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Biomedical subjects

C Wilson

Publications and source records attributed to C Wilson.

At least 271 records · Page 15Linked to original sources
PubMed1995

Gonadotrophin and gonadal steroid response to a single dose of a long-acting agonist of gonadotrophin-releasing hormone in ovulatory and anovulatory women with polycystic ovary syndrome.

OBJECTIVE: A previously published study has identified that anovulatory women with PCOS have an increased response of 17 alpha-hydroxyprogesterone (17OHP) and androstenedione to a GnRH analogue suggesting dysregulation of cytochrome P450c17 alpha. The object of this study was to compare the responses of the pituitary-ovarian axis to a single dose of a long-acting GnRH agonist (GnRHa) in both ovulatory and anovulatory women with PCOS with those in normal subjects. DESIGN: Comparative study of responses of LH, FSH and ovarian steroids to buserelin and the adrenal steroid response to synthetic ACTH in two groups of women with hyperandrogenaemia and polycystic ovaries: those with anovulatory menses or amenorrhoea and those with equally elevated serum testosterone concentrations but regular menses. Results in both groups of women with PCO were compared with those in normal subjects. SUBJECTS AND METHODS: Twenty-four women with hyperandrogenism and PCO (14 had oligo or amenorrhoea, 10 regular cycles) and 12 weight matched controls with normal ovaries, regular cycles and neither clinical nor biochemical evidence of hyperandrogenism. Subjects were given synthetic ACTH (Synacthen) 250 micrograms i.v. on day 1 of the study and blood collected at 30 and 60 minutes thereafter. On the evening of day 1, dexamethasone treatment was commenced to suppress adrenal androgens. GnRHa 100 micrograms s.c. was given on day 2 and blood samples collected at 30-minute intervals for 4 hours and once more at 24 hours after the injection. RESULTS: The acute responses of both immunoactive and bioactive LH to GnRHa were significantly greater in the ovulatory PCO group (ovPCO) than controls but the response was greater in anovulatory women with polycystic ovaries (anovPCO) than in either ovPCO or controls, throughout the 24-hour study period. Despite the discrepancy in LH concentrations, basal serum concentrations of androstenedione were equally elevated in anovulatory and ovulatory women with PCO, compared with controls. There was a small but significant increase in androstenedione following GnRHa in both PCO groups at 24 hours but not in controls. A similar pattern was observed in the response of 17OHP to GnRHa although the response was significantly higher than controls in anovPCO women only. By contrast, the responses of both androstenedione and 17OHP to 250 micrograms synthetic ACTH were similar in PCO women to those in controls. CONCLUSIONS: These data provide evidence for ovarian hypersecretion of androgens in ovulatory, as well as anovulatory women with PCO, supporting the concept of abnormal regulation of 17-hydroxylase and (17,20-lyase activity in the ovary. The finding of an equal degree of hyperandrogenaemia in ovPCO and anovPCO groups, even though LH levels were much higher in the latter, suggests that hypersecretion of LH is not the primary cause of ovarian hyperandrogenism. Hyperandrogenism in PCOs may therefore represent an intrinsic abnormality of ovarian theca-interstitial cell function.

17-alpha-Hydroxyprogesterone↗
PubMed1995

Shared amino acid sequences between major histocompatibility complex class II glycoproteins, type XI collagen and Proteus mirabilis in rheumatoid arthritis.

OBJECTIVES: To show molecular similarity between two sequences of Proteus mirabilis (haemolysin--ESRRAL; urease--IRRET) with HLA-DR antigens (EQRRAA) which are associated with rheumatoid arthritis (RA) and type XI collagen (LRREI), respectively; and, in patients with RA, to measure levels of antibody against a 16-mer synthetic peptide containing the ESRRAL sequence, and the haemolysin and urease proteins of Proteus mirabilis. METHODS: The homologous sequences EQRRAA and ESRRAL were modelled with Alchemy III, using the crystalline structure of DRB1*0101 (HLA-DR1). Sera from 40 patients with RA, 30 with ankylosing spondylitis (AS), and 30 controls were tested against synthetic ESRRAL peptide and the haemolysin of Proteus mirabilis by enzyme linked immunosorbent assay. Similar tests were also carried out on sera from 20 patients with RA, 40 with AS, and 15 controls, against Proteus mirabilis urease. RESULTS: Molecular modelling of the homologous sequences ESRRAL/EQRRAA and IRRET/LRREI showed stereochemical similarities. Antibodies to the 16-mer synthetic peptide containing the ESRRAL sequence, the haemolysin, and urease proteins were significantly increased in RA patients compared with AS patients (p < 0.001) and healthy controls (p < 0.001). No such increases were observed with three control peptides including the EDERAA sequence of DRB1*0402 (HLA-DR4/Dw10), the haemolysin proteins of Streptococcus pyogenes and Vibrio parahaemolyticus, and the urease of Bacillus pasteurii. CONCLUSION: The additive effect of the immune responses to the two Proteus mirabilis antigens, haemolysin (ESRRAL) and urease (IRRET), could be relevant in the aetiopathogenesis of RA.

Adult↗
PubMed1995

Prevalence and correlates of depressive syndromes among adults visiting an Indian Health Service primary care clinic.

Depression is common among patients visiting primary care clinics. In order to describe the prevalence of depressive syndromes in an American Indian primary care clinic population and to help define the clinical correlates of depressive syndromes in this setting, a clinic-based research study of depression was undertaken by the Indian Health Service (IHS). One hundred and six patients from an IHS primary care clinic were systematically enlisted for participation in the study. Participants completed the Inventory for Diagnosing Depression (IDD). Twenty-two (20.7%) responded with answers scoring positive for a depressive syndrome. Nine of these 22 (8.9% of the 106 participants) met IDD criteria for a major depressive syndrome. A diagnosis of depression, a past history of depression, use of mental health facilities, unexplained pains, and antidepressant medication use were associated with the presence of a depressive syndrome.

Adult↗
PubMed1995

Accumulation of extracellular matrix and developmental dysregulation in the pancreas by transgenic production of transforming growth factor-beta 1.

Transgenic mice expressing transforming growth factor-beta 1 (TGF-beta 1) in the pancreatic beta-islet cells directed by human insulin promoter were produced to study in vivo effects of TGF-beta 1. Fibroblast proliferation and abnormal deposition of extracellular matrix were observed from birth onward, finally replacing almost all the exocrine pancreas. Cellular infiltrates comprising macrophages and neutrophils were also observed. Plasminogen activator inhibitor was induced in the transgenic pancreas as well as fibronectin and laminin, partly explaining accumulation of extracellular matrix. TGF-beta 1 inhibited proliferation of acinar cells in vivo as evidenced by decreased bromodeoxyuridine incorporation. Development of pancreatic islets was dysregulated, resulting in small islet cell clusters without formation of normal adult islets; however, the overall islet cell mass was not significantly diminished. Additional transgenic lines with less pronounced phenotypes had less expression of TGF-beta 1 transgene. These findings suggest that TGF-beta 1 might be a mediator of diseases associated with extracellular matrix deposition such as chronic pancreatitis, and this mouse model will be useful for further analysis of the in vivo effects of TGF-beta 1, including its potential for immunosuppression.

Animals↗
PubMed1995

Dopaminergic correlates of motivated behavior: importance of drive.

In vivo brain microdialysis was used to monitor changes in dopamine (DA) release in the nucleus accumbens (NAc) during anticipatory and consummatory components of feeding behavior. During 10 daily training sessions, rats were first confined to one compartment of a testing chamber for 10 minutes. During this period (anticipatory phase) they were prevented from gaining access to a highly palatable liquid meal by a wire mesh screen. The screen was then removed and the animals were permitted to consume the meal for 20 min (consummatory phase). On removal of the screen, the latency to begin drinking decreased and the amount consumed increased as a function of days of training, both measures reaching asymptotic levels by day 7. Trained animals were implanted with dialysis probes in the NAc on day 10, and on day 12 DA release was monitored during the feeding session. Compared to controls, trained animals failed to show significantly greater increases in accumbal DA release during the anticipatory phase, all groups showing small (approximately 10%) increases on being placed in the test chamber. In contrast, compared to controls, DA release increased significantly in the NAc during consumption of the palatable meal. The magnitude of this increase was significantly enhanced (30% vs 71% peak increase) in animals that were 20 hr food deprived at the time of testing. The latter animals also showed a statistically significant increase (24%) in DA release during the anticipatory phase. A subsequent experiment in which consumption of the palatable liquid was limited to 5 ml in deprived and nondeprived animals indicated that only part of the deprivation-induced potentiation of accumbal DA release could be attributed to the larger volume consumed by the deprived animals. That is, the same volume and rate of consumption of a small amount of the liquid diet produced a significantly greater increase in accumbal DA release in deprived than in nondeprived animals (42% vs 23% peak increase). Feeding-induced increases in accumbal DA release were not due to postingestional factors as direct injections of the liquid diet into the stomach by gavage failed to produce this effect. The results of these experiments indicate (1) that consummatory rather than anticipatory aspects of feeding are robustly associated with increases in DA release in the NAc, and (2) that motivational state can influence the magnitude of the neurochemical events that are associated with goal-directed behaviors.

Animals↗
PubMed1995

Strain related variations in adenovirally mediated transgene expression from mouse hepatocytes in vivo: comparisons between immunocompetent and immunodeficient inbred strains.

High efficiency gene transfer and gene expression in hepatocytes in vivo can be achieved using recombinant adenoviral vectors. However, the persistence of gene expression in different experimental animal models has been variable. To determine if similar differences could be observed in a single species, persistence of gene expression was studied in inbred strains of mice using a recombinant adenoviral vector that expresses human alpha 1-antitrypsin. Marked variability in the persistence of gene expression ranging from several weeks (C3H/HeJ and Balb/c) to more than 3 months [C57Bl/6, B10.A(2R) and B10.BR] was observed when this vector was transduced in different strains of inbred mice. This variability did not correlate with H-2 type. To evaluate the role of T and B cell immunity in the persistence of gene expression, congenic C3H-scid and Balb/c-scid mice were studied and found to have indefinite gene expression from transduced hepatocytes. These animals unlike their immunocompetent counter-parts were able to undergo secondary transduction of hepatocytes with a different recombinant adenoviral vector. These findings suggest that as yet unidentified genetic loci influence the persistence of adenovirus-mediated hepatic gene expression in vivo, and these effects are mediated at least in part, by the antigen specific immune system.

Adenoviridae↗
PubMed1995

Phosphorus-32-chromic phosphate for ovarian cancer: I. Fractionated low-dose intraperitoneal treatments in conjunction with platinum analog chemotherapy.

UNLABELLED: For many years, 32P-chromic phosphate (32P-CP) intraperitoneal instillations and platinum analogue chemotherapy have been used to treat disseminated ovarian cancer. To investigate possible enhancement of 32P-CP irradiation due to the concomitant administration of chemotherapy, in vitro studies were undertaken. Based on those laboratory investigations, a clinical regimen of combined 32P-CP and platinum analogue chemotherapy was developed. METHODS: In vitro enhancement of 32P-CP cytotoxicity by cisplatin was studied in cultured human ovarian adenocarcinoma (CHOA) cell lines and in a fibroblast cell strain. In addition, ovarian cancer cells obtained from the malignant abdominal ascites and pleural effusions of 10 individual patients were also studied ex vivo. As part of routine clinical care, 30 patients with disseminated ovarian adenocarcinoma underwent up to eight monthly cycles of platinum analogue chemotherapy with concomitant intraperitoneal instillation of 5 mCi of 32P-CP at each monthly chemotherapy cycle. RESULTS: There was an enhanced and possibly supra-additive effect of cisplatin on the cytotoxicity from 32P-CP irradiation. For the 30 patients, the survival rate at 3 yr was 63%. CONCLUSION: Phosphorus-32 CP low-dose intraperitoneal treatments in conjunction with platinum analogue chemotherapy is a promising approach for the treatment of disseminated intraperitoneal ovarian cancer.

Adenocarcinoma↗
PubMed1995

Elevation in anti-Proteus antibodies in patients with rheumatoid arthritis from Bermuda and England.

OBJECTIVE: To determine whether patients with rheumatoid arthritis (RA) from Bermuda and England have an increased anti-Proteus antibody titer when compared to healthy Bermudian and English controls, and to ascertain whether any increase in antibody titer is specific by testing 4 other microbes, Escherichia coli and 3 normal anaerobic bowel bacteria. METHODS: Antibody titers were measured by ELISA and indirect immunofluorescence (IIFA) under coded conditions. RESULTS: Elevated titers of anti-Proteus antibodies were demonstrated in 34 patients with active RA from Bermuda when compared to 33 healthy Bermudian controls by ELISA (p < 0.001) and IIFA (p < 0.001). An elevation of anti-Proteus antibodies was also observed in 34 patients with RA from England when compared to 30 healthy English controls again by ELISA (p < 0.001). A similar antibody elevation in 31 patients with RA from England was observed when compared to 30 healthy controls when measured by IIFA (p < 0.001). However, there was no significant elevation in antibody titers against E. coli or the 3 normal bowel flora isolates in the patients with RA from both countries compared to their respective controls, when measured by ELISA. CONCLUSION: A specific elevation in the immune response to Proteus mirabilis has been demonstrated in patients with RA from both Bermuda and England. However, this study cannot distinguish between antibody association with disease per se and association with disease activity. The role of Proteus in RA and the effect of anti-Proteus therapy in patients with RA merits further study.

Adult↗
PubMed1994

Prediction of bone graft strength using dual-energy radiographic absorptiometry.

STUDY DESIGN: A biomechanical study of anterior iliac crest bone was done to investigate a relationship between the compressive strength of tricortical iliac crest grafts and bone mineral density (BMD) of the iliac crest measured by dual-energy x-ray absorptiometry (DEXA). OBJECTIVES: This study investigated the potential usefulness of DEXA for measuring BMD of the iliac crest and documented bone graft strength predictability by BMD measurements. SUMMARY OF BACKGROUND DATA: The corticocancellous iliac bone is frequently used as an interbody graft for anterior spine fusion. The decreased compressive strength of bone graft may lead to collapse, pseudarthrosis and recurrence of symptoms, particularly in the osteoporotic patient. The DEXA accurately determines BMD of the spine and the hip, but no previous studies are available on the pelvis. METHODS: The BMDs were measured on the intact pelvis of the elderly and the corresponding tricortical grafts, using DEXA. The strut and Smith-Robinson type grafts were placed under axial loading using Material Testing System. Load to failure and compressive strength were obtained and statistically correlated to BMDs. RESULTS: There was a high correlation between the BMDs of the intact pelvis and each graft (R = 0.8, P < 0.001). The ultimate load to failure and compressive stress were linearly correlated to the BMD of the intact pelvis (R = 0.82, P < 0.001, R = 0.78, P < 0.001, respectively) as well as to the BMD of the graft (R = 0.77, P < 0.001, R = 0.75, P < 0.001, respectively). CONCLUSIONS: These results suggest that the biomechanical strength of the iliac bone graft is very dependent on its BMD, and DEXA has a potential clinical value in predicting iliac bone graft strength for cervical spine fusion.

Absorptiometry, Photon↗
PubMed1994

Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms.

Human apolipoprotein (apo) E4 (arginine at residue 112) preferentially associates with very low density lipoproteins (VLDL), and apoE3 (cysteine at 112) associates with high density lipoproteins. It has been postulated that the amino-terminal domain, which contains residue 112, influences the lipoprotein preference by interacting with the carboxyl-terminal domain, which contains the lipid-binding region. To delineate the region in the carboxyl-terminal domain mediating lipoprotein binding and involved in isoform preference, we produced truncated apoE3 and apoE4 variants (terminating at residues 251, 260, 266, or 272) in Escherichia coli and assessed them for lipoprotein association. This analysis suggested that residues 260-272 contain important determinants for complete lipoprotein association and isoform preferences. To determine whether positive charge at residue 112 was an absolute requirement for the apoE4 VLDL preference, we compared the distributions of rabbit apoE (equivalent to apoE3, with cysteine at a position corresponding to 112), canine apoE (arginine at the corresponding site), and cysteamine-treated rabbit apoE (cysteine converted to a positively charged residue). Surprisingly, all distributed like human apoE3, suggesting that positive charge at a position corresponding to 112 was not directly responsible for the isoform preference and that other residues in the amino-terminal domain were involved. To determine which residues were involved, the structure of the apoE4 22-kDa fragment (the amino-terminal two-thirds of the molecule) was determined to 2.5 A by x-ray crystallography. Compared with the known four-helix bundle structure of apoE3, the only significant differences in the apoE4 structure were that glutamic acid 109 formed a salt bridge with arginine 112 and that the arginine 61 side chain was displaced to a new position. Site-directed mutagenesis of glutamic acid 109 in apoE3 and arginine 61 in apoE4 demonstrated that the position of the arginine 61 side chain in apoE4 was critical in determining apoE4 lipoprotein distribution, suggesting that arginine 61 interacted with the carboxyl-terminal domain to direct binding to VLDL.

Animals↗
PubMed1994

Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein.

BACKGROUND: Apolipoprotein-E (apo-E), a 34kDa blood plasma protein, plays a key role in directing cholesterol transport via its interaction with the low density lipoprotein (LDL) receptor. The amino-terminal domain of apo-E forms an unusually elongated four-helix bundle arranged such that key basic residues involved in LDL receptor binding form a cluster at the end of one of the helices. A common apo-E variant, apo-E2, corresponding to the single-site substitution Arg158-->Cys, displays minimal LDL receptor binding and is associated with significant changes in plasma cholesterol levels and increased risk of coronary heart disease. Surprisingly, the site of mutation in this variant is physically well removed (> 12A) from the cluster of LDL receptor binding residues. RESULTS: We now report the refined crystal structure of the amino-terminal domain of apo-E2, at a nominal resolution of 3.0A. This structure reveals significant conformational changes relative to the wild-type protein that may account for reduced LDL receptor binding. Removal of the Arg158 side chain directly disrupts a pair of salt bridges, causing a compensatory reorganization of salt bridge partners that dramatically alters the charge surface presented by apo-E to its receptor. CONCLUSIONS: It is proposed that the observed reorganization of surface salt bridges is responsible for the decreased receptor binding by apo-E2. This reorganization, essentially functioning as a mutationally induced electrostatic switch to turn off receptor binding, represents a novel mechanism for the propagation of conformational changes over significant distances.

Apolipoprotein E2↗
PubMed1994

D-penicillamine induced polymyositis causing complete heart block.

We describe a 63-year-old female patient with rheumatoid arthritis who developed complete heart block and features of polymyositis within a few weeks of starting treatment with D-penicillamine. We believe she is one of only three published patients in whom complete heart block accompanies penicillamine-induced polymyositis. The literature on penicillamine myositis is reviewed with special emphasis on cardiac problems. Patients taking D-penicillamine who develop features suggestive of polymyositis may develop insidious, but potentially life-threatening cardiac involvement and must be carefully monitored.

Arthritis, Rheumatoid↗
PubMed1994

Walking trajectory and hand movements in unilateral left neglect: a vestibular hypothesis.

This is the first systematic study of walking trajectories in unilateral neglect. Six patients with unilateral left neglect approached and walked through a doorway, and all six deviated to the right of centre when doing so. Four out of six significantly centred their walking trajectories by making left hand movements while approaching the doorway. The group effect of walking with no hand movements vs walking with hand movements was statistically significant. Age-matched control patients showed a similar but significant smaller rightward deviation. The results are interpreted in terms of recent research in limb activation effects on neglect (Robertson and North, Neuropsychologia 30, 553-563, 1992), and also in the light of research showing close anatomical correspondence between the cortical projections of the vestibular nerve on the one hand, and the hand/arm representational fields of the central sulcus on the other.

Adult↗
PubMed1994

Receptor tyrosine kinase signalling: not so complex after all?

Receptor tyrosine kinases (RTKs) transmit intercellular signals that control many cellular events including proliferation, differentiation and cell survival. Ligand-bound RTKs regulate a complex network of intracellular signalling pathways. However, activation of just one of these pathways, which involves Ras and MAP kinase, is both necessary and sufficient to mediate the diverse developmental effects of several invertebrate RTKs. This article discusses these findings, which suggest that RTK-induced activation of MAP kinase in invertebrates acts as a simple developmental switch in multiple cell types, and considers the evidence that the Ras-MAP-kinase pathway also plays a similar role in vertebrates.

Journal Article↗
PubMed1994

Role for endothelin in the renal responses to radiocontrast media in the rat.

1. The involvement of endothelin in the renal responses to radiocontrast media was examined in the rat in vitro and in vivo using BQ123, a selective endothelin (ETA) receptor antagonist, and phosphoramidon, an endothelin-converting enzyme inhibitor. 2. For experiments in vitro, an isolated perfused rat kidney was employed perfusing in closed circuit with an albumin-based Krebs-Henseleit solution. The effects of BQ123 and phosphoramidon on the renal responses to iotrolan (iso-osmolar radiocontrast media) and diatrizoate (high-osmolar radiocontrast media) were examined. In vivo, renal conductance was measured using a Doppler flow probe in the anaesthetized rat pretreated with indomethacin, and the effects of BQ123 and phosphoramidon on the renal response to intravenous diatrizoate were examined. 3. In vitro, iotrolan and diatrizoate both produced a biphasic effect on the glomerular filtration rate, characterized by a transient increase followed by a sustained fall. Pretreatment with BQ123 (10 mumol/l), but not phosphoramidon (1 mmol/l), prevented both the increase and the sustained fall in glomerular filtration rate induced by radiocontrast media. 4. In vitro, iotrolan and diatrizoate both produced a sustained fall in renal perfusate flow. An initial increase in renal perfusate flow was only observed with diatrizoate. Pretreatment with BQ123 (10 mumol/l), but not with phosphoramidon (1 mmol/l), markedly inhibited the sustained fall in renal perfusate flow produced by both iotrolan and diatrizoate. BQ123 (10 mumol/l), however, markedly potentiated the renal vasodilatation produced by diatrizoate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗