Biomedical subjects

C Lombard

Publications and source records attributed to C Lombard.

At least 19 recordsLinked to original sources

PubMed2003

Impact of on-site testing for maternal syphilis on treatment delays, treatment rates, and perinatal mortality in rural South Africa: a randomised controlled trial.

BACKGROUND: Syphilis remains a significant cause of preventable perinatal death in developing countries, with many women remaining untested and thus untreated. Syphilis testing in the clinic (on-site testing) may be a useful strategy to overcome this. We studied the impact of on-site syphilis testing on treatment delays and rates, and perinatal mortality. METHODS: We conducted a cluster randomised controlled trial among seven pairs of primary healthcare clinics in rural South Africa, comparing on-site testing complemented by laboratory confirmation versus laboratory testing alone. Intervention clinics used the on-site test conducted by primary care nurses, with results and treatment available within an hour. Control clinics sent blood samples to the provincial laboratory, with results returned 2 weeks later. RESULTS: Of 7134 women seeking antenatal care with available test results, 793 (11.1%) tested positive for syphilis. Women at intervention clinics completed treatment 16 days sooner on average (95% confidence interval: 11 to 21), though there was no significant difference in the proportion receiving adequate treatment at intervention (64%) and control (69%) clinics. There was also no significant difference in the proportion experiencing perinatal loss (3.3% v 5.1%; adjusted risk difference: -0.9%; 95% CI -4.4 to 2.7). CONCLUSIONS: Despite reducing treatment delays, the addition of on-site syphilis testing to existing laboratory testing services did not lead to higher treatment rates or reduce perinatal mortality. However on-site testing for syphilis may remain an important option for improving antenatal care in settings where laboratory facilities are not available.

Adult↗

PubMed2002

Evaluation of a video based health education strategy to improve sexually transmitted disease partner notification in South Africa.

OBJECTIVES: To evaluate the feasibility and impact of a health education intervention promoting partner notification for sexually transmitted diseases (STDs). METHODS: The research setting was a busy public health clinic in a rural district in KwaZulu Natal, South Africa. A before/after quantitative study design was used to measure the effect of an audiovisual presentation of a compelling love drama, posters, and pamphlets. Measures collected from all consenting STD index patients during a 6 week pre-intervention (control) phase were compared with those collected during a 6 week intervention phase. A qualitative evaluation assessed whether the intervention accurately portrayed the intended educational messages. RESULTS: 150 index patients (55% female) were interviewed in the control phase and 185 index patients (64% female) in the intervention phase. The intervention phase showed improvements on several measures of self efficacy about notifying casual partners, such as a belief among index patients that a greater proportion of their casual partners would see the importance of seeking treatment as a result of their notification interaction. The rate of contact cards returned per index patient was 0.27 in the intervention phase, compared with 0.20 in the control phase (95% CI for the rate difference: -0.05, 0.17). The qualitative research found that the intervention was thoroughly enjoyed by patients and clinicians, but a fundamental problem with it was that patients received confused messages about the relation between HIV/AIDS and other STDs. This has potentially negative consequences for partner notification. CONCLUSION: The intervention needs further development, and then could provide a highly acceptable, cost effective model for health education in clinics in developing countries.

Adult↗

PubMed2001

CD44-deficient mice exhibit enhanced hepatitis after concanavalin A injection: evidence for involvement of CD44 in activation-induced cell death.

Administration of Con A induces severe injury to hepatocytes in mice and is considered to be a model for human hepatitis. In the current study, we investigated the role of CD44 in Con A-induced hepatitis. Intravenous administration of Con A (20 mg/kg) caused 100% mortality in C57BL/6 CD44-knockout (KO) mice, although it was not lethal in C57BL/6 CD44 wild-type (WT) mice. Administration of lower doses of Con A (12 mg/kg body weight) into CD44 WT mice induced hepatitis as evident from increased plasma aspartate aminotransferase levels accompanied by active infiltration of mononuclear cells and neutrophils, and significant induction of apoptosis in the liver. Interestingly, CD44 KO mice injected with similar doses of Con A exhibited more severe acute suppurative hepatitis. Transfer of spleen cells from Con A-injected CD44 KO mice into CD44 WT mice induced higher levels of hepatitis when compared with transfer of similar cells from CD44 WT mice into CD44 WT mice. The increased hepatitis seen in CD44 KO mice was accompanied by increased production of cytokines such as TNF-alpha, IL-2 and IFN-gamma, but not Fas or Fas ligand. The increased susceptibility of CD44 KO mice to hepatitis correlated with the observation that T cells from CD44 KO mice were more resistant to activation-induced cell death when compared with the CD44 WT mice. Together, these data demonstrate that activated T cells use CD44 to undergo apoptosis, and dysregulation in this pathway could lead to increased pathogenesis in a number of diseases, including hepatitis.

Adjuvants, Immunologic↗

PubMed2001

Strategies for partner notification for sexually transmitted diseases.

BACKGROUND: Partner notification has been practiced for decades, with substantial resources directed towards it, and with little evidence on whether it has made a public health impact on disease transmission. Most of the evaluations were not randomized controlled trials, and were conducted in the United States, prior to the HIV/AIDS epidemic. There are reasons to question whether partner notification for gonorrhoea and chlamydia is applicable to HIV. It is also questionable whether interventions for the developed world are applicable to the developing world. OBJECTIVES: This review aims to compare the effects of various sexually transmitted disease (STD) partner notification strategies, including to compare provider referral with contract and patient referral, and to compare different patient referral strategies to each other. In addition to updating previous reviews, it addresses partner notification in developing countries as well as in developed countries, with particular consideration for HIV/AIDS. It attempts to address some of the methodological limitations of earlier reviews. SEARCH STRATEGY: The search strategy included MEDLINE, EMBASE, Psychological Abstracts, Sociological Abstracts, the Cochrane Controlled Trials register, the proceedings of the International AIDS Conferences and the International Society for STD Research meetings. SELECTION CRITERIA: The review includes published or unpublished randomised controlled trials (RCTs) comparing two or more partner notification strategies for people diagnosed with STDs. DATA COLLECTION AND ANALYSIS: For each comparison within each study, the difference in the rate of partners elicited, notified, medically evaluated, harmed, etc, the 95% confidence interval, and if significant, the numbers needed to treat (NNT) were calculated. MAIN RESULTS: We found 11 RCTs, including 8014 participants. Only two trials were conducted in developing countries, and only two trials were conducted among HIV positive patients. There was some risk of bias in all the included trials. The review found moderately strong evidence that: 1. provider referral alone, or the choice between patient and provider referral, when compared with patient referral among patients with HIV or any STD, increases the rate of partners presenting for medical evaluation; 2. contract referral, when compared with patient referral among patients with gonorrhoea, results in more partners presenting for medical evaluation; 3. verbal, nurse-given health education together with patient-centred counselling by lay workers, when compared with standard care among patients with any STD, results in small increases in the rate of partners treated. REVIEWER'S CONCLUSIONS: There is a need for evaluations of interventions combining provider training and patient education, and for evaluations conducted in developing countries. All partner notification evaluations, but especially those among HIV positive patients, need to measure potential harmful effects, such as domestic violence, to ensure that partner notification does more good than harm.

Chlamydia Infections↗

PubMed2001

The acrosome index, radical buffer capacity and number of isolated progressively motile spermatozoa predict IVF results.

BACKGROUND: The accuracy by which a number of newly described semen variables can predict either total fertilization failure (TFF) or pregnancy outcome in IVF, has not previously been investigated. The study aim was, therefore, to determine prospectively the predictive value of these variables. METHODS: The semen variables investigated were the post-wash total progressively motile sperm cell count (TPMC(post-wash)), the acrosome index (AI), 'cytoplasmic residues' and normal sperm morphology, evaluated according to the strict criteria ('strict criteria'), as well as the fast and slow total radical trapping antioxidant potential ('fast TRAP' and 'slow TRAP' respectively). RESULTS: The study group (n = 87) showed a mean (+/- SD) number of 10.2 +/- SD retrieved oocytes, 12.6% TFF, a mean fertilization rate of 59.7% and a pregnancy rate of 19.5% (17/87). TFF was significantly predicted by TPMC(post-wash), 'strict criteria', AI and 'cytoplasmic residues' (all P < 0.05). The outcome after embryo transfer was significantly predicted by AI and 'fast TRAP'. Semen samples with an AI <5% and a 'fast TRAP' <1.14 mmol/l in particular did not result in any pregnancies after IVF-embryo transfer. CONCLUSIONS: Of all the measured and calculated semen variables, TPMC(post-wash) was the best predictor of TFF, whilst AI and 'fast TRAP' were the best predictors of pregnancy after IVF.

Acrosome Reaction↗

PubMed2001

Obsessive-compulsive disorder and a novel polymorphism adjacent to the oestrogen response element (ERE 6) upstream from the COMT gene.

Family and twin studies have consistently provided evidence for involvement of genetic mechanisms in obsessive-compulsive disorder (OCD). This has given rise to association studies involving several candidate genes in an endeavour to identify susceptibility factors. One of the more promising candidate genes appears to be the catecol-O-methyltransferase (COMT) gene. Recent association studies in North American and Afrikaner populations have reported a likely association between a functional polymorphism of COMT (linked with COMT enzyme activity levels) and OCD. COMT expression has been demonstrated to be regulated by oestrogen through the oestrogen-response elements (EREs) in the promoter region of the gene. In the light of this association, the authors tested for an association between a novel polymorphism (C --> T transition) adjacent to ERE 6 in the promoter area of COMT and OCD in 48 Afrikaners and 48 ethnically matched controls. The C --> T transition was not significantly associated with OCD (P = 0.93) or gender (P = 0.67). These findings, although limited by a small sample size, suggest that the novel polymorphism adjacent to ERE 6 in the promoter area of COMT does not play a major role in the genetic predisposition to OCD.

Catechol O-Methyltransferase↗

PubMed2001

Exposure to violence and its relationship to psychopathology in adolescents.

OBJECTIVES: This study aimed to establish prevalence of adolescents' exposure to violence and related symptoms in the South African context and to explore relationships between exposure and symptoms. SETTING: Four high schools in Cape Town, South Africa. METHODS: Self report questionnaires were administered to 104 students. Types of violence explored included: witnessing or being a victim of violence perpetrated by someone known to the child or in the home and witnessing or being a victim of violence perpetrated by a stranger. The Harvard Trauma Scale, Beck Depression Inventory, and Zung Self-Rating Anxiety Scale were used to assess potentially related symptoms. RESULTS: The majority of children had been exposed to at least one type of violence, and exposure to the one type of violence was related to the other type. Symptoms of post-traumatic stress disorder and depression appear to be related to most types of exposure to violence, but anxiety symptoms only to exposure to violence perpetrated by someone known to the child or in the home. CONCLUSIONS: Rates of exposure to violence, and related symptoms, were unacceptably high. Symptoms were associated with exposure to violence.

Adolescent↗

PubMed2000

Syndrome packets and health worker training improve sexually transmitted disease case management in rural South Africa: randomized controlled trial.

BACKGROUND: Sexually transmitted diseases (STD) are important co-factors in HIV transmission. We studied the impact of health worker training and STD syndrome packets (containing recommended drugs, condoms, partner notification cards and information leaflets) on the quality of STD case management in primary care clinics in rural South Africa. METHODS: A randomized controlled trial of five matched pairs of clinics compared the intervention with routine syndromic management. Outcomes were measured by simulated patients using standardized scripts, and included the proportion given recommended drugs; correctly case managed (given recommended drugs plus condoms and partner cards); adequately counselled; reporting good staff attitude; and consulted in privacy. RESULTS: At baseline, the quality of STD case management was similarly poor in both groups. Only 36 and 46% of simulated patients visiting intervention and control clinics, respectively, were given recommended drugs. After the intervention, intervention clinics provided better case management than controls: 88 versus 50% (P < 0.01) received recommended drugs; 83 versus 12% (P < 0.005) were correctly case managed; 68 versus 46% (P = 0.06) were adequately counselled; 84 versus 58% experienced good staff attitude (P = 0.07); and 92 versus 86% (P = 0.4) were consulted privately. A syndrome packet cost US$1.50; the incremental cost was US$6.80. The total intervention cost equalled 0.3% of annual district health expenditure. INTERPRETATION: A simple and affordable health service intervention achieved substantial improvements in STD case management. Although this is a critical component of STD control and can reduce HIV transmission, community-level interventions to influence health-seeking behaviour are also needed.

Adolescent↗

PubMed2000

Impact on perinatal mortality of missed opportunities to treat maternal syphilis in rural South Africa: baseline results from a clinic randomized controlled trial.

OBJECTIVE: To demonstrate the impact on perinatal mortality of inadequate treatment for maternal syphilis despite adequate screening. METHOD: In 12 clinics providing antenatal care in Hlabisa, South Africa 1783 pregnant women were screened for syphilis at their first antenatal visit between June and October 1998. Pregnancy outcome was determined among those with syphilis. RESULTS: A total of 158 women were diagnosed with syphilis: prevalence 9% (95% CI 8-10%). Mean gestation at first antenatal visit was 24 weeks. Thirty women (19%) received no treatment and 96 (61%) received all three recommended doses of penicillin. Among those receiving at least one dose, mean delay to the first dose was 20 days. Among those fully treated mean delay to treatment completion was 34 days. Pregnancy outcome was known for 142 women (90%) and there were 17 perinatal deaths among 15 women (11%). Eleven of 43 women (26%) who received one or fewer doses of penicillin experienced a perinatal death whilst only four of 99 women (4%) who received two or more doses of penicillin did so (P = 0.0001). Protection from perinatal death increased with the number of doses of penicillin: linear modelling suggests that one dose reduced the risk by 41%, two doses by 65% and three doses by 79%, compared with no doses. A dose-specific, categorical model confirmed reduction in risk by 79% for all three doses. CONCLUSION: Despite effective screening, many pregnant women with syphilis remain inadequately treated, resulting in avoidable perinatal mortality. Delays in starting and finishing treatment, as well as incomplete treatment occur. Near-patient syphilis testing in the antenatal clinic with early treatment could improve treatment of syphilis and reduce perinatal mortality, and a randomized trial to test this is underway.

Adolescent↗

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↗