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Biomedical subjects

S J Williams

Publications and source records attributed to S J Williams.

At least 19 recordsLinked to original sources
PubMed2006

58Ni: an unpaired band crossing at new heights of angular momentum for rotating nuclei.

High-spin states in 58Ni have been investigated by means of the fusion-evaporation reaction 28Si(32S, 2p)58Ni at 130 MeV beam energy. Discrete-energy levels are observed in 58Ni at record-breaking 42 MeV excitation energy and angular momenta in excess of 30h. The states form regular rotational bands with unprecedented high rotational frequencies. A comparison with configuration dependent cranked Nilsson-Strutinsky calculations reveals an exceptional two-band crossing scenario, the interaction strength of which is strongly shape dependent.

Journal Article↗
PubMed2006

Argon plasma coagulation in the management of symptomatic gastrointestinal vascular lesions: experience in 100 consecutive patients with long-term follow-up.

BACKGROUND: The long-term efficacy of argon plasma coagulation (APC) in the management of gastrointestinal vascular lesions has not been evaluated in a large and well-defined series. The impact of APC on transfusion requirements and hemoglobin, and technical parameters including complications and number of treatment sessions, is assessed in this series. METHODS: Patients who underwent APC for bleeding gastrointestinal vascular lesions were identified via interrogation of an established endoscopic database, excluding patients with radiation proctitis, tumors, residual polypectomy tissue and acute ulcer bleeding. Follow-up data were collected via interview with patients and referring doctors, review of medical records, and follow-up blood tests. RESULTS: One hundred patients were enrolled, males = 46, median age = 74 yr (range: 19-99 yr). Median follow-up time was 16 months (range: 4-47 months). Lesions treated were arteriovenous malformations (n = 74) and gastric antral vascular ectasia (n = 26). Fifty-three patients required transfusion. In this group, median hemoglobin improved from 66 g/L (range: 35-114) to 111 g/L (range: 55-155, p < 0.001). Median transfusion velocity fell from 2 units/month (range: 0.1-6) to 0 units/month (range: 0-4, p < 0.001). Transfusion requirement was abolished in 77%. In non-transfusion-requiring patients, median hemoglobin improved from 105 g/L (range: 58-143) to 123 g/L (range: 79-158, p < 0.001). No complications occurred. CONCLUSIONS: APC is effective and safe in the management of gastrointestinal vascular lesions.

Adult↗
PubMed2005

Small rat islets are superior to large islets in in vitro function and in transplantation outcomes.

Barriers to the use of islet transplantation as a practical treatment for diabetes include the limited number of available donor pancreata. This project was designed to determine whether the size of the islet could influence the success rate of islet transplantations in rats. Islets from adult rats were divided into two groups containing small (diameter <125 microm) or large (diameter >150 microm) islets. An average pancreas yielded three times more small islets than large. Smaller islets were approximately 20% more viable, with large islets containing a scattered pattern of necrotic and apoptotic cells or central core cell death. Small islets in culture consumed twice as much oxygen as large islets when normalized for the same islet equivalents. In static incubation, small islets released three times more insulin under basal conditions than did large islets. During exposure to high glucose conditions, the small islets released four times more insulin than the same islet equivalencies of large islets, and five times more insulin was released by the small islets in response to glucose and depolarization with K+. Most importantly, the small islets were far superior to large islets when transplanted into diabetic animals. When marginal islet equivalencies were used for renal subcapsular transplantation, large islets failed to produce euglycemia in any recipient rats, whereas small islets were successful 80% of the time. The results indicate that small islets are superior to large islets in in vitro testing and for transplantation into the kidney capsule of diabetic rats.

Animals↗
PubMed2005

Increased myogenic tone in 7-month-old adult male but not female offspring from rat dams exposed to hypoxia during pregnancy.

Intrauterine growth restriction (IUGR) increases the risk of cardiovascular disease later in life. Vascular dysfunction occurs in adult offspring from animal models of IUGR including maternal undernutrition, but the influence of reduced fetal oxygen supply on adult vascular function is unclear. Myogenic responses, essential for vascular tone regulation, have not been evaluated in these offspring. We hypothesized that 7-mo-old offspring from hypoxic (12% O(2); H) or nutrient-restricted (40% of control; NR) rat dams would show greater myogenic responses than their 4-mo-old littermates or control (C) offspring through impaired modulation by vasodilators. Growth restriction occurred in male H (P < 0.01), male NR (P < 0.01), and female NR (P < 0.02), but not female H, offspring. Myogenic responses in mesenteric arteries from males but not females were increased at 7 mo in H (P < 0.01) and NR (P < 0.05) vs. C offspring. There was less modulation of myogenic responses after inhibition of nitric oxide synthase (P < 0.05), prostaglandin H synthase (P < 0.005), or both enzymes (P < 0.001) in arteries from 7-mo male H vs. C offspring. Thus reduced vasodilator modulation may explain elevated myogenic responses in 7-mo male H offspring. In contrast, there was increased modulation of myogenic responses in arteries from 7-mo female H vs. C or NR offspring after inhibition of both enzymes (P < 0.05). Thus increased vasodilator modulation may maintain myogenic responses in female H offspring at control levels. In summary, vascular responses in adult offspring from adverse intrauterine environments are impaired in a gender-specific, age-dependent, and maternal insult-dependent manner, with males more profoundly affected.

Animals↗
PubMed2005

Expression of alpha5 integrin (Itga5) is elevated in the rat myometrium during late pregnancy and labor: implications for development of a mechanical syncytium.

The underlying mechanisms controlling uterine contractions during labor are still poorly understood. Integrins are heterodimeric, transmembrane receptors composed of alpha and beta subunits that can be found in focal adhesions. Because these structures play an important role in the regulation of smooth muscle contractility and cell adhesion, we hypothesized that alpha5 integrin mRNA (Itga5) and protein (ITGA5) expression would be induced in the rat myometrium during late pregnancy and labor. Itga5 mRNA expression was significantly increased (P < 0.05) from Day 17 to labor, noticeably decreasing 1 day postpartum (PP). Immunoblot analysis illustrated a continual increase in ITGA5 levels during pregnancy, labor, and PP, with levels reaching significance at labor (P < 0.05). Analysis of ITGA5 expression by immunocytochemistry demonstrated that it is primarily localized to myometrial cell membranes in the longitudinal muscle layer of the myometrium from before pregnancy to Day 6, and in both the longitudinal and circular muscle layers from Day 15 to PP. Treatment of late-pregnant rats with progesterone blocked labor and resulted in sustained expression of Itga5 mRNA expression to Day 24. In addition, immunocytochemistry experiments showed ITGA5 was detectable at higher levels in cell membranes of both myometrial layers in progesterone-treated animals on Days 23 and 24, compared with vehicle controls. We propose that ITGA5, with its sole known partner, ITGB1, may be important in promoting cellular cohesion during late pregnancy. This process may aid the development of a mechanical syncytium for efficient force transduction during the sustained, coordinated, and powerful contractions of labor.

Animals↗
PubMed2005

Small heat shock protein 27 (Hsp27) expression is highly induced in rat myometrium during late pregnancy and labour.

The underlying mechanisms that regulate uterine contractions during labour are still poorly understood. A candidate regulatory protein is heat shock protein 27 (Hsp27). It belongs to the small heat shock protein family and can regulate actin cytoskeleton dynamics, act as a chaperone, and may regulate contractile protein activation. As a result, we hypothesized that Hsp27 expression would be highly induced during late pregnancy and labour. Hsp27 mRNA expression was significantly elevated (P <0.05) on days 17 to 22 of gestation. In addition, immunoblot analysis demonstrated that detection of total Hsp27 increased (P <0.05) between day 21 and 1 day post-partum (PP) inclusive. Since phosphorylation of Hsp27 has been reported to be a prerequisite for smooth muscle contraction, we examined the temporal and spatial expression of Ser-15 phosphorylated Hsp27. Immunoblot analysis showed that the detection of Ser-15 phosphorylated Hsp27 significantly increased (P <0.05) between days 19 and 23 (active labour) inclusive, in parallel with detection of total Hsp27. Immunocytochemical analysis of Ser-15 phosphorylated Hsp27 expression in situ demonstrated that phosphorylated Hsp27 in circular muscle became detectable in peri-nuclear and membrane regions on days 19 to 22, but was primarily restricted to the cytoplasm on days 23 to PP. In contrast, phosphorylated Hsp27 in longitudinal muscle was primarily detected in myocyte membranes on days 15 to 22, and then also became detectable in the cytoplasm of myocytes on days 23 and PP. Our results demonstrate that Hsp27 expression is highly upregulated during late pregnancy and labour and suggest that Hsp27 is a potential candidate contraction-associated protein.

Animals↗
PubMed2004

Investigation of quantitative secondary electron imaging of semiconducting polymer materials using environmental scanning electron microscopy.

The development of environmental scanning electron microscopy has opened the way for the examination of a wide variety of new sample types that were previously inaccessible to conventional scanning electron microscope techniques. With the advent of such a new methodology comes also the potential for new contrast mechanisms. We investigated the use of environmental scanning electron microscopy on semiconducting organic polymer materials. We observed contrast from these materials in secondary electron images, this contrast being attributed to differences in electron yield due to the polymer's electronic structure. Further study of these materials, and specifically the influence of film thickness on signal, has indicated a significant effect as the secondary electrons move through the sample. Systematic studies such as these are needed for a full understanding of the relationship between electronic properties and signal and, hence, the ability to probe structure-property relationships in greater depth.

Environment↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2001

Human trypsinogen in colorectal cancer.

Trypsinogen (TRY), the precursor to the serine protease trypsin, is found in the pancreas and mediates digestive proteolysis in the small intestine. Differential display of cDNAs expressed by human colorectal tumor tissues compared with adjacent normal colonic mucosa identified an isoform of TRY (TRY2) up-regulated in colorectal cancers. Northern blot analysis of RNA isolated from a series of 28 malignant colon tumors and corresponding normal mucosa showed that TRY transcripts were up-regulated 2- to 33-fold in 29% of tumors. Further, TRY mRNA was expressed in 6 colorectal cancer cell lines, with highest levels detected in the metastatic tumor lines SW620 and HT29. Immunostaining for TRY protein expression showed intense immunoreactivity in the supranuclear cytoplasm of colon tumors in 16% of tissue specimens. To evaluate the relative contributions of 2 isoforms of TRY, TRY1 and TRY2, to total TRY mRNA expression, a semi-quantitative multiplex RT-PCR assay was developed. TRY2 mRNA was detected in all 6 colorectal tumor cell lines, whereas TRY1 mRNA was expressed only in the metastatic tumor lines, showing that the high levels of TRY expression in the metastatic tumor lines are likely due to up-regulation of TRY1. Evaluation of TRY1 and TRY2 mRNA expression by multiplex RT-PCR in a series of 20 colon tumor tissues representative of the range of tumor progression showed that TRY2 mRNA was expressed much more commonly than TRY1 mRNA in normal mucosa (26% vs. 6%) as well as in primary tumor tissues (65% vs. 15%). These data demonstrate that TRY2 is the dominant TRY in colon tissue and suggest that up-regulation of TRY1 expression in colon tumors may be associated with a metastatic phenotype.

Colorectal Neoplasms↗
PubMed2001

Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells.

Transmembrane mucins are glycoproteins involved in barrier function in epithelial tissues. To identify novel transmembrane mucin genes, we performed a tblastn search of the GenBanktrade mark EST data bases with a serine/threonine-rich search string, and a rodent gene expressed in bone marrow was identified. We determined the cDNA sequence of the human orthologue of this gene, MUC13, which localizes to chromosome band 3q13.3 and generates 3.2-kilobase pair transcripts encoding a 512-amino acid protein comprised of an N-terminal mucin repeat domain, three epidermal growth factor-like sequences, a SEA module, a transmembrane domain, and a cytoplasmic tail (GenBanktrade mark accession no. ). MUC13 mRNA is expressed most highly in the large intestine and trachea, and at moderate levels in the kidney, small intestine, appendix, and stomach. In situ hybridization in murine tissues revealed expression in intestinal epithelial and lymphoid cells. Immunohistochemistry demonstrated the human MUC13 protein on the apical membrane of both columnar and goblet cells in the gastrointestinal tract, as well as within goblet cell thecae, indicative of secretion in addition to presence on the cell surface. MUC13 is cleaved, and the beta-subunit containing the cytoplasmic tail undergoes homodimerization. Including MUC13, there are at least five cell surface mucins expressed in the gastrointestinal tract.

Amino Acid Sequence↗
PubMed2001

Improved survival with early fluid resuscitation following hemorrhagic shock.

Recent studies have questioned the benefits of early fluid resuscitation in hemorrhagic shock. The purpose of the current study is to evaluate the effects of early fluid resuscitation (HSE) (15 minutes), delayed fluid resuscitation (HSD) (60 minutes), and no fluid resuscitation (HSU) on cytokine levels, hepatic resting membrane potential (Em), renal function, and mortality. Eighty male Sprague-Dawley rats (350-450 g) were hemorrhaged 35% of their total blood volume and then received 40, 80, or 100 ml of crystalloid per kilogram as intravenous fluids (IVFs). The implementation of HSE resulted in stabilization of the Em (-29 mV), which was significantly different from that seen with HSD or HSU (-24 and -29 mV, respectively). The timing of resuscitation did not affect the elevation of tumor necrosis factor (TNFalpha) levels. The interleukin-6 (IL-6) levels for the HSE group were 81, 101, and 274 pg/ml for 40, 80, and 100 ml/kg, respectively. In contrast, HSD group IL-6 levels were 440, 566, and 632 pg/ml for 40, 80, and 100 ml/kg (p < 0.0001). IL-6 levels for the HSU group was 427 pg/ml, which was significantly different from that of the HSE group (p < 0.05). Urine output was present in 58% of the HSE rats but only 24% in the HSD rats and 0% of the HSU rats. Mortality was 11% for HSE, 58% for HSD, and 50% for HSU rats. Despite the recent studies questioning the benefits of early fluid resuscitation, these data show marked improvement in hepatic stability, the presence of urine output, decreased IL-6 levels, and significantly lower mortality when IVFs were given early after hemorrhagic shock. Furthermore, excessive fluid resuscitation (100 ml/kg) resulted in an increased inflammatory cytokine level and mortality and may account for the controversy.

Animals↗
PubMed2001

Steroidal control of male hamster sexual behavior in Me and MPOA: effects of androgen dose and tamoxifen.

Steroids stimulate male sexual behavior through interconnected limbic nuclei, including the medial amygdala (Me) and medial preoptic area (MPOA). Although Me and MPOA each can transduce hormonal cues to induce sexual activity in castrated male hamsters, simultaneous stimulation of Me and MPOA fails to amplify mating. The present study extends our investigations of redundancy in the hormonal control of mating by testing the behavioral effects of (1) increasing steroid dose in a single brain region or (2) locally blocking steroid action with an estrogen antagonist. In Experiment 1, sexually experienced castrates received a single testosterone implant in Me, bilateral testosterone implants, or a single implant of a highly potent androgen, 7a-methyl-19-nortestosterone (MENT). These treatments stimulated mating behavior: 2 weeks after surgery, mounting was observed in > or =50% of the males in each group. In Experiment 2, castrated males received intracerebral implants of the estrogen antagonist tamoxifen in Me or MPOA, combined with systemic testosterone replacement. Tamoxifen in MPOA had minimal effects on the recovery of mating behavior. With tamoxifen in Me, mounts and intromissions were significantly reduced 18 days after surgery. However, the percent of males in each group that expressed mounts, intromissions or ejaculations was not different. Thus, in Experiment 1, increasing the amount of steroid does not amplify mating. Likewise, local blockade of hormone action in Experiment 2 does not prevent behavior. These findings support the concept that steroids are largely permissive for male sex behavior. Steroid stimulation of either Me or MPOA is sufficient for sexual activity. Conversely, neither Me nor MPOA has an absolute requirement for hormones to facilitate expression of mating.

Amygdala↗
PubMed2001

Protein--carbohydrate interactions: learning lessons from nature.

Protein--carbohydrate interactions are at the heart of many important biological processes including signalling, recognition and catalysis. A deeper understanding of these interactions at the molecular level will enable the development of novel, effective and highly selective therapeutics. Glycosyltransferases and glycosidases, carbohydrate-processing enzymes responsible for the synthesis and breakdown of oligosaccharides, have emerged as important targets in the fight against bacterial and fungal pathogenesis, cancer and AIDS. Binding and recognition phenomena are essential processes by which the body exerts control over complex biological functions. In this regard, heparin has retained ongoing interest reflecting its importance as a major pharmaceutical. Recent studies on heparin have shed light onto the mechanisms of cross-reactivity that cause life-threatening side effects and have provided impetus for the development of more selective anti-clotting agents. Important targets for therapeutic intervention are the binding processes mediated through multivalent protein--carbohydrate interactions, such as the interactions of bacterial toxins with cell-surface receptors.

Carbohydrate Metabolism↗
PubMed2001

The impact of the Human Genome Project on medical genetics.

The near completion of the Human Genome Project stands as a remarkable achievement, with enormous implications for both science and society. For scientists, it is the first step in a complex process that will lead to important advances in the diagnosis and treatment of many diseases. Society, meanwhile, must prevent genetic discrimination, and protect genetic privacy through appropriate legislation.

Ethics, Medical↗
PubMed2001

Training needs for physician leaders.

The results of a national panel survey of physician leaders are presented here. Although these perspectives are not drawn from a random national sample of all physician leaders, they do provide valuable insight from a group of key decision makers. Current technical and skill areas applicable to medical leadership, and projected future needs, are addressed. While medical leadership at present is focused on clinical medicine, perceptions of future directions for medical leadership suggests the increasing need for education related to specific technical skills as well as enhancement of personal characteristics. The results reported here help provide a platform for further elucidation of training needs for an audience of present and future physician leaders.

Data Collection↗