Biomedical subjects

S Edwards

Publications and source records attributed to S Edwards.

At least 19 recordsLinked to original sources

PubMed2026

Two iPSC lines with frameshift mutations in FTSJ1 as models for X-linked non-syndromic intellectual disability.

CRISPR/Cas9 was used to introduce two different FTSJ1 frameshift mutations into an existing human male iPSC line (UMGWi004-B). No additional genomic or chromosomal changes were detected. The modified iPSC express different stem cell markers and can be induced to differentiate into cells from all three germ layers. FTSJ1 is ubiquitously expressed and mutations in this X-chromosomal gene are involved in an intellectual developmental disorder (OMIM: #309549). These cells can be used to model the disease at the cellular and organoid level in their original state or after differentiation into cell types of interest.

Journal Article↗

PubMed2007

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia.

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.

Age Factors↗

PubMed2006

Vitronectin in human hepatic tumours contributes to the recruitment of lymphocytes in an alpha v beta3-independent manner.

The degree of lymphocyte infiltration is a prognostic factor in liver cancer, but to date the mechanisms by which lymphocytes infiltrate into and are retained in hepatic tumours are poorly understood. We hypothesised that the extracellular matrix glycoprotein vitronectin, a major component of the stroma of hepatic tumours, might play a role in the recruitment and retention of tumour-infiltrating lymphocytes (TIL). Thus, we investigated the ability of vitronectin to support migration and adhesion of TIL isolated from hepatocellular carcinoma and colorectal hepatic metastases. Soluble vitronectin-induced dose-dependent migration of TIL in in vitro chemotaxis and haptotaxis assays and vitronectin in tissue sections was able to support TIL adhesion to tumour stroma. Neither adhesion nor migration was inhibited by a function blocking mAb against the major vitronectin receptor alpha v beta3 and we were unable to detect alpha v beta3 on TIL in vitro or in vivo on tumour tissue. However, TIL did express high levels of urokinase-type plasminogen activator receptor (uPAR) and inhibitory antibodies and amiloride both significantly inhibited TIL adhesion to vitronectin and reduced transendothelial migration of lymphocytes across liver endothelium in vitro. Thus, we provide evidence that vitronectin in liver tumours can support the recruitment and retention of effector lymphocytes by an uPAR-dependent mechanism.

Cell Adhesion↗

PubMed2006

Diversity of TMPRSS2-ERG fusion transcripts in the human prostate.

TMPRSS2-ERG gene fusions have recently been reported to be present in a high proportion of human prostate cancers. In the current study, we show that great diversity exists in the precise structure of TMPRSS2-ERG hybrid transcripts found in human prostates. Fourteen distinct hybrid transcripts are characterized, each containing different combinations of sequences from the TMPRSS2 and ERG genes. The transcripts include two that are predicted to encode a normal full-length ERG protein, six that encode N-terminal truncated ERG proteins and one that encodes a TMPRSS2-ERG fusion protein. Interestingly, distinct patterns of hybrid transcripts were found in samples taken from separate regions of individual cancer-containing prostates, suggesting that TMPRSS2-ERG gene fusions may be arising independently in different regions of a single prostate.

Gene Expression Regulation, Neoplastic↗

PubMed2006

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells.

Amplification and overexpression of the E2F3 gene at 6p22 in human bladder cancer is associated with increased tumour stage, grade and proliferation index, and in prostate cancer E2F3 overexpression is linked to tumour aggressiveness. We first used small interfering RNA technology to confirm the potential importance of E2F3 overexpression in bladder cancer development. Knockdown of E2F3 expression in bladder cells containing the 6p22 amplicon strongly reduced the extent of bromodeoxyuridine (BrdU) incorporation and the rate of cellular proliferation. In contrast, knockdown of CDKAL1/FLJ20342, another proposed oncogene, from this amplicon had no effect. Expression cDNA microarray analysis on bladder cancer cells following E2F3 knockdown was then used to identify genes regulated by E2F3, leading to the identification of known E2F3 targets such as Cyclin A and CDC2 and novel targets including pituitary tumour transforming gene 1, Polo-like kinase 1 (PLK1) and Caveolin-2. For both bladder and prostate cancer, we have proposed that E2F3 protein overexpression may cooperate with removal of the E2F inhibitor retinoblastoma tumor suppressor protein (pRB) to drive cellular proliferation. In support of this model, we found that ectopic expression of E2F3a enhanced the BrdU incorporation, a marker of cellular proliferation rate, of prostate cancer DU145 cells, which lack pRB, but had no effect on the proliferation rate of PC3 prostate cancer cells that express wild-type pRB. BrdU incorporation in PC3 cells could, however, be increased by overexpressing E2F3a in cells depleted of pRB. When taken together, these observations indicate that E2F3 levels have a critical role in modifying cellular proliferation rate in human bladder and prostate cancer.

Cell Line, Tumor↗

PubMed2006

Fear of litigation.

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Dental Care↗

PubMed2006

CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.

OBJECTIVE: To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group. METHODS: Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. RESULTS: Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett-like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto-temporal predominance and high amplitudes. CONCLUSIONS: The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting.

Adolescent↗

PubMed2006

British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006).

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Antiretroviral Therapy, Highly Active↗

PubMed2006

OIE laboratory standards for avian influenza.

The principles are outlined by which the Office International des Epizooties (OIE) recognises diagnostic laboratory test procedures, based on the validation data and the fitness for purpose of any given test. The latest proposals for a definition of notifiable avian influenza are described, together with the place of vaccination, as part of the effort to control influenza in domestic poultry.

Animals↗

PubMed2006

Development of a framework for international certification by OIE of diagnostic tests validated as fit for purpose.

Historically, the OIE has focused on test methods applicable to trade and the international movement of animals and animal products. With its expanding role as the World Organisation for Animal Health, the OIE has recognised the need to evaluate test methods relative to specific diagnostic applications other than trade. In collaboration with its international partners, the OIE solicited input from experts through consultants' meetings on the development of guidelines for validation and certification of diagnostic assays for infectious animal diseases. Recommendations from the first meeting were formally adopted and have subsequently been acted upon by the OIE. A validation template has been developed that specifically requires a test to be fit or suited for its intended purpose (e.g. as a screening or a confirmatory test). This is a key criterion for validation. The template incorporates four distinct stages of validation, each of which has bearing on the evaluation of fitness for purpose. The OIE has just recently created a registry for diagnostic tests that fulfil these validation requirements. Assay developers are invited to submit validation dossiers to the OIE for evaluation by a panel of experts. Recognising that validation is an incremental process, tests methods achieving at least the first stages of validation may be provisionally accepted. To provide additional confidence in assay performance, the OIE, through its network of Reference Laboratories, has embarked on the development of evaluation panels. These panels would contain specially selected test samples that would assist in verifying fitness for purpose.

Animal Diseases↗

PubMed2006

Transportation of reagents, reference materials and samples: the international perspective.

The International Regulations for the transport of infectious substances, which could include reagents, reference material and samples, are based on the 13th revision of the United Nations Model Regulations and are the standard for transport of infectious substances by all means of transportation. The 13th revision, effective January 2005 and further amended in March and July 2005, made major improvements in these shipping regulations. They specifically exempt certain substances, including those that have been neutralized or inactivated to destroy any pathogens and samples from "normal" animals. Infectious substances are divided into Category A, which includes primarily cultures of the more pathogenic agents and Category B, which includes all other substances that do not meet the Category A criteria. Tissue specimens, submitted for diagnosis, are included in Category B. Category A shipments must have a Dangerous Goods Certificate and meet other requirements; Category B shipments do not. The National requirements, such as import permits, and certain airline restrictions must also be met.

Indicators and Reagents↗

PubMed2006

Animal production systems in the industrialised world.

The production of food from animal origin is relatively stable in the industrialised world. However, animal production systems are changing dramatically with respect to location, herd size and specialisation. Increased pressure from a critical public is moving animal-based production towards systems such as organic production and loose-housing systems which allow the animals to better express normal behaviour. The focus on food safety promotes systems with a high degree of biosecurity, often associated with an increase in herd size and self-containment. The globalisation of agricultural trade and increased competition also favours an increase in herd size and specialisation. These trends also lead to regions with livestock-dense areas, giving rise to environmental concerns. Therefore, good farming practice regulations and systems to provide a higher level of transparency, such as quality risk management programmes, are being developed.

Animal Husbandry↗

PubMed2005

Post-awakening cortisol secretion during basic military training.

Salivary free cortisol concentrations in the first 30 min after awakening were assessed in 12 healthy army recruits at the beginning, middle and end of an 11-week intensive physical training course. To ensure strict adherence to protocol saliva collection was supervised and collected on each sampling day immediately on waking and again 15 and 30 min later. Self-rated psychological assessments of state levels of stress, arousal and fatigue were performed in the evening of each sampling day. A within-subjects repeated-measures analysis of participants who completed the course (12 of the original 20) showed a significant main effect of cortisol concentration across all three sampling points after awakening (F((2,22))=54.516, p<0.0001) and a significant main effect of weeks into the training course (F((3,33))=4.390, p=0.010). Further analysis of this effect of measurement-week revealed that at weeks 3 and 6 total cortisol secretion estimated by area under the curve was lower (F((3,33))=4.602, p=0.008) compared to the beginning and end of the course. Surprisingly self-reported stress, arousal and fatigue did not differ significantly across weeks, despite the large dropout rate (40%) and self-evident pressures of the course. We conclude that when controlling for many confounding variables, including participant adherence, post-awakening cortisol levels are sensitive to stressful challenge over a period of weeks.

Adolescent↗

PubMed2005

Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population.

AIMS/HYPOTHESIS: Insulin resistance is associated with abnormalities in lipid and glucose metabolism, which are major components of metabolic syndrome and risk factors for vascular disease. This study examined the effect of tesaglitazar (Galida), a novel, dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, on lipid and glucose metabolism in patients with evidence of insulin resistance. METHODS: A 12-week, multicentre, randomised, double-blind, placebo-controlled, dose-finding study compared the efficacy and safety of oral tesaglitazar (0.1, 0.25, 0.5 and 1.0 mg/day) and placebo in 390 non-diabetic patients with hypertriglyceridaemia (plasma triglyceride concentration >1.7 mmol/l) and abdominal obesity (waist-to-hip ratio >0.90 for men and >0.85 for women). RESULTS: A 1.0-mg dose of tesaglitazar reduced fasting triglycerides (the primary endpoint) by 37% (95% CI: -43% to -30%; p<0.0001), non-HDL-cholesterol by 15% (95% CI: -20% to -10%; p<0.0001) and NEFA by 40% (95% CI: -51% to -27%; p<0.0001), and increased HDL-cholesterol by 16% (95% CI: 8 to -24%; p<0.0001). At the end of treatment there was a dose-dependent increase in patients with pattern A LDL particle diameter (40% at baseline vs 87% at 12 weeks for tesaglitazar 1.0 mg). Tesaglitazar produced significant reductions in fasting insulin concentration (-35%; p<0.0001) and plasma glucose concentration (-0.47 mmol/l; p<0.0001). Respiratory infection and gastrointestinal symptoms were the most common adverse events and were similarly frequent in all groups. CONCLUSIONS/INTERPRETATION: Tesaglitazar was well tolerated and produced significant, dose-dependent improvements in lipid and glucose metabolism and insulin sensitivity. Tesaglitazar may have the potential to prevent vascular complications and delay progression to diabetes in these patients.

Alkanesulfonates↗

PubMed2005

Expression analysis onto microarrays of randomly selected cDNA clones highlights HOXB13 as a marker of human prostate cancer.

In a strategy aimed at identifying novel markers of human prostate cancer, we performed expression analysis using microarrays of clones randomly selected from a cDNA library prepared from the LNCaP prostate cancer cell line. Comparisons of expression profiles in primary human prostate cancer, adjacent normal prostate tissue, and a selection of other (nonprostate) normal human tissues, led to the identification of a set of clones that were judged as the best candidate markers of normal and/or malignant prostate tissue. DNA sequencing of the selected clones revealed that they included 10 genes that had previously been established as prostate markers: NKX3.1, KLK2, KLK3 (PSA), FOLH1 (PSMA), STEAP2, PSGR, PRAC, RDH11, Prostein and FASN. Following analysis of the expression patterns of all selected and sequenced genes through interrogation of SAGE databases, a further three genes from our clone set, HOXB13, SPON2 and NCAM2, emerged as additional candidate markers of human prostate cancer. Quantitative RT-PCR demonstrated the specificity of expression of HOXB13 in prostate tissue and revealed its ubiquitous expression in a series of 37 primary prostate cancers and 20 normal prostates. These results demonstrate the utility of this expression-microarray approach in hunting for new markers of individual human cancer types.

Biomarkers, Tumor↗

PubMed2005

Prophylactic nasogastric decompression after abdominal surgery.

BACKGROUND: Routine use of nasogastric tubes after abdominal operations is intended to hasten the return of bowel function, prevent pulmonary complications, diminish the risk of anastomotic leakage, increase patient comfort and shorten hospital stay. OBJECTIVES: To investigate the efficacy of routine nasogastric decompression after abdominal surgery in achieving each of the above goals. SEARCH STRATEGY: Search terms were nasogastric, tubes, randomised, using MEDLINE, EMBASE, Cochrane Controlled Trials Register, and references of included studies. SELECTION CRITERIA: Patients having abdominal operations of any type, emergency or elective, who were randomised prior tot he completion of the operation to receive a nasogastric tube and keep it in place until intestinal function had returned, versus those receiving either no tube or early tube removal, in surgery, in recovery or within 24 hours of surgery. Excluded will be randomised studies involving laparoscopic abdominal surgery and patient groups having gastric decompression through gastrostomy. DATA COLLECTION AND ANALYSIS: Data were abstracted onto a form that assessed study eligibility, as defined above, quality related to randomizations, allocation concealment, study size and dropouts, interventions, including timing and duration of intubation, outcomes that included time to flatus, pulmonary complications, wound infection, anastomotic leak, length of stay, death, nausea, vomiting, tube reinsertion, subsequent ventral hernia. MAIN RESULTS: 28 studies fulfilled eligibility criteria, encompassing 4194 patients, 2108 randomised to routine tube use, and 2087 randomised to selective or No Tube use. Patients not having routine tube use had an earlier return of bowel function (p<0.00001), an insignificant trend toward decrease in pulmonary complications (p=0.07) and an insignificant trend toward increase in risk of wound infection (p=0.08) and ventral hernia (0.09). Anastomotic leak was no different between groups (p=0.70). Patient comfort, nausea, vomiting and length of stay seemed to favour No Tube, but the heterogeneity encountered in these analyses make rigorous conclusion difficult to draw for these outcomes. No adverse events specifically related to tube insertion (direct tube trauma) were reported. Other outcomes were reported with insufficient frequency to be informative. AUTHORS' CONCLUSIONS: Routine nasogastric decompression does not accomplish any of its intended goals and so should be abandoned in favour of selective use of the nasogastric tube.

Abdomen↗

PubMed2005

Systematic review of prophylactic nasogastric decompression after abdominal operations.

Abdomen↗

PubMed2005

Female body image following acquired brain injury.

PRIMARY OBJECTIVE: To investigate body image concerns and psycho-emotional health in females with acquired brain injury (ABI). RESEARCH DESIGN: Between subjects design. METHODS AND PROCEDURES: Thirteen females with ABI and thirteen matched controls were assessed on a number of variables relating to body image, self-esteem and affect. MAIN OUTCOMES AND RESULTS: Indicated that women with ABI had a different profile of body image dissatisfaction than controls and that in some areas it was significantly worse. The women with ABI had significantly lower self-esteem and higher levels of depression than controls and this related to body image. CONCLUSION: Significant changes in body image and self-concept are potentially damaging to quality of life post-injury and suggest a role for targeted therapeutic work with women with ABI.

Adult↗