PubMed Health⌕ Search

Biomedical subjects

B C Williams

Publications and source records attributed to B C Williams.

At least 55 records · Page 3Linked to original sources
PubMed1997

In vitro expression of endothelin-1 (ET-1) and the ETA and ETB ET receptors by the prostatic epithelium and stroma.

RT-PCR analysis of total RNA prepared from the prostate cancer cell lines DU145 and PC3 and from primary epithelial cells indicated the presence of endothelin-1 (ET-1) messenger RNA (mRNA). Neither the LNCaP cell line nor primary prostatic stromal cells possess ET-1 mRNA transcripts. Seventy-two-hour-conditioned media derived from DU145, PC3, and primary epithelia contain immunoreactive ET concentrations equivalent to 0.814 +/- 0.048, 0.330 +/- 0.050, and 0.856 +/- 0.055 fmol/mL/10(6) cells after 72 h, respectively. Basal immunoreactive ET secretion was exhibited by LNCaP (0.029 +/- 0.009 fmol/mL/10(6) cells after 72 h) and stromal cells (0.067 +/- 0.007 fmol/ mL/10(6) cells after 72 h). Examination of ETA and ETB gene expression by RT-PCR demonstrates that ET receptor mRNA is almost completely undetectable in the prostate cancer cell lines. Both ETA and ETB mRNAs are detectable in primary cultures of prostatic epithelia and stroma. Competitive binding studies demonstrate a single class of binding site in both primary benign epithelia (dissociation constant = 1.85 x 10(-10) mol/L; maximal binding capacity = 2.7 x 10(4) binding sites/cell), and stroma (dissociation constant = 1.93 x 10(-10) mol/L; maximal binding capacity = 3.7 x 10(5) binding sites/cell). Use of selective ET receptor antagonists confirmed that the predominant stromal receptor subtype expressed in vitro is ETB. This receptor seems not to be coupled to mitogenic pathways because no growth response to exogenous ET-1 or cooperation between ET-1 and bFGF could be observed. Similarly, no effect of ET-1 or the ET-converting enzyme inhibitor, phosphoramidon, on benign epithelial cells could be observed over a 4-day period.

Binding, Competitive↗
PubMed1997

The Drosophila kinesin-like protein KLP3A is required for proper behavior of male and female pronuclei at fertilization.

Drosophila melanogaster females homozygous for mutations in the gene encoding the kinesin-like protein KLP3A are sterile (Williams et al., 1995). We have investigated the basis of this sterility. The eggs produced by KLP3A mutant mothers are fertilized by sperm, and female meiosis appears to occur normally. However, the large majority of these embryos arrest their development soon thereafter with a characteristic phenotype. The four nuclei produced by female meiosis associate together in a polar body-like structure, while a bipolar spindle is established around the metaphase-arrested male pronucleus. Thus, the major defect caused by depletion of the KLP3A protein is either in specification of the female pronucleus, or in migration of the male and female pronuclei toward each other. We have also found that the KLP3A protein is located throughout the metaphase spindle during meiosis and the early embryonic mitotic divisions, but later accumulates specifically at the midzone of these same spindles during telophase. The protein is also present on two other microtubule structures: the sperm aster; and the radial, monastral array of microtubules established between the two meiosis II spindles. We discuss these results in light of possible functions of the KLP3A protein in pronuclear specification and migration.

Anaphase↗
PubMed1996

Multiple signal transduction systems regulate angiotensin II type 1 (AT1) receptor mRNA expression in bovine adrenocortical cells.

Regulation of AT1 receptor mRNA expression is an important determinant of angiotensin II-induced steroidogenesis. We have PCR-amplified the bovine adrenal AT1 receptor coding region using primers designed from the published bovine AT1 receptor sequence. This has been used as a probe on Northern blots to detect changes in the levels of AT1 receptor mRNA in primary cultures of bovine zona fasciculata cells in response to activation of several different signal transduction mechanisms in addition to two major adrenal steroid products, cortisol and aldosterone. AT1 receptor mRNA decreased in response to 6hr AII (10 nM) treatment, but returned to basal levels following 48h AII treatment. This effect was mimicked by the phorbol ester PMA (1 microM) and the calcium ionophore A23187 (1 microM), both singly and in combination. Activation of the cAMP pathway by ACTH (1 nM) and 8-bromo-cAMP (0.1 microM) also decreased AT1 receptor mRNA levels. In contrast, both IGF-1 (10 ng/ml) and potassium ions (12 mM) increased the levels of AT1 receptor mRNA. Finally, cortisol (10 microM) but not aldosterone (100 nM) decreased AT1 receptor mRNA. We conclude that the regulation of AT1 receptor mRNA in bovine zona fasciculata cells could involve several different signal transduction systems in addition to adrenocortical steroids themselves.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Forskolin treatment directs steroid production towards the androgen pathway in the NCI-H295R adrenocortical tumour cell line.

The human adrenocortical tumour cell line, NCI-H295, secretes steroids on the mineralocorticoid, glucocorticoid and adrenal androgen pathways. We have investigated the effects of 96 h treatment of cells in monolayer culture with either forskolin (10 microM) (a direct activator of adenylate cyclase), angiotensin II (10 nM) or no agonist ('control') on the steroidogenic phenotype of this cell line. Androstenedione, cortisol and corticosterone secreted into the medium in response to a subsequent 4 hour treatment with angiotensin II (10nM) indicated that the steroidogenic phenotype of NCI-H295 cells changes away from 17-deoxysteroid biosynthesis towards adrenal androgen production in response to forskolin. The NCI-H295R cell line therefore serves as a useful model for investigation of the differential regulation of the steroidogenic pathways in the human adrenal cortex.

Adrenal Cortex Neoplasms↗
PubMed1996

The role of L-aromatic amino acid decarboxylase in serotonin-stimulated aldosterone secretion in response to salt intake.

In this study we tested a new hypothesis namely that serotonin (5-hydroxytryptamine, 5-HT) could be synthesised within the zona glomerulosa of the rat adrenal gland from exogenous 5-hydroxytryptophan (5-HTP) by the enzyme L-aromatic amino acid decarboxylase (L-AAAD). A specific monoclonal antibody against L-AAAD showed that the enzyme was present predominantly in the adrenal medulla but also in the zona glomerulosa and zona fasciculata. Wistar rats, maintained on a normal (NS), low (LS) or high (HS) salt diet for one week, were sacrificed by decapitation, blood samples taken and the adrenal glands removed. Plasma aldosterone concentrations were significantly higher in the LS diet group (2.91 +/- 0.35 nM) and significantly lower in the HS diet group (0.261 +/- 0.55 nM) compared with the NS diet group (1.025 +/- 0.133 nM) (p < 0.001). Capsules from the LS diet group synthesised significantly higher maximal levels of 5-HT (2615.463 +/- 480.88 nM/mg protein) than capsules from the NS (1219.117 +/- 150.259 nM/mg protein) and the HS (968.477 +/- 214.485 nM/mg protein) salt diet groups (p < 0.05). Maximal aldosterone secretion in adrenal capsules obtained from rats on the LS diet (73.428 +/- 4.053 nM/mg protein) was significantly higher than in those obtained from rats on the NS diet (41.658 +/- 1.87 nM/mg protein) (p < 0.05). Maximal aldosterone secretion in adrenal capsules from the HS diet group (30.624 +/- 2.114 nM/mg protein) was significantly lower than in the capsules from both the LS and NS groups (p < 0.05). Carbidopa (10(-4) M), a specific inhibitor of L-AAAD, markedly attenuated the secretion of aldosterone when adrenal capsules from all three salt diet groups were incubated with 10(-4) M 5-HTP (p < 0.05), but had no significant effect on basal aldosterone secretion. These results clearly demonstrate that L-AAAD is not only present in the medulla, but also in the zona glomerulosa and zona fasciculata of the rat adrenal gland. In addition, 5-HT can be synthesised in the zona glomerulosa/capsular region of the rat adrenal gland and both its biosynthesis and its ability to stimulate aldosterone secretion is increased by sodium depletion and attenuated by sodium loading. This raises the interesting possibility that L-AAAD could play a role in the regulation of aldosterone secretion during sodium deficiency in the rat by converting circulating 5-HTP (which is present in blood at concentrations exceeding 1 micromolar) into 5-HT within the adrenal cortex.

5-Hydroxytryptophan↗
PubMed1996

Effects of ecstasy on aldosterone secretion in the rat in vivo and in vitro.

This study investigated the effects of Methylenedioxymethamphetamine (MDMA) on aldosterone and renin secretion via, (1) acute administration of MDMA to conscious Wistar rats, and (2) superfusion of whole rat adrenal capsules with 1 microM and 10 microM MDMA, in the presence of 5-HT. In study 1 basal aldosterone levels increased significantly from 3.490 +/- 1.1 nmol/l to 12.099 +/- 2 nmol/l after administration of MDMA (P < 0.05). Control rats showed no significant increase in aldosterone secretion. Basal plasma renin activity (PRA) was 6.86 +/- 1.65 ng/ml/hr in the MDMA treated animals increasing to 228.56 +/- 34.1 ng/ml/hr after administration (P < 0.05). In study 2 the aldosterone response to 5-HT was potentiated by 1 microM and 10 microM MDMA. No consistent stimulation of aldosterone was observed by MDMA alone. In conclusion, acute administration of MDMA to conscious rats causes activation of the renin-angiotensin-aldosterone system. In addition, MDMA can potentiate the direct action of 5-HT on aldosterone secretion in vitro by a mechanism which could be associated with the 5-HT transporter.

Adrenal Glands↗
PubMed1996

Bipolar spindle attachments affect redistributions of ZW10, a Drosophila centromere/kinetochore component required for accurate chromosome segregation.

Previous efforts have shown that mutations in the Drosophila ZW10 gene cause massive chromosome missegregation during mitotic divisions in several tissues. Here we demonstrate that mutations in ZW10 also disrupt chromosome behavior in male meiosis I and meiosis II, indicating that ZW10 function is common to both equational and reductional divisions. Divisions are apparently normal before anaphase onset, but ZW10 mutants exhibit lagging chromosomes and irregular chromosome segregation at anaphase. Chromosome missegregation during meiosis I of these mutants is not caused by precocious separation of sister chromatids, but rather the nondisjunction of homologs. ZW10 is first visible during prometaphase, where it localizes to the kinetochores of the bivalent chromosomes (during meiosis I) or to the sister kinetochores of dyads (during meiosis II). During metaphase of both divisions, ZW10 appears to move from the kinetochores and to spread toward the poles along what appear to be kinetochore microtubules. Redistributions of ZW10 at metaphase require bipolar attachments of individual chromosomes or paired bivalents to the spindle. At the onset of anaphase I or anaphase II, ZW10 rapidly relocalizes to the kinetochore regions of the separating chromosomes. In other mutant backgrounds in which chromosomes lag during anaphase, the presence or absence of ZW10 at a particular kinetochore predicts whether or not the chromosome moves appropriately to the spindle poles. We propose that ZW10 acts as part of, or immediately downstream of, a tension-sensing mechanism that regulates chromosome separation or movement at anaphase onset.

Anaphase↗
PubMed1996

Activation of the endothelin B receptor causes a dose-dependent accumulation of cyclic GMP in human platelets.

Endothelins modulate in vitro aggregation of human platelets in a bi-directional manner. Thus endothelin-1 has been shown to act as a potentiator of primary aggregation and an inhibitor of secondary aggregation. The endothelin receptors and corresponding second messengers which cause these effects have not yet been characterised. This study investigated the effect of endothelin-1, an agonist at both the ETA and the ETB receptors and sarafotoxin (SRTX) S6c, a selective ETB agonist, on human platelet cyclic nucleotide levels. Neither endothelin-1 (10(-11) -10(-7) M) nor SRTX S6c (10(-11) -10(-7) M) significantly altered platelet cAMP levels. In contrast, both agonists produced a dose-dependent increase in platelet cGMP. From these data, we conclude that activation of the ETB receptor in human platelets is responsible for an increase in platelet cGMP and may contribute to the inhibition of platelet aggregation caused by the endothelins.

Adult↗
PubMed1996

Mechanisms of changes in renal handling of sodium following transjugular intrahepatic portal systemic stent-shunt (TIPSS).

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic stent-shunt (TIPSS) reduces the portal pressure gradient and leads to better control of ascites. The aim of this study was to evaluate (1) changes in renal handling of sodium following TIPSS and (2) the mechanism of these changes. DESIGN: Prospective study. SETTING: Tertiary referral centre for liver diseases. METHODS: Eighteen patients with ascites undergoing TIPSS for recurrent variceal haemorrhage (16) (3 or more hospital admissions because of variceal haemorrhage whilst being treated endoscopically) or refractory ascites (2) were studied. Urinary sodium (UNa), creatinine clearance (CrCl), plasma renin activity (PRA), atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP), Angiotensin II (AII) and lithium clearance (LiCl) were measured before and 3 months after TIPSS when portography was performed and the portal pressure gradient (PPG) also measured. All patients were haemodynamically stable and had received no diuretics for at least 1 week before blood sampling. RESULTS: Improvement in ascites was achieved in all patients in whom TIPSS was inserted successfully (reduction in PPG to < 12 mmHg). PPG was reduced from a mean of 19 (+/-6) to 8.8 (+/-3.4) mmHg (P < 0.001). Urinary sodium and creatinine clearance improved significantly following TIPSS (P < 0.001, P < 0.001, respectively). PRA, All, cGMP and LiCl were abnormal before TIPSS and improved significantly following TIPSS (P < 0.007, P < 0.001, P < 0.001 and P < 0.01, respectively). ANP was not significantly different from normal controls and did not change significantly following TIPSS. Changes in UNa did not correlate with the Pugh score or the change in PPG. CONCLUSION: The results of this study show that TIPSS is associated with significant improvement in UNa, CrCl, PRA, AII, cGMP and LiCl. The change in UNa following TIPSS was independent of the severity of underlying liver disease or the change in PPG.

Adult↗
PubMed1996

Patterns and determinants of health services use and mortality after VA nursing home care.

Risk factors for institutionalization and death for up to four years for a nationwide cohort (n = 6,488) of males discharged alive from Department of Veterans Affairs (DVA) nursing homes were identified through linked records of the DVA. Two-year cumulative probabilities of nursing home readmission, hospitalization, and death among nursing home dischargees were 0.30, 0.61, and 0.24, respectively. Using multivariate survival analyses, chronic functional impairments and past nursing home use were important predictors of nursing home readmission, whereas hospitalizations for exacerbations of chronic medical conditions were predictors of hospitalization and death. Past hospitalizations predicted all three outcomes. Differences in risk factors for nursing home readmission as compared with hospitalization or death among DVA nursing home dischargees suggest that high-risk patients can be identified at nursing home discharge and that different types of interventions will be necessary to decrease nursing home readmission as compared with hospitalization or death. Future development of linked record systems across multiple settings, both within and outside the DVA, will help to further characterize persons at high risk of institutionalization or death and to design and evaluate targeted interventions to decrease this risk.

Cohort Studies↗
PubMed1995

Measuring attending physician performance in a general medicine outpatient clinic.

OBJECTIVE: To determine which aspects of outpatient attending physician performance (e.g., clinical ability, teaching ability, interpersonal conduct) were measurable and separable by resident report. DESIGN: Self-administered evaluation form. SETTING: University internal medicine resident continuity clinic. PARTICIPANTS: All residents with their continuity clinic at the university hospital evaluated the two attendings who staffed their clinic for the academic years of 1990-1991, 1991-1992, and 1992-1993 (average of 85 total residents per year). The overall response rate was 74%. ANALYSIS: Exploratory analyses were conducted on a preliminary evaluation form in the first two years of the study (236 evaluations of 20 different clinic attendings) and confirmatory analyses using factor analysis and generalizability analysis were performed on the third year's data (142 evaluations of 15 different clinic attendings). Analysis of variance was used to evaluate factors associated with evaluation scores. RESULTS: Analyses demonstrated that the residents did not distinguish between the attendings' clinical and teaching abilities, resulting in a single four-item scale that was named the Clinical/Teaching Excellence Scale, measured on a five-point scale from poor to outstanding (Cronbach's alpha = 0.92). A large amount of the variance for this scale score was associated with attending identity (adjusted R2 = 46%). However, two alternative approaches to evaluating the performance of the attending (preference for him or her to the "average" attending and perceived impact of the attending on residents' clinical skills) did not provide useful information independent of the Clinical/Teaching Excellence Scale. The ratings of three separate conduct scales [availability in clinic (Availability Scale), treating residents and patients with respect (Respect Scale), and time efficiency in staffing cases (Slow Staffing Scale)] were separable from each other and from the rating of clinical/teaching excellence. For the Clinical/Teaching Excellent Scale, as few as four evaluations produced good interrater reliability and eight evaluations produced excellent reliability (reliability coefficients were 0.70 and 0.84, respectively). CONCLUSIONS: Although this evaluation instrument for measuring clinic attending performance must be considered preliminary, this study suggests that relatively few attending evaluations are required to reliably profile an individual attending's performance, that attending identity is associated with a large amount of the scale score variation, and that special issues of attending performance more relevant to the outpatient setting than the inpatient setting (availability in clinic and sensitivity to time efficiency) should be considered when evaluating clinic attending performance.

Analysis of Variance↗
PubMed1995

The Drosophila kinesin-like protein KLP3A is a midbody component required for central spindle assembly and initiation of cytokinesis.

We describe here a new member of the kinesin superfamily in Drosophila, KLP3A (Kinesin-Like-Protein-at-3A). The KLP3A protein localizes to the equator of the central spindle during late anaphase and telophase of male meiosis. Mutations in the KLP3A gene disrupt the interdigitation of microtubules in spermatocyte central spindles. Despite this defect, anaphase B spindle elongation is not obviously aberrant. However, cytokinesis frequently fails after both meiotic divisions in mutant testes. Together, these findings strongly suggest that the KLP3A presumptive motor protein is a critical component in the establishment or stabilization of the central spindle. Furthermore, these results imply that the central spindle is the source of signals that initiate the cleavage furrow in higher cells.

Amino Acid Sequence↗
PubMed1995

Blood and urine 5-hydroxytryptophan and 5-hydroxytryptamine levels after administration of two 5-hydroxytryptamine precursors in normal man.

Six healthy male subjects received equimolar amounts of two 5-hydroxytryptamine (5-HT) precursors, 5-hydroxy-L-tryptophan (5-HTP) and gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP), on two occasions in a randomised cross-over study. There were marked increases in urinary 5-HTP and 5-HT excretion after infusion of both compounds. Mean urinary excretion rate of 5-HT, which was < 0.7 nmol min-1 before dosing, rose to a peak value of 412 +/- 92 nmol min-1 at the end of 5-HTP infusion and 303 +/- 29 nmol min-1 after administration of glu-5-HTP. This occurred without significant changes in blood 5-HT levels measured in platelet-rich plasma. These findings provide further evidence that the increase in urine 5-HT after administration of both 5-HT precursors is largely due to 5-HT synthesised within the kidney.

5-Hydroxytryptophan↗
PubMed1995

N omega-nitro-L-arginine methyl ester reduces the incidence of IDDM in BB/E rats.

Evidence that nitric oxide (NO) is involved in cytokine-mediated islet beta-cell dysfunction and destruction in vitro has led to the hypothesis that increased production of NO may contribute to the pathogenesis of insulin-dependent diabetes mellitus (IDDM). This study demonstrates that oral administration of N omega-nitro-L-arginine methyl ester (an inhibitor of NO synthase) from 30 to 150 days of age significantly reduced (P < 0.05) the incidence of IDDM in diabetes-prone BB/E rats. This supports the idea that NO plays a significant role in the pathogenesis of IDDM in this animal model.

Administration, Oral↗
PubMed1994

The M3 muscarinic receptor mediates acetylcholine-induced cortisol secretion from bovine adrenocortical zona fasciculata/reticularis cells.

In order to characterize the receptor subtype mediating acetylcholine (ACh)-induced cortisol secretion from purified bovine adrenocortical zona fasciculata/reticularis cells in primary culture, the potencies of a range of selective muscarinic antagonists of ACh-induced steroidogenesis were assessed by Schild analysis. Basal secretion of cortisol was 10.2 +/- 1.4 pmol/well/30 min. ACh stimulated a dose-dependent increase in cortisol secretion and was maximally effective at 10(-5) M, at which concentration cortisol secretion was 143.4 +/- 12.9 pmol/well/30 min. Hexahydro-sila-difenidol and para-fluoro-hexa-hydro-sila-difenidol were potent competitive antagonists of ACh-stimulated cortisol secretion, with pA2 values of 8.68 +/- 0.28 and 7.96 +/- 0.29, respectively. Pirenzepine (pA2 = 6.95 +/- 0.28) and methoctramine (pA2 = 6.06 +/- 0.27) were relatively weak competitive antagonists. The pA2 values determined in this study are characteristic of the M3 muscarinic receptor, and we conclude that this receptor subtype mediates ACh-induced cortisol secretion from bovine zona fasciculata/reticularis cells.

Acetylcholine↗
PubMed1994

A central 5-HT2 receptor mechanism plays a key role in the proestrous surge of luteinizing hormone in the rat.

The role of serotonin (5-HT) in generating the spontaneous preovulatory surge of luteinizing hormone (LH) has been investigated by studying the effect of ketanserin (a mixed 5-HT2/alpha 1 adrenoreceptor antagonist); the selective 5-HT2 receptor antagonist, ritanserin; and the selective alpha 1 adrenoreceptor antagonist, prazosin, on the plasma concentrations of LH during the afternoon of proestrus in conscious Wistar rats. Sequential blood samples for hormone estimation were taken through intra-atrial cannulae previously implanted under halothane anesthesia. All three drugs blocked the LH surge; ketanserin, but not ritanserin or prazosin, also blocked basal LH release. These results provide the first robust evidence for the fact that a 5-HT2 receptor as well as an alpha 1 adrenoreceptor mechanism is involved in the LH surge generator.

Animals↗
PubMed1994

Spontaneous development of malignant phase hypertension in transgenic Ren-2 rats.

Spontaneous development of malignant phase hypertension in TGR(mREN2)27 heterozygotes occurs as a consequence of crossing TGR(mREN2)27 homozygotes with Edinburgh Sprague-Dawley rats. Similarities to human malignant phase hypertension are seen with an accelerated rise in blood pressure, fibrinoid necrosis of renal afferent arterioles, renal failure and evidence of renin-angiotensin system activation. It appears that introduction of an additional genetic factor or factors into a monogenic model of hypertension results in malignant phase hypertension.

Animals↗