Biomedical subjects

C Lombard

Publications and source records attributed to C Lombard.

At least 37 records · Page 2Linked to original sources

PubMed1999

Specific nonpeptide photoprobes as tools for the structural study of the angiotensin II AT(1) receptor.

The aim of this work was to obtain photoactivatable nonpeptide antagonists of the angiotensin II AT(1) receptor. Based on structure-function relationships, two chemical structures as well as appropriate synthetic schemes were chosen as a frame for the design of radiolabeled azido probes. The feasibility of the strategy was first assessed by the synthesis of two tritiated ligands 21 and 22 possessing a high affinity for the AT(1) receptor and a low nonspecific binding to membrane or cell preparations. We then prepared two unlabeled azido derivatives 7 and 14 which retained a fairly high affinity for the AT(1) receptor. The latter compound proved to be suitable for receptor irreversible labeling and was prepared in its tritiated form 28. This tritiated azido nonpeptide probe displayed a K(d) value of 11.8 nM and a low nonspecific binding. It was suitable for specific and efficient covalent labeling of the recombinant AT(1A) receptor stably expressed in CHO cells. The electrophoretic pattern of the specifically labeled entity was strictly identical to that of purified receptor photolabeled with a biotinylated peptidic photoactivatable probe. This new tool should be useful for the mapping of the nonpeptide receptor binding site. These potential applications are discussed in light of the current knowledge of molecular mechanisms of G-protein coupled receptor activation and inactivation.

Angiotensin II↗

PubMed1999

N-glycosylation requirements for the AT1a angiotensin II receptor delivery to the plasma membrane.

The purpose of this work was to investigate the role of N-glycosylation in the expression and pharmacological properties of the the rat AT1a angiotensin II (AII) receptor. Glycosylation-site suppression was carried out by site-directed mutagenesis (Asn-->Gln) of Asn176 and Asn188 (located on the second extracellular loop) and by the removal of Asn4 at the N-terminal end combined with the replacement of the first four amino acids by a 10 amino acid peptide epitope (c-Myc). We generated seven possible N-glycosylation-site-defective mutants, all tagged at their C-terminal ends with the c-Myc epitope. This double-tagging strategy, associated with photoaffinity labelling, allowed evaluation of the molecular masses and immunocytochemical cellular localization of the various receptors transiently expressed in COS-7 cells. We showed that: (i) each of the three N-glycosylation sites are utilized in COS-7 cells; (ii) the mutant with three defective N-glycosylation sites was not (or was very inefficiently) expressed at the plasma membrane and accumulated inside the cell at the perinuclear zone; (iii) the preservation of two sites allowed normal receptor delivery to the plasma membrane, the presence of only Asn176 ensuring a behaviour similar to that of the wild-type receptor; and (iv) all expressed receptors displayed unchanged pharmacological properties (Kd for 125I-sarcosine1-AII; sarcosine1-AII-induced inositol phosphate production). These results demonstrate that N-glycosylation is required for the AT1 receptor expression. They are discussed in the light of current knowledge of membrane-protein maturation and future prospects of receptor overexpression for structural studies.

Amino Acid Sequence↗

PubMed1999

A longitudinal evaluation of extraction versus nonextraction treatment with special reference to the posttreatment irregularity of the lower incisors.

A tendency exists in contemporary orthodontics to pursue a completely non-extraction philosophy. Moreover, it has been shown that the extraction versus non-extraction debate is still with us. Controversy exists as to which treatment decision will eventually lead to orthodontic stability. It is thus imperative to conduct investigations on long-term changes of the dentition in both treatment regimens. The present study serves as an example of such a longitudinal study. A random sample, inclusive of both extraction and non-extraction treatments, was examined with respect to long-term stability and an assessment was made as to whether one treatment option favors success over the other. It was concluded that the correct initial treatment choice will not only lead to correction of the malocclusion, but will also ensure clinically acceptable stability with no significant differences between extraction and non-extraction treatments.

Bicuspid↗

PubMed1999

Blood pressure and social support observations from Mamre, South Africa, during social and political transition.

OBJECTIVE: Social support, by moderating cardiovascular reactivity, has been demonstrated to attenuate the effects of stress on blood pressure in American communities. This is the first report to examine the relationship between social support and blood pressure in a South African context, during a period of infrastructure modernisation and political change. METHODS: A total of 1240 residents (542 men, 698 women) of mixed ethnic origin, older than 14 years and stratified by age and sex, participated in a survey to determine risk factors for hypertension and cardiovascular diseases. Social support was assessed by a questionnaire developed in consultation with the community. It was defined by interactions that may threaten family harmony (score 1) and by networking between relatives, friends, colleagues and neighbours (score 2). RESULTS: Mean blood pressure of the sample was 130/79 mm Hg (s.d. 25/14 mm Hg). Hypertension prevalence was 26.9%. Only 36% of women compared to 57.3% of men (P < 0.0001) were employed. More women (29%) than men (22%) reported threats to family harmony, but social support networks were similarly perceived by both sexes. Systolic and diastolic blood pressure correlated weakly with score 1 (r = 0.096, P < 0.0007) but no association was observed with score 2. Score 1 was not associated with blood pressure by multiple regression analysis, that included confounding by age, sex, BMI, alcohol consumption and smoking status. CONCLUSIONS: Neither threats to family harmony nor networking between relatives, friends or neighbours, significantly influences blood pressure in this community. Measures of social support thought to moderate blood pressure may have limited cross-cultural application. Attitudinal changes during socio-political transition may impact on the generalisability of instruments for measurement.

Adolescent↗

PubMed1999

Constitutive activation of the human bradykinin B2 receptor induced by mutations in transmembrane helices III and VI.

We report that mutation of specific residues in the human B2 bradykinin (BK) receptor induces its marked constitutive activation, evaluated through inositol phosphate production in COS-7 cells expressing the wild-type or mutant receptors. We provide evidence for a strikingly high constitutive activation of the B2 receptor induced by alanine substitution of the Asn113 residue, located in the third transmembrane domain. These results are reminiscent of our previous finding that mutation of the homologous Asn111 residue induces constitutive activation of the AT1 angiotensin II receptor. BK overstimulation of the constitutively activated mutant N113A receptor was also observed. Phe replacement of the Trp256 residue, fairly conserved in transmembrane domain VI of G protein-coupled receptors, also induced a less prominent but significant constitutive activation. Interestingly, the peptidic HOE 140 compound and an original nonpeptidic compound LF 16 0335, which both behaved as inverse agonists of the wild-type receptor expressed in COS-7 cells, became potent and efficient agonists of the two constitutively activated mutant N113A and W256F receptors. These parallel changes observed for two chemically unrelated series can serve as a basis for future studies of structure-function relationships and modeling of activation processes, based on a detailed analysis of the network of helix-helix interactions, which stabilize the inactive receptor conformation and undergo rearrangements on transition to activated states.

Animals↗

PubMed1999

Potentiation of isoniazid activity against Mycobacterium tuberculosis by melatonin.

The limited number of effective antituberculosis drugs available necessitates optimizing current treatments. We show that melatonin, which is synthesized in the pineal gland, can cause at least a threefold increase in the efficacy of isoniazid. This suggests that tuberculosis chemotherapy can be improved by innate molecules such as melatonin.

Antioxidants↗

PubMed1999

The changes in circulating hepatocyte growth factor after partial hepatectomy in the baboon.

There is no established model of regenerative liver resection in the baboon, and no study comparing the circulating hepatocyte growth factor (HGF) response with the DNA synthetic response after liver resection. A mean 20% partial hepatectomy (PH) was performed in 19 baboons and a sham operation comprising liver mobilisation only was performed in 20 baboons. Blood HGF levels were measured up to 5 days after either procedure, using the human HGF enzyme-linked immunosorbent assay (ELISA) kit (Otsuka, Japan). The white cell count (WCC), aspartate transaminase (AST) and bilirubin were also measured. Liver regeneration, reflected by an increase in DNA synthesis, was determined from serial liver biopsies in 23 baboons, using a tritiated thymidine assay of liver thymidine kinase (TK). Liver resection and WCC had a significant influence on circulating HGF levels. There was a linear relationship between WCC and circulating HGF levels, which was independent of PH. For a constant value of WCC, resection produced a peaking of HGF over time, with the maximal levels occurring between 2 and 3 days, compared with the linear response in HGF in sham-operated baboons. Liver damage, as reflected by AST levels, was found to have no significant influence on circulating HGF levels. The 20% PH produced a significant increase in liver TK, with maximum levels evident between 2 and 4 days. Accordingly in this baboon model of PH the increase in biologically active, circulating HGF preceded the increase in liver DNA synthesis over 5 days. This observation supports the role of HGF in hepatocyte proliferation and as an initiator of liver regeneration, and suggests that further investigation into the potential endocrine action of HGF could be studied in this established liver regenerative primate model.

Animals↗

PubMed1998

Anthropometric profile of a black population of the Cape Peninsula in South Africa.

This study describes the anthropometry of an urban black population living in the Cape Peninsula, South Africa. A random sample of 986 selected adults aged 15-64 years and 163 children aged three to six years, included data on heights, weights, and mid-upper arm circumferences and calculation of the body mass index (BMI). The mean height of men was 168.3 cm and that of women 158.3 cm. Mean weight, BMI and mid-upper arm circumference for men were 66.2 kg, 23.4 and 28.1 cm and for women 69.8 kg, 27.8 and 30.6 cm respectively. The prevalence of underweight in men (BMI < 20) was 19% and in women (BMI < 19) 3.7%; 22% of the men were overweight (BMI > or = 25) and 7.9% obese (BMI > or = 30), while 36.4% of women were overweight (BMI > or = 24) and 34.4% obese (BMI > or = 30). More than half of the women above the age of 35 years were obese. Anthropometry of the three to six year old children was calculated for stunting, wasting and underweight, expressed in terms of the National Centre for Health Statistics standards, and revealed co-existing evidence of growth retardation and wasting with emergent obesity. These findings suggest that a part of this community, who may have been nutritionally deprived during childhood, has moved from undernutrition to extreme overnutrition without having achieved optimal nutritional status. Complexities that need to be considered when planning strategies to address malnutrition in the black South African population are identified.

Adolescent↗

PubMed1997

Mutation of Asn111 in the third transmembrane domain of the AT1A angiotensin II receptor induces its constitutive activation.

A preliminary model of the rat AT1A angiotensin II (AII) receptor (Joseph, M. P., Maigret, B., Bonnafous J.-C., Marie, J., and Scheraga, H. A. (1995) J. Protein Chem. 14, 381-398) has predicted an interaction between Asn111 located in transmembrane domain (TM) III and Tyr292 (TM VII) in the nonactivated receptor; a disruption of this interaction upon AII activation would allow Tyr292 to interact with the conserved Asp74 (TM II). The previous verification that Tyr292 is essential for receptor coupling to phospholipase C (Marie, J., Maigret, B., Joseph, M. P., Larguier, R., Nouet, S., Lombard, C., and Bonnafous, J.-C. (1994) J. Biol. Chem. 269, 20815-20818) prompted us to check the possible alterations in receptor properties upon Asn111 --> Ala mutation. The mutated receptor (N111A) displayed: (i) strong constitutive activity, with amplification of the maximal phospholipase C response to AII; (ii) agonist behavior of the AT2-specific ligand CGP 42112A, [Sar1, Ile8]AII, and [Sar1,Ala8]AII, antagonists of the wild-type receptor; (iii) inverse agonism behavior of the non-peptide ligands DuP 753, LF 7-0156, and LF 8-0129. The results are discussed in the light of the allosteric ternary complex models and other described examples of constitutive activation of G protein-coupled receptors.

Alanine↗

PubMed1997

Molecular epidemiology and transmission dynamics of Mycobacterium tuberculosis in rural Africa.

The relative contribution of reactivated and recently acquired tuberculosis to the disease burden in developing countries is unknown, as are the settings within which most transmission occurs. In an attempt to answer these questions, we combined molecular techniques (restriction fragment length polymorphism analysis) and conventional epidemiology (risk factor analysis and contact tracing) to study 246 consecutive cases of smear-positive tuberculosis in rural South Africa. We estimate that 29-43% of the cases were recently acquired, as they were clustered. We were unable to identify firm transmission links between 73% of clustered cases. Our findings suggest that most smear-positive tuberculosis in rural Africa is both recently acquired and casually transmitted. Tuberculosis control may depend more on promoting early presentation, rapid diagnosis and vaccine development than on chemotherapy.

Adult↗

PubMed1997

On-site HIV testing in resource-poor settings: is one rapid test enough?

OBJECTIVE: To determine the feasibility, accuracy and cost-effectiveness of a rapid, on-site, HIV testing strategy in a rural hospital, and to assess its impact on test turnaround time and the proportion of patients post-test counselled. DESIGN: Prospective comparison of two testing strategies [double rapid test on-site versus central enzyme-linked immunosorbent assay (ELISA)-based testing], and an economic evaluation. SETTING: Hlabisa Hospital, a rural South African district hospital. PATIENTS: A total of 454 consecutive adult inpatients requiring and consenting to HIV testing as part of their clinical management. MAIN OUTCOME MEASURES: Concordance between rapid tests, and between the rapid and ELISA strategies, test turnaround time, proportion of patients post-test counselled, and cost-effectiveness. RESULTS: HIV seroprevalence was 49.6%. Both rapid tests were concordant in all patients [one-sided 95% confidence interval (CI) of probability, 99.3-100]. The rapid strategy was 100% sensitive (95% CI, 97.9-100) and 99.6% specific (95% CI, 97.2-100) compared with the ELISA strategy. The mean interval between ordering a test and post-test counselling fell from 21 days prior to the introduction of the rapid test strategy to 4.6 days after its introduction (P < 0.00001). The proportion of patients post-test counselled increased to 96% from 17% after the introduction of the rapid test strategy (P < 0.00001). By using a double rapid test strategy the cost per patient post-test counselled was almost halved to US$ 11. Accuracy of the rapid strategy was not substantially increased by performing two tests. CONCLUSION: In high prevalence, resource-poor settings, rapid, on-site HIV testing is feasible, accurate and highly cost-effective, substantially increasing the number of patients post-test counselled. A single rapid test may be sufficient.

AIDS Serodiagnosis↗

PubMed1997

The epidemiology of incomplete abortion in South Africa. National Incomplete Abortion Reference Group.

OBJECTIVE: To describe the epidemiology of incomplete abortion (spontaneous miscarriage and illegally induced) in South Africa. DESIGN: Multicentre, prospective, descriptive study. SETTING: Fifty-six public hospitals in nine provinces (a stratified, random sample of all hospitals treating gynaecological emergencies). PATIENTS: All women of gestation under 22 weeks who presented with incomplete abortion during the 2-week study period. MAIN OUTCOME MEASURES: Incidence of, morbidity associated with and mortality from incomplete abortion. MAIN RESULTS: An estimated 44686 (95% CI 35633-53709) women per year were admitted to South Africa's public hospitals with incomplete abortion. An estimated 425 (95% CI 78-735) women die in public hospitals from complications of abortion. Fifteen per cent (95% CI 13-18) of patients have severe morbidity while a further 19% (95% CI 16-22) have moderate morbidity, as assessed by categories designed for the study which largely reflect infection. There were marked inter-provincial differences and inter-age group differences in trimester of presentation and proportion of patients with appreciable morbidity. CONCLUSIONS: Incomplete abortions and, in particular, unsafe abortions are an important cause of mortality and morbidity in South Africa. The methods used in this study underestimate the true incidence for reasons that are discussed. A high priority should be given to the prevention of unsafe abortion.

Abortion, Incomplete↗

PubMed1997

Halothane hepatitis in a South African population--frequency and the influence of gender and ethnicity.

AIM: To review post-anaesthetic hepatitis in a South African population, given that halothane use is restricted in other countries because of the high mortality and morbidity of its associated type II (idiosyncratic) hepatitis, even though it is still widely used in South Africa. STUDY DESIGN: Descriptive, retrospective analysis. PATIENTS AND METHODS: Hepatitis cases that occurred after inhalational anaesthetic use were identified by means of a computer search of Groote Schuur Hospital records, 1980-1994. Cases of hepatitis caused by circulatory failure and viral hepatitis were excluded. RESULTS: Twenty-six episodes occurred in 22 patients (mean age 49.05 years, range 32-65 years), of whom 15 were women. This gave an estimated incidence of 3.53/100,000 anaesthetics (95% confidence interval 2.06-5.0/100,000). All had pyrexia (mean 38.7 +/- 0.72 degrees C), malaise, anorexia or nausea and vomiting, with onset a mean of 4.27 +/- 3.5 days after exposure. Jaundice occurred in 86%, rash in 13.6%; 17 patients (77%) were obese. Alanine and aspartate aminotransferase levels were raised 47.49 +/- 61.8 and 55.9 +/- 54.5 times the upper limit of normal. Seven patients died and 1 underwent liver transplantation. Hepatitis occurred after the first exposure in only 2 patients (9%). Men and women had a similar risk, but the estimated relative risk for whites v. black or coloured patients was 3.33 (95% confidence interval 1.45-7.23; P = 0.003) controlling for gender. Awareness of the condition was suboptimal, and in 3 patients re-exposure to halothane occurred after an initial episode of typical halothane hepatitis. CONCLUSION: Halothane hepatitis remains a major cause of morbidity and mortality in South Africa. It is more common in whites, but there was no gender-related excess risk.

Adult↗

PubMed1997

[Hemorrhagic pericardial effusion in dogs. A retrospective study of 10 cases (1989-1994) with a review of the literature].

After an introduction on pathophysiological and etiological aspects of idiopathic hemorrhagic pericardial effusion, ten dogs affected with this condition are described. Clinical signs permitted to establish a diagnosis of suspicion in all cases. Electrocardiography, thoracic radiography and echocardiography allowed confirmation of the diagnosis. Echocardiography was the most sensitive method available. Six dogs had idiopathic pericardial effusion. A subtotal pericardectomy was performed in two of these dogs. In four dogs, the effusion was caused by a tumor. Two dogs with mesothelioma were euthanized because of poor prognosis. Heart base tumors were found in the two other dogs. One of them is still alive and well one year after subtotal pericardectomy. The other one was euthanized due to deterioration of his condition two years after the operation. Idiopathic hemorrhagic pericardial effusion carries a good prognosis if appropriately treated (pericardiocentesis, possibly subtotal pericardectomy). Pericardial effusion is also frequently associated with tumors. In such cases, prognosis and therapy essentially depend on the type of tumor.

Animals↗

PubMed1997

Shared vision--a health education project designed to enhance adherence to anti-tuberculosis treatment.

SETTING: Two adjacent Cape Town Local Authority health clinics in Cape Town, South Africa, were selected. Clinic A was designated the 'intervention clinic' and Clinic B the 'control clinic.' OBJECTIVE: To assess whether the combined strategy of a patient-centred interview plus the issuing of a patient education booklet would have the effect of increasing the adherence of notified pulmonary tuberculosis (TB) patients to prescribed treatment. DESIGN: A controlled intervention study was implemented using a cohort of the first 60 consecutive patients notified with pulmonary TB at both Clinic A and Clinic B; the patient cohort thus consisted of 120 patients. RESULTS: The risk of patient non-adherence to anti-tuberculosis treatment was significantly reduced at the intervention clinic compared to the control clinic. CONCLUSION: The results of this study indicate the need for further operational research to assist health providers in developing standardised protocols of health education to enhance adherence to treatment in patients who require protracted treatment regimens.

Attitude to Health↗

PubMed1996

Tuberculosis in the community: 1. Evaluation of a volunteer health worker programme to enhance adherence to anti-tuberculosis treatment.

SETTING: A voluntary health worker project (Operation Elsies River) was started in a high incidence tuberculosis (TB) area in the Western Cape of South Africa, in order to assist the local TB Control programme with case-holding. OBJECTIVE: To evaluate the effectiveness of this group of volunteers in enhancing adherence of notified TB patients to tuberculosis treatment. DESIGN: A cohort study was conducted with 351 TB patients (203 children and 148 adults). RESULTS: The data from the child and the adult groups were analysed separately. The child group was more adherent to TB treatment than adults. The supervision option with staff dedicated to the treatment of TB, such as the clinic and the SANTA crèche, achieved better adherence results for pre-school children. The supervision modalities for adults did not differ in their adherence performance even following adjustment for confounders. CONCLUSION: The supervision option provided by the volunteers did not significantly improve the adherence of adult patients to antituberculosis treatment.

Adolescent↗

PubMed1996

The lipid and lipoprotein profile of the urban black South Africa population of the Cape Peninsula - the BRISK study.

OBJECTIVE: To determine the lipid and lipoprotein profile of the urban black South African population of the Cape Peninsula. DESIGN: Cross-sectional design. SETTING: The seven black residential areas of the Cape Peninsula. PARTICIPANTS: A stratified proportional sample was drawn from the study area. The sample consisted of 422 men and 544 women aged between 15 and 64 years. OUTCOME MEASURES: Lipid and lipoprotein levels. Risk levels for coronary heart disease (CHD). RESULTS: The total cholesterol (TC level) was low compared with other South African groups studied. Men had a mean TC of 3.98 mmol/l and women 4.15 mmol/l. Low-density lipoprotein cholesterol (LDLC) values for men (2.03 mmol/l) were lower than those for women (2.30 mmol/l). Men (1.35 mmol/l) and women (1.37 mmol/l) had similar high-density lipoprotein cholesterol (HDLC) levels. Both sexes had a prevalence of protective HDL/TC ratios above 30% for all age groups. High HDL3C levels and low HDL2C levels were found in both men and women. Apolipoprotein A and B followed the trends of HDLC and LDLC and showed no difference between the sexes. The plasma triglyceride (TG) levels increased with age in both sexes. Men displayed higher TG levels than women in all age groups. Seventeen per cent of men and 26% of women had a moderate-to-high risk for CHD, given their TC levels. Other lipid-related risk factors indicated low risk for CHD.

Adolescent↗

PubMed1996

[ECG abnormalities in Airedale terriers].

Because of bradyarrhythmic complications under anesthesia in two Airedale Terriers, we performed a prospective search of ECG-abnormalities in healthy dogs of that breed. Resting ECG's were screened for routine abnormalities. None of the 42 dogs investigated so far had a completely normal ECG. Among the common abnormalities were: deviation of the mean electrical axis (MEA) in 32 dogs, low voltage QRS-complexes in 22 dogs, and AV-blocks 1st degree in 14 dogs. None of the recorded abnormalities with the exception of AV-blocks, were considered predictors of anesthetic complications. Because of the high frequency of recorded abnormalities, we are continuing this prospective study.

Anesthesia↗