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Biomedical subjects

T M Davis

Publications and source records attributed to T M Davis.

At least 37 records · Page 2Linked to original sources
PubMed2001

Pituitary-adrenal function in uncomplicated falciparum malaria.

To investigate pituitary-adrenal function in acute uncomplicated falciparum malaria, we performed an overnight dexamethasone suppression test in 13 Vietnamese adults with acute malaria and 6 healthy controls. After blood samples were taken for serum cortisol and plasma ACTH at 23.00 hours on the admission day, 1 mg dexamethasone was given and further samples were taken at 08.00, 16.00 and 23.00 hours the next day. The patients received conventional antimalarial and supportive treatment. Baseline plasma ACTH concentrations in the patients [3.9 (0.2-41.2) pmol/l] and controls [3.4 (1.1-4.3) pmol/l] were similar (p=0.51), and exhibited a similar fall after dexamethasone to 0.6 (0.2-2.5) and 0.9 (0.7-1.6) pmol/l at 08.00 hours respectively (p<0.03 vs 23.00 hour values). Serum cortisol levels before dexamethasone were higher in the patients than in the controls [456 (102-821) vs 145 (64-183) nmol/l respectively; p=0.007] and the overnight fall was less in the patients [208 (26-340) and 23 (15-46) nmol/l at 08.00 hours respectively; p<0.001 vs 23.00 hour values and between groups]. Between 08.00 and 23.00 hours, plasma ACTH and serum cortisol remained suppressed in the controls. In the patients, the serum cortisol continued to fall progressively towards control values. These data suggest that there is a raised set point for cortisol inhibition of ACTH secretion but normal corticotrophin responsiveness to dexamethasone in uncomplicated malaria. A raised serum cortisol after dexamethasone in the patients might reflect the combination of a prolonged cortisol half-life and the stimulatory effects of cytokines on the adrenal cortex, with a consequent protective effect against complications such as hypoglycemia.

Adrenal Glands↗
PubMed2000

Progression of skeletal muscle damage during treatment of severe falciparum malaria.

To assess the relationship between severity of malaria and progression of skeletal muscle damage during initial treatment, we studied 28 Thai adults with slide-positive falciparum malaria. Six had uncomplicated malaria (Group 1), 12 had severe non-cerebral malaria (Group 2) and ten had cerebral malaria (Group 3). There were no significant differences between baseline serum creatine kinase (CK) levels in the three groups (P=0.071). There was no change in serum CK during the first 48 h of treatment in Group 1 cases. In Group 2 patients, the median peak serum CK was nine times that at baseline while in Group 3, serum CK peaked at a median concentration 20 times that at presentation. In Groups 2 and 3, the peak serum CK occurred at least 24 h after presentation in more than half the patients, and was independent of intramuscular injections and convulsions during initial therapy. These longitudinal data suggest that: (i) severe falciparum malaria is associated with skeletal muscle damage that increases during initial therapy especially in patients with coma; (ii) the effect of other major treatment or infection-specific factors that are associated with muscle damage does not diminish this relationship; and (iii) cerebral malaria in combination with a high baseline and rising serum CK should pre-empt monitoring and management strategies aimed at preserving renal function including renal dialysis.

Adolescent↗
PubMed2000

Determination of the refractive index increments of small molecules for correction of surface plasmon resonance data.

The refractive index increments (RIIs) of several important low-molecular-weight compounds that bind to DNA or RNA were determined with a differential refractometer for correction of data obtained on surface plasmon resonance (SPR) biosensors. Although the ability to investigate small molecule-macromolecule interactions by SPR is relatively new, the technique is rapidly becoming a primary method to screen focused combinatorial libraries and to quantitatively characterize the interactions between compounds identified as binders and target macromolecules. The most widely used SPR analysis software, BIAevaluation (Biacore, Inc.), assumes that the RIIs of ligand and macromolecule are identical. While the assumption is reasonable for studies involving like molecules such as protein-protein interactions, results presented here demonstrate that RII values for small molecules can be significantly different than those of protein or nucleic acid receptors. The results also show that the RII values can vary greatly depending on the structure of the small molecule. Indeed, the RIIs of the molecules investigated here differ by a factor of 2. Any difference in the RII of interacting molecules must be considered for complete analysis of SPR data. Failure to correct for RII differences can result in serious error in data interpretation, especially for systems involving a ligand:receptor stoichiometry greater than 1. The results serve as the beginning of an SPR correction database for the RIIs of small molecules. Additionally, the results can be used to approximate the RIIs of a variety of other small molecules.

Molecular Weight↗
PubMed2000

Unexpected formation of glycals upon attempted C-alkylation of protected glycosylacetylenes.

Treatment of 3,7-anhydro-4,5,6,8-tetra-O-benzyl-1,2-dideoxy-D-glycero-D-galacto-oct-1 -ynitol (beta-D-mannosyl acetylene, 1) with 5 equivalents of n-butyllithium at either 0 or -78 degrees C resulted in the elimination of benzyl alcohol to yield 3,7-anhydro-5,6,8-tri-O-benzyl-1,2,4-trideoxy-D-arabino-oct-3-en-1-yn itol (glycal acetylene, 3) as the major product. Additional studies showed that 3 is also produced from two isomers of 1 with alpha-D-mannosyl and beta-D-glucosyl stereochemistry, but in lower yields. Furthermore, substrates in which the acetylene moiety is replaced by either a methyl or phenyl group do not produce a glycal product under these conditions. Finally, treatment of 1 with phenyllithium provides 3 in low yield. Deuterium labeling studies suggest that the reaction proceeds through an E2, rather than an E1cB, mechanism.

Acetylene↗
PubMed2000

In vitro antimalarial activity of trovafloxacin, a fourth-generation fluoroquinolone.

Trovafloxacin, a recently-developed fourth-generation fluoroquinolone, is more potent than other quinolone drugs against a wide range of organisms including Toxoplasma gondii. We assessed the in vitro antimalarial activity of trovafloxacin against three laboratory-adapted Plasmodium falciparum isolates and compared the results with those of ciprofloxacin and norfloxacin. Synchronous and asynchronous cultures were exposed to a range of drug concentrations, and growth inhibition was assessed using 3H-hypoxanthine incorporation. All isolates, both synchronous and asynchronous, exhibited comparable sensitivities with trovafloxacin (EC50 range, 1.8 x 10(-5) to 3.7 x 10(-5) mol/l) and ciprofloxacin (2.0 x 10(-5) to 3.9 x 10(-5) mol/l), but were less sensitive to norfloxacin (5.4 x 10(-5) to 6.6 x 10(-4) mol/l). These results confirm that ciprofloxacin is twice as potent as norfloxacin against P. falciparum in vitro, but also show that trovafloxacin and ciprofloxacin have similar antimalarial potency. The EC50 concentrations of all three drugs were generally higher than those achieved after conventional doses in humans, suggesting that their clinical application may be limited to combination therapy. Recent reports of hepatotoxicity with trovafloxacin may also prevent the use of this drug in humans. However, newer fourth-generation quinolones may prove safer and have similar antimalarial potency.

Animals↗
PubMed2000

Reduced pulmonary function and its associations in type 2 diabetes: the Fremantle Diabetes Study.

To determine whether diabetes is associated with reduced lung function, we studied 421 Anglo-Celt/European subjects, representing 20.5% of all patients with type 2 diabetes identified in an urban Australian catchment area of 120097 people. In addition to collection of detailed demographic and diabetes-specific data, spirometry was performed and forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), vital capacity (VC) and peak expiratory flow (PEF) measured. When expressed as a percentage of those predicted (%pred) for age, sex and height, the means of all spirometric measures were reduced by > or =9.5%. After controlling for smoking, age and gender in a linear regression model, HbA(1c) was not associated with any measure of lung function (P>0.13) but diabetes duration was significantly associated with FEV1(%pred) and PEF(%pred) (P< or =0.04) and had borderline associations with FVC(%pred) and VC(%pred) (P< or =0.064). In separate analyses controlling for smoking alone, age, body mass index (BMI), coronary heart disease (CHD) and retinopathy were independently and inversely associated with FVC(%pred), FEV1(%pred) and VC(%pred) (P<0.05). In sub-group analyses, these three spirometric measures were associated with BMI, CHD and diabetes duration in males, and age and BMI in females. Pulmonary function is reduced in type 2 diabetes. Diabetes duration seems a more important influence than glycaemic control, but obesity and vascular disease may also contribute.

Adult↗
PubMed2000

The antimalarial agent mefloquine inhibits ATP-sensitive K-channels.

The aim of this study was to determine whether antimalarial agents inhibit ATP-sensitive potassium (K(ATP)) channels and thereby contribute to the observed side-effects of these drugs. Mefloquine (10 - 100 microM), but not artenusate (100 microM), stimulated insulin release from pancreatic islets in vitro. Macroscopic K(ATP) currents were studied in inside-out patches excised from Xenopus oocytes expressing cloned K(ATP) channels. Mefloquine (IC(50) approximately 3 microM), quinine (IC(50) approximately 3 microM), and chloroquine inhibited the pancreatic beta-cell type of K(ATP) channel Kir6.2/SUR1. Artenusate (100 microM) was without effect. Mefloquine and quinine also blocked a truncated form of Kir6.2 (Kir6. 2DeltaC36) when expressed in the absence of SUR1. The extent of block was similar to that observed for Kir6.2/SUR1 currents. Our results suggest that inhibition of the beta-cell K(ATP) channel accounts for the ability of quinoline-based antimalarial drugs to stimulate insulin secretion, and thereby produce hypoglycaemia. The results also indicate that quinoline-based antimalarial agents inhibit K(ATP) channels by interaction with the Kir6.2 subunit. This subunit is common to beta-cell, neuronal, cardiac, skeletal muscle, and some smooth muscle K(ATP) channels suggesting that K(ATP) channel inhibition may contribute to the other side effects of these drugs, which include cardiac conduction abnormalities and neuropsychiatric disturbances.

Adenosine Triphosphate↗
PubMed2000

Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes.

AIMS: Gliclazide pharmacokinetics and pharmacodynamics were assessed in 9 Caucasians and 10 Australian Aborigines with uncomplicated type 2 diabetes. METHODS: Subjects were on a stable dose of 80 mg gliclazide twice daily, took 160 mg on the morning of study and had a standard breakfast. No further gliclazide was given over the next 48 h. Regular blood samples were drawn for serum glucose, insulin and gliclazide assay. Gliclazide was measured using h.p.l.c. Noncompartmental analysis was used to describe primary data. A multicompartment model incorporating entero-hepatic recirculation was fitted to group mean serum gliclazide profiles. RESULTS: The Caucasians were older than the Aborigines (mean +/- s.d. age 53.4 +/- 12.2 vs 40.3 +/- 6.9 years, P < 0.05) but had similar diabetes duration, body mass index and glycated haemoglobin. Noncompartmental analysis revealed no between-group differences in gliclazide kinetics. Post-breakfast serum glucose and insulin responses were also similar apart from a longer time to maximum concentration (tmax) for glucose amongst the Aborigines (2.6 +/- 0.4 vs 2.2 +/- 0. 3 h in Caucasians; P = 0.024). Gliclazide tmax exhibited a skewed unimodal distribution and was not associated with gliclazide maximum concentration, or glucose or insulin responses. Most patients had a serum gliclazide profile suggestive of enterohepatic recirculation and/or biphasic absorption. Model-derived estimates of the extent of putative enterohepatic recirculation were 30% and 20% of dose in Caucasians and Aborigines, respectively. CONCLUSIONS: Gliclazide is equally effective in Caucasian and Aboriginal diabetic patients. The pharmacokinetics of oral gliclazide appear more complex than previously thought. Gliclazide pharmacodynamics are unrelated to rate and extent of absorption, consistent with a threshold concentration for hypoglycaemic effect.

Adult↗
PubMed2000

Autoantibodies to glutamic acid decarboxylase in diabetic patients from a multi-ethnic Australian community: the Fremantle Diabetes Study.

AIMS: To investigate ethnic/racial differences in the prevalence of serum antibodies to glutamic acid decarboxylase (GADA) and ICA512/IA-2 in diabetic patients from a large, urban community. METHODS: A cross-sectional sample of 1,381 diabetic patients aged 11-98 years, representing 61% of those identified in a postcode-defined population base of 120,097 people were studied. Diabetes was classified on clinical grounds. Serum GADA and anti-ICA512/IA-2 were measured by radioimmunoprecipitation assay. RESULTS: Anglo-Celts formed 62% of the sample, southern Europeans 18%, other Europeans 8% and Asians 3%. GADA prevalence in Type 1 and Type 2 diabetes mellitus was 46.0% and 4.2%, respectively, amongst Anglo-Celts and 22.2% and 1.7% in southern Europeans. The prevalence of anti-ICA512/IA-2 in Type 1 diabetes was 17.4% and, in a sample of 233 patients with Type 2 diabetes, 0.8%. GADA-positive Type 2 patients had a lower body mass index and greater glycosylated haemoglobin, and were more likely to be taking insulin, than GADA-negative Type 2 diabetic subjects (P < 0.05), consistent with the phentoype of latent autoimmune diabetes of adults (LADA). In both Type 1 and Type 2 diabetes, there was a strong inverse association between GADA and serum triglycerides (P < 0.001). CONCLUSIONS: The relatively low GADA prevalence in Anglo-Celt patients with Type 1 diabetes is a feature of this community-based study and suggests that GADA levels do fall with time, given the older age of the sample and a relatively long period between diagnosis and sampling. Southern Europeans had an even lower GADA prevalence, regardless of diabetes type. Variations in GADA frequency in diabetic patients of differing European ethnicity has implications for clinical management and healthcare planning.

Adolescent↗
PubMed2000

The diagonal ear lobe crease (Frank's sign) is not associated with coronary artery disease or retinopathy in type 2 diabetes: the Fremantle Diabetes Study.

BACKGROUND: The diagonal ear lobe crease (ELC) has been suggested as a simple marker of vascular disease in the general population but there are few data from diabetic patients despite their increased risk of angiopathy. AIM: To determine whether the ELC is a clinically useful sign of coronary artery disease (CAD) or retinopathy in type 2 diabetes. METHODS: One thousand and twenty-two patients from the multi-ethnic urban catchment area of Fremantle Hospital in Western Australia were studied. This sample represents 79% of the type 2 diabetic subjects recruited to the ongoing Fremantle Diabetes Study and 49% of all 2072 patients with type 2 diabetes identified through active case detection in a postcode-defined region of 120,097 people. In addition to other comprehensive data relating to diabetes and its management, the presence of an ELC and evidence of both CAD and retinopathy were ascertained for each patient. RESULTS: The prevalence of ELC was 55%. Patients with an ELC were more likely to have CAD than those without an ELC (p=0.019), but the proportions with retinopathy were not significantly different (p=0.085). The sensitivity and specificity of ELC for detecting CAD were 60% and 48%, and for retinopathy 61% and 47% respectively. The patients with an ELC were significantly older, more likely to be male and had a higher systolic blood pressure than those without (p<0.02). After adjusting for known vascular risk factors, socioeconomic variables and ethnicity in a logistic regression model, an ELC was neither a significant independent predictor of CAD (p=0.45) nor of retinopathy (p=0.14). CONCLUSIONS: The ELC is of little value as a sign of the presence of diabetic vascular complications.

Adult↗
PubMed2000

Glycemic control in older subjects with type 2 diabetes mellitus in the Fremantle Diabetes Study.

OBJECTIVES: We investigated whether there were differences in glycemic control in older compared with younger subjects with type 2 diabetes mellitus enrolled in the Fremantle Diabetes Study, a prospective study of diabetes care, control, and complications in an urban setting. DESIGN: Cross-sectional observational study. SETTING: University teaching hospital clinical research center. PARTICIPANTS: A total of 1,205 patients with type 2 diabetes mellitus, 404 (33.3%) of whom were aged over 70 years and 83 (6.9%) aged over 80 years. MEASUREMENTS: Fasting plasma glucose, HbA1c, body mass index, and waist/hip ratio. RESULTS: In multiple linear regression analysis, age was inversely associated with glycemic control whereas duration of diabetes and treatment with either oral hypoglycemic agents or insulin were positively associated with glycemic control. For most age groups there was a significant worsening of glycemic control with duration of diabetes. Octogenarians differed significantly from younger age groups in that those with longer diabetes duration did not demonstrate the increase in hyperglycemia seen in other age groups. As a result, significantly greater proportions of these oldest diabetic subjects had satisfactory glycosylated hemoglobin levels compared with younger subjects. CONCLUSIONS: Octogenarians do not demonstrate the usual progressive deterioration of glycemic control with diabetes duration seen in type 2 diabetes mellitus. The reasons for this difference are unknown but are likely to have clinical significance with regard to therapy and the development of diabetic complications.

Administration, Oral↗
PubMed2000

Pharmacokinetics of retinyl palmitate and retinol after intramuscular retinyl palmitate administration in severe malaria.

Retinol (vitamin A alcohol) is an accepted adjunctive treatment in infections such as measles. There is also indirect evidence from in vitro, animal and human studies that retinol supplementation may be beneficial in severe malaria. There have, however, been no studies that have examined the pharmacokinetics of acute retinol supplementation in severe illness. To establish whether mobilization of intramuscular retinyl palmitate (RP) and its availability as retinol are adequate in complicated falciparum malaria, we administered a single dose of 400000 i.u. of RP to six Vietnamese adults with severe malaria. Another 28 patients were not given RP. All patients had blood samples taken over 96 h for RP and retinol assay using HPLC, and received conventional anti-malarial and supportive therapy. Admission serum retinol concentrations were below the lower limit of the reference range (<1.0 micromol/l) in 74% of the 34 patients. In supplemented patients, analysis of serum RP between 0 and 96 h using a multi-compartmental model revealed a median (range) delay in mobilization of 6.9 h (0.7-15.1 h), a bioavailability of 55% (19-100%) and an elimination half-life of 13.5 h (4.2-23.7 h). The area under the serum retinol curve expressed as an absolute or percentage change from baseline was greater in supplemented than in unsupplemented patients (P<0.05). The separation in median serum retinol concentrations in the two groups was maximal at 48 h. The model-derived retinol half-life [1.5 (0.7-15.8) h] suggested rapid uptake, metabolism and/or excretion. In conclusion, there is variable RP bioavailability in severe malaria, but a significant if delayed increase in serum retinol over that associated with recovery from the infection. In severe infections, RP supplementation appears simple, well tolerated and of potential benefit once anti-microbial and supportive therapy have been established.

Adult↗
PubMed1999

Risk factors for stroke in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 29.

OBJECTIVE: To investigate modifiable and nonmodifiable risk factors for stroke in type 2 diabetes mellitus. PATIENTS AND METHODS: A total of 3776 patients aged 25 to 65 years newly diagnosed as having type 2 diabetes mellitus without known cardiovascular or other serious disease were studied for a median of 7.9 years. An initial stepwise evaluation of risk factors was done in 2704 patients with all risk factors measured, with the final Cox model analysis being of 3776 patients who had complete data on the selected variables. RESULTS: Of 3776 patients, 99 (2.6%) had a stroke. Significant risk factors for stroke in a multivariate model were age (estimated hazard ratio [95% confidence interval], 4.78 [2.56-8.92] for > or =60 vs <50 years), male sex (1.63 [1.08-2.47)] vs female), hypertension (2.47 [1.64-3.74)] vs normotension), and in 3728 patients who had electrocardiography at study entry, atrial fibrillation (8.05 [3.52-18.44] vs sinus rhythm). Obesity, lack of exercise, smoking, poor glycemic control, hyperinsulinemia, dyslipidemia, and microalbuminuria were not significantly associated with stroke in the model. CONCLUSION: In patients with type 2 diabetes, aggressive antihypertensive therapy and routine anticoagulation therapy for atrial fibrillation may reduce the risk of stroke.

Adult↗
PubMed1999

Rapid and reliable serological diagnosis of enteric fever: comparative sensitivity and specificity of Typhidot and Typhidot-M tests in febrile Malaysian children.

The Typhidot test, which detects IgM and IgG antibodies to a Salmonella typhi-specific outer membrane protein, is as sensitive as, and more specific than, the Widal test in the diagnosis of enteric fever in Malaysian children. It is easier and quicker to perform. In order to increase diagnostic accuracy in an area of high endemicity, the Typhidot-M test has been developed in which IgG is first removed. This theoretically allows improved detection of IgM, and thus would differentiate new from recent infections. We evaluated both tests in 134 unselected febrile children admitted to the General Hospital Kota Bharu, Malaysia. The children were divided into two groups: (i) those who were blood and/or stool culture positive for S. typhi and/or who had clinical features strongly suggestive of enteric fever (n = 62); and (ii) those who were both culture-negative and had clinical evidence of another diagnosis (n = 72). The sensitivity and specificity of the Typhidot and Typhidot-M tests were identical at 90.3 and 93.1%, respectively. Both tests had comparable sensitivity but greater specificity than those of the Widal test (91.9 and 80.6%, respectively). When used together, a positive result for Typhidot and/or Typhidot-M was more specific than either test alone (95.2%) but specificity was lower (87.5%). We conclude that the Typhidot and Typhidot-M tests have comparatively high diagnostic accuracy, suggesting that IgM can be detected in children who may have a predominant IgG response to S. typhi. Using these tests in combination increases the negative predictive value but at the cost of a lower positive predictive value.

Antibodies, Bacterial↗
PubMed1999

Substance abuse and sexual trauma in a female veteran population.

An increasing number of researchers have explored connections between substance abuse, posttraumatic stress disorder (PTSD), and sexual assault histories in civilian women. Despite literature suggesting the prevalence of substance abuse and sexual assault for female veterans, few studies have investigated these variables in a female veteran population. Thus, this paper was designed to provide preliminary information about this group of women. The results of this preliminary study suggest a high incidence of PTSD related to sexual trauma in a substance-abusing population of female veterans and a high incidence of substance abuse among female veterans who presented requesting help for sexual trauma. Suggestions for future study include examination of comparison samples of female veterans with and without PTSD and substance abuse across a variety of dimensions, including psychiatric symptoms, substance use, treatment utilization, and impact of treatment. Implications for assessment are highlighted.

Adult↗
PubMed1999

Relative bradycardia is not a feature of enteric fever in children.

We investigated pulse-temperature relationships in 66 children with enteric fever (group 1) and in 76 with other infections (group 2). Group 1 children were older than group 2 children (mean age +/- SD, 91 +/- 36 vs. 66 +/- 32 months, respectively; P < .001) and had mean oral temperatures +/- SD similar to those of group 2 children (38.3 +/- 1.0 vs. 38.3 +/- 0.9 degrees C, respectively; P > .2); however, group 1 children had lower mean baseline pulse rates +/- SD than did group 2 children (119 +/- 25 vs. 127 +/- 28 beats/min, respectively; P < .001). In a multiple linear regression model, pulse rate was independently associated with age (inversely; P < .001) and oral temperature (positively; P < .006) but not with diagnostic group or gender (P > .5). After adjustment of the mean initial pulse rate +/- SD to age of 72 months, there was no difference between group 1 and group 2 children (126 +/- 24 vs. 126 +/- 20 beats/min, respectively; P > .5). From 4 to 72 hours after commencement of treatment, the mean oral temperature in group 1 patients was approximately 0.3 degrees C higher than that in group 2 patients, and the age-adjusted pulse rate was 5 beats/min higher in group 1 children than in group 2 children. These data suggest that relative bradycardia is not characteristic of enteric fever in children.

Bacterial Infections↗