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Biomedical subjects

B Williams

Publications and source records attributed to B Williams.

At least 19 recordsLinked to original sources
PubMed2006

Lysophosphatidic acid downregulates tissue inhibitor of metalloproteinases, which are negatively involved in lysophosphatidic acid-induced cell invasion.

Ovarian cancer is a highly metastatic disease. Lysophosphatidic acid (LPA) levels are elevated in ascites from ovarian cancer patients, but its potential role in ovarian cancer metastasis has just begun to be revealed. In this work, we show that LPA stimulates invasion of primary ovarian cancer cells, but not ovarian epithelial or borderline ovarian tumor cells, although these benign cells indeed respond to LPA in cell migration. We have found that LPA downregulates tissue inhibitor of metalloproteinases (TIMPs). TIMP2 and TIMP3 play functional role in LPA-induced invasion as negative regulators. G(i) protein, phosphatidylinositol-3 kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), cytosolic phospholipase A(2) and urokinase type plasminogen activator (uPA) are required for LPA-induced cells invasion. TIMP3 may affect two independent downstream targets, vascular endothelial growth factor receptor and p38 MAPK. In vivo, LPA stimulates tumor metastasis in an orthotopic ovarian tumor model, which can be inhibited by a PI3K inhibitor, LY294002. In summary, LPA is likely a key component for promoting ovarian metastasis in vivo. LPA downregulates TIMP3, which may have targets other than metalloproteinases. Our in vivo metastasis mouse model is useful for studying the efficacy of therapeutic regimes of ovarian cancer.

Animals↗
PubMed2006

MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis.

Previous research on adults has shown that a functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene moderates the impact of childhood maltreatment on risk for developing antisocial behavior. Thus far, attempts to replicate this finding have been mixed. The current study (i) presents new data investigating this finding in a sample of 975 seven-year-old boys, and (ii) evaluates the extant data by conducting a meta-analysis of published findings. We replicated the original finding by showing that the MAOA polymorphism moderates the development of psychopathology after exposure to physical abuse, we extended the finding to childhood closer in time to the maltreatment experience, and we ruled-out the possibility of a spurious finding by accounting for passive and evocative gene-environment correlation. Moreover, meta-analysis demonstrated that across studies, the association between maltreatment and mental health problems is significantly stronger in the group of males with the genotype conferring low vs high MAOA activity. These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life.

Adolescent↗
PubMed2006

Mechanical stretch has contrasting effects on mediator release from bronchial epithelial cells, with a rho-kinase-dependent component to the mechanotransduction pathway.

INTRODUCTION: In vivo, the airway epithelium stretches and relaxes with each respiratory cycle, but little is known about the effect this pattern of elongation and relaxation has on bronchial epithelial cells. We have used a model of cell deformation to measure the effect of stretch on inflammatory cytokine release by the BEAS 2B cell line, and to examine the method of mechanotransduction in these cells. METHODS: BEAS 2B cells were cyclically stretched using the Flexercell system. IL-8 and RANTES protein and RNA levels were measured after different elongations, rates and duration of stretch. An inhibitor of Rho (Ras Homologous)-associated kinases was used, to assess the effect of blocking downstream of integrin signalling. Immunofluorescent staining of paxillin was used to study the effect of stretch on the distribution of focal contacts and the organisation of the actin cytoskeleton. RESULTS: IL-8 release by BEAS 2B cells was increased by cytokine stimulation and stretch, whereas RANTES levels in the cell supernatant decreased after stretch in a dose-, time- and rate-dependent manner. Thirty percent elongation at 20 cycles/min for 24h increased IL-8 levels by over 100% (P < 0.01). Blocking rho kinase using Y-27632 inhibited the effect of stretch on IL-8 release by the BEAS 2B cells. Immunofluorescent staining demonstrated that stretch caused dramatic disassembly of focal adhesions and resulted in the redistribution of paxillin to the peri-nuclear region. CONCLUSION: This study demonstrates a marked effect of stretch on bronchial epithelial cell function. We propose that stretch modulates epithelial cell function via the activation of rho kinases. The observation that stretch promotes focal adhesion disassembly suggests a mechanism whereby focal adhesion turnover (coordination of assembly and disassembly) is essential for mechanotransduction in bronchial epithelial cells.

Amides↗
PubMed2006

ESH-ESC guidelines for the management of hypertension.

The following is a brief statement of the 2003 European Society of Hypertension (ESH)-European Society of Cardiology (ESC) guidelines for the management of arterial hypertension. The continuous relationship between the level of blood pressure and cardiovascular risk makes the definition of hypertension arbitrary. Since risk factors cluster in hypertensive individuals, risk stratification should be made and decision about the management should not be based on blood pressure alone, but also according to the presence or absence of other risk factors, target organ damage, diabetes, and cardiovascular or renal damage, as well as on other aspects of the patient's personal, medical and social situation. Blood pressure values measured in the doctor's office or the clinic should commonly be used as reference. Ambulatory blood pressure monitoring may have clinical value, when considerable variability of office blood pressure is found over the same or different visits, high office blood pressure is measured in subjects otherwise at low global cardiovascular risk, there is marked discrepancy between blood pressure values measured in the office and at home, resistance to drug treatment is suspected, or research is involved. Secondary hypertension should always be investigated. The primary goal of treatment of patient with high blood pressure is to achieve the maximum reduction in long-term total risk of cardiovascular morbidity and mortality. This requires treatment of all the reversible factors identified, including smoking, dislipidemia, or diabetes, and the appropriate management of associated clinical conditions, as well as treatment of the raised blood pressure per se. On the basis of current evidence from trials, it can be recommended that blood pressure, both systolic and diastolic, be intensively lowered at least below 140/90 mmHg and to definitely lower values, if tolerated, in all hypertensive patients, and below 130/80 mmHg in diabetics. Lifestyle measures should be instituted whenever appropriate in all patients, including subjects with high normal blood pressure and patients who require drug treatment. The purpose is to lower blood pressure and to control other risk factors and clinical conditions present. In most, if not all, hypertensive patients, therapy should be started gradually, and target blood pressure achieved progressively through several weeks. To reach target blood pressure, it is likely that a large proportion of patients will require combination therapy with more than one agent. The main benefits of antihypertensive therapy are due to lowering of blood pressure per se. There is also evidence that specific drug classes may differ in some effect or in special groups of patients. The choice of drugs will be influenced by many factors, including previous experience of the patient with antihypertensive agents, cost of drugs, risk profile, presence or absence of target organ damage, clinical cardiovascular or renal disease or diabetes, patient's preference.

Age Factors↗
PubMed2006

Telomere length in small-for-gestational-age babies.

OBJECTIVE: Short telomeres are associated with adult cardiovascular disease. Our aim was to determine whether small-for-gestational-age (SGA) newborns have shortened telomeres compared with appropriately grown controls. DESIGN: Prospective cohort study. SETTING: Large tertiary referral unit in Trent, UK. POPULATION: Seventy-two women who delivered at 35-42 weeks of gestation were recruited; 34 delivered SGA babies (less than or equal to the third birthweight centile) and 38 had appropriately grown babies (greater than the tenth centile). METHODS: Maternal and cord blood samples were collected at delivery. A Southern blot of DNA from these samples was hybridised with a 32P-labelled telomeric probe and telomere length was measured. MAIN OUTCOME MEASURES: Mean maternal and newborn telomere length. RESULTS: Maternal and newborn telomere lengths were significantly correlated in both the SGA and the control groups (r2 = 0.25, P < 0.0001). Telomere lengths were similar in both maternal (control 8.41 +/- 0.9 kb versus SGA 8.29 +/- 1.0 kb, P = 0.57) and newborn (control 10.36 +/- 1.5 kb versus SGA 10.33 +/- 1.3 kb, P = 0.93) cohorts in the two groups. CONCLUSIONS: Intrauterine events associated with impaired fetal growth do not appear to be associated with increased telomere shortening.

Adult↗
PubMed2006

The internationalisation of prehospital education: a merging of ideologies between Australia and the USA.

The aim of this project was to promote internationalisation of prehospital education collaboratively between students and teachers from EMS Education and Training, Montana, USA, and Monash University Centre for Ambulance and Paramedic Studies (MUCAPS), Victoria, Australia. The project required students and teachers to engage in a series of face to face lectures, which was reinforced through distance education strategies, such as online learning. The overall project aim was to establish an objective and descriptive view of the internationalisation of prehospital and community based emergency health education using e-learning as the educational approach. A cross sectional survey design using paper based evaluation was adopted in this project. Results revealed a positive student reaction, with flexible pedagogical processes broadening student learning and facilitating an international dimension otherwise not achievable. Given the current state of globalisation, internationalisation has the capacity to improve educational standards, quality, student interactions and specific learning outcomes in prehospital education.

Attitude of Health Personnel↗
PubMed2005

Patient perspectives on multiple medications versus combined pills: a qualitative study.

BACKGROUND: A growing number of patients are taking multiple medications. Unfortunately, adherence may fall as drug numbers and procedural complexity increase. While there are plausible theoretical reasons why combining pills might improve non-adherence, patients' attitudes are unknown. AIM: To explore attitudes and practices to medication regimens among patients already in receipt of multiple medications, and to assess whether a combined tablet would be perceived as advantageous. DESIGN: Qualitative study. METHODS: Ninety-two men and women aged >40 years currently receiving both antihypertensive and cholesterol-lowering medications took part in 14 focus groups. RESULTS: Drugs were seen as unwelcome but necessary. Some took drugs flexibly by changing dose timing, thereby increasing the complexity of their regimen. A routine was seen as the key to coping with multiple medications, although it was sometimes threatened by changes in prescriptions and life circumstances. While some participants welcomed a combined pill, there was uncertainty about whether a combination that mirrored their current doses would be available. There were also concerns about tablet size, allergies, the attribution of side-effects, timing of tablets throughout the day, and the ability to alter dose levels. CONCLUSION: While some patients would be willing to try a combined pill and would appreciate the associated convenience, they are likely to have a number of concerns that prescribers should address. Willingness to move to combined therapy may be hindered if drug combinations that mirror personalized and trusted regimens are not available.

Aged↗
PubMed2005

Sequential FISH analysis using competitive displacement of labelled peptide nucleic acid probes for eight chromosomes in human blastomeres.

BACKGROUND: The aim was to introduce a new strategy based on peptide nucleic acid (PNA) probes and competitive displacement for using fluorescence in-situ hybridization (FISH) analysis on human blastomeres. METHODS: Sequential FISH analysis with PNA probes and competitive displacement was performed using three different probe sets. The first set consisted of labelled probe only. The second and third sets included labelled as well as unlabelled probe, corresponding to the labelled probes in the previous cycles. The probes for enumeration were for chromosome 1, 13, 16, 17, 18, 21, X and Y. RESULTS: The performance of PNA probes was similar to the established DNA probes. The strategy of competitive displacement resulted in a destabilization of already bound probe before the next FISH cycle at only 50 degrees C, which allowed for up to five sequential FISH cycles without loss of signal. CONCLUSIONS: PNA probes are a good alternative to DNA probes in the present set-up, since the low temperature required both for binding and destabilization of PNA probes minimizes the loss of signal, and several FISH cycles can therefore be carried out before FISH errors occur.

Aneuploidy↗
PubMed2005

Cell-based selection of internalizing fully human antagonistic antibodies directed against FLT3 for suppression of leukemia cell growth.

FMS-like tyrosine kinase 3 (FLT3) receptor is highly expressed in an array of hematological malignancies including approximately 90% of acute myelogenous leukemia (AML). Ligand stimulation of the receptor promotes the survival and proliferation of leukemia cells. Strategies targeting FLT3 using monoclonal antibodies may therefore constitute an effective therapeutic approach for these leukemia. Towards this, we selected a naïve antibody phage display library on both recombinant FLT3 receptor protein and FLT3-expressing leukemia cells using a tailored selection scheme that was designed to isolate antagonistic phage antibodies that not only interfere with receptor/ligand binding but also trigger receptor internalization upon cell surface binding. Phage antibodies were screened first for their ability to bind to cell surface receptor and induce receptor internalization, followed by their activity in blocking ligand-receptor interaction and neutralizing ligand-stimulated receptor activation and cell proliferation. We identified three fully human antibodies, EB10, A2IN, and D4-3, which bound specifically to both soluble and cell surface-expressed FLT3. All three antibodies were shown to be internalized upon binding to cell surface-expressed receptor in a time-dependent fashion. EB10 and D4-3 blocked ligand binding to the receptor with IC(50)s of 14 and 7 nM, respectively. Further, EB10 and D4-3 inhibited FLT3 ligand-induced receptor phosphorylation and cell proliferation in EOL-1 leukemia cells. Taken together, these results suggest that both EB10 and D4-3 may represent excellent therapeutic candidates for the treatment of FLT3-expressing human leukemia, both as unmodified antibodies and as conjugates of cytotoxic agents.

Antibodies, Monoclonal↗
PubMed2005

Decreasing strabismus surgery.

AIM: To determine whether there has been a consistent change across countries and healthcare systems in the frequency of strabismus surgery in children over the past decade. METHODS: Retrospective analysis of data on all strabismus surgery performed in NHS hospitals in England and Wales, on children aged 0-16 years between 1989 and 2000, and between 1994 and 2000 in Ontario (Canada) hospitals. These were compared with published data for Scotland, 1989-2000. RESULTS: Between 1989 and 1999-2000 the number of strabismus procedures performed on children, 0-16 years, in England decreased by 41.2% from 15 083 to 8869. Combined medial rectus recession with lateral rectus resection decreased from 5538 to 3013 (45.6%) in the same period. Bimedial recessions increased from 489 to 762, oblique tenotomies from 43 to 121, and the use of adjustable sutures from 29 to 44, in 2000. In Ontario, operations for squint decreased from 2280 to 1685 (26.1%) among 0-16 year olds between 1994 and 2000. CONCLUSION: The clinical impression of decrease in the frequency of paediatric strabismus surgery is confirmed. In the authors' opinion this cannot be fully explained by a decrease in births or by the method of healthcare funding. Two factors that might have contributed are better conservative strabismus management and increased subspecialisation that has improved the quality of surgery and the need for re-operation. This finding has a significant impact upon surgical services and also on the training of ophthalmologists.

Adolescent↗
PubMed2005

Case based learning--a review of the literature: is there scope for this educational paradigm in prehospital education?

This paper discusses the findings of a literature review of case based learning (CBL) from a multidisciplinary health science education perspective and attempts to draw comparisons with the available literature relating to prehospital education and CBL.CBL is an exciting educational prospect in which to develop research capacity, strategies, and opportunities. This paper provides an examination of the literature exploring the major consistencies and inconsistencies, and reveals areas of potential future research for prehospital education institutions.

Consumer Behavior↗
PubMed2005

Combination aerosol therapy to treat Burkholderia cepacia complex.

Burkholderia cepacia infection in cystic fibrosis (CF) patients is associated with significant morbidity and mortality, yet no definitive treatment is currently available. This report describes a new approach to treat B. cepacia infection in CF patients, using a combination of amiloride and tobramycin aerosols. Four adults with the typical clinical syndrome of CF were recruited after repeated positive sputum cultures for B. cepacia. Aerosols of amiloride and tobramycin were given three times daily for 1-6 months, and repeated sputum cultures were collected to assess efficacy. Three of the four patients treated with the combined therapy eradicated B. cepacia from their sputum cultures for at least 2 yrs, and there were no adverse events. This novel combination may provide a new therapeutic option for Burkholderia cepacia infections. Furthermore, the strategy of combining antibiotics with ion transport agents may have ramifications for the treatment of other multi-resistant organisms.

Administration, Inhalation↗
PubMed2004

Women's perceptions of decision-making about hysterectomy.

OBJECTIVE: To explore women's views of decision-making relating to hysterectomy. DESIGN: Structured questionnaire and in-depth interview surveys. SETTING: A teaching hospital and a district general hospital in northeast Scotland. SAMPLE: Women scheduled for hysterectomy for benign menstrual problems. METHODS: Pre-operative questionnaires were sent to a consecutive sample of women booked for hysterectomy. A purposive sample was interviewed post-operatively. MAIN OUTCOME MEASURES: Women's experiences of, and satisfaction with, information provision, communication and decision-making processes; the relationship between views of decision-making processes and decisions made. RESULTS: One hundred and four women (66%) returned questionnaires. Most responded positively to structured questions about the process by which the decision to have a hysterectomy was reached. Almost all (97%) reported satisfaction with the decision made. Twenty women were interviewed post-operatively. A number, including some who had responded positively on the questionnaire, described aspects of the decision-making process that were suboptimal. Women's perceptions of the decision-making process, including the way their doctors communicated with them, did impinge on their views of the course of action selected. Some women had residual doubts about the appropriateness of hysterectomy. CONCLUSIONS: In a significant minority of women, there are important shortcomings in current patterns of information provision and communication relating to decision-making. These are unlikely to be picked up by conventional structured patient feedback surveys. Further efforts are required to ensure that women are adequately informed and involved in decisions about gynaecological treatments.

Adult↗
PubMed2004

Telomere attrition and accumulation of senescent cells in cultured human endothelial cells.

The human umbilical vein endothelial cell (HUVEC) is an important model of the human endothelium that is widely used in vascular research. HUVECs and the adult endothelium share many characteristics including progression into senescence as the cells age. Despite this, the shortening of telomeres and its relationship to the progression into senescence are poorly defined in HUVECs. In this study of several HUVEC lines we show notable consistency in their growth curves. There is a steady decline in the growth rate of HUVECs grown continually in culture and we estimate complete cessation of growth after approximately 70 population doublings. The HUVECs lose telomeric DNA at a consistent rate of 90 base pairs/population doubling and show a progressive accumulation of shortened telomeres (below 5 kilobases). This telomeric loss correlates with the accumulation of senescent HUVECs in culture as assessed by staining for beta-galactosidase activity at pH 6. Although the telomere length of a large population of cells is a relatively crude measure, we suggest that in HUVECs a mean telomere length (as measured by terminal restriction fragment length) of 5 kilobases is associated with entry into senescence. These data demonstrate the strong relationship between telomere attrition and cell senescence in HUVECs. They suggest that DNA damage and subsequent telomere attrition are likely to be key mechanisms driving the development of endothelial senescence in the pathogenesis of vascular disease.

Cell Line↗
PubMed2004

Developing specialist healthcare for older people: a challenge for the European Union.

The state of health in the European Union is better than ever before. This is due to spectacular progress made over the second half of this century in terms of medical research, health services provision and living conditions. However, older people require more, and substantially different, health and care services than younger people. The central challenge of the policy makers is to ensure that future health care policies will provide an adequate and cost effective response to the changes brought about by demographic trends.

Aged↗