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Biomedical subjects

M Molyneux

Publications and source records attributed to M Molyneux.

18 recordsLinked to original sources
PubMed2006

Randomised trial of vitamin A supplementation in pregnant women in rural Malawi found to be anaemic on screening by HemoCue.

OBJECTIVE: To assess the effects of vitamin A supplementation in women with anaemia during pregnancy. DESIGN: Single-centre randomised controlled trial. SETTING: Rural community in southern Malawi, central Africa. POPULATION: Seven hundred women with singleton pregnancies at 12-24 weeks measured by ultrasound scan and with haemoglobin <11.0 g/dl by HemoCue screening method. Analysis was by intention to treat. All received iron and folate, and sulphadoxine/pyrimethamine for antimalarial prophylaxis. METHODS: Women were randomised to receive oral supplementation with daily 5000 or 10,000 iu vitamin A, or placebo. MAIN OUTCOME MEASURES: Anaemia, as assessed by Coulter counter, severe anaemia, iron status and indices of infection. RESULTS: Vitamin A deficiency was, in this rural population, less common than predicted. Vitamin A supplementation had no significant impact on anaemia, severe anaemia, iron status and indices of infection. Vitamin A stores were less likely to be depleted at the end of pregnancy in supplemented groups. CONCLUSIONS: Vitamin A supplementation programmes to reduce anaemia should not be implemented in similar antenatal populations in rural sub-Saharan Africa unless evidence emerges of positive benefit on substantive clinical outcomes. Introducing public health interventions of unknown benefit and with unclear biological mechanisms can divert scarce resources from clinical and social interventions more likely to impact maternal mortality.

Administration, Oral↗
PubMed2001

Salicylates, nitric oxide, malaria, and Reye's syndrome.

Reye's syndrome virtually disappeared from much of the world after the use of salicylate in febrile children was successfully discouraged. This severe sepsis-like disease was thought to be caused by a hypersensitivity to salicylates in children with mild viral infections, although no mechanism consistent with this proposal was ever established. Salicylate toxicity in African children has been noted to have many clinical features in common with severe falciparum malaria, including acidosis, altered consciousness, convulsions, and hypoglycaemia. Salicylates are widely available in various formulations in many African countries, and are commonly used for initial treatment of the symptoms that malaria shares with other diseases. There is now experimental evidence that salicylate increases and prolongs the activity of key elements along the signalling pathway through which interferon gamma generates inducible nitric oxide synthase (iNOS), and we have shown that iNOS is strongly expressed in fatal malaria and other acute fevers in African children. We further propose that, in areas where salicyaltes are still used to treat the symptoms of febrile illnesses in children, this mechanism could exacerbate potentially serious infectious diseases, including falciparum malaria. In contrast, the absence of salicylate use in children in some Pacific islands could contribute to the milder outcome of falciparum malaria than is observed in Africa. Widespread expression of iNOS has also been seen in the tissues of a patient with fatal clinically defined Reye's syndrome. This finding suggests that Reye's syndrome can be mediated through salicylate enhancement of iNOS expression, the initial trigger in this instance usually being a viral infection.

Africa↗
PubMed2001

Nucleotide diversity of the TNF gene region in an African village.

The wide variety of disease associations reported at the TNF locus raises the question of how much variation exists within a single population. To address this question, we sequenced the entire TNF gene in 72 chromosomes from healthy residents of a village in The Gambia, West Africa. We found 12 polymorphisms in 4393 nucleotides, of which five have not been previously described, giving an estimated nucleotide diversity (theta) of 5.6 x 10(-4). A significantly higher frequency of polymorphisms was found in the promoter region than in the coding region (8/1256 vs 0/882 nucleotides, P = 0.02). All polymorphisms with the exception of one rare allele were found to be present in Malawi, which is both geographically and genetically distant from The Gambia. Genotyping of 424 Gambian and 121 Malawian adults showed a significant frequency difference between the two populations for eight of the 12 polymorphisms, but the average fixation index across the variable sites was relatively low (F(ST) = 0.007). We conclude that, at the TNF locus, the nucleotide diversity found within a single African village is similar to the global value for human autosomal genes sampled across different continents.

Adolescent↗
PubMed2000

Molecular approaches to epidemiology and clinical aspects of malaria.

Malaria is a problem of global importance, responsible for 1-2 million deaths per year, mainly in African children, as well as considerable morbidity manifested as severe anaemia and encephalopathy in young children. Fundamental to the development of new tools for malaria control in humans is an increased understanding of key features of malaria infection, such as the diversity of outcome in different individuals, the understanding of different manifestations of the disease and of the mechanisms of immunity that allow clinical protection in the face of ongoing low-grade infection (concomitant immunity or premunition). Here, Graham Brown and colleagues review some of the ways in which molecular approaches might be used to increase our understanding of the epidemiology and clinical manifestations of malaria, as discussed at the Molecular Approaches to Malaria conference (MAM2000), Lorne, Australia, 2-5 February 2000.

Animals↗
PubMed1999

Cytokine expression in the brain in human cerebral malaria.

Evidence from clinical studies and murine models supports a role for cytokines in the pathogenesis of human cerebral malaria (CM). In this study, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to investigate expression of mRNA for transforming growth factor (TGF)-beta, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha in human postmortem tissue. Immunohistochemistry was used to examine the distribution of cytokine protein. TGF-beta was expressed in normal brain, in CM, and in meningitis and encephalitis. IL-1beta was absent from normal brain but was detected in CM and other cerebral infections. TNF-alpha mRNA was expressed only in CM, although TNF-alpha protein was also seen in meningitis. Cytokine mRNA expression in the brain did not correlate with the density of parasitized erythrocytes detected using RT-PCR for major surface protein-2. This report of RT-PCR on postmortem human tissues infected with CM demonstrates induction of the proinflammatory cytokines TNF-alpha and IL-1beta in the brain.

Antigens, Protozoan↗
PubMed1998

Acute bacterial meningitis in children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi in 1996-97.

To design appropriate interventions, we collected clinical and demographic data prospectively on all children aged one day to 14 years admitted with a diagnosis of bacterial meningitis (BM) from April 1st 1996 to March 31st 1997 to the Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi. During the study period 267 children (2.7% of all paediatric admissions) were found to have BM; 83% were under 5 years of age, 61% under one year and 23% under one month. The most common causative organisms in the post neonatal period (n=206) were Streptococcus pneumoniae (27%), Haemophilus influenzae type b (Hib) 21%, and Salmonella typhimurium (6%). In the neonatal group (< 1 month, n=61) the most common causes were Streptococcus agalactiae (23%), S. typhimurium (15%), S. pneumoniae (11.5%) and other Gram negative rods (11.5%). Nineteen of 21 salmonella infections were in children under one year of age and all S. agalactiae were in infants under three months. There was delay on presentation: the average length of fever was 4.6 days, 39.5% had convulsed prior to arrival and 57% had an altered level of consciousness. An initial diagnosis of malaria had probably contributed to the delay in 22.5% (42 of 186 tested). 48% were < 80% weight for age, with 18% < 60%) weight for age. The overall mortality was 40%. The outcome was worst in salmonella infections, particularly neonatal salmonella BM with a case fatality rate (CFR) of 89% (8 of 9 cases). Coma on presentation worsened prognosis (mortality 64% if Blantyre Coma Score < 3, 26% if > 3). 15% of survivors had sequelae on discharge. 20% of Hib isolates were resistant to chloramphenicol, but all salmonellae were sensitive. 5% of S. pneumoniae were resistant to penicillin and 8% to chloramphenicol. Earlier access to adequate health care and awareness of BM in a malaria-endemic area would reduce mortality and morbidity. Vaccination against Hib infection would have reduced death by 18 (17%) and prevented sequelae in 7 cases.

Acute Disease↗
PubMed1992

Ethical dilemmas in malaria drug and vaccine trials: a bioethical perspective.

Malaria is a disease of developing countries whose local health services do not have the time, resources or personnel to mount studies of drugs or vaccines without the collaboration and technology of western investigators. This investigative collaboration requires a unique bridging of cultural differences with respect to human investigation. The following debate, sponsored by The Institute of Medicine and The American Society of Tropical Medicine and Hygiene, raises questions concerning the conduct of trans-cultural clinical malaria research. Specific questions are raised about the difficulties of informed consent in different cultural settings and whether there is any role for community involvement. Discussants debate whether drug and vaccine trials not approved in an industrialised country are ever defensible if performed in a third-world setting. Potential conflicting priorities between investigators are discussed and ideas regarding conflict resolution are offered.

Antimalarials↗
PubMed1990

Viral gastro-enteritis in children in Malawi.

In a 2-month survey of 186 children with gastro-enteritis attending an out-patient clinic in Malawi, 42% were infected with rotavirus (HRV), 9% Cryptosporidium, 4.2% adenovirus, 1.2% Astrovirus and 0.6% Norwalk agent and small round featureless viruses. We believe this to be the first report of HRV in Malawi and the first of Astrovirus in Africa. Almost all the HRV infections were in children under 12 months old, 40% were in children under 6 months and 64% of children were being breastfed at presentation. Signs of respiratory tract infection were not unique to HRV gastro-enteritis. Polyacrylamide gel electrophoresis of HRV dsRNA from 25 of the faecal samples revealed that each had the same long electropherotype.

Adenoviridae Infections↗
PubMed1988

C-reactive protein and bacterial meningitis.

We have studied prospectively the C-reactive protein values in the cerebrospinal fluid of 54 patients with bacterial meningitis, tuberculous meningitis, and severe malarial infection and convulsions without infections of the central nervous system. CSF CRP above 1 mg/l was observed in 23 out of 28 patients with bacterial meningitis (sensitivity of 82%). The specificity was 73% at the 1 mg/l level. Five out of 19 patients with severe malarial infection had CSF CRP levels above 1 mg/l. Two patients with TB meningitis were also studied. Both of them had CSF CRP above 1 mg/l. Five patients with febrile convulsions or sepsis without meningitis had CSF CRP below 1 mg/l. It is concluded that CSF CRP would not be used as a useful discriminatory test in areas where malaria and TB meningitis are common.

C-Reactive Protein↗
PubMed1975

Delayed hypersensitivity to influenza virus in man.

Delayed hypersensitivity to influenza antigen has been demonstrated in man by means of skin tests and 'in vitro' lymphocyte transformation. Adjuvanted influenza vaccine enhances this response, in contrast to non-adjuvanted vaccine in commercial use.

Antibodies, Viral↗
PubMedDate not supplied

Blood-brain barrier function in cerebral malaria in Malawian children.

Cerebral malaria (CM) is a serious complication of Plasmodium falciparum infection. Binding of parasitized erythrocytes to cerebral endothelium plays a key role in disease pathogenesis. Central nervous system signs and symptoms (coma, seizures, raised intracranial pressure) predominate in African children, whereas in adults, multiorgan system failure is more common. In this study we investigated whether changes in blood-brain barrier (BBB) structure and function are compatible with the signs and symptoms observed in Malawian children with CM. Immunohistochemistry on autopsy brain tissues from eight cases of CM showed activation of endothelial cells and macrophages, and disruption of endothelial intercellular junctions in vessels containing sequestered parasitized erythrocytes, but no gross leakage of plasma proteins. Examination of the partition of albumin between circulating plasma and the cerebrospinal fluid from 72 cases of CM showed subtle but measurable changes compatible with impaired BBB function in malaria. These findings suggest that BBB breakdown occurs in areas of parasite sequestration in CM in African children.

Antigens, CD↗