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Biomedical subjects

I Harper

Publications and source records attributed to I Harper.

At least 19 recordsLinked to original sources
PubMed2001

Melatonin protects against ischaemic-reperfusion myocardial damage.

OBJECTIVES: Melatonin, a hormonal product of the pineal gland, is now known to be a multi-faceted free radical scavenger and anti-oxidant. Since little information is available regarding the action of melatonin on the heart, we studied the effects of melatonin on adult ventricular myocytes subjected to chemical hypoxia and reoxygenation. METHODS: Adult rat ventricular myocytes were preloaded with tetramethylrhodamine (TMRM) in combination with one of the following fluorophores: dichlorodihydrofluorescein diacetate (DCDHF), dihydrorhodamine 123 (DHR) or fluo 3 (Fluo) and then investigated with confocal laser scanning microscopy. Chemical hypoxia was induced by addition of 1.5 mM KCN and 20 mM deoxyglucose to the superfusion buffer. Melatonin (50-100 microM) was added at intervals during the protocol. RESULTS: Cells subjected to 12.5 min chemical hypoxia showed marked morphological changes, increased fluorescence intensity of DCDHF, DHR and Fluo, suggesting Ca2+ accumulation and generation of H2O2 and reactive oxygen species. The number of cells showing increased fluorescence also increased significantly. Melatonin (50 and 100 microM) caused a significant reduction in morphological changes, number of cells with increased fluorescence and fluorescence intensity of DHR and Fluo, (but not DCDHF). CONCLUSION: Melatonin effectively reduced damage induced by chemical hypoxia in adult cardiomyocytes, probably by virtue of its effects on reactive oxygen species generation and intracellular Ca2+ accumulation.

Aniline Compounds↗
PubMed2001

Substrate utilization during exercise in formerly morbidly obese women.

The purpose of this study was to compare substrate utilization during fasting and submaximal exercise in morbidly obese women after weight loss (WL) with that in weight-matched controls (C). WL were studied in the weight-stable condition approximately 24 mo after gastric bypass surgery. Energy intake (self-reported) and expenditure ((2)H(2)(18)O) were also compared. The respiratory exchange ratio during exercise at the same absolute (15 W) workload was significantly (P < or = 0.05) elevated in WL vs. C (0.90 +/- 0.02 vs. 0.83 +/- 0.03); this was reflected as lower fat utilization in WL (29.7 +/- 4.8 vs. 53.2 +/- 9.7% of energy from fat). Respiratory exchange ratio during exercise at the same relative (65% of maximal O(2) uptake) intensity was also significantly (P < 0.05) elevated in WL (0.96 +/- 0.01 vs. 0.89 +/- 0.02), and fat use was concomitantly depressed (12.4 +/- 3.0 vs. 34.3 +/- 9.9% of energy from fat). Resting substrate utilization, daily energy expenditure, and self-reported relative macronutrient intake did not differ between groups. These data suggest that lipid oxidation is depressed during physical activity in WL. This defect may, at least in part, contribute to a propensity for the development of morbid obesity.

Adult↗
PubMed2001

A Ser311Cys mutation in the human dopamine receptor D2 gene is associated with reduced energy expenditure.

Brain dopaminergic pathways play a major role in the control of movement. Absence of the murine dopamine D2 receptor gene (drd2) produces bradykinesia and hypothermia. A Ser311Cys mutation of the human DRD2 produces a marked functional impairment of the receptor and is associated with higher BMI in some populations. We hypothesized that the Ser311Cys mutation of DRD2 may inhibit energy expenditure. Here we report that total energy expenditure (doubly labeled water) measured in 89 nondiabetic Pima Indians was 244 kcal/ day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.056). The 24-h resting energy expenditure (respiratory chamber) measured in 320 nondiabetic Pimas was also 87 kcal/day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.026). These findings are the first evidence that a genetic mutation is associated with reduced energy expenditure in humans. Because the impact of this mutation on human obesity is small, we suggest that either the energy deficit induced is not large enough to significantly influence body weight in this population and/or that the Cys311-encoding allele is also associated with reduced energy intake.

Adult↗
PubMed2000

Cytoskeletal regulation of the platelet glycoprotein Ib/V/IX-von willebrand factor interaction.

Shear-induced binding of von Willebrand factor (vWf) to the platelet glycoprotein (GP) Ib/V/IX complex plays a key role in initiating platelet adhesion and aggregation at sites of vascular injury. This study demonstrated that pretreating human platelets with inhibitors of actin polymerization, cytochalasin D or latrunculin B, dramatically enhances platelet aggregation induced by vWf. The effects of these inhibitors were specific to the vWf-GPIbalpha interaction because they enhanced vWf-induced aggregation of Glanzmann thrombasthenic platelets and Chinese hamster ovary (CHO) cells transfected with GPIb/V/IX. Moreover, cytochalasin D enhanced the extent of platelet aggregation induced by high shear stress (5000 s(-1)) and also lowered the shear threshold required to induce aggregation from 3000 s(-1) to as low as 500 s(-1). Studies of CHO cells expressing GPIbalpha cytoplasmic tail truncation mutants that failed to bind actin-binding protein-280 (deletion of residues 569-610 or 535-568) demonstrated that the linkage between GPIb and actin-binding protein-280 was not required for vWf-induced actin polymerization, but was critical for the enhancing effects of cytochalasin D on vWf-induced cell aggregation. Taken together, these studies suggest a fundamentally important role for the cytoskeleton in regulating the adhesive function of GPIb/V/IX.

Actin Cytoskeleton↗
PubMed1999

The von Willebrand factor-glycoprotein Ib/V/IX interaction induces actin polymerization and cytoskeletal reorganization in rolling platelets and glycoprotein Ib/V/IX-transfected cells.

Platelet adhesion to sites of vascular injury is initiated by the binding of the platelet glycoprotein (GP) Ib-V-IX complex to matrix-bound von Willebrand factor (vWf). This receptor-ligand interaction is characterized by a rapid on-off rate that enables efficient platelet tethering and rolling under conditions of rapid blood flow. We demonstrate here that platelets adhering to immobilized vWf under flow conditions undergo rapid morphological conversion from flat discs to spiny spheres during surface translocation. Studies of Glanzmann thrombasthenic platelets (lacking integrin alpha(IIb)beta(3)) and Chinese hamster ovary (CHO) cells transfected with GPIb/IX (CHO-Ib/IX) confirmed that vWf binding to GPIb/IX was sufficient to induce actin polymerization and cytoskeletal reorganization independent of integrin alpha(IIb)beta(3). vWf-induced cytoskeletal reorganization occurred independently of several well characterized signaling processes linked to platelet activation, including calcium influx, prostaglandin metabolism, protein tyrosine phosphorylation, activation of protein kinase C or phosphatidylinositol 3-kinase but was critically dependent on the mobilization of intracellular calcium. Studies of Oregon Green 488 1, 2-bis(o-amino-5-fluorophenoxy)ethane-N,N,N',N-tetraacetic acid tetraacetoxymethyl ester-loaded platelets and CHO-Ib/IX cells demonstrated that these cells mobilize intracellular calcium in a shear-dependent manner during surface translocation on vWf. Taken together, these studies suggest that the vWf-GPIb interaction stimulates actin polymerization and cytoskeletal reorganization in rolling platelets via a shear-sensitive signaling pathway linked to intracellular calcium mobilization.

Actins↗
PubMed1998

Lack of efficacy of propofol in the treatment of early postoperative nausea and vomiting.

The anti-nauseant efficacy of low-dose propofol was investigated in a blinded, randomized trial. Patients who complained of nausea and/or vomiting following laparoscopic gynaecological surgery and who requested antiemetic were randomly assigned to receive placebo, propofol 3 mg, propofol 9 mg or propofol 27 mg by intravenous injection. Nausea, vomiting and sedation were recorded by a blinded observer for 90 minutes following administration of the test drug, prior to discharge, and 24 hours following surgery. Rescue antiemetic (droperidol 1.0 mg i.v.) was available from 10 minutes after administration of test drug. Propofol failed to reduce nausea scores and did not reduce the incidence of vomiting. Numbers of patients receiving rescue antiemetic were similar in the four treatment groups. In the first 10 minutes following test drug administration, sedation scores were increased by propofol in a dose-related manner. We conclude that, in the dose range studied, propofol is ineffective for the treatment of nausea and vomiting occurring soon after laparoscopic gynaecological surgery.

Adult↗
PubMed1998

A 'Well Woman Clinic' in Bangalore: one strategy to attempt to decrease the transmission of HIV infection.

Samraksha, a non-governmental organization (NGO) in Bangalore, South India, was established in 1993 to take steps to control the spread of HIV infection. As a result of their interactions the Samraksha team recognized the urgent need for management of sexually transmitted diseases (STDs) as a crucial component of their work. Samraksha approached Action Health, a UK-based charity, for assistance. This paper outlines the needs assessment and the process of setting up a Well Woman Clinic for commercial sex workers (CSWs) and other vulnerable groups in Bangalore. The pilot project has been running for over a year and has gained credibility both with vulnerable women and with professionals. Furthermore it has officially become a government resource centre for the training of doctors and health-care staff in the management of STDs, and provides formal training sessions for the staff at each of the primary health-care centres in Bangalore. Thus STD management is being integrated with the current primary health-care provision for women throughout Bangalore. Factors influencing the successful development of such a service are considered.

Ambulatory Care Facilities↗
PubMed1997

Serum C-reactive protein as a marker for infection and inflammation in regular dialysis patients.

Serum C-reactive protein (CRP) concentration was measured in 98 hemodialysis (HD) patients and 68 continuous ambulatory peritoneal dialysis patients (CAPD). The effect, if any, of a HD session on serum CRP level and the usefulness of CRP in diagnosing and monitoring proven inflammatory disease were studied. Seventy-five percent of CAPD patients without evidence of inflammation had CRP levels within the quoted normal range (< 10 mg/l), as compared with only 47% of HD patients also without evidence of overt inflammation (p < 0.001). No significant change in the CRP level was detected during a hemodialysis session. Twenty-four patients with overt inflammation (due mainly to infection) were studied, 22 of whom had CRP levels of > 50 mg/l. These increased CRP levels fell with treatment. A CRP level of > 50 mg/l proved highly suggestive of a significant inflammatory process and a value of < 10 mg/l always excluded it. The total period of time on the regular dialysis program was not related to the CRP level. A subclinical inflammatory response resulting in a raised CRP is very common in our hemodialysis patients and less so in CAPD patients. Possible reasons for this are discussed. However, CRP is still useful in the diagnosis and monitoring of response to treatment of inflammatory disease if the level is > 50 mg/l or serial/baseline measurements are available for comparison. Whether any relationship exists between elevation of CRP and the well-documented increased risk of cardiovascular death in dialysis patients is currently unknown.

Adolescent↗
PubMed1997

Tuberculosis control in remote districts of Nepal comparing patient-responsible short-course chemotherapy with long-course treatment.

SETTING: A tuberculosis programme in hill and mountain districts of Nepal supported by an international non-governmental organisation (NGO). OBJECTIVE: To evaluate under programme conditions the effectiveness of unsupervised monthly-monitored treatment using an oral short-course regimen. DESIGN: In this prospective cohort study, outcomes for new cases of smear-positive tuberculosis starting treatment over a two-year period in four districts in which a 6-month rifampicin-containing regimen was introduced as first-line treatment (subjects) were compared to outcomes for similarly defined cases in four districts where a 12-month regimen with daily streptomycin injections in the intensive phase continued to be used (controls). RESULTS: Of 359 subjects started on the 6-month regimen, 85.2% completed an initial course of treatment compared to 62.8% of 304 controls started on the 12-month regimen (P < 0.001); 78.8% of subjects and 51.0% of controls were confirmed smear-negative at the end of treatment (P < 0.001). The case-fatality rate during treatment was 5.0% among subjects and 11.2% among controls (P = 0.003). Among those whose status was known at two years, 76.9% of subjects were smear-negative without retreatment, compared to 60.9% of controls (P < 0.001). CONCLUSION: In an NGO-supported tuberculosis control programme in remote districts of Nepal, patient-responsible short-course therapy supported by rapid tracing of defaulters achieved acceptable outcomes. Where access and health care infrastructure are poor, district-level tuberculosis teams responsible for treatment planning, drug delivery and programme monitoring can be an appropriate service model.

Administration, Oral↗
PubMed1996

Tuberculosis case finding in remote mountainous areas--are microscopy camps of any value? Experience from Nepal.

SETTING: In the remote hills of North-East Nepal tuberculosis case-finding is believed to be low. The Britain-Nepal Medical Trust (BNMT), a well funded non-governmental organisation supporting Tuberculosis Control Programmes in this area, has a stable structure and sufficiently high case-holding to explore ways to increase case-finding. OBJECTIVES: To increase case-finding without decreasing case-holding, by expanding outreach services into remote areas away from existing health services. DESIGN: Between 1990 and 1993, 45 temporary outreach tuberculosis diagnostic "microscopy camps' were run in the eight districts covered by the BNMT (population 1330000). Camp-diagnosed patients were followed up by cohort. RESULTS: The camps did not appreciably increase the low rate of case-finding. However, the percentage of women who attended the camps was significantly higher than at existing services, as was the number diagnosed with smear-positive tuberculosis. The cured treatment completion rate of this camp-diagnosed cohort was 76%. Cost analysis revealed a low overall additional cost to the programme; however, it would be prohibitively expensive for an under-funded government health service. CONCLUSIONS: The implications of these camps go beyond tuberculosis control in their ability to reach those who would otherwise not utilise health care facilities.

Adult↗
PubMed1993

Effects of beta-blockers and Ca(2+)-antagonists on the response of the isolated working rat heart to adrenergic stimulants after cardioplegic arrest.

During coronary artery bypass graft (CABG) surgery, patients pretreated with the combination of beta-blocking drugs and Ca2+ antagonists for control of myocardial ischemia often respond inadequately to adrenergic stimulants administered after cardioplegic arrest. In this study, the effects of the combination of a beta-blocker (propranolol) and a Ca2+ antagonist (nifedipine) on the spontaneous recovery, as well as the adrenergic response of the isolated, perfused, working rat heart after a period of cardioplegic arrest were evaluated. After pretreatment of the animals with propranolol and/or nifedipine, hearts were removed, perfused in the presence of pretreatment drugs, subjected to 45 minutes of normothermic cardioplegic arrest, reperfused, and finally stimulated with exponentially increasing concentrations of a sympathomimetic drug. Propranolol, and to a lesser extent nifedipine, protected the hearts during cardioplegic arrest, as indicated by the improved recovery and maximum response to adrenergic stimulation after cardioplegia. Isoprenaline, a beta-stimulant, (at a 100 x higher than conventional concentration), elicited an adequate inotropic and chronotropic response. Stimulation by the alpha, beta-stimulant adrenaline or dobutamine improved only the inotropic response of propranolol and combination treated hearts. Cautious extrapolation of the results to human may suggest continuation of drug therapy of patients before CABG surgery.

Adenine Nucleotides↗
PubMed1993

Patient-controlled analgesia with low dose background infusions after lower abdominal surgery in children.

Forty-five children (aged 6-12 yr) undergoing appendicectomy received one of three analgesic regimens using patient-controlled analgesia (PCA) with morphine: no background infusion (BO); background infusion 4 micrograms kg-1 h-1 (B4); background infusion 10 micrograms kg-1 h-1 (B10). Total consumption of morphine was greater in group B10 compared with groups B0 (P < 0.01) and B4 (P < 0.05). There was no significant difference in morphine consumption in groups B0 and B4. All three groups self-administered similar amounts of morphine and there were no significant differences in pain scores or incidence of excessive sedation. Group B4 suffered less hypoxaemia compared with groups B0 (P < 0.01) and B10 (P < 0.001). Group B10 suffered more nausea and vomiting than groups B0 (P < 0.001) and B4 (P < 0.001), but there was no significant difference in the incidence of nausea and vomiting between groups B0 and B4. Groups B4 and B10 spent more time at night asleep than group B0 (P < 0.05). There were no significant differences between the groups in the amount of time spent asleep during the day. Inclusion of a background infusion of morphine 4 micrograms kg-1 h-1 in a PCA regimen for children did not increase the incidence of side effects and was associated with less hypoxaemia and a better sleep pattern than no background infusion.

Analgesia, Patient-Controlled↗
PubMed1992

Energy expenditure of elite female runners measured by respiratory chamber and doubly labeled water.

To determine whether female athletes have unusually low energy requirements as suggested by many food intake studies, energy expenditure (EE) and intake were assessed in nine elite distance runners [26 +/- 3 (SD) yr, 53 +/- 4 kg, 12 +/- 3% body fat, and 66 +/- 4 ml.kg-1.min-1 maximal O2 uptake]. Subjects were admitted to a metabolic ward for 40 h during which 24-h sedentary EE was measured in a respiratory chamber. Free-living EE was then assessed by the doubly labeled water method for the next 6 days while the women recorded all food intake, daily body weight, and training mileage (10 +/- 3 miles/day). Energy intakes estimated from free-living EE (2,826 +/- 312 kcal/day) and body weight changes (-84 +/- 71 g/day) averaged 221 +/- 550 kcal/day in excess of those calculated from food records (2,193 +/- 466 kcal/day). The energy cost of training (1,087 +/- 244 kcal/day) was calculated as the difference between free-living EE and 24-h EE in the respiratory chamber (1,681 +/- 84 kcal/day) corrected for the thermic effect of food of the extra energy intake. These data do not support the hypothesis that training as a distance runner results in metabolic adaptations that lower energy requirements in women.

Adaptation, Physiological↗
PubMed1990

Effect of a high-carbohydrate, low-saturated-fat diet on apolipoprotein B and triglyceride metabolism in Pima Indians.

The mechanisms by which high-carbohydrate, low-saturated-fat diets lower LDL cholesterol (LDLC) concentrations are unknown. In this study, kinetics of VLDL, intermediate density lipoprotein (IDL), and LDL apoprotein B and VLDL triglyceride were determined in seven nondiabetic (ND) and seven non-insulin-dependent diabetic (NIDDM) Pima Indian subjects on high-fat and high-carbohydrate (HICHO) diets. Metabolic changes were similar in ND and NIDDM. On the HICHO diet, LDLC decreased (131 +/- 8 vs. 110 +/- 7 mg/dl, P less than 0.0001) in all subjects. Mean fasting and 24-h triglyceride (TG) concentrations were unchanged, as were mean production rates and fractional clearance rates (FCR) of VLDL apoB and VLDL TG. The mean VLDL apoB pool size (303 +/- 20 vs. 371 +/- 38 mg, P = 0.01) increased owing to a decrease in the mean transport rate (10.7 +/- 1.1 vs. 8.4 +/- 0.9 mg/kg fat-free mass (ffm) per day, P less than 0.0001) and the mean rate constant (2.3 +/- 0.2 vs. 1.5 +/- 0.2, P less than 0.001) for the VLDL apoB to IDL apoB conversion pathway. The mean transport rate of VLDL apoB to LDL apoB via IDL (10.2 +/- 0.9 vs. 8.0 +/- 0.8 mg/kg ffm per day, P less than 0.001) decreased. Mean LDL apoB concentrations decreased (70 +/- 5 vs. 61 +/- 5 mg/dl, P less than 0.001) on the HICHO diet. Means for total LDL apoB transport rate, LDL apoB FCR, and LDLC/apoB ratios were unchanged. In summary, the HICHO diet decreased the activity of mechanisms that convert VLDL to LDL, which contributed to the decrease in LDLC in all subjects. There was also evidence in some subjects for increased activity of LDL apoB clearance mechanisms, and a decrease in the LDLC to apoB ratio.

Apolipoproteins B↗