 3-10 min, whereas Giemsa staining may take 45 min or even longer. This is an important advantage for the organization of health services and the provision of effective treatment of malaria cases. The national malaria control programme of Tanzania, together with the Japan International Co-operation Agency, began to introduce the AO method in Tanzania in 1994. So far, AO staining has been introduced in 70 regional and district hospitals, and 400 laboratory technicians have been trained to use the method. The results of this introduction, which are reviewed here and have several important implications, indicate that AO is a viable alternative technique for the laboratory diagnosis of malaria in highly endemic countries.

Hemoglobin concentration in children in a malaria holoendemic area is determined by cumulated Plasmodium falciparum parasite densities.

In malaria holoendemic areas children are anemic, but the exact influence of falciparum malaria on hemoglobin (Hb) concentration remains largely unsettled. Prospective data were therefore collected in children < 24 months of age during five months in a Tanzanian village. Children with mean asymptomatic parasitemia > or = 400/microl had lower median Hb levels during the study than those with mean density < 400/microl. The difference was 9.7 g/L (95% confidence interval [CI] 2.8-17). In children with one or more clinical malaria episodes, the median Hb was 8.3 g/L (95% CI 0.9-16) lower than those without episode. If early treatment failure was recorded, the immediate effect on Hb was particularly important with a mean drop of 17 g/L. Interestingly, at study-end the Hb concentration represented a function of the area under the parasitemia curve (AUPC) during the previous five months, adjusting for age. In conclusion, stepwise deterioration in median Hb levels was found by asymptomatic parasitemia, clinical malaria episode, and most significantly, treatment failure.

An analysis of anemia and child mortality.

The relationship of anemia as a risk factor for child mortality was analyzed by using cross-sectional, longitudinal and case-control studies, and randomized trials. Five methods of estimation were adopted: 1) the proportion of child deaths attributable to anemia; 2) the proportion of anemic children who die in hospital studies; 3) the population-attributable risk of child mortality due to anemia; 4) survival analyses of mortality in anemic children; and 5) cause-specific anemia-related child mortality. Most of the data available were hospital based. For children aged 0-5 y the percentage of deaths due to anemia was comparable for reports from highly malarious areas in Africa (Sierra Leone 11.2%, Zaire 12.2%, Kenya 14.3%). Ten values available for hemoglobin values <50 g/L showed a variation in case fatality from 2 to 29.3%. The data suggested little if any dose-response relating increasing hemoglobin level (whether by mean value or selected cut-off values) with decreasing mortality. Although mortality was increased in anemic children with hemoglobin <50 g/L, the evidence for increased risk with less severe anemia was inconclusive. The wide variation for mortality with hemoglobin <50 g/L is related to methodological variation and places severe limits on causal inference; in view of this, it is premature to generate projections on population-attributable risk. A preliminary survival analysis of an infant cohort from Malawi indicated that if the hemoglobin decreases by 10 g/L at age 6 mo, the risk of dying becomes 1.72 times higher. Evidence from a number of studies suggests that mortality due to malarial severe anemia is greater than that due to iron-deficiency anemia. Data are scarce on anemia and child mortality from non-malarious regions. Primary prevention of iron-deficiency anemia and malaria in young children could have substantive effects on reducing child mortality from severe anemia in children living in malarious areas.

Acute haemolysis in childhood falciparum malaria.

Acute haemolysis associated with clinical episodes of high-level Plasmodium falciparum parasitaemia was studied in 20 children from an holoendemic area (coastal Tanzania). The change in blood haemoglobin (Hb) concentration ranged from -46 to g/L during the 72-h observation period and was linearly related to maximum parasitaemia. Balance studies between loss of blood Hb, increase in plasma Hb and appearance of Hb in the urine indicated that extravascular clearance of red cells was the predominant mode of erythrocyte clearance. Most subjects, however, showed minor signs of intravascular haemolysis. The plasma Hb was << 1% of blood Hb and haemoglobinuria was detected in 14/20 children but the excretion of Hb in urine was < 0.5% of total Hb loss. Haemoglobinuria was, however, a marker of severe haemolysis, since the maximum blood Hb loss in children without haemoglobinuria was 10 g/L. Erythrocyte-bound opsonins known to induce erythrophagocytosis, i.e., complement C3c fragments and autologous IgG, were increased in all patients. In the patients with major haemolysis, the changes correlated to the haemolysis over time. Hence, a similar mechanism for predominantly extravascular erythrocyte clearance may be operative in acute malarial anaemia, normal erythrocyte senescence and other forms of acute haemolysis.

Micronutrient and iron supplementation and effective antimalarial treatment synergistically improve childhood anaemia.

The control of childhood anaemia in malaria holoendemic areas is a major public health challenge for which an optimal strategy remains to be determined. Malaria prevention may compromise the development of partial immunity. Regular micronutrient supplementation has been suggested as an alternative but its effectiveness remains unsettled. We therefore conducted a randomised placebo-controlled intervention trial with 207 Tanzanian children aged 5 months to 3 years on the efficacy of supervised supplementation of low-dose micronutrients including iron (Poly Vi-Sol with iron) three times per week, with an average attendance of >/= 90%. The mean haemoglobin (Hb) level increased by 8 g/l more in children on supplement (95% CI 3-12) during the 5-month study. All age groups benefited from the intervention including severely anaemic subjects. The mean erythrocyte cell volume (MCV) increased but Hb in children >/= 24 months improved independently of MCV and no relation was found with hookworm infection. The data therefore suggest that micronutrients other than iron also contributed to Hb improvement. In the supplement group of children who had received sulfadoxine-pyrimethamine (SP) treatment, the mean Hb level increased synergistically by 22 g/l (95% CI 13-30) compared to 7 g/l (95% CI 3-10) in those without such treatment. Supplementation did not affect malaria incidence. In conclusion, micronutrient supplementation improves childhood anaemia in malaria holoendemic areas and this effect is synergistically enhanced by temporary clearance of parasitaemia.

Acute adenolymphangitis due to bancroftian filariasis in Rufiji district, south east Tanzania.

A longitudinal prospective surveillance for acute adenolymphagitis (ADL) was carried out in three villages in Rufiji district. A sample population of 3000 individuals aged 10 years and above was monitored fortnightly for a period of 12 months. The annual incidence of ADL was found to be 33 per 1000 population and was significantly higher in males than females (52.7/1000 and 18.7/1000 respectively). ADL episodes were more frequent in the age group of 40 years and above. Individuals with chronic manifestations seemed to be more vulnerable to ADL attacks with 62.2% of the total episodes occurring in this group. Furthermore, individuals with lymphoedema experienced more frequent acute episodes compared to those with hydrocele and 'normal exposed'. ADL episodes ranged from one to five per annum and the majority of the affected (60.4%) experienced a single episode. The average duration of an ADL episode was 8.6 days and in 72.5% of the episodes the affected individuals were incapacitated and unable to do their normal activities for an average duration of 3.7 days. The physical incapacitation associated with ADL episodes emphasizes the significance of lymphatic filariasis as a major public health problem of substantial socio-economic consequences.

Current clinical efficacy of chloroquine for the treatment of Plasmodium falciparum infections in urban Dar es Salaam, United Republic of Tanzania.

Reported is the use of a 14-day WHO protocol, which takes into account the clinical, parasitological and haematological responses to antimalarial drugs, to determine the efficacy of chloroquine in the treatment of uncomplicated malaria in young children (n = 200) in urban Dar es Salaam. Chloroquine failure was found in 43% of the children. Of these, 12.5% were considered to be early treatment failures and were given a single dose of sulfadoxine-pyrimethamine. Fever subsided in all children treated with sulfadoxine-pyrimethamine and there were no parasitological failures. In addition, children treated with sulfadoxine-pyrimethamine because of early treatment failure with chloroquine had better haematological recovery than the chloroquine-sensitive group. It is concluded that chloroquine can no longer be considered an effective therapy for P. falciparum malaria in young children in Dar es Salaam.

Chloroquine treatment for uncomplicated childhood malaria in an area with drug resistance: early treatment failure aggravates anaemia.

Childhood anaemia is a major public health problem in malaria holoendemic areas. We assessed the effects of antimalarial treatment in an area with drug-resistant falciparum malaria on haemoglobin levels in small children by applying the 1996 World Health Organization in vivo method for the evaluation of standard chloroquine treatment at the community level. In Fukayosi village, coastal Tanzania, 117 children aged 5-36 months with clinical malaria episodes were treated with chloroquine syrup (25 mg/kg). Early treatment failure (ETF) occurred in 20% and late treatment failure (LTF) in 22% of cases. Age > 1 year and malnutrition were protective factors against ETF. The evidence that chloroquine treatment could not prevent an exacerbation of anaemia was (i) the fact that the fall in haemoglobin level after 72 h was significantly greater in ETF than in children with LTF and an adequate clinical response, and (ii) the absence of any haematological improvement at follow-up in children receiving chloroquine alone, even in true treatment successes. In contrast, pyrimethamine/sulfadoxine administered to treatment failures improved the haemoglobin level significantly > 21 d after treatment started (mean difference 14 g/L, 95% confidence interval 2.1-27). We conclude that, when chloroquine treatment of childhood malaria is associated with a 20% ETF rate, the haemoglobin response is unsatisfactory and there is a need to change the recommended first-line treatment.

Social and cultural factors affecting rates of regular retreatment of mosquito nets with insecticide in Bagamoyo District, Tanzania.

Insecticide-treated mosquito nets have an impact on mortality and morbidity in young children under controlled conditions. When integrated into larger control programs, there is the danger that rates of regular retreatment of the nets with insecticide will drop, greatly limiting their effectiveness as a public health intervention. In Bagamoyo District, Tanzania, rates of retreatment dropped significantly when payment for the insecticide was introduced. A series of neighbourhood (hamlet) meetings were held in all study villages to discuss people's concerns about the insecticide and ways to increase rates of retreatment. Although changes were made in the procedure for retreatment, rates of retreatment remained lower than expected and showed marked variation within as well as between villages. We then conducted unstructured key informant interviews as well as informal discussions in a village with strong variation between different sectors of the villages in rates of retreatment. While logistical problems were most frequently cited as reasons not to bring nets for retreatment, political and social divisions within the community provided a better explanation. This is borne out by the low response to rearrangements in logistics which made retreating the nets significantly easier for households, and the higher response when changes were made in the channels of communication as well as the logistic features. It is clearly more difficult for villagers to appreciate the benefits of the insecticide than those of the nets. Great emphasis needs to be placed on the insecticide and its beneficial effects from the outset for any large-scale programme to be sustainable.

Community based studies on childhood mortality in a malaria holoendemic area on the Tanzanian coast.

Demographic surveillance of children under 5 years of age was undertaken over a 2 year period in a rural area of coastal Tanzania where holoendemic malaria conditions exist. The mean annual entomological innoculation rate (EIR) during the period under study was 234 infective bites per person. There were 192 deaths in children and 1130 live births during the 2 years. Of these, 148 were infant deaths giving an infant mortality rate of 131/1000 live births (95% CI 101, 154). There were 44 deaths in children 1-4 years of age and the overall child mortality rate was 10/1000 (95% CI 6.1, 14.3). Using verbal autopsy questionnaires, 56% of the deaths under 4 years were tentatively attributed to malaria.