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Biomedical subjects

John Wright

Publications and source records attributed to John Wright.

At least 19 recordsLinked to original sources
PubMed2024

Common genetic variants associated with urinary phthalate levels in children: A genome-wide study.

INTRODUCTION: Phthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes. OBJECTIVE: In this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS). METHODS: The study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void pooled urine collected at the mean age of 8&#xa0;years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value&#xa0;<&#xa0;1E-05) was done with the FUMA web-tool. RESULTS: We identified four genome-wide significant (p-value&#xa0;<&#xa0;5E-08) loci at chromosome (chr) 3 (FECHP1 for oxo-MiNP_oh-MiNP ratio), chr6 (SLC17A1 for MECPP_MEHHP ratio), chr9 (RAPGEF1 for MBzP), and chr10 (CYP2C9 for MECPP_MEHHP ratio). Moreover, 115 additional loci were found at suggestive significance (p-value&#xa0;<&#xa0;1E-05). Two CNVs located at chr11 (MRGPRX1 for oh-MiNP and SLC35F2 for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion. CONCLUSION: Through genome-wide screenings we identified known and novel loci implicated in phthalate metabolism in children. Genes annotated to these loci participate in detoxification, transmembrane transfer, and renal excretion.

Humans↗
PubMed2006

Transcatheter closure of ventriculopulmonary artery communications in staged Fontan procedures.

BACKGROUND: Ventricle-pulmonary artery connections in patients after the Fontan procedure lead to ineffective volume loading and can cause long term problems. In patients with a cavopulmonary shunt anterograde pulmonary blood flow is frequently maintained, but can cause significant volume loading of the heart or complicate the subsequent Fontan procedure. OBJECTIVE: To evaluate the use of transcatheter closure of a ventricle-pulmonary artery communication in the setting of a cavopulmonary shunt or after the Fontan procedure. PATIENTS AND METHODS: Retrospective study at a tertiary referral centre. Eight patients (age 1.5-18 years, mean 7.8 years). INDICATIONS: cardiac failure or persistent pleural effusions after cavopulmonary shunt (n = 2) or after Fontan (n = 3) and abolishing the volume load of the single ventricle prior to Fontan completion (n = 3). RESULTS: Devices used: Rashkind Umbrella (n = 1), Amplatzer PDA (n = 7) and Amplatzer ASD (n = 1). One patient required two devices. There were no procedural complications. All 3 patients with prolonged pleural effusions (1 post CP shunt and 2 post Fontan) showed complete resolution between 4 and 10 days after catheter closure. Two patients underwent transcatheter occlusion for progressive ventricular dilatation and cardiac failure. The first patient was post Fontan and showed gradual improvement in ventricular function. The second patient (post CP shunt) was in end stage cardiac failure due to severe AV valve regurgitation. The patient died 48 hours after an uncomplicated procedure due to ventricular failure and electromechanical dissociation (non-procedure-related cardiac death). Three patients underwent catheter closure to off-load the systemic ventricle prior to the Fontan procedure. The device had to be removed prior to release in one patient, due to unsatisfactory position. CONCLUSIONS: Transcatheter closure of ventricle-pulmonary artery communication is a safe and effective technique in the treatment of selected patients after cavopulmonary shunt or Fontan procedure with early or late complications due to inappropriate pulmonary blood flow. This intervention should also be considered in the preparation for the Fontan procedure in selected patients with ventricular overload.

Adolescent↗
PubMed2006

A phase II study of PS-341 (Bortezomib) in advanced or metastatic urothelial cancer. A trial of the Princess Margaret Hospital and University of Chicago phase II consortia.

BACKGROUND: Based on evidence of activity in epithelial tumors in preclinical and Phase I studies, its novel mechanism of action, and its tolerability we undertook a study of bortezomib [PS-341], a reversible proteasome inhibitor, for patients with advanced or metastatic urothelial cancer. PATIENTS AND METHODS: Patients with advanced or metastatic unresectable urothelial carcinoma were enrolled onto this multicenter, phase II trial. Patients with measurable disease were treated with bortezomib 1.3 mg/m2/day (twice weekly for 2 weeks out of 3) by intravenous infusion on days 1, 4, 8, and 11 every 21 days. A two stage phase II design was used. RESULTS: Twenty-one patients were enrolled and twenty were eligible and received treatment. Eighty-five percent of patients had previous chemotherapy regimens. No objective responses were observed, median time-to-progression was 8.1 weeks (95% confidence interval [CI] 6.4 to 9), and median overall survival is estimated to be 15 weeks (95% CI 3.6 - NA). A total of 15 patients experienced a grade 3-4 adverse event. The most common were alkaline phosphatase (20% patients), lymphopenia (20% patients), myalgia (15% patients), dyspnea (15% patients) and thrombosis/embolism (15% patients). CONCLUSION: Single-agent bortezomib is an ineffective treatment for progressive-cisplatin-refractory urothelial carcinoma and should not be considered for future clinical trials in this population of patients.

Aged↗
PubMed2006

Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex.

A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Galphas), (b) calcium release (Galphaq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Galphao/i and Galphaq). BIM-46174 inhibits the growth of a large panel of human cancer cell lines, including anticancer drug-resistant cells. Exposure of cancer cells to BIM-46174 leads to caspase-3-dependent apoptosis and poly(ADP-ribose) polymerase cleavage. National Cancer Institute COMPARE analysis for BIM-46174 supports its novel pharmacologic profile compared with 12,000 anticancer agents. The growth rate of human tumor xenografts in athymic mice is significantly reduced after administration of BIM-46174 combined with either cisplatin, farnesyltransferase inhibitor, or topoisomerase inhibitors. Our data validate the feasibility of targeting heterotrimeric G-protein functions downstream the GPCRs to improve anticancer chemotherapy.

Animals↗
PubMed2006

Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.

PURPOSE: A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs). Because tipifarnib undergoes extensive hepatic metabolism, MTD is doubled in patients on EIAEDs. The population included 67 patients with glioblastoma multiforme (GBM) and an exploratory group of 22 patients with anaplastic glioma (AG). PATIENTS AND METHODS: Patients received tipifarnib (300 and 600 mg bid for 21 days every 4 weeks in non-EIAED and EIAED patients, respectively). All patients were assessable for efficacy and safety. RESULTS: Two AG patients (9.1%) and eight GBM patients (11.9%) had progression-free survival (PFS) more than 6 months. Among the latter eight GBM patients, six of 36 patients (16.7%; 95% CI, 7% to 32%) were not receiving EIAEDs and two of 31 patients (6.5%; 95% CI, 1% to 20%) were receiving EIAEDs. Four patients had partial responses in group A GBM and one patient had a partial response group B GBM. An exploratory comparison of PFS between GBM groups A and B was statistically significant (P = .01). Patients not receiving EIAEDs had a higher incidence and increased severity of hematologic events. However, the incidence and severity of rash (the previously determined dose-limiting toxicity in patients receiving EIAEDs) seemed similar in EIAED and non-EIAED subgroups. CONCLUSION: Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.

Adult↗
PubMed2006

Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children's Oncology Group report.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors. PATIENTS AND METHODS: Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques. RESULTS: There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m(2) with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed. CONCLUSION: Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.

Acetylation↗
PubMed2006

Phase II clinical trial design: methods in translational research from the Genitourinary Committee at the Eastern Cooperative Oncology Group.

Given the increase in novel agents and difficulty with planning and completing many phase III studies, various phase II trial design options should be considered to more effectively guide phase III trial plans. The need for novel phase II trial designs has increased, given the number of novel molecular targeted therapies now available for testing, an abundance of cytostatic agents, and limited resources to conduct phase III studies for all interesting agents or combinations. This review will focus on options for phase II trial designs. We review randomized phase II designs with placebo control, randomized selection designs, and randomized discontinuation designs. As agents become available for testing in the clinic, the strengths and weaknesses of different phase II trial designs should be considered to optimize a trial development plan that guides phase III trial decisions more effectively.

Advisory Committees↗
PubMed2006

Suitability of canine herpesvirus as a vector for oral bait vaccination of foxes.

Studies were conducted to evaluate the feasibility of using canine herpesvirus (CHV) as a vaccine vector for bait-delivered oral vaccination of wild foxes. To test the viability of CHV in baits, CHV was freeze-dried, incorporated into different baits, stored, and the remaining viral infectivity tested in cell culture after varying periods of time at different storage temperatures. Experimental baits (mouse carcasses) and commercial baits (FOXOFF and PROBAIT) were prepared with either liquid or freeze-dried CHV and tested in two fox trials for their capacity to induce CHV-specific antibodies following oral baiting. Freeze-drying and storage temperatures below 0 degrees C had a stabilizing effect to virus infectivity. When stored at -20 degrees C, freeze-dried CHV retained its full infectivity for up to 3 months in PROBAIT baits, the remaining infectivity in FOXOFF baits was 100-fold less. Oral baiting with CHV induced antiviral serum antibodies in all vaccinated foxes (20/20). None of the vaccinated foxes became ill or shed infectious virus into the environment although viral DNA was detected in body secretions as evaluated by PCR. The results indicate that CHV can be freeze-dried and stored over extended periods of time without loosing much of its infectivity. This is the first report of CHV being used for oral bait vaccination of foxes. It appears that CHV is well suited for use as a recombinant vector for wild canids.

Administration, Oral↗
PubMed2006

Multiscale hybrid linear models for lossy image representation.

In this paper, we introduce a simple and efficient representation for natural images. We view an image (in either the spatial domain or the wavelet domain) as a collection of vectors in a high-dimensional space. We then fit a piece-wise linear model (i.e., a union of affine subspaces) to the vectors at each downsampling scale. We call this a multiscale hybrid linear model for the image. The model can be effectively estimated via a new algebraic method known as generalized principal component analysis (GPCA). The hybrid and hierarchical structure of this model allows us to effectively extract and exploit multimodal correlations among the imagery data at different scales. It conceptually and computationally remedies limitations of many existing image representation methods that are based on either a fixed linear transformation (e.g., DCT, wavelets), or an adaptive uni-modal linear transformation (e.g., PCA), or a multimodal model that uses only cluster means (e.g., VQ). We will justify both quantitatively and experimentally why and how such a simple multiscale hybrid model is able to reduce simultaneously the model complexity and computational cost. Despite a small overhead of the model, our careful and extensive experimental results show that this new model gives more compact representations for a wide variety of natural images under a wide range of signal-to-noise ratios than many existing methods, including wavelets. We also briefly address how the same (hybrid linear) modeling paradigm can be extended to be potentially useful for other applications, such as image segmentation.

Algorithms↗
PubMed2006

Drug-induced cutaneous vasculitis in patients with non-Hodgkin lymphoma treated with the novel proteasome inhibitor bortezomib: a possible surrogate marker of response?

Bortezomib is the first proteasome inhibitor to be approved for use in haematological malignancies. Although a rash has been described as a common adverse event associated with the drug, it has not been well characterised. Based on three phase II studies of bortezomib in patients with non-Hodgkin lymphoma (140 assessable patients), we identified 26 patients who developed a unique erythematous maculopapular rash during treatment, six of whom underwent cutaneous biopsy. Punch biopsy in six patients revealed a perivascular lymphocytic infiltrate without evidence of lymphoma, consistent with a non-necrotising cutaneous vasculitis. The combined overall response rate was 41%. The response in the 26 patients who developed a rash was 73%, compared with 33% in patients who did not. The odds ratio for response given the development of a rash was 4.6 (95% CI, 1.7-12.4, P = 0.001). This is the first report to characterise a vasculitic rash associated with bortezomib, and to show a relationship between development of the rash and response to treatment. Unlike classic hypersensitivity type reactions, this vasculitic rash may not necessarily prompt cessation of drug. In fact, the development of an isolated cutaneous vasculitis may portend a better clinical response to bortezomib in some patients.

Aged↗
PubMed2006

Experience of wrong site surgery and surgical marking practices among clinicians in the UK.

BACKGROUND: Little is known about the incidence of "wrong site surgery", but the consequences of this type of medical error can be severe. Guidance from both the USA and more recently the UK has highlighted the importance of preventing error by marking patients before surgery. OBJECTIVE: To investigate the experiences of wrong site surgery and current marking practices among clinicians in the UK before the release of a national Correct Site Surgery Alert. METHODS: 38 telephone or face-to-face interviews were conducted with consultant surgeons in ophthalmology, orthopaedics and urology in 14 National Health Service hospitals in the UK. The interviews were coded and analysed thematically using the software package QSR Nud*ist 6. RESULTS: Most surgeons had experience of wrong site surgery, but there was no clear pattern of underlying causes. Marking practices varied considerably. Surgeons were divided on the value of marking and varied in their practices. Orthopaedic surgeons reported that they marked before surgery; however, some urologists and ophthalmologists reported that they did not. There seemed to be no formal hospital policies in place specifically relating to wrong site surgery, and there were problems associated with implementing a system of marking in some cases. The methods used to mark patients also varied. Some surgeons believed that marking was a limited method of preventing wrong site surgery and may even increase the risk of wrong site surgery. CONCLUSION: Marking practices are variable and marking is not always used. Introducing standard guidance on marking may reduce the overall risk of wrong site surgery, especially as clinicians work at different hospital sites. However, the more specific needs of people and specialties must also be considered.

Hospitals, Public↗
PubMed2006

Learning from death: a hospital mortality reduction programme.

PROBLEM: There are wide variations in hospital mortality. Much of this variation remains unexplained and may reflect quality of care. SETTING: A large acute hospital in an urban district in the North of England. DESIGN: Before and after evaluation of a hospital mortality reduction programme. STRATEGIES FOR CHANGE: Audit of hospital deaths to inform an evidence-based approach to identify processes of care to target for the hospital strategy. Establishment of a hospital mortality reduction group with senior leadership and support to ensure the alignment of the hospital departments to achieve a common goal. Robust measurement and regular feedback of hospital deaths using statistical process control charts and summaries of death certificates and routine hospital data. Whole system working across a health community to provide appropriate end of life care. Training and awareness in processes of high quality care such as clinical observation, medication safety and infection control. EFFECTS: Hospital standardized mortality ratios fell significantly in the 3 years following the start of the programme from 94.6 (95% confidence interval 89.4, 99.9) in 2001 to 77.5 (95% CI 73.1, 82.1) in 2005. This translates as 905 fewer hospital deaths than expected during the period 2002-2005. LESSONS LEARNT: Improving the safety of hospital care and reducing hospital deaths provides a clear and well supported goal from clinicians, managers and patients. Good leadership, good information, a quality improvement strategy based on good local evidence and a community-wide approach may be effective in improving the quality of processes of care sufficiently to reduce hospital mortality.

England↗
PubMed2006

Prevalence and predictors of dating violence among adolescent female victims of child sexual abuse.

The purpose of this study was to advance knowledge of dating violence behaviors among adolescent victims of child sexual abuse (CSA), first, by determining the prevalence of psychological and physical dating violence and the reciprocity of violence, and second, by investigating the influence of certain CSA characteristics to dating violence. Respondents included 126 females ages 13 to 17 years. More than 45% reported experiencing some sort of physical violence in their dating relationships. Psychological violence was reciprocal in more than 90% of the cases. Multiple regression analysis revealed a significant contribution of CSA characteristics. Multiple regression analyses revealed that the duration of the sexual abuse and the presence of violence or completed intercourse during the abuse could significantly contribute to dating violence above and beyond other known risk factors. Discussion underscores the need to gain a better understanding of CSA and other risk factors that might influence violent dating behaviors.

Adolescent↗
PubMed2006

What does the use of a computerized checklist mean for patient-centered care? The example of a routine diabetes review.

The authors examine the interaction between nurses and patients with type 2 diabetes during routine consultations in primary care settings in the United Kingdom. Through preconsultation interviews, the authors identified the patients' expectations. The article draws on videotaped consultations with 25 patients with type 2 diabetes. Using conversation analysis, the authors examine the use of a rigid agenda, imposed via a computerized checklist, and consider how far this is able to suppress the patient's agenda. They consider the potential impact for the patient and the factors that might encourage the clinician, and the nurse specifically, to adopt a narrowly task-based approach to the consultation. They identify two potentially conflicting strands within contemporary diabetes care, patient-centered practice and an emphasis on biomedical audit, and suggest that achievement of the former might be compromised by the demands of the latter.

Adolescent↗
PubMed2006

International health links: an evaluation of partnerships between health-care organizations in the UK and developing countries.

Increasingly, international health links are evolving between UK health-care institutions and those in developing countries, the core aims of which are to seek the transfer of ideas, knowledge, skills and training. This study aimed to evaluate established health links, what constitutes them and how they are supported. Benefits and challenges associated with the links, as perceived both by link coordinators in the UK and their overseas partners, were explored. Fourteen links between health-care organizations in the UK and those in developing countries were identified and interviews were successfully conducted with 22 link coordinators: 13 in the UK and nine in developing countries. The interviews indicated that health links offer mutual benefits to both partners in terms of shared skills and the promotion of global awareness. Links can act as important catalysts; stimulating increases in institutional capacity for research and training. They provide opportunities for personal and professional development of staff and promote the development of friendships and supportive networks between diverse communities. Many of the health links showed signs of evolving from uniprofessional links between individual institutions into broader, multidisciplinary community partnerships. The main challenges facing health links arise from cultural differences, funding problems, communication difficulties and bureaucracy. There was broad agreement that greater recognition of the value and importance of health links by the NHS and closer collaboration between government departments to provide support and resources could promote wider and more effective link partnerships.

Africa South of the Sahara↗