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Biomedical subjects

David Thomas

Publications and source records attributed to David Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2005

Hepatic angiomyolipoma and hepatic stellate cells share a similar gene expression profile.

BACKGROUND AND AIMS: Angiomyolipomas (AMLs) of the liver are rare neoplasms composed of large epithelioid cells with intermixed fat and blood vessels. Hepatic AMLs have no clear normal-cell counterpart in the liver. However, AMLs and stellate cells both are positive for neural crest-derived markers including HMB-45 antigen. METHODS: To further explore the similarities between hepatic AMLs and stellate cells, gene expression of a hepatic AML was studied by cDNA microarray. Real-time polymerase chain reaction was used to confirm gene expression. Hepatic stellate cells can be quiescent, activated, or have a myofibroblastic phenotype depending on their state of activation. Expression of known markers of activated stellate cells was compared between the AML, activated primary mouse stellate cells, and stellate cell lines with activated and myofibroblastic phenotypes. Next, 5 novel genes from the AML were selected because they were not previously known to be markers of stellate cells and mRNA expression measured in the activated mouse stellate cells and in myofibroblastic stellate cell lines. Finally, expression levels of 10 novel genes were determined in 5 cirrhotic and 5 noncirrhotic human livers. RESULTS: Overexpression of known markers of activated stellate cells including transforming growth factor beta (TGF- beta ), smooth muscle actin, and collagen was found in the hepatic AML. Three of 5 novel markers that were identified in the AML, RRAD (Ras-related associated with diabetes), CTSK (cathepsin K), and NIBAN were also found to be overexpressed in activated stellate cells compared with quiescent or myofibroblastic stellate cells. In addition, 9 of 10 novel genes overexpressed in AML were also overexpressed in cirrhotic human livers versus noncirrhotic livers. CONCLUSIONS: Hepatic AMLs share a similar gene expression profile and may differentiate toward activated stellate cells.

Angiomyolipoma↗
PubMed2005

The organisational response to patient complaints: a case study in Taiwan.

PURPOSE: To explore and evaluate how hospital staff respond to patient complaints. DESIGN/METHODOLOGY/APPROACH: A teaching hospital with 1,500 beds in Taiwan was purposefully chosen as a case study of hospital response to patients' complaints. Data was obtained through interviews with quality surveying managers (n = 53), government managers (n = 4), staff of non-government organizations (n = 3) and a senior social worker, as well as analysis of documents (September 2001-April 2002). FINDINGS: Using the managerial-operational-technical framework developed by the researchers, the study demonstrated problematic aspects of handling complaints at the case hospital. It was revealed that: complaint handlers were not sufficiently empowered, information sharing was limited within the organization, communication among professional staff and with management was inadequate, the physical safety of workers had been threatened, and improvements could not be sustained. Moreover, it became apparent that the case study hospital generally responded to patient complaints in a reactive and defensive manner. ORIGINALITY/VALUE: It is evident that the hospital did not use patient complaints as a source of learning that could have promoted higher standards of care. The case study reveals some of the constraints and identifies requirements for appropriate use of information and feedback from patients. The study raises some issues requiring further research to ensure more appropriate use of patient complaints to improve quality of care.

Data Collection↗
PubMed2005

Food and botanical groupings and risk of breast cancer: a case-control study in Shanghai, China.

Breast cancer incidence rates more than double in Chinese women as they migrate from China to Hong Kong to the United States, suggesting that environmental factors contribute to the international variation in breast cancer incidence. Several dietary factors, which differ between the United States and the Chinese population, including intake of soy, meat, and fruits and vegetables, have been suggested to affect breast cancer risk. This report describes results from a case-control study of diet and risk of breast cancer nested in a randomized trial of breast self exam in Shanghai, China. Participating breast cancer cases (n = 378) and frequency age-matched controls (n = 1,070) completed a comprehensive food frequency questionnaire and a risk factor questionnaire. After adjustment for age, total energy intake, and total years of breast-feeding, women in the highest quartile of fruit and vegetable intake (> or =3.8 servings/d) were significantly less likely to have breast cancer (odds ratio, 0.48; 95% confidence interval, 0.29-0.78) as compared with women in the lowest quartile of intake (< or =2.3 servings/d). Egg consumption was also significantly inversely associated with risk of breast cancer (odds ratio for > or =6.0 eggs/wk versus < or =2.0 eggs/wk is 0.56; 95% confidence interval, 0.35-0.91). There was no difference in soy consumption between cases and controls. None of the associations with a single botanical family explained the strong inverse relationship between fruits and vegetables and breast cancer risk. These results provide additional evidence in support of the important role of fruits and vegetables in breast cancer prevention.

Adult↗
PubMed2004

WHEATSHEAF: an algorithm to average protein structure ensembles.

A new algorithm is described that forms a single structure representative of ensembles of structures from files in the format used by the Protein Data Bank. A first attempt is made by averaging in the space spanned by bond lengths, inter-bond rotations and symmetry-multiplied dihedral rotations. This normally produces well formed regular secondary-structure elements, but the intervening less well ordered regions are often distorted because of the invalidity of averaging large rotations about divergent axes. For this reason, the algorithm includes a second stage that pulls the interatomic distances towards more fully representative values. Results produced by this method have proved better as judged by conventional quality checks than any input structure in nearly all cases tested so far, especially for the backbone, and much better than those produced by commonly used alternative methods.

Algorithms↗
PubMed2004

The STATs in cell stress-type responses.

In the early 1990's, a new cell signaling pathway was described. This new paradigm, now known as the JAK/STAT pathway, has been extensively investigated in immune-type cells in response to interferons and interleukins. However, recent evidence suggests that the JAK/STAT pathway also mediates diverse cellular responses to various forms of biological stress including hypoxia/reperfusion, endotoxin, ultraviolet light, and hyperosmolarity. The current literature describing the JAK/STAT pathway's role in cellular stress responses has been reviewed herein, but it is clear that our knowledge in this area is far from complete.

Journal Article↗
PubMed2004

Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses.

Tissue transglutaminase (TG2) affects cell-matrix interactions in cell spreading, migration and extracellular matrix (ECM) reorganisation. Using fibroblasts deficient in TG2 or overexpressing normal or crosslinking-deficient enzyme, we show that the extracellular crosslinking activity and intracellular G-protein function in signal transduction contribute differentially to regulation of cell-matrix interactions. TG2-deficient cells displayed normal attachment but delayed spreading on ECM substrata and defects in motility unrelated to crosslinking. Blocking antibodies to TG2 failed to induce similar defects in normal fibroblasts. TG2-deficient fibroblasts had defects in focal adhesion turnover and stress fibre formation, showed changes in focal adhesion kinase (FAK) phosphorylation and failed to activate protein kinase C alpha (PKCalpha). Phospholipase C (PLC) and PKCalpha inhibitors blocked spreading of normal fibroblasts whilst PKC activators induced spreading in TG2-deficient cells. In contrast, ECM remodelling was not only compromised by TG2 deficiency but also by overexpression of dominant negative enzyme and TG inhibitors. TG2 activity increased matrix tension and was required for membrane type 1-MMP (MT1-MMP)-dependent activation of MMP-2. Our results demonstrate that TG2 is involved in the control of dynamic adhesion formation in cell spreading and migration via regulation of phospholipase C activity. By virtue of its crosslinking activity, the enzyme plays a central role in regulating ECM remodelling.

Cell Adhesion↗
PubMed2004

Immune-deficient Drosophila melanogaster: a model for the innate immune response to human fungal pathogens.

We explored the host-pathogen interactions of the human opportunistic fungus Candida albicans using Drosophila melanogaster. We established that a Drosophila strain devoid of functional Toll receptor is highly susceptible to the human pathogen C. albicans. Using this sensitive strain, we have been able to show that a set of specific C. albicans mutants of different virulence in mammalian infection models are also impaired in virulence in Drosophila and remarkably display the same rank order of virulence. This immunodeficient insect model also revealed virulence properties undetected in an immunocompetent murine model of infection. The genetic systems available in both host and pathogen will enable the identification of host-specific components and C. albicans genes involved in the host-fungal interplay.

Animals↗
PubMed2004

Analysis of tensile bond strengths using Weibull statistics.

Tensile strength tests of restorative resins bonded to dentin, and the resultant strengths of interfaces between the two, exhibit wide variability. Many variables can affect test results, including specimen preparation and storage, test rig design and experimental technique. However, the more fundamental source of variability, that associated with the brittle nature of the materials, has received little attention. This paper analyzes results from micro-tensile tests on unfilled resins and adhesive bonds between restorative resin composite and dentin in terms of reliability using the Weibull probability of failure method. Results for the tensile strengths of Scotchbond Multipurpose Adhesive (3M) and Clearfil LB Bond (Kuraray) bonding resins showed Weibull moduli (m) of 6.17 (95% confidence interval, 5.25-7.19) and 5.01 (95% confidence interval, 4.23-5.8). Analysis of results for micro-tensile tests on bond strengths to dentin gave moduli between 1.81 (Clearfil Liner Bond 2V) and 4.99 (Gluma One Bond, Kulzer). Material systems with m in this range do not have a well-defined strength. The Weibull approach also enables the size dependence of the strength to be estimated. An example where the bonding area was changed from 3.1 to 1.1 mm diameter is shown. Weibull analysis provides a method for determining the reliability of strength measurements in the analysis of data from bond strength and tensile tests on dental restorative materials.

Acid Etching, Dental↗
PubMed2004

Postal reminders can improve attendance at orthodontic clinics.

DESIGN: A randomised controlled trial in an NHS hospital orthodontic clinic. INTERVENTION: Participants either received an appointment or an appointment plus a reminder at least 2 weeks before their appointment. The reminder letter was sent with a stamped addressed postcard, which the patient was asked to return, to confirm the appointment. OUTCOME MEASURE: Patient attendance at the clinic. RESULTS: A total of 231 patients were entered into the study. Patients who received a reminder and returned the confirmation were significantly less likely to fail the appointment than those who did not receive a reminder. 27% of girls failed appointments compared with 15% of boys. Those from areas of high social deprivation were more likely to fail to attend appointment than people who were more affluent. CONCLUSIONS: The use of postal reminders for orthodontic consultation appointments appears to result in a useful increase of appointments that are kept or cancelled in advance but does not counteract the effect of social deprivation on attendance.

Clinical Trial↗
PubMed2004

Hashimoto's encephalopathy: an unusual cause of seizures in the intensive care unit.

OBJECTIVE: To present a case study of Hashimoto's encephalopathy. DESIGN: Case report. SETTING: Paediatric Intensive Care Unit, Nottingham University Hospital, UK. PATIENTS: Two adolescent females presented with encephalopathy and raised venous lactate. Both had subtle signs of neurocognitive deterioration before initial presentation. Extensive investigation revealed elevated antithyroid antibody titer, suggesting Hashimoto's encephalopathy. INTERVENTIONS: Steroid administration. MEASUREMENTS AND MAIN RESULTS: Symptoms rapidly resolved in both cases after steroid treatment. CONCLUSION: Hashimoto's encephalopathy should be considered in cases of unexplained encephalopathy presenting to the intensive care unit. Teenage girls with an antecedent history suggestive of thyroid disease or progressive cognitive decline warrant special attention. Antithyroid antibody titers should be measured even if standard thyroid function tests are normal. Although the etiology is unknown, prompt steroid responsiveness suggests an inflammatory or autoimmune disorder, and patients should be treated accordingly.

Adolescent↗
PubMed2004

Do referrals from primary dental care for treatment using general anaesthesia comply with General Dental Council guidelines?

OBJECTIVES: To investigate the quality of information in referrals for patients aged under 16 years referred for dental extraction under general anaesthesia (GA), to ascertain the knowledge and expectations of the parents of these patients, and to determine whether the number of teeth extracted in secondary care coincides with that of the referring dentist. DESIGN: Retrospective study of referrals of all patients aged under 16 years referred to community dental clinics in Berkshire, Buckinghamshire, Northamptonshire and Oxfordshire over a 26-day period. RESULTS: The majority (62.2%) of the 251 referrals examined were for extractions under GA. Of these, 125 were by letter and 117 using a pro forma. Significantly more pro formas (33) than letters (8) contained a full medical history (P < 0.001). A treatment plan was included in significantly more pro formas (76) than letters (49) (P < 0.01). Few referrals contained a note about the discussion of alternatives to a GA procedure and only 37% (58/156) of parents reported that the referring general dental practitioner had discussed alternative treatments with them. A total of 551 primary teeth were indicated for removal but 846 teeth were eventually removed. CONCLUSIONS: Our findings indicate a need for parents of patients referred for GA procedures to be better informed about alternatives. Improvement in the quality of referrals, perhaps with the aid of standard pro formas, would also facilitate more effective management of referred patients.

Adolescent↗
PubMed2004

The role of unstructured extensions in the rotational diffusion properties of a globular protein: the example of the titin i27 module.

The possibility of predicting the overall shape of a macromolecule in solution from its diffusional properties has gained increasing importance in the structural genomic era. Here we explore and quantify the influence that unstructured and flexible regions have on the motions of a globular protein, a situation that can occur from the presence of such regions in the natural sequence or from additional tags. I27, an immunoglobulin-like module from the muscle protein titin, whose structure and properties are well characterized, was selected for our studies. The backbone dynamics and the overall tumbling of three different constructs of I27 were investigated using (15)N NMR relaxation collected at two (15)N frequencies (60.8 and 81.1 MHz) and fluorescence depolarization spectroscopy after labeling of a reactive cysteine with an extrinsic fluorophore. Our data show that the presence of disordered tags clearly exerts a frictional drag that increases with the length of the tags, thus affecting the module tumbling in solution. We discuss the use and the limitations of current approaches to hydrodynamic calculations, especially when having to take into account local flexibility.

Algorithms↗
PubMed2004

The co-regulation of medical discipline: challenging medical peer review.

The medical profession has always fiercely defended its right to self-regulation on the basis of peer review. However, in New South Wales, Australia, the profession has willingly surrendered these rights in favour of a disciplinary system known as co-regulation or collaborative regulation, under which disciplinary processes are shared with a "lay" body, the Health Care Complaints Commission. The system constitutes a unique situation in the history of medical regulation. This article examines the origin and operations of co-regulation and comes to the conclusion that its successful operation over the last decade raises questions about whether peer review is indispensable as the basis of medical regulation.

Cooperative Behavior↗
PubMed2003

STI-571 inhibits in vitro angiogenesis.

Compounds that block angiogenesis are effective in the treatment of certain cancers and other angiogenesis-related diseases. Many of these compounds specifically target the rapidly proliferating and migrating endothelial cell. However, angiogenesis is a multi-faceted process involving heterotypic interactions between various cell types. For example, PDGFBB is an important cytokine secreted by endothelial cells that attracts smooth muscle cells to surround and stabilize a nascent vessel. Therefore, we hypothesized that STI-571, a tyrosine kinase inhibitor with PDGFbeta receptor activity, would inhibit angiogenesis through an anti-migratory effect on smooth muscle cells. We demonstrate that STI-571 completely inhibits in vitro angiogenesis in fibrinogen-embedded mouse aorta. Furthermore, this angiostatic property was due mainly to an anti-migratory and anti-proliferative effect upon smooth muscle cells. These data suggest that STI-571, in addition to its efficacy in the treatment of certain cancers, may also prove to be clinically useful in diseases characterized by unregulated angiogenesis.

Animals↗
PubMed2003

DePIE: Designing Primers for Protein Interaction Experiments.

Several primer prediction and analysis programs have been developed for diverse applications. However, none of these existing programs can be directly used for the design of primers in protein interaction experiments, since proteins may have transmembrane domains (TMDs) and/or a signal peptide that must be excluded from experiments. Furthermore, it is frequently the case that a short restriction sequences must be added to each primer in order to clone PCR products into a given destination vectors for expression. DePIE, a web-based primer design tool, was developed to address these deficiencies. The program takes as input NCBI protein accession numbers and returns primer information including nucleotide sequences, thermodynamic melting temperature of the nucleotide sequences and the target positions. DePIE is implemented in JAVA, PERL and PHP and has proven to be very efficient in designing primers for our interaction experiments. DePIE services can be accessed at the web site: http://biocore.unl.edu/primer/primerPI.html.

DNA Primers↗
PubMed2003

Pallidotomy and incidental sequence learning in Parkinson's disease.

Converging evidence from animal research and human brain imaging studies, points to an important role of cortical-striatal motor circuitry in the incidental learning of serial order information. To date, attempts to address this role through the study of patients with striatal disorder have proved inconclusive. The present study examined the impact of a therapeutic lesion of the globus pallidus in patients with Parkinson's disease. The lesion, which blocks a primary output of the putamen to the motor cortices, eliminated incidental learning relative both to controls and unoperated patients. The finding offers support for models proposing that context detection within the striatum is a central process in serial order learning. An unexpected effect of the lesion was to significantly reduce the response time to random stimuli relative to an ordered series, the opposite of the normal pattern. It is speculated that this may reflect an unconscious alerting response to novelty, a process suggested to involve the ventral striatum and its cortical targets. Research on Parkinson's disease patients undergoing functional basal ganglia surgery may shed further light on the mechanisms and neuronal substrate of serial order learning in humans.

Aged↗