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Biomedical subjects

David Thompson

Publications and source records attributed to David Thompson.

At least 19 recordsLinked to original sources
PubMed2025

Generation of C9orf72 repeat knock-in iPSC lines for modelling ALS and FTD.

Induced pluripotent stem cell (iPSC) models are powerful tools for neurodegenerative disease modelling, as they allow mechanistic studies in a human genetic environment and they can be differentiated into a range of neuronal and non-neuronal cells. However, these models come with inherent challenges due to line-to-line and clonal variability. To combat this issue, the iPSC Neurodegenerative Disease Initiative (iNDI) has generated an iPSC repository using a single clonal reference line, KOLF2.1J, into which disease-causing mutations and revertants are introduced via gene editing. Here we describe the generation and validation of lines carrying the most common causative mutation for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a repeat expansion in the C9orf72 gene, for the iNDI collection of neurodegenerative iPSC models. We demonstrate that these C9orf72 knock-in lines differentiate efficiently into neurons and display characteristic C9orf72-associated pathologies, including reduced C9orf72 levels and the presence of dipeptide repeat proteins (DPRs) and RNA foci, which increase in abundance over time in culture. These pathologies are not present in revertant cells lacking the repeat expansion. These repeat expansion and revertant cell lines are now available to academic and for-profit institutions through the JAX iPS cell repository and will help to facilitate and standardise iPSC-based ALS/FTD research.

Journal Article↗
PubMed2006

ATP binding and ATP hydrolysis play distinct roles in the function of 26S proteasome.

The 26S proteasome degrades polyubiquitinated proteins by an energy-dependent mechanism. Here we define multiple roles for ATP in 26S proteasome function. ATP binding is necessary and sufficient for assembly of 26S proteasome from 20S proteasome and PA700/19S subcomplexes and for proteasome activation. Proteasome assembly and activation may require distinct ATP binding events. The 26S proteasome degrades nonubiquitylated, unstructured proteins without ATP hydrolysis, indicating that substrate translocation per se does not require the energy of hydrolysis. Nonubiquitylated folded proteins and certain polyubiquitylated folded proteins were refractory to proteolysis. The latter were deubiquitylated by an ATP-independent mechanism. Other folded as well as unstructured polyubiquitylated proteins required ATP hydrolysis for proteolysis and deubiquitylation. Thus, ATP hydrolysis is not used solely for substrate unfolding. These results indicate that 26S proteasome-catalyzed degradation of polyubiquitylated proteins involves mechanistic coupling of several processes and that such coupling imposes an energy requirement not apparent for any isolated process.

Adenosine Triphosphate↗
PubMed2006

Outcomes of thromboprophylaxis with enoxaparin vs. unfractionated heparin in medical inpatients.

BACKGROUND: Clinical trials have shown low-molecular weight heparin (LMWH) to be at least as safe and efficacious as unfractionated heparin (UFH) for preventing venous thromboembolism (VTE) in acutely-ill medical inpatients. OBJECTIVE: To compare clinical and economic outcomes among acutely-ill medical inpatients receiving the LMWH enoxaparin versus UFH prophylaxis in clinical practice. METHODS: Using a large, multi-hospital, US database, we identified persons aged > or =40 years hospitalized for > or =6 days for an acute medical condition (including circulatory disorders, respiratory disorders, infectious diseases, or neoplasms) from Q4 1999 to Q1 2002. From these patients, those who received thromboprophylaxis with either enoxaparin or UFH were identified. Surgical patients and those requiring or ineligible for anticoagulation were excluded. We compared the incidence of deep-vein thrombosis (DVT), pulmonary embolism (PE), and all VTE (i.e., DVT and/or PE). Secondary outcomes were occurrence of side-effects, length of hospital stay and total costs. RESULTS: 479 patients received enoxaparin prophylaxis and 2,837 received UFH. The incidence of VTE was 1.7% with enoxaparin prophylaxis versus 6.3% with UFH (RR = 0.26; p < 0.001). Occurrence of side effects, length of stay (10.00 days with enoxaparin vs. 10.26 days with UFH; p = 0.348) and total costs ($18,777 vs. $17,602; p = 0.463) were similar in the 2 groups. CONCLUSION: We observed a 74% lower risk of VTE among patients receiving enoxaparin prophylaxis versus UFH prophylaxis. There was no significant difference in side effects or economic outcomes. These results provide evidence that the LMWH enoxaparin is more effective than UFH in reducing the risk of VTE in current clinical practice.

Journal Article↗
PubMed2006

A comparison of pharmacy students' confidence and test performance.

OBJECTIVES: The objectives of this study were to estimate student retention of knowledge regarding the management of patients with hypertension and dyslipidemia, measure student clinical confidence, and identify the relationship between clinical confidence and actual performance on a knowledge assessment test. METHODS: This was a sequential cross-sectional study to evaluate knowledge retention and clinical confidence of second-year pharmacy students. To measure student clinical confidence, a 12-item clinical confidence questionnaire was administered. To measure student retention of knowledge, a 21-question knowledge assessment test was administered. At least 1 test question was related to each question asked in the clinical confidence questionnaire. RESULTS: One hundred eight students completed the study. The percentage of students correctly answering test questions decreased from a baseline of 70.4% +/- 5.8% to 60.9% +/- 5.8% four months later (p = 0.02) in spite of the students rating their clinical confidence from moderate to high in all areas. The proportion of students answering questions correctly was similar across the different levels of confidence. CONCLUSION: Overall, retention of knowledge appears to decline over a 4-month period of time. Furthermore, while students perceived moderate to high confidence, student knowledge did not match perceived confidence.

Clinical Competence↗
PubMed2006

Expression of TECK/CCL25 and MEC/CCL28 chemokines and their respective receptors CCR9 and CCR10 in porcine mucosal tissues.

CCL25 and CCL28 (also named TECK and MEC) are CC chemokines primarily expressed by thymic dendritic cells and mucosal epithelial cells. The cognate receptors of CCL25 and CCL28, named CCR9 and CCR10, are mainly expressed on T lymphocytes for CCR9 and IgA(+) and IgM(+) plasmablasts for CCR9 and CCR10, respectively. In human and mouse, chemokines CCL25 and CCL28 play an important role in attracting immune cells to the gastrointestinal tract and in controlling segmental specialization of the intestinal immune system. To investigate if CCL25 and CCL28 play a similar role in the pig and to better understand lymphocyte trafficking in this species, we cloned porcine CCL25 and CCR10 and measured expression of CCL25, CCL28, CCR9, and CCR10 transcripts by real-time and conventional PCR in various tissues from newborn and young piglets, and adult sows. The results of the expression analyses show that (i) expression of CCL25 mRNA is mainly restricted to the small intestine, (ii) CCL28 mRNA expression is detectable in all tested epithelial mucosal surfaces with the highest levels of expression in the mammary gland, trachea and large intestine, (iii) high levels of expression of CCR9 mRNA in CD3+ T lymphocytes, gut-associated lymphoid tissues (GALT), and the small intestine, (iv) high levels of expression of CCR10 mRNA in GALT, the large intestine, the small intestine, and the mammary gland, and (v) up-regulation of CCL28 mRNA expression during lactation in the mammary gland. This pattern of expression, which is discussed in the context of compartmentalization of the porcine common mucosal immune system into upper aero-digestive tract, small intestine and large intestine, suggests a key role for CCL28 in the recruitment of IgA secreting cells into the mammary gland enabling the passive transfer of IgA antibodies from mother to infant.

Age Factors↗
PubMed2006

Effect of glucagon-like peptide-1 (7-37) on beta-cell function after islet transplantation in type 1 diabetes.

Islet transplantation can improve glycemic control in patients with type 1 diabetes and reduce or eliminate the need for insulin. Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose induced insulin secretion, and has a trophic effect on beta-cells. We evaluated the effect of GLP-1 on insulin secretion after islet transplantation. Patients underwent hyperglycemic glucose clamp studies 1 month after their last transplant. GLP-1 was infused during the second hour of the hyperglycemic clamp. Results were compared to normal control subjects and patients with type 2 diabetes who underwent an identical hyperglycemic clamp. First phase insulin release was absent in patients, while second phase insulin was not significantly reduced (control: 118+/-29 pM; type 2 diabetes: 68+/-20 pM; transplant: 99+/-18 pM, p=ns for all). GLP-1 had a significant incretin effect on transplanted islets but the response was less than controls (control: 2108+/-344 pM; type 2 diabetes: 929+/-331 pM; transplant: 329+/-112 pM, p<0.0001 control versus transplant). Islet transplant patients had no evidence of resistance to insulin mediated glucose disposal. We conclude that transplanted islets retain the ability to respond to GLP-1.

Adult↗
PubMed2006

Targeting errors in the ICU: use of a national database.

The authors believe that as we move from viewing adverse event reporting system as punitive, and as the safety culture improves, reporting will likely increase. Voluntary incident reporting systems can be used to improve patient safety in the ICU by identifying broken or inadequate systems that lead to adverse events [26]. Voluntary external reporting systems such as the ICUSRS can be used to target errors and produce evidence-based best practice measures to improve patient safety in the ICU.

Adverse Drug Reaction Reporting Systems↗
PubMed2006

Cystic adventitial disease of the femoral vein presenting as deep vein thrombosis: a case report and review of the literature.

Cystic adventitial disease of veins is a rare condition. We report the case of a 28-year-old man who presented with a swollen leg secondary to obstruction of the common femoral vein as a result of this disease. He underwent excision of the cyst and made a full recovery. The presentation, investigation, treatment and pathology of this condition is discussed.

Adult↗
PubMed2006

Operating room briefings: working on the same page.

This tool, which takes one or two minutes to use, provides a structured approach to promote effective interdisciplinary communication and teamwork in the operating room--or any other area, such as an intensive care unit, inpatient unit, or outpatient clinic.

Humans↗
PubMed2006

The development of a new measure of quality of life for children with congenital cardiac disease.

The purpose of the study was to develop a questionnaire measuring health-related R1 quality of life for children and adolescents with congenital heart disease, the ConQol, that would have both clinical and research applications. We describe here the process of construction of a questionnaire, the piloting and the development of a weighted scoring system, and data on the psychometric performance of the measure in a sample of 640 children and young people recruited via 6 regional centres for paediatric cardiology from across the United Kingdom. The ConQol has two versions, one designed for children aged from 8 to 11 years, and the other for young people aged from 12 to 16 years. Initial findings suggest that it is a valid and reliable instrument, is acceptable to respondents, and is simple to administer in both a research and clinical context.

Adolescent↗
PubMed2006

Is self-care a cost-effective use of resources? Evidence from a randomized trial in inflammatory bowel disease.

OBJECTIVES: To determine if a whole-system approach to self-management in inflammatory bowel disease (IBD), using a guidebook developed with patients and physicians trained in patient-centred care, leads to cost-effective use of health system resources. METHODS: Cost-effectiveness analysis over a one-year time horizon comparing the whole systems self-management approach to treatment with usual treatment. Nineteen hospitals in the northwest England were randomized to the intervention or to be controls; 651 patients (285 at intervention sites and 366 at control sites) with established IBD were included. The economic evaluation related differential health service costs, from a UK NHS perspective, to differences in quality-adjusted life years (QALYs) based on patients' responses to the EQ-5D. RESULTS: The intervention was associated with a mean reduction in costs of 148 pounds sterling per patient and a small mean reduction in QALYs of 0.00022 per patient compared with the control group. This resulted in an incremental cost per QALY gained of 676,417 pounds sterling for treatment as usual and a probability of around 63% that the whole-system approach to self-management is cost-effective, assuming a willingness to pay up to 30,000 pounds sterling for an additional QALY. CONCLUSIONS: Although there is uncertainty associated with these estimates, more widespread use of this method in chronic disease management seems likely to reduce health care costs without evidence of adverse effect on patient outcomes.

Cost-Benefit Analysis↗
PubMed2005

Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type 1 diabetes mellitus.

HYPOTHESIS: A local multiorgan donor pancreas procurement program can provide a source for optimized isolation of purified viable islets for transplantation into patients with type 1 diabetes mellitus receiving best medical therapy. DESIGN: Prospective before-after cohort study. SETTING: Tertiary referral center. PATIENTS: Glycemic control was assessed in 10 patients with diabetes-induced renal dysfunction who were enrolled in a best medical therapy program and then crossed over to islet transplantation. INTERVENTIONS: Thirty human pancreata were retrieved from local multiorgan donors and consecutively processed with intraductal collagenase perfusion, continuous digestion, and density gradient purification (group 1, n = 9) or similarly processed but impure tissue fractions cultured in vitro and then repurified to retrieve additional islets (group 2, n = 21). Islets were implanted by percutaneous portal embolization, providing more than 10 000 islet equivalents (IE) per kilogram of body weight (infusions from 1-3 donors per patient) under cover of antithymocyte globulin, sirolimus, or mycophenolate mofetil and tacrolimus. MAIN OUTCOME MEASURES: Islet yields, purity, and cell viability (caspase 3, terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine 5-triphosphate nick-end labeling stain, and insulin secretion in vitro) were compared. In patients, monitored metabolic parameters were C-peptide secretion, insulin requirements, glycemic excursion, and hemoglobin A(1c) (HbA(1c)). RESULTS: For group 1 vs group 2, no differences were observed in pancreas age (43 vs 44 years), cold storage (5 vs 4 hours), or weight (73 vs 82 g). Group 2 yielded 453 690 IE vs 214 109 IE in group 1 (P = .002). Grafts contained 50% or more endocrine cells in both groups. No difference occurred in cell viability or insulin secretion. Islets from 90% of group 2 pancreata met release criteria for transplantation. C-peptide secretion was detected in all recipients and persisted with a median follow-up to 12 months (range, 6-21 months) after full islet transplantation. Daily insulin dependence was reversed in all patients for at least 3 months. Five patients resumed small insulin doses. Compared with the best care program, all patients had improved metabolic stability. The mean +/- SE HbA(1c) level at entry into the study was 7.8% +/- 0.5%, and this decreased to 6.9% +/- 0.2% after best care (P = .38) and further to 6.2% +/- 0.2% at 6 months after transplantation (P = .002 vs entry; P = .15 vs best care; analysis of variance). CONCLUSIONS: Local pancreas donor retrieval with islet isolation and culture conditioning enabled an offer of islets for transplantation for 90% of consecutively processed pancreata. Isolated islets secreted insulin during prolonged follow-up after implantation into patients, yielding metabolic control comparable with that achieved by best medical therapy.

Adult↗
PubMed2005

Clinical presentation and delayed treatment of cholangitis in older people.

Acute cholangitis is more common in older people, and increasing age is a determinant of morbidity and mortality, as is early biliary decompression by ERCP. This study aims to identify factors that may contribute to delays in the diagnosis and treatment of older people with acute cholangitis. Case notes of 122 patients (45 aged < 75 years, 77 > 75 years) with a final diagnosis of acute cholangitis who underwent ERCP were reviewed for presenting clinical features (pain, jaundice, rigors, fever, falls, incontinence, confusion), liver function tests, blood count, and the interval from admission to diagnosis, ultrasonography, and ERCP. The most common symptom at presentation was abdominal pain (81%), followed by jaundice (55%). These symptoms were no less common in older patients. Charcot's triad was present in only 15.6% of young and 18.8% of older patients. Jaundice was not detected in 16% of significantly hyperbilirubinemic older patients, but only the presence of functional symptoms was associated with significant diagnostic delay (median, 1 day [range: 0-11] vs. 9.5 days [3-25]; P< 0.001) and delay in performing ERCP (median: 4 days [0-24] vs. 16.5 days [2-29], P< 0.001). Overall mortality was 10%, and the incidence of septic shock was similar in both groups. Charcot's classical triad is infrequent in patients suffering from acute cholangitis. Given the greater difficulty assessing jaundice in older people and the confounding effect of falls, incontinence, and confusion, a routine policy of liver function tests, with further investigation of abnormal results in such presentations, may reduce delays in diagnosing and treating acute cholangitis.

Abdominal Pain↗
PubMed2005

Effectiveness of a mutual support group for families of patients with schizophrenia.

AIM: This paper reports a study to examine the effectiveness of a 12-session mutual support group for Chinese families caring for a relative with schizophrenia compared with a psycho-educational group and routine family support services in Hong Kong. BACKGROUND: Schizophrenia is a disruptive and distressing illness for patients and their families. With the current trend of community care for mental illness, there is evidence that family intervention reduces patient relapse and re-hospitalization, satisfies the health needs of families and enhances their coping capabilities. METHODS: A randomized controlled trial was conducted from May 2002 to June 2003 with 96 Chinese families of a relative with schizophrenia selected from two psychiatric outpatient clinics in Hong Kong. Families were randomly assigned to receive mutual support (n = 32), psycho-education (n = 33) or standard care only (n = 31). The interventions were delivered at outpatient clinics over a 6-month period. Pre- and post- (1 week and 6 months) testing took place and families' functioning, mental health service utilization, patients' level of functioning and duration of re-hospitalization were measured. RESULTS: At both post-test periods, family caregivers and patients in the mutual support group reported statistically significant improvements on family and patients' level of functioning, when compared with their counterparts in the psycho-education and standard care groups. CONCLUSIONS: The findings support the use of mutual support groups as an effective modality of family intervention in a Chinese population caring for a family member with schizophrenia to improve both family and patient functioning.

Activities of Daily Living↗