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Biomedical subjects

J S Davidson

Publications and source records attributed to J S Davidson.

At least 19 recordsLinked to original sources
PubMed2006

Association of pre-eclampsia with the R563Q mutation of the beta-subunit of the epithelial sodium channel.

The R563Q mutation of the beta-subunit of the epithelial sodium channel (ENaC) is associated with hypertension in black and mixed ancestry (MA) men and women in South Africa. The frequency of the R563Q mutation in black and MA women with pre-eclampsia (n= 230) and in controls (n= 198) was studied. The R563Q mutation was found in 7.8% of the women with pre-eclampsia and in 2.6% of controls (P= 0.014). This remained significant if the black women were analysed separately (P= 0.031). We have demonstrated that a genetic variant of the ENaC is associated with pre-eclampsia. This has implications for understanding the pathogenesis and treatment of pre-eclampsia.

Adult↗
PubMed2001

Simple treatment for torus fractures of the distal radius.

Torus (buckle) fractures of the distal radius are common in childhood. Based on the results of a postal questionnaire and a prospective, randomised trial, we describe a simple treatment for this injury, which saves both time and money. Over a six-month period, we randomised 201 consecutive patients with this injury to treatment with either a traditional forearm plaster-of-Paris cast or a 'Futura-type' wrist splint. All patients were treated for a period of three weeks, followed by clinical and radiological review. There was no difference in outcome between the two groups, and all patients had a good result. Only one patient did not tolerate the splint which was replaced by a cast. The questionnaire showed a marked variation in the way in which these injuries are treated with regard to the method and period of immobilisation, the number of follow-up visits and radiographs taken. We suggest that a 'Futura-type' wrist splint can be used to treat these fractures. The patient should be reviewed on the following day to confirm the diagnosis and to give appropriate advice. There is no evidence that further follow-up is required. This simple treatment has major benefits in terms of cost and reduction of the number of attendances.

Adolescent↗
PubMed2001

Screening for primary aldosteronism--normal ranges for aldosterone and renin in three South African population groups.

OBJECTIVE: To establish normal ranges for plasma aldosterone, renin and aldosterone/renin (A/R) ratio in South African normotensives under typical outpatient conditions, and to estimate the prevalence of primary aldosteronism (PA) among hypertensives in primary care settings. DESIGN AND METHODS: One hundred and thirty-six normotensive subjects and 154 sex- and age-matched hypertensives at three primary care clinics had measurements of blood pressure, plasma creatinine, K+, aldosterone, plasma renin activity, and spot urine for urinary Na+/creatinine ratio. Medication was not withdrawn before testing. RESULTS: Mean plasma renin activity in black normotensive subjects (0.95 +/- 1.25 ng/ml/h, mean +/- standard deviation (SD)) was significantly lower than in white (2.09 +/- 1.12 ng/ml/h; P < 0.0001) and coloured (1.81 +/- 1.86 ng/ml/h, P = 0.013) normotensives. Mean plasma aldosterone in black normotensives (306 +/- 147 pmol/l) was also significantly lower than in white (506 +/- 324 pmol/l, P = 0.0002) and coloured (418 +/- 304 pmol/l, P = 0.0148) normotensives. In hypertensives, there were no significant differences in renin or aldosterone levels between the three population groups. Urinary Na+/creatinine ratios, an index of Na+ intake, were not significantly different in the three population groups. None of the normotensives had an A/R ratio > or = 1,000 plus aldosterone > or = 750, while 7.1% of hypertensives exceeded these levels, suggesting that they are appropriate criteria for screening for PA. CONCLUSIONS: A large fraction of black normotensive subjects had low renin and aldosterone levels compared with whites, suggesting a salt-retaining tendency in black subjects. These results have important implications for the interpretation of plasma renin and aldosterone levels in hypertensive patients. In primary care settings, 7.1% of hypertensives had biochemical results indicating the need for investigation of PA.

Aldosterone↗
PubMed2000

Using the World-Wide-Web to obtain feedback on the quality of surgical residency training.

BACKGROUND: Resident feedback can lead to an improvement in teaching performance. Compliance with our previous rotation evaluation system has been poor. METHODS: Rotation evaluation forms were integrated to the departmental World-Wide-Web site. Anonymously completed evaluations are automatically sent to an appointed surgery professor via electronic mail (e-mail). They are then collated and transmitted to program directors. RESULTS: Ninety-two percent (24 of 26) of our surgical residents have an e-mail account. During the 2-month trial, 18 residents completed 48 evaluations. This represents a 75% (18 of 24) compliance rate among residents with e-mail capabilities. The response rate was 82% (9 of 11) for core residents, 64% (7 of 11) for third- and fourth-year residents, and 50% (2 of 4) for chiefs. A second 2-month trial yielded a 75% (18 of 24) response rate and 43 evaluations. CONCLUSIONS: The World-Wide-Web is a user-friendly medium suitable to obtain valuable feedback on the quality of residency training. Compliance was improved using this new system.

Evaluation Studies as Topic↗
PubMed2000

Skin-stretching device for intraoperative primary closure of radial forearm flap donor site.

The use of a skin-stretching device to close radial forearm donor-site defects in patients being treated for intraoral cancer is described. Intraoperative application of the device achieved primary closure of the donor site during the time course of the reconstructive procedure with no requirement for additional operative time. The device was used successfully in seven patients with two instances of marginal skin necrosis and delayed healing but good long-term functional and cosmetic outcomes in all cases.

Equipment Design↗
PubMed2000

Desensitization and internalization of human and xenopus gonadotropin-releasing hormone receptors expressed in alphaT4 pituitary cells using recombinant adenovirus.

Nonmammalian vertebrates express at least two forms of GnRH and distinct forms of GnRH receptor (GnRH-R) have coevolved with their ligands. Mammalian and nonmammalian GnRH-R have key structural differences (notably the lack of C-terminal tails in mammalian GnRH-R) and comparative studies are beginning to reveal their functional relevance. However, cellular context and receptor density influence G protein-coupled receptor function and may be important variables in such work using heterologous expression systems. Here we report a comparative study using alphaT4 cells (gonadotrope progenitors that lack endogenous GnRH-R) transfected with a mammalian (human) or nonmammalian (Xenopus laevis type I) GnRH-R. Because conventional transfection strategies proved inefficient, recombinant adenovirus expressing these receptors were constructed, enabling controlled and efficient GnRH-R expression. When expressed in alphaT4 cells at physiological density, these GnRH-Rs retain the pharmacology of their endogenous counterparts (as judged by ligand specificity in radioligand binding and inositol phosphate accumulation assays) but do not activate adenylyl cyclase and are not constitutively active. Moreover, the Xenopus GnRH-R rapidly desensitizes and internalizes in these cells, whereas the human GnRH-R does not, and the internalization rates are not dependent upon receptor number. These data extend studies in COS, HEK, and GH3 cells showing that other GnRH-R with C-terminal tails desensitize and internalize rapidly, whereas tail-less mammalian GnRH-R do not. Retention of these distinctions at physiological receptor density in gonadotrope lineage cells, supports the argument that the evolution of nondesensitizing mammalian GnRH-Rs is functionally relevant and related to the development of mammalian reproductive strategies.

Adenoviridae↗
PubMed2000

The aldosterone/renin ratio as a screening test for primary aldosteronism.

OBJECTIVE: To investigate the utility of random outpatient plasma aldosterone and renin measurements in screening for primary aldosteronism (PA) in hypertensive patients. DESIGN: Clinical records of hypertensive patients who had aldosterone and renin determinations over a 3-year period were analysed retrospectively. The patients were arbitrarily classified into five groups defined according to the aldosterone level and the aldosterone/renin (A/R) ratio: PA (plasma aldosterone > 500, A/R ratio > or = 1,000; essential hypertension (EHT) (aldosterone < 1,000, A/R < 1000); secondary hyperaldosteronism (SHA) (aldosterone > or = 1,000, A/R < 400); low-renin hypertension (LRHT) (aldosterone < 500, A/R > or = 1,000); miscellaneous hyperaldosteronism (MHA) (aldosterone > or = 1,000, A/R 400-1000). SETTING: A hypertension clinic in a large teaching hospital. PATIENTS AND RESULTS: The sample of 216 hypertensives were classified as follows: EHT 51%, LRHT 8%, PA 32%, SHA 7%, and MHA 3%. Mean plasma potassium values were significantly lower (P < 0.0001) in the PA group compared with essential hypertensives, but plasma K+ was of little utility in identifying individual patients with PA, as 71% were normokalaemic. Adrenal computed tomography scans were performed on 38 of 69 patients with PA, and revealed definite unilateral or bilateral adrenal masses in 7 and probable unilateral masses in a further 4. Five patients underwent unilateral adrenalectomy, confirming adrenal adenomas in 4 and nodular hyperplasia in 1. The minimum prevalence of PA due to adrenal adenoma or hyperplasia was 3.3% of all hypertensives and 10.1% of patients with biochemical PA defined by A/R ratio. Patients with biochemical PA had more target organ damage, and in general responded more favourably to regimens with spironolactone than to conventional therapy. CONCLUSIONS: A random outpatient aldosterone and renin measurement identifies a group of hypertensives with biochemical PA in which there is a significant prevalence of adrenal adenomas, increased prevalence of target organ damage and a good response to spironolactone. These results have major implications for the investigation and management of patients with severe or resistant hypertension.

Adult↗
PubMed1999

A new photoreactive antagonist cross-links to the N-terminal domain of the gonadotropin-releasing hormone receptor.

A new photoreactive gonadotropin-releasing hormone (GnRH) antagonist [Ac-(4-azidobenzoyl)-D-Lys1, D-4-Cl-Phe2, D-Trp3, D-Arg6, D-Ala10]GnRH (PAnt-1) was synthesized and shown to bind covalently to mouse and human GnRH receptors after ultraviolet irradiation. PAnt-1 exhibited high binding affinity (Ki = 3.1 +/- 0.8 nM), and high crosslinking efficiency as shown by loss of 78% of binding sites following crosslinking at saturating concentration. Crosslinking resulted in irreversible receptor blockade as shown by inhibition of GnRH-stimulated inositol phosphate production. PAnt-1 has a photoreactive group at residue 1 of the peptide, a region believed to be critical in determining antagonist versus agonist properties of GnRH analogues. The attachment site of PAnt- to the receptor was localized between residues 11 and 19 of the extracellular N-terminal domain of the receptor by peptide mapping studies using natural sequence differences between human, mouse and sheep GnRH receptors, as well as a panel of GnRH receptor constructs with a series of engineered protease cleavage sites. A disulphide bridge between Cys14 and Cys200 was cleaved during crosslinking, suggesting that Cys14 is the crosslinked residue. These results suggest that peptide GnRH antagonists bind to the receptor with the N-terminal end of the peptide positioned in a site comprising the constrained regions of the N-terminal domain and second extracellular loop in the vicinity of the Cys14-Cys200 disulphide bridge.

Affinity Labels↗
PubMed1999

The tail of the gonadotrophin-releasing hormone receptor: desensitization at, and distal to, G protein-coupled receptors.

In recent years a general scheme for the rapid desensitization and cycling of G protein-coupled receptors (GPCRs) has emerged. In this scheme agonist-induced phosphorylation (most often in the receptors' C-terminal tail) causes association with beta-arrestin which not only reduces the efficiency of G-protein activation, but also targets these desensitized receptors for internalization, after which they may be either proteolytically degraded or resensitized and recycled back to the cell surface. Although sustained stimulation of pituitary gonadotrophs with gonadotrophin-releasing hormone (GnRH) is known to cause a pronounced desensitization of GnRH-stimulated gonadotrophin secretion, the discovery that mammalian GnRH receptors do not possess C-terminal tails raised the question of whether receptor desensitization is involved. This review outlines data demonstrating that tail-less mammalian GnRH receptors can be considered as natural desensitization and internalization deficient 'mutants'. This is in stark contrast to non-mammalian GnRH receptors which do possess tails and conform to the general scheme. In the absence of receptor desensitization, post receptor mechanisms take on increasing importance for desensitization of GnRH action via mammalian GnRH receptors. The down regulation of Ins(1,4,5)P3 receptors and consequent desensitization of GnRH effects on cytosolic Ca2+ are discussed as a novel mechanism for such desensitization.

Animals↗
PubMed1999

The lack of gonadotrophin-releasing hormone (GnRH) receptor desensitisation in alphaT3-1 cells is not due to GnRH receptor reserve or phosphatidylinositol 4,5-bis-phosphate pool size.

The phospholipase C (PLC)-activating gonadotrophin-releasing hormone (GnRH) receptor is thought not to rapidly desensitise in alphaT3-1 cells. This extremely unusual characteristic raises the concern that it might be a feature of the cell type, rather than the receptor per se. Here we have used video imaging to establish whether the effects of endogenous PLC-activating G-protein coupled receptors (GPCRs) on Ca2+ ion concentration [Ca2+]i desensitise in these cells. Oxytocin, endothelin-1, methacholine, and UTP all caused [Ca2+]i increases which underwent rapid homologous desensitisation in that they were transient and responses to repeat stimuli were attenuated whereas subsequent responses to GnRH were not. To test whether receptor reserve obscures functional desensitisation of GnRH receptors, a photoaffinity antagonist (Pant-1), was used to effect a partial and irreversible receptor blockade. UV crosslinking in medium with 1000 nM Pant-1 reduced GnRH receptor number to 20 +/- 5% and reduced maximal buserelin-stimulated [3H]IP(X) accumulation to 57 +/- 5%, demonstrating removal of receptor reserve. In control alphaT3-1 cells the initial rate of GnRH-stimulated [3H]IP(X) accumulation was maintained for at least 5 min and GnRH caused a sustained increase in Ins(1,4,5)P3 mass (confirming the resistance of GnRH receptors to desensitisation) and Pant-1 pre-treatment reduced the magnitude of these responses without altering their temporal profiles. In alphaT3-1 cells stably transfected with recombinant human muscarinic receptors (alphaT3-1/M3), responses to methacholine were characteristic of desensitising GPCRs (transient Ins(1,4,5)P3 and curvilinear [3H]IP(X) responses) and were unaltered by Pant-1. To test the relevance of phospholipid pool size, alphaT3-1/M3 cells were pre-treated with GnRH or methacholine in medium with LiCl (to deplete PtdIns(4,5)P2 pools). These pre-treatments reduced subsequent responses to methacholine and GnRH comparably, indicating access to a shared PtdIns(4,5)P2 pool. Partial depletion of this pool (GnRH pre-treatment in medium with LiCl) reduced the magnitude of the [3H]IP(X) and Ins(1,4,5)P3 responses to methacholine and GnRH, without altering their temporal profiles. Thus the GnRH receptor does not undergo rapid homologous desensitisation in alphaT3-1 cells in spite of the fact that they can desensitise other endogenous (and recombinant) PLC-activating GPCRs, and the lack of desensitisation cannot be attributed to the existence of GnRH receptor reserve or access to an atypically large or rapidly re-cycled PtdIns(4,5)P2 pool. This unique functional characteristic (mammalian GnRH receptors are the only PLC-activating GPCRs known not to rapidly desensitise) almost certainly therefore reflects the atypical structure of these receptors (mammalian GnRH receptors are the only PLC-activating GPCRs known to lack C-terminal tails).

Animals↗
PubMed1999

Antimicrobial activity of lidocaine against bacteria associated with nosocomial wound infection.

The authors characterized the in vitro antibacterial properties of clinical doses of lidocaine on isolates of a variety of bacterial pathogens commonly encountered in the setting of nosocomial wound infection (Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus) as well as a number of resistant strains of methicillin-resistant S. aureus and vancomycin-resistant enterococci. Time-kill studies were carried out on bacteria exposed to various clinical concentrations of lidocaine (0%, 1%, 2%, and 4%) with and without epinephrine (1:100,000). Minimum inhibitory concentrations and minimum bactericidal concentrations were determined for some strains using a broth macrodilution method recommended by the National Committee of Clinical Laboratory Standards. Lidocaine demonstrated a dose-dependent inhibition of growth for all strains of bacteria tested. The greatest sensitivity to lidocaine was shown by gram-negative organisms; the least sensitive was S. aureus. The addition of epinephrine to the local anesthetic had no effect on the susceptibility of the bacteria to lidocaine. These observations suggest that the surgical benefit of local anesthesia may extend beyond its analgesic properties and may have a role in the prophylaxis and, in the case of methicillin- and vancomycin-resistant bacteria, the treatment of surgical wound infection, mandating a wider application of this modality.

Anti-Bacterial Agents↗
PubMed1998

Functional microdomains in G-protein-coupled receptors. The conserved arginine-cage motif in the gonadotropin-releasing hormone receptor.

An Arg present in the third transmembrane domain of all rhodopsin-like G-protein-coupled receptors is required for efficient signal transduction. Mutation of this Arg in the gonadotropin-releasing hormone receptor to Gln, His, or Lys abolished or severely impaired agonist-stimulated inositol phosphate generation, consistent with Arg having a role in receptor activation. To investigate the contribution of the surrounding structural domain in the actions of the conserved Arg, an integrated microdomain modeling and mutagenesis approach has been utilized. Two conserved residues that constrain the Arg side chain to a limited number of conformations have been identified. In the inactive wild-type receptor, the Arg side chain is proposed to form an ionic interaction with Asp3.49(138). Experimental results for the Asp3. 49(138) --> Asn mutant receptor show a modestly enhanced receptor efficiency, consistent with the hypothesis that weakening the Asp3. 49(138)-Arg3.50(139) interaction by protonation of the Asp or by the mutation to Asn favors activation. With activation, the Asp3. 49(138)-Arg3.50(139) ionic bond would break, and the unrestrained Arg would be prevented from orienting itself toward the water phase by a steric clash with Ile3.54(143). The mutation Ile3.54(143) --> Ala, which eliminates this clash in simulations, causes a marked reduction in measured receptor signaling efficiency, implying that solvation of Arg3.50(139) prevents it from functioning in the activation of the receptor. These data are consistent with residues Asp3.49(138) and Ile3.54(143) forming a structural motif, which helps position Arg in its appropriate inactive and active receptor conformations.

Amino Acid Sequence↗
PubMed1998

Histologic staging in malignant melanoma: cross-sectional area revisited.

BACKGROUND AND OBJECTIVES: Tumor thickness is considered the single most important predictor of survival in clinically localized malignant melanoma. A recent study found tumor volume a more sensitive predictor of survival than thickness. Volume measurement, however, is complicated, time consuming, and based on biologically imprecise mathematical models of tumor configuration. This report compares the prognostic power of cross-sectional area (CSA), a simpler measurement than volume, with tumor thickness. METHODS: Forty-five patients with clinically localized malignant melanoma and a minimum 5-year follow-up post excision with negative resection margins were retrospectively followed for disease recurrence or death. Digitalized histologic images of each tumor were made from the original pathology slides and stored on a compact disc. Maximum tumor thickness and CSA were calculated for each primary melanoma using an image analysis program and compared for predictive accuracy of 5-year survival. RESULTS: CSA was positively correlated with maximum tumor thickness (r = 0.76). Both measures had a similar predictive accuracy for survival. Patients with melanomas less than 8 mm2 had superior 5-year (94%) and disease-free survival rates (78%) compared to patients with melanomas exceeding 8 mm2 (5-year survival, 62%; 5-year disease-free survival, 23%). CONCLUSIONS: CSA is an easily calculated measurement that is as predictive for 5-year survival as is Breslow's thickness. Prospective assessment of CSA is warranted.

Adult↗
PubMed1998

The role of antibiotics and timing of repair in flexor tendon injuries of the hand.

The use of antibiotics and the timing of repair in the management of flexor tendon injuries of the hand have never been specifically addressed in the literature. In a retrospective study, 140 patients treated for simple open flexor tendon injuries were evaluated for postoperative wound infection. Patients were divided into four groups on the basis of early or late repair and use of parenteral perioperative antibiotic therapy. No significant differences were found among groups with respect to the low incidence of infectious complications observed. There is no evidence that mandates the use of prophylactic antibiotics and immediate repair in these types of injuries.

Adult↗
PubMed1998

A high affinity gonadotropin-releasing hormone (GnRH) tracer, radioiodinated at position 6, facilitates analysis of mutant GnRH receptors.

Cloning of GnRH receptors from several animal species has made it possible to investigate receptor function using site-directed mutagenesis. However, many mutant GnRH receptors exhibit decreased ligand binding, which makes analysis of their ligand binding characteristics technically difficult. To increase the affinity of binding to the GnRH receptor, a novel tracer ligand, 125I-[His5,D-Tyr6]GnRH, was designed and synthesized to allow radioiodination at position 6 rather than the usual position 5. In competition binding assays, total binding of 125I-[His5,D-Tyr6]GnRH was higher than binding of a conventional tracer ligand, 125I-[D-Ala6,N-MeLeu7,Pro9NHEt]GnRH. The bindable fractions and specific activities of both peptides were similar, and the receptor binding affinities of the unlabeled peptides were indistinguishable. However, comparison of the radiolabeled peptides in saturation binding assays showed that the affinity of the peptide, 125I-[His5,D-Tyr6]GnRH, (Kd, 0.19 nM), was approximately 2-fold higher than that of the conventional tracer. The increased binding of 125I-[His5,D-Tyr6] GnRH has allowed the development of a sensitive GnRH receptor binding assay for analysis of mutant GnRH receptors that exhibit decreased ligand binding.

Animals↗
PubMed1998

A single amino acid substitution in transmembrane helix VI results in overexpression of the human GnRH receptor.

OBJECTIVE: Construction of constitutively active mutants of the GnRH receptor, a member of the G-protein coupled receptor superfamily, would facilitate investigation of the mechanism of receptor activation. DESIGN: Point mutations were introduced in the human GnRH receptor in positions corresponding to those which caused constitutive activity in other G-protein coupled receptors. The effects of these mutations on ligand binding, receptor intracellular signaling and receptor expression were determined. METHODS: Wild type and mutated receptor cDNAs were expressed in COS-1 cells. Basal and agonist-stimulated inositol phosphate production and ligand binding were determined. In addition, receptor mRNA levels, cell surface receptor stability and rate of internalization were measured. RESULTS AND CONCLUSIONS: Although none of the mutant receptors exhibited constitutive activity, mutation of Phe-2 72 in transmembrane helix VI to Leu increased cell surface receptor numbers, with unchanged affinities for radiolabeled agonist, superagonist and antagonist peptides compared with wild type receptor. The cell surface receptor stability and rate of internalization were similar for wild type and F272L GnRH receptors. Thus a single amino acid mutation in transmembrane helix VI causes an increase in cell surface receptor numbers, which appears to result from an increased rate of receptor protein translation, processing or insertion into membranes.

Amino Acid Substitution↗