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Biomedical subjects

N White

Publications and source records attributed to N White.

At least 19 recordsLinked to original sources
PubMed2001

Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18.

Salmonella enterica serovar Typhi (S. typhi) is the aetiological agent of typhoid fever, a serious invasive bacterial disease of humans with an annual global burden of approximately 16 million cases, leading to 600,000 fatalities. Many S. enterica serovars actively invade the mucosal surface of the intestine but are normally contained in healthy individuals by the local immune defence mechanisms. However, S. typhi has evolved the ability to spread to the deeper tissues of humans, including liver, spleen and bone marrow. Here we have sequenced the 4,809,037-base pair (bp) genome of a S. typhi (CT18) that is resistant to multiple drugs, revealing the presence of hundreds of insertions and deletions compared with the Escherichia coli genome, ranging in size from single genes to large islands. Notably, the genome sequence identifies over two hundred pseudogenes, several corresponding to genes that are known to contribute to virulence in Salmonella typhimurium. This genetic degradation may contribute to the human-restricted host range for S. typhi. CT18 harbours a 218,150-bp multiple-drug-resistance incH1 plasmid (pHCM1), and a 106,516-bp cryptic plasmid (pHCM2), which shows recent common ancestry with a virulence plasmid of Yersinia pestis.

Chromosome Mapping↗
PubMed2001

Drugs for neglected diseases: a failure of the market and a public health failure?

Infectious diseases cause the suffering of hundreds of millions of people, especially in tropical and subtropical areas. Effective, affordable and easy-to-use medicines to fight these diseases are nearly absent. Although science and technology are sufficiently advanced to provide the necessary medicines, very few new drugs are being developed. However, drug discovery is not the major bottleneck. Today's R&D-based pharmaceutical industry is reluctant to invest in the development of drugs to treat the major diseases of the poor, because return on investment cannot be guaranteed. With national and international politics supporting a free market-based world order, financial opportunities rather than global health needs guide the direction of new drug development. Can we accept that the dearth of effective drugs for diseases that mainly affect the poor is simply the sad but inevitable consequence of a global market economy? Or is it a massive public health failure, and a failure to direct economic development for the benefit of society? An urgent reorientation of priorities in drug development and health policy is needed. The pharmaceutical industry must contribute to this effort, but national and international policies need to direct the global economy to address the true health needs of society. This requires political will, a strong commitment to prioritize health considerations over economic interests, and the enforcement of regulations and other mechanisms to stimulate essential drug development. New and creative strategies involving both the public and the private sector are needed to ensure that affordable medicines for today's neglected diseases are developed. Priority action areas include advocating an essential medicines R&D agenda, capacity-building in and technology transfer to developing countries, elaborating an adapted legal and regulatory framework, prioritizing funding for essential drug development and securing availability, accessibility, distribution and rational use of these drugs.

Communicable Diseases, Emerging↗
PubMed2001

Occupational respiratory diseases in South Africa--results from SORDSA, 1997-1999.

OBJECTIVES: To describe the nature and extent of work-related respiratory diseases reported to the national Surveillance of Work-related and Occupational Respiratory Diseases in South Africa (SORDSA) reporting scheme. The causative agents and industrial categories in which they occurred are also characterised. DESIGN: Voluntary monthly reporting of newly diagnosed cases by pulmonologists, occupational medicine practitioners and occupational health nurses. SETTING: Medical and occupational health referral centres in the nine provinces of South Africa. SUBJECTS: Cases were workers from non-mining industries or ex-miners, suffering from a newly diagnosed occupational respiratory disease, reported to SORDSA between October 1996 and December 1999. OUTCOME MEASURES: Frequencies of reported occupational respiratory disease by year, reporting source, province and sex. Frequencies of short- and long-latency diseases by industry and causative agent. RESULTS: There was incomplete reporting coverage of the nine provinces in the first 3 years. Reporting was most comprehensive from Gauteng, KwaZulu-Natal and the Western Cape. Diseases with long latency periods made up 76.2% of the cases. Pneumoconiosis, even in non-mining industries, was the most frequently reported disease, followed by inhalation accidents. Occupational asthma was the fourth most reported disease. Apart from the prominence of pneumoconiosis, the results obtained by SORDSA are similar to those from a British occupational lung disease surveillance scheme. This study showed that newly diagnosed cases of occupational lung disease occurred in many industries and were caused by a variety of agents. CONCLUSION: SORDSA has contributed insight into the nature, extent and distribution of occupational respiratory diseases in South Africa. It has also highlighted important causes of occupational respiratory diseases in South Africa, as well as hazardous industries. The data indicate that South Africa has a widespread occupational lung disease problem, and provide a platform for targeted prevention strategies.

Accidents, Occupational↗
PubMed2000

Hypoglycemia in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with macrosomia, macroglossia, abdominal wall defects, hypoglycemia in the neonatal period and embryonal cancers of infancy and early childhood. The frequency of hypoglycemia in this population is between 30% and 50%. The majority of infants with hypoglycemia will be asymptomatic and have resolution of the hypoglycemia within the first 3 days of life. Less than 5% will have hypoglycemia beyond the neonatal period requiring either continuous feeding or a partial pancreatectomy. The cause of hypoglycemia is unclear, but direct and indirect evidence supports a hyperinsulinemia as the major factor. Recent identification of the majority of genes associated with BWS in the 11p15 region and the genotype of persistent hyperinsulinemia hypoglycemia of childhood also in the 11p15 region may provide a molecular basis for hypoglycemia in BWS, particularly for the occasional patients with hypoglycemia requiring a partial pancreatectomy. Detailed genotype phenotype evaluations are needed and should provide an insight as to why patients with BWS have hypoglycemia.

Beckwith-Wiedemann Syndrome↗
PubMed2000

The influence of the composition of the nursing staff on primary bloodstream infection rates in a surgical intensive care unit.

OBJECTIVES: To determine the risk factors for acquisition of nosocomial primary bloodstream infections (BSIs), including the effect of nursing-staff levels, in surgical intensive care unit (SICU) patients. DESIGN: A nested case-control study. SETTING: A 20-bed SICU in a 1,000-bed inner-city public hospital. PATIENTS: 28 patients with BSI (case-patients) were compared to 99 randomly selected patients (controls) hospitalized > or =3 days in the same unit. RESULTS: Case- and control-patients were similar in age, severity of illness, and type of central venous catheter (CVC) used. Case-patients were significantly more likely than controls to be hospitalized during a 5-month period that had lower regular-nurse-to-patient and higher pool-nurse-to-patient ratios than during an 8-month reference period; to be in the SICU for a longer period of time; to be mechanically ventilated longer; to receive more antimicrobials and total parenteral nutrition; to have more CVC days; or to die. Case-patients had significantly lower regular-nurse-to-patient and higher pool-nurse-to-patient ratios for the 3 days before BSI than controls. In multivariate analyses, admission during a period of higher pool-nurse-to-patient ratio (odds ratio [OR]=3.8), total parenteral nutrition (OR=1.3), and CVC days (OR=1.1) remained independent BSI risk factors. CONCLUSIONS: Our data suggest that, in addition to other factors, nurse staffing composition (ie, pool-nurse-to-patient ratio) may be related to primary BSI risk. Patterns in intensive care unit nurse staffing should be monitored to assess their impact on nosocomial infection rates. This may be particularly important in an era of cost containment and healthcare reform.

Case-Control Studies↗
PubMed2000

Facial paralysis secondary to acute otitis media.

We describe a case of facial paralysis in a 19-month-old male recently diagnosed with acute otitis media. Results of his physical examination was remarkable for left-sided peripheral facial nerve palsy with an associated middle ear infection. Physicians should understand the etiology, pathophysiology, treatment options, and prognosis of facial palsy in association with otitis media.

Acute Disease↗
PubMed2000

Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria.

The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (P < or = 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunate-associated antimalarial activity.

Administration, Oral↗
PubMed2000

Cerebral malaria.

Cerebral malaria may be the most common non-traumatic encephalopathy in the world. The pathogenesis is heterogeneous and the neurological complications are often part of a multisystem dysfunction. The clinical presentation and pathophysiology differs between adults and children. Recent studies have elucidated the molecular mechanisms of pathogenesis and raised possible interventions. Antimalarial drugs, however, remain the only intervention that unequivocally affects outcome, although increasing resistance to the established antimalarial drugs is of grave concern. Artemisinin derivatives have made an impact on treatment, but other drugs may be required. With appropriate antimalarial drugs, the prognosis of cerebral malaria often depends on the management of other complications-for example, renal failure and acidosis. Neurological sequelae are increasingly recognised, but further research on the pathogenesis of coma and neurological damage is required to develop other ancillary treatments.

Adult↗
PubMed1999

Antimalarial drug resistance and combination chemotherapy.

Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10,000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.

Animals↗
PubMed1999

Epizootiology of Chlamydia infections in two free-range koala populations.

The prevalence of Chlamydia pecorum and Chlamydia pneumoniae infections in two free-range koala populations was assessed using genus-specific PCR combined with species-specific DNA probe hybridisation. Population A had a very high overall level of chlamydial infection (85%) with significantly more of these infections being due to C. pecorum (73%) compared to C. pneumoniae (24%). The second population had a much lower prevalence of infection (10%) with equal levels of both species. An important finding of this study was that. while five of 24 C. pecorum-infected koalas had clinical signs of the disease (both ocular and urogenital sites), none out of seven C. pneumoniae-infected koalas had signs of clinical disease. This suggests that C. pecorum may be the more pathogenic of the two chlamydial species infecting this host. The level of infection (assessed by intensity of the specific hybridisation signal) also differed between chlamydial species, with C. pecorum infections ranging from low to high grade whereas C. pneumoniae infections were always low grade. When the age of infected koalas was examined, 58% of young, sexually immature koalas were found to have C. pecorum infections, increasing to 100% of koalas in the older age groups. This suggests that, in this population at least, young koalas are readily infected with C. pecorum from their mothers. While the infection levels with C. pneumoniae were too low to be statistically significant, again, sexually immature koalas were found to be infected. The recent separation of chlamydial infections in koalas into two species is beginning to indicate different epizootiologies for koala C. pecorum compared to koala C. pneumoniae.

Age Factors↗
PubMed1999

Evidence of blood-brain barrier dysfunction in human cerebral malaria.

Patients infected with the malaria parasite Plasmodium falciparum may develop a diffuse reversible encephalopathy, termed cerebral malaria. It is unclear how the intraerythrocytic parasite, which sequesters in the cerebral microvasculature but does not enter the brain parenchyma, induces this neurological syndrome. Adhesion of parasitized red blood cells in the brain microvasculature is mediated by specific receptors on the host endothelium, including intercellular adhesion molecule (ICAM)-1, CD36 and CD31. Leucocyte binding to cerebral endothelial cells in culture induces intracellular signalling via ICAM-1. The hypothesis that parasitized red blood cells binding to receptors on cerebral endothelial cells causes changes in the integrity of the blood-brain barrier was tested. Immunohistochemistry was used to examine the blood-brain barrier in human cerebral malaria, with antibodies to macrophage and endothelial activation markers, intercellular junction proteins, and plasma proteins. The distribution of the cell junction proteins occludin, vinculin and ZO-1 were altered in cerebral malaria cases compared to controls. While fibrinogen was the only plasma protein detected in the perivascular space, there was widespread perivascular macrophage activation, suggesting that these cells had been exposed to plasma proteins. It was concluded that functional changes to the blood-brain barrier occur in cerebral malaria, possibly as a result of the binding of parasitized red blood cells to cerebral endothelial cells. These changes require further examination in vitro.

Adolescent↗
PubMed1999

Serum markers for Down's syndrome in women who have had in vitro fertilisation: implications for antenatal screening.

To examine the Down's syndrome screening positive rate among in vitro fertilisation (IVF) pregnancies, we measured second trimester serum marker levels in singleton IVF pregnancies (cases) and in five non-IVF pregnancies (controls) matched to each case for gestational age, age of mother, and duration of storage of the serum sample. There were 151 IVF pregnancies in which alpha fetoprotein, unconjugated oestriol (uE3), free beta-human chorionic gonadotrophin (hCG) and total hCG were measured, 104 IVF pregnancies in which free alpha-hCG was measured, and 39 IVF pregnancies in which inhibin A was measured. Median uE3 levels were 6% lower (P = 0.003), median free beta-hCG 9% higher (P = 0.024), and median total hCG 14% higher (P = 0.026) in IVF pregnancies compared with controls. The screen positive rate in the IVF pregnancies (28%) was about twice as high as that in controls (17%). High hCG levels may be explained by progesterone remaining high in IVF pregnancies. The low uE3 levels remain unexplained. In Down's syndrome screening in IVF pregnancies hCG and uE3 values should be adjusted to avoid the high screen positive rate.

Biomarkers↗
PubMed1999

Long-term respiratory health effects of the herbicide, paraquat, among workers in the Western Cape.

OBJECTIVE: To evaluate the possible effects of paraquat spraying among workers on deciduous fruit farms in the Western Cape, South Africa. Paraquat is a commonly used herbicide world wide and is a well documented cause of pulmonary fibrosis in studies of laboratory animals and in humans after exposure to a high dose (usually accidental or as parasuicide). The respiratory effects of long term, low dose exposure to paraquat have not been fully evaluated. METHODS: A cross sectional study of 126 workers. Administered questionnaires generated information on exposure, respiratory symptoms, and potential confounding variables. Spirometry and gas transfer were measured and chest radiographs performed. Oxygen desaturation on exercise testing was by oximetry during a modified stage one exercise test. RESULTS: No association was found between long term exposure to paraquat and reported symptoms, spirometry (forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC) and gas transfer (TLCO and KCO) or chest radiography. Multivariate analysis showed a significant relation between measures of long term exposure to paraquat and arterial oxygen desaturation during exercise independent of short term exposure. CONCLUSION: Previous studies have not shown a significant relation between measures of exposure to paraquat and standard tests of lung function. Arterial oxygen desaturation during exercise represents a more sensitive test. The findings indicate that working with paraquat under usual field conditions is associated with abnormal exercise physiology in a dose dependent fashion independent of recent exposure and acute poisoning events.

Adult↗
PubMed1999

Malaria: new developments in treatment and prevention.

Malaria still kills some 0.5-2.5 million people per year in the tropics. Resistance to the cheap, most commonly used antimalarials continues to spread alarmingly and could outpace drug development. The artemisinin derivatives have had an important clinical impact both on the treatment of resistant falciparum malaria and on the incidence of disease in low-transmission areas. A few promising new antimalarials are being tested clinically but there is an imperative need for cheap, well-tolerated drugs that can be used in short courses, and for strategies to delay the onset of drug resistance. Bed nets have been shown to reduce the incidence of severe malaria in many areas but an effective vaccine is urgently needed.

Antimalarials↗