Biomedical subjects

Nicholas J White

Publications and source records attributed to Nicholas J White.

At least 163 records · Page 9Linked to original sources

PubMed2002

The clinical significance of cerebrospinal fluid levels of kynurenine pathway metabolites and lactate in severe malaria.

A retrospective study of 261 Vietnamese adults with severe malaria was conducted to determine the relationship between cerebrospinal fluid (CSF) levels of metabolites of the kynurenine pathway, the incidence of neurologic complications, and the disease outcome. Three metabolites were measured: the excitotoxin quinolinic acid (QA); the protective receptor antagonist kynurenic acid (KA); and the proinflammatory mediator picolinic acid (PA). These measurements were related prospectively to CSF lactate levels. QA and PA levels were elevated, compared with those of controls. There was no difference in the levels of KA between these groups. Although >40% of malaria patients had QA CSF concentrations in the micromolar range, there was no association with convulsions or depth of coma. Levels of QA and PA were associated significantly with death, but a multivariate analysis suggested that these elevations were a consequence of impaired renal function. CSF lactate remained an independent and significant predictor of poor outcome.

Adolescent↗

PubMed2002

Axonal injury in cerebral malaria.

Impairment of consciousness and other signs of cerebral dysfunction are common complications of severe Plasmodium falciparum malaria. Although the majority of patients make a complete recovery a significant minority, particularly children, have sequelae. The pathological process by which P. falciparum malaria induces severe but usually reversible neurological complications has not been elucidated. Impairment of transport within nerve fibers could induce neurological dysfunction and may have the potential either to resolve or to progress to irreversible damage. Beta-amyloid precursor protein (beta-APP) immunocytochemistry, quantified using digital image analysis, was used to detect defects in axonal transport in brain sections from 54 Vietnamese cases with P. falciparum malaria. The frequency and extent of beta-APP staining were more severe in patients with cerebral malaria than in those with no clinical cerebral involvement. Beta-APP staining was often associated with hemorrhages and areas of demyelination, suggesting that multiple processes may be involved in neuronal injury. The age of focal axonal damage, as determined by the extent of the associated microglial response, varied considerably within tissue sections from individual patients. These findings suggest that axons are vulnerable to a broad range of cerebral insults that occur during P. falciparum malaria infection. Disruption in axonal transport may represent a final common pathway leading to neurological dysfunction in cerebral malaria.

Adult↗

PubMed2002

Molecular characterization of dihydrofolate reductase in relation to antifolate resistance in Plasmodium vivax.

The genes encoding the wild-type and six (five single and one double) mutant dihydrofolate reductase (DHFR) domains of the human malaria parasite, Plasmodium vivax (Pv), were cloned and expressed in Escherichia coli. The catalytic activities and the kinetic parameters of the purified recombinant wild-type and the mutant PvDHFRs were determined. Generally, all the PvDHFR mutants yielded enzymes with poorer catalytic activities when compared to the wild type enzyme. The widely used antifolates, pyrimethamine and cycloguanil, were effective inhibitors of the wild-type PvDHFR, but were approximately 60 to >4000 times less active against the mutant enzymes. In contrast to the analogous S108N mutation of Plasmodium falciparum DHFR (PfDHFR), the single S117N mutation in PvDHFR conferred approximately 4000- and approximately 1600-fold increased resistance to pyrimethamine and cycloguanil, respectively, compared to the wild-type PvDHFR. The S58R+S117N double mutant PvDHFR was 10- to 25-fold less resistant than the S117N mutant to the inhibitors, but also exhibited higher kcat/Km value than the single mutant. The antifolate WR99210 was equally effective against both the wild-type and SP21 (S58R+S117N) mutant DHFRs, but was much less effective against some of the single mutants. Data on kinetic parameters and inhibitory constant suggest that the wild-type P. vivax is susceptible to antimalarial antifolates and that point mutations in the DHFR domain of P. vivax are responsible for antifolate resistance.

Animals↗

PubMed2002

The assessment of antimalarial drug efficacy.

Antimalarial drug efficacy in uncomplicated malaria should be assessed parasitologically in large, community-based trials, enrolling the age groups most affected by clinical disease. For rapidly eliminated drugs, a 28-day follow-up is needed, but, for slowly eliminated drugs, up to nine weeks could be required to document all recrudescences, and, when possible, the drug levels should also be measured. The WHO 14-day assessments are neither sensitive nor specific. In tropical Plasmodium vivax and Plasmodium ovale infections treated with chloroquine, the first relapse is usually suppressed by residual drug levels. A relapse cannot be distinguished confidently from a recrudescence. Host immunity is a major contributor to the therapeutic response, and can make failing drugs appear effective.

Animals↗

PubMed2002

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development.

Rolling back malaria is possible. Tools are available but they are not used. Several countries deploy, as their national malaria control treatment policy, drugs that are no longer effective. New and innovative methods of vector control, diagnosis, and treatment should be developed, and work towards development of new drugs and a vaccine should receive much greater support. But the pressing need, in the face of increasing global mortality and general lack of progress in malaria control, is research into the best methods of deploying and using existing approaches, particularly insecticide-treated mosquito nets, rapid methods of diagnosis, and artemisinin-based combination treatments. Evidence on these approaches should provide national governments and international donors with the cost-benefit information that would justify much-needed increases in global support for appropriate and effective malaria control.

Animals↗

PubMed2002

Evaluation of the World Health Organization standard tourniquet test and a modified tourniquet test in the diagnosis of dengue infection in Viet Nam.

OBJECTIVES: A positive tourniquet test is one of several clinical parameters considered by the World Health Organization to be important in the diagnosis of dengue haemorrhagic fever, but no formal evaluation of the test has been undertaken. As many doctors remain unconvinced of its usefulness, this study was designed to assess the diagnostic utility of both the standard test and a commonly employed modified test. METHODS: A prospective evaluation of the standard sphygmomanometer cuff tourniquet test, compared with a simple elastic cuff tourniquet test, was carried out in 1136 children with suspected dengue infection admitted to a provincial paediatric hospital in southern Viet Nam. RESULTS: There was good agreement between independent observers for both techniques, but the sphygmomanometer method resulted in consistently greater numbers of petechiae. This standard method had a sensitivity of 41.6% for dengue infection, with a specificity of 94.4%, positive predictive value of 98.3% and negative predictive value of 17.3%. The test differentiated poorly between dengue haemorrhagic fever (45% positive) and dengue fever (38% positive). The simple elastic tourniquet was less sensitive than the sphygmomanometer cuff, but at a threshold of 10 petechiae (compared with the WHO recommendation of 20) per 2.5 cm2 the sensitivity for the elastic tourniquet rose to 45% (specificity 85%). Other evidence of bleeding was frequently present and the tourniquet test provided additional information to aid diagnosis in only 5% of cases. CONCLUSION: The conventional tourniquet test adds little to the diagnosis of dengue in hospitalized children. The simple, cheap elastic tourniquet may be useful in diagnosing dengue infection in busy rural health stations in dengue endemic areas of the tropics. A positive test should prompt close observation or early hospital referral, but a negative test does not exclude dengue infection.

Adolescent↗

PubMed2002

Seizures and raised intracranial pressure in Vietnamese patients with Japanese encephalitis.

Japanese encephalitis (JE) causes at least 10 000 deaths each year. Death is presumed to result from infection, dysfunction and destruction of neurons. There is no antiviral treatment. Seizures and raised intracranial pressure (ICP) are potentially treatable complications, but their importance in the pathophysiology of JE is unknown. Between 1994 and 1997 we prospectively studied patients with suspected CNS infections referred to an infectious disease referral hospital in Ho Chi Minh City, Vietnam. We diagnosed Japanese encephalitis virus (JEV), using antibody detection, culture of serum and CSF, and immunohistochemistry of autopsy material. We observed patients for seizures and clinical signs of brainstem herniation, measured CSF opening pressures (OP) and, on a subset of patients, performed EEGs. Of 555 patients with suspected CNS infections, 144 (26%) were infected with JEV (134 children and 10 adults). Seventeen (12%) patients died and 33 (23%) had severe sequelae. Of the 40 patients with witnessed seizures, 24 (62%) died or had severe sequelae, compared with 26 (14%) of 104 with no witnessed seizures [odds ratio (OR) 4.50, 95% confidence interval (CI) 1.94-10.52, P < 0.0001]. Patients in status epilepticus (n = 25), including 15 with subtle motor seizures, were more likely to die than those with other seizures (P = 0.003). Patients with seizures were more likely to have an elevated CSF OP (P = 0.033) and to develop brainstem signs compatible with herniation syndromes (P < 0.0001). Of 11 patients with CSF OP > or =25 cm, five (46%) died, compared with seven (9%) of 80 patients with lower pressures [OR 8.69, 95% CI 1.73-45.39, P = 0.005). Of the 50 patients with a poor outcome, 35 (70%) had signs compatible with herniation syndromes (including 19 with signs of rostro-caudal progression), compared with nine (10%) of those with better outcomes (P < 0.0001). Of 11 patients with CSF OP > or =25 cm, five (46%) died, compared with seven (9%) of 80 patients with lower pressures (OR 8.69, 95% CI 1.73-45.39, P = 0.005). The combination of coma, multiple seizures, brainstem signs and illness for 7 or more days was an accurate predictor of outcome, correctly identifying 42 (84%) of 50 patients with a poor outcome and 82 (87%) of 94 with a better outcome. These findings suggest that in JE, seizures and raised ICP may be important causes of death. The outcome may be improved by measures aimed at controlling these secondary complications.

Adolescent↗

PubMed2002

Emergence in Vietnam of Streptococcus pneumoniae resistant to multiple antimicrobial agents as a result of dissemination of the multiresistant Spain(23F)-1 clone.

Surveillance for Streptococcus pneumoniae resistant to penicillin and other antimicrobial agents is necessary to define the optimal empirical antibiotic therapy for meningitis in resource-poor countries such as Vietnam. The clinical and microbiological features of 100 patients admitted to the Centre for Tropical Diseases in Ho Chi Minh City, Vietnam, between 1993 and 2002 with invasive pneumococcal disease were studied. A penicillin-nonsusceptible pneumococcus (MIC, > or =0.1 micro g/ml) was isolated from the blood or cerebrospinal fluid of 8% of patients (2 of 24) between 1993 and 1995 but 56% (20 of 36) during 1999 to 2002 (P < 0.0001). Pneumococcal isolates resistant to penicillin (MIC, > or =2.0 micro g/ml) increased from 0% (0 of 24) to 28% (10 of 36) (P = 0.002). Only one isolate was ceftriaxone resistant (MIC, 2.0 micro g/ml). Penicillin-nonsusceptible pneumococci were isolated from 78% of children younger than 15 years (28 of 36) compared with 25% of adults (16 of 64) (P = 0.0001). Isolation of a penicillin-nonsusceptible pneumococcus in adults with meningitis was independently associated with referral from another hospital (P = 0.005) and previous antibiotic therapy (P = 0.025). Multilocus sequence typing showed that 86% of the invasive penicillin-resistant pneumococcus isolates tested (12 of 14) were of the Spain(23F)-1 clone. The serotypes of >95% of the penicillin-nonsusceptible pneumococci were included in the currently available pneumococcal vaccines. Our findings point to the recent introduction and spread of the Spain(23F)-1 clone of penicillin-resistant pneumococci in Vietnam. Simple clinical predictors can be used to guide empirical antibiotic therapy of meningitis. Pneumococcal vaccination may help to control this problem.

Adolescent↗

PubMed2002

Oral artesunate dose-response relationship in acute falciparum malaria.

The combination of an oral artemisinin derivative (usually artesunate) and mefloquine has become standard treatment for multidrug-resistant falciparum malaria in several parts of Southeast Asia. The doses of artesunate used in monotherapy and combination treatment have largely been derived empirically. In order to characterize the in vivo dose-response relationship for artesunate and thus rationalize dosing, 47 adult patients with acute uncomplicated falciparum malaria and parasitemia > or = 1% were randomized to receive a single oral dose of artesunate varying between 0 and 250 mg together with a curative dose of oral mefloquine. Acceleration of parasite clearance was used as the pharmacodynamic variable. An inhibitory sigmoidal maximum effect (Emax) pharmacodynamic model typical of a dose-response curve was fitted to the relationship between dose and shortening of parasite clearance time (PCT). The Emax was estimated as 28.6 oral h, and the 50% effective concentration was 1.6 mg/kg of body weight. These results imply that there is no reduction in PCTs with the use of single doses of artesunate higher than 2 mg/kg, and this therefore reflects the average lower limit of the maximally effective dose.

Acute Disease↗

PubMed2002

Comparison of oral artesunate and dihydroartemisinin antimalarial bioavailabilities in acute falciparum malaria.

Plasma antimalarial activity following oral artesunate or dihydroartemisinin (DHA) treatment was measured by a bioassay in 18 patients with uncomplicated falciparum malaria. The mean antimalarial activity in terms of the bioavailability of DHA relative to that of artesunate did not differ significantly from 1, suggesting that DHA can be formulated to be an acceptable oral alternative to artesunate.

Acute Disease↗

PubMed2002

Development and evaluation of rapid urinary antigen detection tests for diagnosis of penicilliosis marneffei.

Penicilliosis, caused by the dimorphic fungus Penicillium marneffei, is an important opportunistic systemic fungal infection affecting immunocompromised individuals living in areas where penicilliosis is endemic. We have demonstrated previously that a urinary enzyme-linked immunosorbent assay (ELISA) with purified rabbit polyclonal antibody against killed whole-fission-form arthroconidia of P. marneffei was specific and highly sensitive for the diagnosis of penicilliosis. In this study, a dot blot ELISA and a latex agglutination (LA) test were developed with the same polyclonal antibody and compared with the ELISA for the detection of P. marneffei urinary antigen. Urine specimens from 37 patients with culture-proven penicilliosis and 300 controls (52 healthy subjects and 248 hospitalized patients without penicilliosis) were tested. Antigen was detected in urine from all 37 (100%) penicilliosis patients by the LA test, 35 (94.6%) penicilliosis patients by the dot blot ELISA, and 36 (97.3%) penicilliosis patients by the ELISA. False-positive results were found by the three assays for 2 (0.7%), 8 (2.7%), and 6 (2%) of 300 controls, respectively. The overall sensitivities of the diagnostic tests were as follows: dot blot ELISA, 94.6%; ELISA, 97.3%; and LA test, 100% (specificities, 97.3, 98, and 99.3%, respectively). The LA test is simple, robust, rapid, and convenient and should prove to be an important addition to the existing diagnostic tests for penicilliosis.

AIDS-Related Opportunistic Infections↗

PubMed2002

Short report: hepatitis b infection and severe Plasmodium falciparum malaria in Vietnamese adults.

We investigated the prevalence of infection with hepatitis B virus among adult Vietnamese patients hospitalized for severe Plasmodiumfalciparum malaria. Sera from patients admitted with severe malaria in Ho Chi Minh City, Vietnam, between May 1991 and January 1996 were assayed for hepatitis B surface antigen (HB(s)Ag) by a commercial enzyme-linked immunosorbent assay kit. The overall prevalence of HB(s)Ag was 23.77% (77 of 324). This was higher than reported estimates of prevalence in the general catchment population for the study hospital (mean, 9.8%; range, 9-16%). No association was found between risk of death caused by severe malaria and HB(s)Ag. Patients admitted with cerebral malaria had a slightly greater risk of registering positive for HB(s)Ag (relative risk, 1.28; 95% confidence interval, 1.04-1.58) relative to other manifestations of severe malaria. Chronic infection with hepatitis B virus may be a risk factor for severe malaria.

Adolescent↗

PubMed2002

Short report: a rapid method for the differentiation of Burkholderia pseudomallei and Burkholderia thailandensis.

A rapid method for the identification and differentiation of Burkholderia pseudomallei and Burkholderia thailandensis colonies is described. It consists of simultaneous use of 2 monoclonal antibody-based latex agglutination test systems. The anti-lipopolysaccharide test reacts with both species, whereas the anti-exopolysaccharide reacts only with B. pseudomallei. Compared with classical biochemical tests, the method is highly reproducible and accurate. It is particularly useful for the identification of the organisms in environmental specimens, which may contain both of these Burkholderia species.

Agglutination Tests↗

PubMed2002

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

Intramuscular administration of high doses of artemether and arteether to experimental mammals produces selective damage to brain stem centers involved predominantly in auditory processing and vestibular reflexes. The relationship between clinical signs of neurotoxicity and neuropathologic toxicity was studied in the mouse. Intramuscular artemether (50-100 mg/kg/day for 28 days) caused dose-dependent neuropathologic damage to the brain stem. There was no pathologic evidence of neuronal death in mice receiving either oral artemether, or oral or intramuscular artesunate, in doses up to 300 mg/kg/day. The neurons in the lower brain stem trapezoid nucleus, the gigantocellular reticular nucleus, and the inferior cerebellar peduncle were the most sensitive to the toxic effects of artemether. All mice with neuropathologic changes also showed behavioral changes, whereas in some mice with gait disturbance, no corresponding histopathologic damage could be detected. Thus clinical assessment was a sensitive measure of neurotoxicity. There may be a reversible component to artemether neurotoxicity.

Animals↗

PubMed2002

Clinical and mycological responses to fluconazole and fluconazole MIC in oropharyngeal candidiasis in HIV-infected patients.

INTRODUCTION: OPC is a common opportunistic infection in HIV-infected patients. Although some patients are asymptomatic, progression of the disease may occur leading to esophageal candidiasis. Fluconazole resistant candidiasis has been reported in several international studies. OBJECTIVES: This study aimed to test the MICs (minimal inhibitory concentrations) to fluconazole of Candida species isolated from mouthwash specimens of 54 HIV positive patients with oral candidiasis. Clinical and mycological responses to fluconazole were also assessed in 16 patients. MATERIAL AND METHOD: This was a prospective study. Mouthwash specimens were cultured on sabouraud dextrose agar twice. Candida species identification was performed and MICs for fluconazole were obtained using NCCLS guidelines. Clinical and mycological responses were assessed on day 14 and 42 in 16 patients who received a 14-day course of fluconazole. RESULTS: 48/54 patients (88.89%) were found to carry pure C. albicans. The other 6 patients (11.11%) had mixed Candida species on cultures. Among these 6 patients, 5 patients had mixed C. albicans and C. glabrata, and 1 patient had C. albicans and C. krusei. Fluconazole MICs of C. albicans, C. glabrata, and C. krusei ranged from 0.125-32 (median=0.250), 4-64 (median=2), and 8 g/L respectively. This study showed that the MICs to fluconazole of oropharyngeal Candida was a good predictor of the therapeutic responses.

Adult↗

PubMedDate not supplied

Assessment of the neurotoxicity of oral dihydroartemisinin in mice.

High doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether, given by intramuscular injection to experimental mammals, produce an unusual pattern of selective damage to brainstem centres predominantly involved in auditory processing and vestibular reflexes. We have shown recently, in adult Swiss albino mice, that constant exposure either from depot intramuscular injection of oil-based artemisinin derivatives, or constant oral intake carries relatively greater neurotoxic potential than other methods of drug administration. Using the same model, oral dihydroartemisinin suspended in water was administered once or twice daily at different doses ranging from 50 to 300 mg/kg/day for 28 days. The neurotoxic potential of the oral dihydroartemisinin was assessed and compared to that of oral artemether and artesunate. Oral artemether, artesunate, and dihydroartemisinin had similar neurotoxic effects with no significant clinical or neuropathological evidence of toxicity at doses below 200 mg/kg/day. These data indicate that once and twice daily oral administration of artemether, artesunate and dihydroartemisinin is relatively safe when compared to intramuscular administration of the oil-based compounds.

Administration, Oral↗

PubMedDate not supplied

The effects of quinine and chloroquine antimalarial treatments in the first trimester of pregnancy.

Quinine (n = 246) was used to treat uncomplicated Plasmodium falciparum and chloroquine (n = 130) was used to treat P. vivax, in a total of 376 episodes of malaria in the first trimester of pregnancy, in 300 Karen women (Thailand, 1995-2000). Parasites were still present on day 6 or 7 in 4.7% (11/234) of episodes treated with quinine. The overall 28 day parasite reappearance rate following quinine was 28.7% (60/209) for primary treatments and 44% (11/25) for re-treatments. Quinine treatment resulted in a high rate of gametocyte carriage: person-gametocyte-weeks = 42.5 (95% CI 27.8-62.1) per 1000 woman-weeks. For P. vivax, the reappearance rate for all episodes by day 28 was 4.5% (5/111). Significantly more women complained of tinnitus following quinine treatment compared to on admission: 64.5% (78/121) vs 31.6% (59/187), P < 0.001. Using survival analysis, the community rate of spontaneous abortion in women who never had malaria in pregnancy, 17.8% (16.5-19.0), did not differ significantly from rates in women treated with quinine: 22.9% (95% CI 15.5-30.3), or chloroquine: 18.3% (95% CI 9.3-27.3), P = 0.42. Pregnancies exposed to quinine or chloroquine and carried to term did not have increased rates of congenital abnormality, stillbirth or low birthweight. These results suggest that therapeutic doses of quinine and chloroquine are safe to use in the first trimester of pregnancy.

Adolescent↗

PubMedDate not supplied

Artesunate-atovaquone-proguanil rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report.

Pregnant women are particularly vulnerable to malaria infections. Multidrug resistance in Plasmodium falciparum seriously compromises treatment in some endemic areas. Between April 1999 and October 2001, we treated and prospectively followed 27 Karen pregnant women with multiple recrudescent P. falciparum infections who were resistant to all other antimalarials with a triple combination of artesunate-atovaquone-proguanil. The treatment was well tolerated and we found no evidence of toxicity for the mothers and the fetus. All but 1 woman were cured (cure rate 96%, 95% CI 89-100). The triple combination of artesunate (4 mg/kg/d), atovaquone (20 mg/kg/d), and proguanil (8 mg/kg/d) may provide a much needed, albeit expensive, 3-d rescue treatment for pregnant women exposed to multidrug- resistant P. falciparum malaria.

Adolescent↗