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Biomedical subjects

J A Simpson

Publications and source records attributed to J A Simpson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Parasite multiplication potential and the severity of Falciparum malaria.

The multiplication rates and invasiveness of Plasmodium falciparum parasites isolated from adult Thai patients hospitalized with uncomplicated malaria (n=34) were compared with those from persons with severe malaria (n=42). To simulate severe malaria and control for host effects, the in vitro cultures were adjusted to 1% parasitemia and used the same red blood cell donor. P. falciparum isolates from persons with severe malaria had initial cycle multiplication rates in vitro that were 3-fold higher than those from uncomplicated malaria (median [95% confidence interval], 8.3 [7. 1-10.5] vs. 2.8 [1.7-3.9]; P=.001). Parasites causing severe malaria exhibited unrestricted red blood cell invasion, whereas those from uncomplicated malaria were restricted to a geometric mean of 40 (31%-53%) of red blood cells. P. falciparum parasites causing severe malaria were less selective and multiplied more at high parasitemias than those causing uncomplicated malaria.

Animals↗
PubMed2000

HSE performance tests for dosimetry services.

In the United Kingdom a dosimetry service that measures and assesses whole-body or part-body doses arising from external radiation must successfully complete a performance test. Results of the performance tests for routine whole-body, routine extremity/skin and special accident dosimetry, carried out over the past six years by the AEA Technology Calibration Service at Winfrith, and DRaStaC, the AWE Calibration Service at Aldermaston, are presented. The test involves irradiating groups of dosemeters to known doses of gamma radiation and determining the bias and relative standard deviations for each dose group. The results are compared with the pass criteria specified by the UK Health and Safety Executive. For routine whole-body dosimetry, both the film badge and thermoluminescent dosemeter (TLD) perform adequately for irradiations between 0.6 and 30 mSv. For higher doses up to 250 mSv, where the slow emulsion of the film is used, the film badge shows poorer performance with a tendency to overestimate the dose. For routine extremity/skin dosimetry there is a wider spread of relative standard deviation results than is seen for routine whole-body dosimetry. This is to be expected since the results will include dosemeters that are based on 'disposable' TLDs and ones based on lithium fluoride powder in sachets. For special accident dosimetry the dosemeters are tested between 0.26 and 6 Gy. For the highest dose group the film badge invariably underestimates the true dose, whereas the TLD has a tendency to overestimate it.

Information Services↗
PubMed2000

Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance.

Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response </=28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.

Antimalarials↗
PubMed2000

A double-blind placebo-controlled study of an infusion of lexipafant (Platelet-activating factor receptor antagonist) in patients with severe sepsis.

Platelet-activating factor (PAF) is a potent endogenous proinflammatory mediator implicated in the pathogenesis of septic shock. A double-blind randomized placebo-controlled trial of an intravenous PAF receptor antagonist (lexipafant) was conducted with 131 adult Thai patients with suspected severe sepsis (66 of whom had positive blood cultures). Detailed serial clinical, biochemical, and cytokine measurements were performed. Lexipafant treatment was well tolerated. The 28-day mortality in the lexipafant group (61.4%) was similar to that in the placebo group (62.6%). There was also no evidence that lexipafant affected clinical or biochemical measures of disease severity or the profile of sequentially measured plasma cytokine levels. PAF may not have an important role in the pathogenesis of severe sepsis.

Bacterial Infections↗
PubMed2000

Therapeutic responses to different antimalarial drugs in vivax malaria.

The therapeutic responses to the eight most widely used antimalarial drugs were assessed in 207 adult patients with Plasmodium vivax malaria. This parasite does not cause marked sequestration, so parasite clearance can be used as a direct measure of antimalarial activity. The activities of these drugs in descending order were artesunate, artemether, chloroquine, mefloquine, quinine, halofantrine, primaquine, and pyrimethamine-sulfadoxine (PS). Therapeutic responses to PS were poor; parasitemias did not clear in 5 of the 12 PS-treated patients, whereas all the other patients made an initial recovery. Of 166 patients monitored for > or =28 days, 35% had reappearance of vivax malaria 11 to 65 days later and 7% developed falciparum malaria 5 to 21 days after the start of treatment. There were no significant differences in the times taken for vivax malaria reappearance among the different groups except for those given mefloquine and chloroquine, in which all vivax malaria reappearances developed >28 days after treatment, suggesting suppression of the first relapse by these slowly eliminated drugs. There was no evidence of chloroquine resistance. The antimalarial drugs vary considerably in their intrinsic activities and stage specificities of action.

Adult↗
PubMed2000

Hypoxemia-induced modification of troponin I and T in canine diaphragm.

Impaired muscle function (fatigue) may result, in part, from modification of contractile proteins due to inadequate O(2) delivery. We hypothesized that severe hypoxemia would modify skeletal troponin I (TnI) and T (TnT), two regulatory contractile proteins, in respiratory muscles. Severe isocapnic hypoxemia (arterial partial pressure of O(2) of approximately 25 Torr) in six pentobarbital sodium-anesthetized spontaneously breathing dogs increased respiratory frequency and electromyographic activity of the diaphragm and internal and external obliques, with death occurring after 131-285 min. Western blot analysis revealed proteolysis of TnI and TnT, 17.5- and 28-kDa fragments, respectively, and higher molecular mass covalent complexes, one of which (42 kDa) contained TnI (or some fragment of it) and probably TnT in the costal and crural diaphragms but not the intercostal or abdominal muscles. These modifications of myofibrillar proteins may provide a molecular basis for contractile dysfunction, including respiratory failure, under conditions of limited O(2) delivery.

Animals↗
PubMed2000

A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria.

The artemisinin derivatives are now used widely in areas with multidrug-resistant Plasmodium falciparum malaria such as Southeast Asia, but concerns remain over their potential for neurotoxicity. Mice, rats, dogs, and monkeys treated with high doses of intramuscular artemether or arteether develop an unusual pattern of focal damage to brain stem nuclei (particularly those involved in auditory processing). To investigate whether a similar toxic effect occurs in patients treated with these compounds, clinical neurologic evaluation, audiometry and early latency auditory evoked responses were measured in a single-blind comparison of 79 patients who had been treated with > or =2 courses of oral artemether or artesunate within the previous 3 years, and 79 age- and sex-matched controls living in a malaria-endemic area on the northwestern border of Thailand. There were no consistent differences in any of these test results between the cases and controls. This study failed to detect any evidence of significant neurotoxicity in patients treated previously with oral artemether or artesunate for acute malaria.

Adolescent↗
PubMed2000

Comparison of analytical methods for cluster randomised trials: an example from a primary care setting.

BACKGROUND: Cluster randomisation is commonly used to evaluate educational and organisational interventions in primary care. We conducted a study where 66 general practices in the North East of Scotland were randomised to receive guidelines and access to a fast-track investigation service for two common urological conditions. Patients were identified from referral letters and recruited upon referral to secondary care. Although these urological conditions are common in secondary care, the number of referrals per general practice can be small; this created a number of issues for the analysis. METHODS: Three general approaches in the analysis of cluster randomised trials; the adjustment of standard tests; analysis at cluster level; and advanced statistical techniques (random effects models and generalised estimating equations) were applied to data from the above trial. The effect of the intervention on both a continuous and a dichotomous outcome was investigated. RESULTS: Spuriously low P values were obtained when conventional tests (which do not account for clustering in the data) were applied. Cluster level analysis of the dichotomous outcome with no account for cluster size resulted in a different conclusion compared with cluster level analysis with weighting, standard tests with adjustment and advanced statistical methods. DISCUSSION: Cluster randomised trials are becoming increasingly common in primary care. Where recruitment of individual patients is generated by referral from primary to secondary care it is likely that the trial will suffer from inherent weaknesses: not all clusters randomised contribute to the analysis; there is the likelihood of single size clusters and variable cluster sizes. Our analysis indicated that the different approaches produced consistent results across continuous outcomes, but for dichotomous outcomes in the cluster level analysis, failure to weight observations would have resulted in a different conclusion.

Cluster Analysis↗
PubMed1999

Effects of Plasmodium vivax malaria in pregnancy.

BACKGROUND: Plasmodium vivax is more common than P. falciparum as a cause of malaria in many parts of the tropics outside Africa. P. falciparum infection has harmful effects in pregnancy, but the effects of P. vivax have not been characterised. We investigated the effects of P. vivax infection during pregnancy. METHODS: Since 1986, pregnant Karen women living in camps for displaced people on the western border of Thailand have been encouraged to attend antenatal clinics. Karen women were screened for malaria and anaemia at each week of pregnancy until delivery, and pregnancy outcome recorded. We compared the effects of P. vivax infection on anaemia and pregnancy outcome with those of P. falciparum and no malaria infection in the first pregnancy recorded at the antenatal clinics. FINDINGS: There were 634 first episodes of pure P. vivax malaria in 9956 women. P. vivax malaria was more common in primigravidae than in multigravidae and was associated with mild anaemia and an increased risk of low birthweight (odds ratio 1.64 [95% CI 1.29-2.08], p<0.001). The birthweight was a mean of 107 g (95% CI 61-154) lower in women with P. vivax infection than in uninfected women. By contrast with P. falciparum malaria, the decrease in birthweight was greater in multigravidae. P. vivax malaria was not associated with miscarriage, stillbirth, or with a shortened duration of pregnancy. INTERPRETATION: P. vivax malaria during pregnancy is associated with maternal anaemia and low birthweight. The effects of P. vivax infection are less striking than those of P. falciparum infection, but antimalarial prophylaxis against P. vivax in pregnancy may be justified.

Adult↗
PubMed1999

A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain.

Microvascular sequestration was assessed in the brains of 50 Thai and Vietnamese patients who died from severe malaria (Plasmodium falciparum, 49; P. vivax, 1). Malaria parasites were sequestered in 46 cases; in 3 intravascular malaria pigment but no parasites were evident; and in the P. vivax case there was no sequestration. Cerebrovascular endothelial expression of the putative cytoadherence receptors ICAM-1, VCAM-1, E-selectin, and chondroitin sulfate and also HLA class II was increased. The median (range) ratio of cerebral to peripheral blood parasitemia was 40 (1.8 to 1500). Within the same brain different vessels had discrete but different populations of parasites, indicating that the adhesion characteristics of cerebrovascular endothelium change asynchronously during malaria and also that significant recirculation of parasitized erythrocytes following sequestration is unlikely. The median (range) ratio of schizonts to trophozoites (0.15:1; 0.0 to 11.7) was significantly lower than predicted from the parasite life cycle (P < 0.001). Antimalarial treatment arrests development at the trophozoite stages which remain sequestered in the brain. There were significantly more ring form parasites (age < 26 hours) in the cerebral microvasculature (median range: 19%; 0-90%) than expected from free mixing of these cells in the systemic circulation (median range ring parasitemia: 1.8%; 0-36.2%). All developmental stages of P. falciparum are sequestered in the brain in severe malaria.

Adolescent↗
PubMed1999

Population pharmacokinetics of mefloquine in patients with acute falciparum malaria.

OBJECTIVE: To construct a population pharmacokinetic model for mefloquine in the treatment of falciparum malaria. BACKGROUND: Mefloquine is the treatment of choice for multidrug-resistant falciparum malaria. The factors that influence the pharmacokinetic properties of mefloquine in acute malaria are not well characterized. METHODS: The pharmacokinetic properties of mefloquine were evaluated in 257 patients with acute falciparum malaria by use of nonlinear mixed-effects modeling. Two different oral dose regimens were used: (1) a split dose of 15 mg base/kg initially followed by 10 mg/kg 24 hours later (n = 159) and (2) a single dose of 25 mg/kg (n = 98). Mefloquine was combined with artesunate in 105 (41%) patients (74 received a split dose and 31 received a single dose). RESULTS: Splitting the mefloquine dose increased the area under the concentration-time curve [AUC(0-infinity)] by 50% (95% confidence interval [CI], 36% to 65%) for monotherapy and by 20% (95% CI, 3% to 40%) for combined therapy. The apparent volume of distribution (V/F) was significantly lower in patients receiving split doses of mefloquine monotherapy (mean, 8.14 L/kg; 95% CI, 7.49 to 8.86 L/kg) compared with a single dose (mean, 20.37 L/kg; 95% CI, 16.26 to 25.51 L/kg). Patients who received mefloquine monotherapy and cleared parasitemia in less than 48 hours had a significantly higher AUC(0-infinity) independent of any confounders, compared with patients with slower parasite clearance (geometric mean [95% CI], 50,373 ng/mL x day [46,121 to 55,017 ng/mL x day] versus 45,583 ng/mL x day [42,306 to 49,125 ng/mL x day]). CONCLUSIONS: The pharmacokinetic properties of mefloquine in malaria were relatively unaffected by demographic variables (other than body weight) or disease severity. If it is assumed that apparent clearance and volume of distribution are unaffected by dose regimen, then splitting the 25 mg/kg mefloquine dose improves oral bioavailability and the therapeutic response in the treatment of acute falciparum malaria.

Acute Disease↗
PubMed1999

Ideals in intimate relationships.

This research examined lay relationship and partner ideals in romantic relationships from both a social-cognitive and an evolutionary perspective. Studies 1 and 2 revealed that the qualities of an ideal partner were represented by 3 factors (partner warmth-trustworthiness, vitality-attractiveness, and status-resources), whereas the qualities of an ideal relationship were represented by 2 factors (relationship intimacy-loyalty and passion). A confirmatory factor analysis in Study 3 replicated these factor structures but found considerable overlap across the partner and relationship dimensions. Studies 4 and 5 produced convergent and discriminant validity evidence for all 5 factors. Study 6 indicated that the higher the consistency between the ideals and related assessments of the current partner and relationship, the more positively the current relationship was evaluated.

Adolescent↗
PubMed1999

Attachment and anger in an anxiety-provoking situation.

In this study, women were told they would engage in an anxiety-provoking activity. Women then waited with their dating partner for the activity to begin. During this 5-min "stress" period, each couple's interaction was videotaped unobtrusively. Each couple was then told that the woman would not have to do the stressful activity, and each couple was unobtrusively videotaped again during a 5-min "recovery" period. The behavior of both partners was then coded during both periods. The major results revealed that more-avoidant men displayed greater anger during the stress period, especially if their partners were more anxious or distressed or sought more support from them. More-avoidant women also displayed greater anger, particularly if they were highly anxious or distressed and received little support or encountered anger from their partners. During the recovery period, highly ambivalent women behaved more negatively toward their partners if they had been more anxious in the stress period or had sought more support from their partners. These results are discussed in terms of attachment theory.

Adolescent↗
PubMed1999

Pharmacokinetics of mefloquine combined with artesunate in children with acute falciparum malaria.

Combining artemisinin or a derivative with mefloquine increases cure rates in falciparum malaria patients, reduces transmission, and may slow the development of resistance. The combination of artesunate, given for 3 days, and mefloquine is now the treatment of choice for uncomplicated multidrug-resistant falciparum malaria acquired on the western or eastern borders of Thailand. To optimize mefloquine administration in this combination, a prospective study of mefloquine pharmacokinetics was conducted with 120 children (4 to 15 years old) with acute uncomplicated falciparum malaria, who were divided into four age- and sex-matched groups. The patients all received artesunate (4 mg/kg of body weight/day orally for 3 days and mefloquine as either (i) a single dose (25 mg/kg) on day 2 with food, (ii) a split dose (15 mg/kg on day 2 and 10 mg/kg on day 3) with food, (iii) a single dose (25 mg/kg) on day 0 without food, or (iv) a single dose (25 mg/kg) on day 2 without food. Delaying administration of mefloquine until day 2 was associated with a mean (95% confidence interval) increase in estimated oral bioavailability of 72% (36 to 109%). On day 2 coadministration with food did not increase mefloquine absorption significantly, and there were no significant differences between patients receiving split- and single-dose administration. In combination with artesunate, mefloquine administration should be delayed until the second or third day after presentation.

Acute Disease↗
PubMed1999

Risk factors for gametocyte carriage in uncomplicated falciparum malaria.

The factors affecting the development of patent Plasmodium falciparum gametocytemia were assessed in 5,682 patients entered prospectively into a series of antimalarial drug trials conducted in an area of low and seasonal transmission on the western border of Thailand. Of the 4,565 patients with admission thick smear assessments, 110 (2.4%) had gametocytemia. During the follow-up period 170 (3%) of all patients developed patent gametocytemia, which in 89% had developed by day 14 following treatment. In a multiple logistic regression model five factors were found to be independent risk factors at presentation for the development or persistence of gametocytemia during follow up; patent gametocytemia on admission (adjusted odds ratio [AOR] = 7.8, 95% confidence interval [CI] = 3.7-16, P < 0.001), anemia (hematocrit <30%) (AOR = 3.9, 95% CI = 2.3-6.5, P < 0.001), no coincident P. vivax malaria (AOR = 3.5, 95% CI = 1.04-11.5, P < 0.04), presentation with a recrudescent infection (AOR = 2.3, 95% CI = 1.3-4.1, P < 0.004), and a history of illness longer than two days (AOR = 3.3, 95% CI = 1.7-6.6, P < 0.001). Patients whose infections responded slowly to treatment or recrudesced subsequently were also more likely to carry gametocytes than those who responded rapidly or were cured (relative risks = 1.9, 95% CI = 1.3-2.7 and 2.8, 95% CI = 2.0-4.0, respectively; P < 0.001). These data provide further evidence of important epidemiologic interactions between P. falciparum and P. vivax, and drug resistance and transmission potential.

Adolescent↗
PubMed1999

Fluctuating asymmetry, sociosexuality, and intrasexual competitive tactics.

Heterosexual men and women were told they were competing with another same-sex individual for a date with an attractive opposite-sex interviewer. After answering 6 questions, participants were asked to tell the competitor why the interviewer should choose them over the competitor. Participants' videotaped behavior was coded for different behavioral tactics. Men who were more symmetrical and who had a more unrestricted sociosexual orientation were more likely to use direct competition tactics than were less symmetrical and restricted men. Restricted men accentuated their positive personal qualities, presenting themselves as "nice guys." Structural equation modeling revealed that fluctuating asymmetry (FA) was directly associated with the use of direct competition tactics. However, the link between FA and presenting oneself as a nice guy was mediated through sociosexuality. No effects were found for women.

Adolescent↗
PubMed1998

Aeromonas hydrophila in burn patients.

Burn wound infection with Aeromonas hydrophila appears to be very uncommon. This study reports on nine cases of A. hydrophila in burn patients treated over a 21 month period at the New Somerset Hospital Burn Unit. The average age of the patients was 31 years (range 24-60 years) and the average TBSA was 33% (range 16-51%). All patients had positive wound cultures for A. hydrophila, obtained on admission or shortly thereafter. One patient also had a positive blood culture. Two patients with small partial thickness burns did not receive antibiotic therapy, and made an uneventful recovery with topical therapy alone. The other seven patients developed clinical signs of septicaemia and required parenteral antibiotics, in addition to topical therapy. One patient died of ARDS, but the other eight recovered and were discharged. No patient had evidence of myonecrosis. Small, superficial burns which culture A. hydrophila can be treated by topical therapy alone. Large and/or deep burns, require antibiotic therapy and debridement of all necrotic tissue, particularly when myonecrosis is present. The antibiotics of choice are the aminoglycosides or the quinolones.

Adult↗