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Biomedical subjects

S J Williams

Publications and source records attributed to S J Williams.

At least 37 records · Page 2Linked to original sources
PubMed2000

The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/SDI1 induced by cisplatin and paclitaxel.

The cyclin-dependent kinase inhibitor p21WAF1/CIP1/SD11 (p21) plays a crucial role in DNA repair, cell differentiation, and apoptosis through regulation of the cell cycle. A2780 human ovarian carcinoma cells, which are sensitive to cisplatin and paclitaxel, express wild-type p53 and exhibit a p53-mediated increase in p21 in response to the chemotherapeutic agents. Here, we demonstrate that phosphatidylinositol 3-kinase (PI3K) and its downstream targets serine/threonine kinases AKT1 and AKT2 (AKT), are required for the full induction of p21 in A2780 cells treated with cisplatin or paclitaxel. Inactivation of the PI3K/AKT signal transduction pathway either by its specific inhibitor LY294002 or by expression of dominant negative AKT inhibited p21 expression but had no inhibitory effect on the expression of the proapoptotic protein BAX by cisplatin and paclitaxel treatment. In addition, overexpression of wild-type or constitutively active AKT in A2780 cells sustained the regulation of p21 induction or increased the level of p21 expression, respectively. Experiments with additional ovarian carcinoma cell lines revealed that PI3K is involved in the expression of p21 induced by cisplatin or paclitaxel in OVCAR-10 cells, which have wild-type p53, but not in OVCAR-5 cells, which lack functional p53. These data indicate that the PI3K/AKT signal transduction pathway mediates p21 expression and suggest that this pathway contributes to cell cycle regulation promoted by p53 in response to drug-induced stress. However, inactivation of PI3K/AKT signaling did not result in significant alteration of the drug sensitivity of A2780 cells, suggesting that the cell death induced by cisplatin or paclitaxel proceeds independently of cell protective effects of PI3K and AKT.

Antineoplastic Agents↗
PubMed2000

Detailed structural analysis of glycosidase/inhibitor interactions: complexes of Cex from Cellulomonas fimi with xylobiose-derived aza-sugars.

Detailed insights into the mode of binding of a series of tight-binding aza-sugar glycosidase inhibitors of two fundamentally different classes are described through X-ray crystallographic studies of complexes with the retaining family 10 xylanase Cex from Cellulomonas fimi. Complexes with xylobiose-derived aza-sugar inhibitors of the substituted "amidine" class (xylobio-imidazole, K(i) = 150 nM; xylobio-lactam oxime, K(i) = 370 nM) reveal lateral interaction of the "glycosidic" nitrogen with the acid/base catalyst (Glu127) and hydrogen bonding of the sugar 2-hydroxyl with the catalytic nucleophile (Glu233), as expected. Tight binding of xylobio-isofagomine (K(i) = 130 nM) appears to be a consequence of strong interactions of the ring nitrogen with the catalytic nucleophile while, surprisingly, no direct protein contacts are made with the ring nitrogen of the xylobio-deoxynojirimycin analogue (K(i) = 5800 nM). Instead the nitrogen interacts with two ordered water molecules, thereby accounting for its relatively weaker binding, though it still binds some 1200-fold more tightly than does xylobiose, presumably as a consequence of electrostatic interactions at the active site. Dramatically weaker binding of these same inhibitors to the family 11 xylanase Bcx from Bacillus circulans (K(i) from 0.5 to 1.5 mM) is rationalized for the substituted amidines on the basis that this enzyme utilizes a syn protonation trajectory and likely hydrolyzes via a (2,5)B boat transition state. Weaker binding of the deoxynojirimycin and isofagomine analogues likely reflects the energetic penalty for distortion of these analogues to a (2,5)B conformation, possibly coupled with destabilizing interactions with Tyr69, a conserved, catalytically essential active site residue.

1-Deoxynojirimycin↗
PubMed2000

Glycosyl fluorides in enzymatic reactions.

Glycosyl fluorides have considerable importance as substrates and inhibitors in enzymatic reactions. Their good combination of stability and reactivity has enabled their use as glycosyl donors with a variety of carbohydrate processing enzymes. Moreover, the installation of fluorine elsewhere on the carbohydrate scaffold commonly modifies the properties of the glycosyl fluoride such that the resultant compounds act as slow substrates or even inhibitors of enzyme action. This review covers the use of glycosyl fluorides as substrates for wild-type and mutant glycosidases and other enzymes that catalyze glycosyl transfer. The use of substituted glycosyl fluorides as inhibitors of enzymes that catalyze glycosyl transfer and as tools for investigation of their mechanism is discussed, including the labeling of active site residues. Synthetic applications in which glycosyl fluorides are used as glycosyl donors in enzymatic transglycosylation reactions for the synthesis of oligo- and polysaccharides are then covered, including the use of mutant glycosidases, the so-called glycosynthases, which are able to catalyze the formation of glycosides without competing hydrolysis. Finally, a short overview of the use of glycosyl fluorides as substrates and inhibitors of phosphorylases and phosphoglucomutase is given.

Enzyme Inhibitors↗
PubMed2000

Hepatic integrity dependent on matrix metalloproteinase inhibition, not tumor necrosis factor alpha or different bleeding rates.

Discrepancies in the levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) following hemorrhagic shock (HS) may be due to the inconsistent rates of bleeding. The purpose of this study was to investigate the effects of rapid versus slow bleeding rates on TNF-alpha levels and if inhibition of TNF-alpha convertase by a matrix metalloproteinase inhibitor (MMPI) affects hepatic integrity in animals exposed to 35% HS. Sprague-Dawley male rats (n = 24, 300-350 g) were divided into four groups: HS 15 (produced over 15 min), HS 30 (produced over 30 min), and HS with MMPI (2.5 mg/kg British Biotech 1101: HS15 + MMPI, HS30 + MMPI). Mean arterial blood pressure (MAP), serum TNF-alpha,levels, and hepatic resting membrane potentials (E(m)) were obtained. A Student t test was performed. TNF-alpha levels for HS 15, HS15 + MMPI, HS 30, and HS 30 + MMPI were 474, 40, 32, and 50 pg/ml, respectively. The hepatic resting membrane potentials for HS 15, HS15 + MMPI, HS 30, and HS 30 + MMPI were -26, -30, -23, and -31 mV, respectively. In conclusion, circulating TNF-alpha levels are affected by the rate of bleeding in hemorrhagic shock. However, despite the differences in the magnitude of TNF-alpha in untreated animals, hepatic integrity was compromised. Interestingly, MMPI, an inhibitor of TNF-alpha convertase, stabilizes the membrane potential in both types of hemorrhagic shock.

ADAM Proteins↗
PubMed2000

Patient reminder letters to promote annual mammograms: a randomized controlled trial.

BACKGROUND: This study assessed the effects of a reminder letter from a physician (relative to a mammography facility letter or no letter) on appointment compliance among women 50-74 years of age due for an annual screening mammogram. METHODS: A total of 1,562 women were randomly as signed to the groups. Each Group 1 subject received a reminder letter from her physician, each Group 2 subject received a reminder letter from her mammography facility, and Group 3 served as a control group. RESULTS: The return rates for Groups 1, 2, and 3 were 47.7, 46.6, and 28.3%, respectively; the overall difference was significant using a chi(2) analysis (P < 0.001). Bonferroni pairwise comparisons indicated no difference between Groups 1 and 2 but significant differences (P < 0.001) between Group 3 and the other two groups. Logistic regression indicated that relative to Group 3, the adjusted odds of returning for Groups 1 and 2 were 2.37 and 2.24, respectively. CONCLUSIONS: Mammography providers and their patients likely will benefit from in-reach reminder systems. Physicians who do not use reminder systems should refer their patients to facilities that use these systems.

Aged↗
PubMed2000

Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.

BACKGROUND: In patients with hepatic metastases from colorectal carcinoma there is a distinct subgroup in whom jaundice is not due to hepatic replacement but rather biliary obstruction. We reviewed our experience with stent insertion in patients with malignant proximal biliary obstruction from metastatic colorectal carcinoma. METHODS: Thirty-three patients were treated between July 1992 and December 1996. Placement of a single stent was attempted at initial endoscopic retrograde cholangiopancreatography. Hilar biliary obstruction was classified according to Bismuth's classification. RESULTS: Successful stent placement was possible in 94% overall and at initial endoscopic retrograde cholangiopancreatography in 39% of patients. Successful stent placement occurred significantly more often in patients with a type I stricture. Cholangitis was the principal complication occurring in 24% of patients. The 30-day mortality rate was 24%, with death occurring significantly less often in patients with a type I or II stricture. Overall, 45% of patients had a 30% fall in bilirubin at 1 week. The median survival was 81 days, with significantly longer survival seen in patients with a type I or II stricture. CONCLUSIONS: Endoscopic stent placement offers effective palliation in most patients with hilar obstruction from colorectal metastases. A subset of patients with type III strictures and greater than 3 intrahepatic metastases often do not benefit from stent insertion.

Adenocarcinoma↗
PubMed1999

Two novel mucin genes down-regulated in colorectal cancer identified by differential display.

Epithelial mucins are large, secreted and cell surface glycoproteins involved in epithelial cell protection, adhesion modulation, and signaling. Using differential display, we have identified two novel mucin cDNAs (dd34 and dd29), hereafter designated MUC11 and MUC12, respectively, that are down-regulated in colorectal cancers. Northern blots demonstrated polydisperse signals characteristic of mucin transcripts in RNA from normal colon that were absent in colorectal cancer. Both cDNAs were mapped by fluorescence in situ hybridization to chromosome band 7q22, the location of the MUC3 mucin gene, thus suggesting that there may be a cluster of mucin genes at this locus. The sequences of both differential display clones were extended by a combination of screening libraries and PCR. The 2.8-kb MUC11 cDNA composite encoded 35 serine/threonine-rich, mucin-like degenerate 28 amino acid tandem repeats. The MUC12 cDNA composite encoded a putative transmembrane mucin containing two extracellular cysteine-rich, EGF-like domains, a coiled-coil region, and a mucin-like domain consisting of 28 amino acid degenerate tandem repeats. Distinct patterns of expression of MUC11, MUC12, and MUC3 mRNAs were observed in a range of normal human tissues. MUC12 mRNA was not expressed in any of six colorectal cancer cell lines examined and was down-regulated or absent in 6 of 15 (40%) tumors compared with matched normal colonic tissue. In contrast, MUC11 showed a different pattern of mRNA expression, with four of these lines showing low levels and the other two lines showing relatively high levels of MUC11 transcripts. Expression of MUC11 was down-regulated in the tumors of 12 of 15 (80%) paired samples. Structural homology of MUC12 with rat, mouse, and human MUC3 and human and rat MUC4/ASGP2 indicate that there is a distinct subfamily of transmembrane mucins with conserved epidermal growth factor domains. The homology of MUC12 with epidermal growth factor-like growth factors and its down-regulation in colorectal cancers, together with known interactions between rat MUC4 and c-erbB-2 growth factor receptors, suggests that MUC12 may be involved in epithelial cell growth regulation.

Amino Acid Sequence↗
PubMed1999

The MUC3 gene encodes a transmembrane mucin and is alternatively spliced.

Epithelial mucins are a family of secreted and cell surface glycoproteins expressed by epithelial tissues and implicated in epithelial cell protection, adhesion modulation and signaling. The gene encoding human MUC3 (hMUC3), localised to chromosome 7q22, is most highly expressed in the small intestine. It has previously been reported to be a non-transmembrane mucin with minimal homology to its suggested orthologues from rat (rMuc3) and mouse (mMuc3). RT-PCR was performed to investigate the carboxyl terminus of the published sequence of hMUC3 from normal colon and small intestine tissues and also from a series of 10 colorectal cancer cell lines. Two distinct PCR products were identified. In contrast to the previously published hMUC3 sequence, which terminates shortly after a single cysteine-rich EGF-like domain, conceptual protein translation of the dominant and largest PCR product identified two extracellular cysteine-rich EGF-like domains separated by an N-glycosylation-rich domain and a potential coiled-coil region, followed by a putative transmembrane region and a 75 amino acid cytoplasmic tail. The smaller of the two PCR products was found to be an alternative splice variant of MUC3 including the first EGF-like domain but lacking part of the second EGF-like domain and the transmembrane region. Nine out of 10 colorectal cancer cell lines were found to express MUC3. Interestingly, one of the cell lines, LoVo, expressed predominantly the alternative splice form lacking a transmembrane domain. Structural homology of the new protein sequence of hMUC3 with rMuc3 and mMuc3 indicates it is closely related to the rodent proteins and is likely to be involved in ligand-binding and intracellular signaling. The new finding that MUC3 encodes a transmembrane molecule presents a new paradigm for the structure of this mucin and the manner in which it may function.

Alternative Splicing↗
PubMed1998

Endoscopic band ligation for non-variceal non-ulcer gastrointestinal hemorrhage.

BACKGROUND: There is no consensus as to the best treatment for non-variceal, non-ulcer gastrointestinal hemorrhage. Endoscopic band ligation is an inexpensive, readily available, and easily learned technique in contrast to conventional thermal methods of endoscopic hemostasis. We present the preliminary results of an open trial using endoscopic band ligation for non-variceal, non-ulcer bleeding in the gastrointestinal tract. METHODS: Eighteen patients were treated by band ligation between June 1996 and November 1997. The lesions treated were: arteriovenous malformations in 10, Dieulafoy's lesions in 4, Mallory-Weiss tear in 2, and post-colonic polypectomy bleeding in 2. RESULTS: Endoscopic band ligation was successful in 17 of 18 cases, with a follow-up period ranging from 2 to 18 months. The remaining case, a duodenal Dieulafoy's lesion, bled again at 24 hours but was successfully treated by adrenalin injection. CONCLUSIONS: Endoscopic band ligation is effective for non-variceal, non-ulcer bleeding. It has the advantage of ease of use and is relatively inexpensive.

Aged↗
PubMed1998

Progress in the endoscopic management of benign biliary strictures.

Benign biliary strictures can now be effectively treated with endoscopic therapy in a variety of clinical situations. Despite recent developments in imaging techniques (endoscopic ultrasound and magnetic resonance imaging), it is often difficult to differentiate benign from malignant biliary strictures. The sensitivity of tissue diagnosis (cytology and needle biopsy) at endoscopic retrograde cholangiopancreatography (ERCP) remains poor (40-50%), and further diagnostic methods are required. Endoscopic therapy offers a definitive treatment in 70-90% of patients following post-operative biliary stricture, including anastomotic strictures following liver transplant. Endoscopic therapy successfully achieves symptomatic, biochemical, and cholangiographic response, and may improve survival in patients with primary sclerosing cholangitis. Strictures secondary to chronic pancreatitis are resistant to standard endoscopic therapy and metallic endoprotheses have been trialed with varying success. Endoscopic therapy is technically difficult and should be performed in specialized centres using a multidisciplinary approach.

Bile Duct Diseases↗
PubMed1997

Cytosolic estrogen receptor concentrations in the lumbosacral spinal cord fluctuate during the estrous cycle.

Estrogen responsive neurons have been anatomically identified with autoradiographic and immunohistochemical techniques and their distribution mapped in the lumbosacral spinal cord of female rats. Such neurons contain estrogen receptors (ERs). The present study was undertaken to: 1) quantify cytosolic estrogen receptor (ER) concentrations in the lumbosacral spinal cord and 2) determine if there is a relationship between cytosolic ER concentrations and fluctuations in serum estradiol (SE2) levels during the estrous cycle. Lumbosacral spinal segments were removed from intact cycling rats during the morning of proestrus, the afternoon of proestrus, and the morning of estrus, metestrus and diestrus. Trunk blood was collected at euthanasia and SE2 levels were determined using radioimmunoassay. Cytosolic ER concentrations were measured using a dextran-charcoal coated tube method. Concentrations of cytosolic ERs were low during estrus and metestrus, increased during diestrus with maximum concentrations during the afternoon of proestrus. These changes in ER concentrations paralleled SE2 levels measured in intact cycling animals; i.e., during estrus SE2 levels were low, but began to rise during metestrus, diestrus, and during the morning of proestrus with a maximum peak increase during the afternoon of proestrus. These data indicate there are fluctuations of cytosolic ER concentrations during the estrous cycle and that these changes coincide with changing SE2 concentrations suggesting that ER content is influenced by SE2.

Animals↗
PubMed1997

Modern medicine and the "uncertain body": from corporeality to hyperreality?

This paper (re)considers the role of medical technology at three interrelated levels: first, the extent to which medical technology renders our bodies increasingly "uncertain" at the turn of the century; second, the analytical purchase which the notion of the (medical) cyborg provides regarding contemporary forms of human embodiment; and finally, at a broader level, the issues this raises in relation to a (late) modernist or postmodernist reading of contemporary medical practice. Key themes here include the plastic body, the bionic body, communal/interchangeable bodies, (genetically) engineered/ chosen bodies, and virtual bodies. The paper concludes with a critical appraisal of these themes and issues, arguing for a late modernist position on medical technology as both a positive and negative rationalising force, and a "life political agenda" in which the "all-too-human" quality of human nature is seen as inviolable.

Bionics↗
PubMed1997

Preventive services in a Medicare managed care environment.

The results of a four year demonstration project of preventive services for Medicare managed care enrollees suggest that health promotion programs can impact health behaviors and outcomes. The study provided selected preventive services to 1,800 Medicare enrollees in a managed care environment. Participants were randomly assigned to control and experimental groups with the experimental group receiving an intervention service package and the control group usual care. The results included enhanced health behavior practices, lower depression, and higher immunization rates among those individuals in the experimental group. This study suggests that selected preventive services can be provided in a managed care environment to Medicare enrollees with likely positive health status and utilization outcomes.

Aged↗
PubMed1997

Evidence for a role for nitric oxide in relation of the frog oesophageal body to electrical field stimulation.

1. Electrical field stimulation (EFS) (1-10 Hz, 30 V, 2 ms) of frog oesophageal body strips resulted in frequency-dependent non-adrenergic, non-cholinergic (NANC) relaxations. 2. Tetrodotoxin (TTX) (10(-6)-10(-5) M) had no effect on EFS evoked relaxations with a 2 ms pulse width. At a pulse width of 0.5 ms only the responses to the highest frequency (10 Hz) were significantly inhibited by TTX at 10(-5) M. Relaxation at 2 ms pulse width were unaffected by omega-conotoxin (10(-6) M), nifedipine (10(-6) M) or cobalt (5 x 10(-4) M). 3. NG-nitro-L-arginine (L-NOARG) (10(-6)-10(-4) M), a nitric oxide synthase (NOS) inhibitor, caused a concentration-dependent inhibition of the EFS-induced NANC relaxant responses. The inhibitory effect of L-NOARG was both prevented and reversed by L-arginine but not D-arginine (5 x 10(-3) M). 4. The phosphodiester type V inhibitor (PDE V), SK&F 96231 (10(-7)-10(-4) M), caused a concentration-dependent potentiation of both the percentage relaxation and the duration of the relaxant responses to EFS. 5. ODQ (10(-7)-10(-5) M), a guanylate cyclase inhibitor, produced a concentration-dependent inhibition of EFS-evoked NANC relaxations. 6. Oxyhaemoglobin (10(-6) M), which binds nitric oxide (NO), inhibited NANC relaxations to EFS. 7. The NO donor sodium nitroprusside (SNP) (10(-8)-10(-4) M) produced a concentration-dependent inhibition of evoked tone. L-NOARG (10(-4) M) had no effect on the SNP evoked relaxations. Preincubation with oxyhaemoglobin (10(-6) M) caused a reduction in the SNP (10(-6)-10(-5) M) induced relaxations. 8. These results suggest NO is the relaxant transmitter of the frog oesophageal body and the source of NO may be non-neuronal.

Adrenergic Agents↗
PubMed1997

An evolving medical leadership position. Tomorrow's Vice President for Medical Affairs.

The role of medical leadership in hospitals and health systems is under constant scrutiny and change. The nature of the Vice President for Medical Affairs (VPMA) position and its relationship to leadership in the health care system is explored through a national panel survey conducted recently. The effective VPMA will: be an aggressive manager able to implement change, address strategic planning and quality of care issues; have a high level of integrity; and be a good communicator and problem solver. The results of the research are presented in three sections. The first section describes the background characteristics and compensation of the VPMAs who participated in the survey. The second section focuses on the current role of the VPMA, including duties and responsibilities, job performance barriers and required skills. The final section addresses respondents' perceptions regarding areas for improvement in the role of the VPMA, as well as projections for future changes in this position.

Data Collection↗
PubMed1996

Estrogen receptor-immunoreactive neurons are present in the female rat lumbosacral spinal cord.

Presence of an estrogen receptor is crucial for cells to respond to estrogen; thus, estrogen-responsive neurons should be identifiable by immunohistochemically staining for the estrogen receptor (ER). Even though spinal neurons are involved in sexual behaviors and innervation of genital organs, little information is available about ER-containing neurons in the spinal cord. Consequently, we have undertaken a study of ER-containing neurons in the female rat lumbosacral cord, an area involved in reproductive functions and predicted to contain estrogen-responsive neurons. In addition, since parasympathetic preganglionic neurons in the lumbosacral cord produce nitric oxide (NO), we also sought to determine if ER-immunoreactive (-IR) neurons contain the enzymes for NO production. Finally, we compared the distribution of ER-IR neurons to the presence of uterine cervix-related neurons. Uterine cervix-related neurons were identified by expression of FOS-immunoreactivity after vaginocervical mechanostimulation (VCS). The lumbosacral spinal cords were removed from intact, ovariectomized, and VCS-treated rats and sections stained by immunohistochemistry. ER-IR was present in the nuclei of neurons located predominately in the dorsal one-half of the spinal cord. Specific sites include the dorsal horn, lamina V, the sacral parasympathetic nucleus (SPN) (which contains preganglionic parasympathetic neurons) and extending into the lateral funiculus, and lamina X. Some ER-IR neurons were NADPH-d-positive and were localized in laminae V and VII. FOS-IR neurons had a distribution pattern similar to the distribution of neurons containing ER. The presence of ER neurons in these regions suggest that they are responsive to circulating estrogen.

Animals↗