PubMed Health⌕ Search

Biomedical subjects

J Cowan

Publications and source records attributed to J Cowan.

At least 19 recordsLinked to original sources
PubMed2004

Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

OBJECTIVES: To evaluate the use of pioglitazone and rosiglitazone, in terms of both clinical and cost-effectiveness in the treatment of type 2 diabetes. DATA SOURCES: Electronic databases and the reference lists of relevant articles, in addition 14 health services research-related resources were consulted via the Internet. REVIEW METHODS: A systematic review of the literature, involving a range of databases, was performed to identify all papers relating to the glitazones. The methodological quality of the included randomised controlled trials (RCTs) was assessed using the Jadad method. A generic proforma for the critical appraisal of modelling studies in health economics was used in systematically reviewing the economic assessment studies identified. This was supplemented by a detailed review of the disease-specific factors within the studies. Where possible, key outcomes were compared. Readers should note that information from the sponsor's submission was submitted in confidence to the National Institute for Clinical Excellence (NICE). Such information was made available to the NICE Appraisals Committee, but has been removed from this version of the report. RESULTS: Of the 1272 studies identified, nine studies met the inclusion criteria. The clinical evidence available showed that glitazones reduce glycosylated haemoglobin by approximately 1%, and are more effective at higher doses than at lower doses. Glitazone treatment is associated with weight gain. No published data were available on the long-term effects of glitazone use. No prospective RCTs were found comparing pioglitazone to rosiglitazone, but the available evidence indicated that the two treatments had similar effects. There are no published economic studies on either pioglitazone or rosiglitazone. Economic evaluations for both glitazones were provided by the manufacturers. Sensitivity analyses undertaken by the assessment team suggest that the cost per quality-adjusted life-year (QALY) of rosiglitazone is most sensitive to dosage and treatment effect, that is, the effect of rosiglitazone on beta-cell function and insulin sensitivity. In the two scenarios where rosiglitazone is compared with metformin and sulfonylurea combination therapy, the cost-effectiveness of rosiglitazone switches from around 10,000 pounds per QALY to being dominated by the comparator strategy. Since the baseline estimate of cost-effectiveness is not robust to changes in the treatment effect and is reliant on the many assumptions included within the metabolic and long-term economic models, caution should be used in interpreting the baseline result. CONCLUSIONS: The clinical evidence available showed that glitazones can reduce glycosylated haemoglobin; however there were no peer-reviewed data available on the long-term effects of their use or any prospective RCTs found comparing pioglitazone with rosiglitazone. No published economic studies on either pioglitazone or rosiglitazone were found, although sensitivity analyses undertaken by the assessment team suggest that the cost per QALY of rosiglitazone is most sensitive to dosage and treatment effect. It is suggested that research already undertaken in this area should be published, preferably in peer-reviewed journals. Direct head-to-head comparisons of the glitazones in combination with metformin or sulfonylurea would be helpful. The current licence arrangements do not allow for routine use of the glitazones in triple oral combination therapy or in combination with insulin. Evidence is emerging of use of the glitazones within such combinations; therefore, prospective RCTs would be useful. These studies could examine short-term transition strategies and longer term management. The impact of the glitazones in delaying transfer to insulin and the impact on long-term outcomes should also be considered for investigation.

Adult↗
PubMed2003

Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of capecitabine and tegafur with uracil (UFT/LV) as first-line treatments for patients with metastatic colorectal cancer, as compared with 5-fluorouracil/folinic acid (5-FU/FA) regimens. DATA SOURCES: Electronic databases, reference lists of relevant articles and sponsor submissions were also consulted. REVIEW METHODS: Systematic searches, selection against criteria and quality assessment were performed to obtain data from relevant studies. Costs were estimated through resource-use data taken from the published trials and the unpublished sponsor submissions. Unit costs were taken from published sources, where available. An economic evaluation was undertaken to compare the cost-effectiveness of capecitabine and UFT/LV with three intravenous 5-FU/LV regimens widely used in the UK: the Mayo, the modified de Gramont regimen and the inpatient de Gramont regimens. RESULTS: The evidence suggests that treatment with capecitabine improves overall response rates and has an improved adverse effect profile in comparison with 5-FU/LV treatment with the Mayo regimen, with the exception of hand-foot syndrome. Time to disease progression or death after treatment with UFT/LV in one study appears to be shorter than after treatment with 5-FU/LV with the Mayo regimen, although it also had an improved adverse effect profile. Neither capecitabine nor UFT/LV appeared to improve health-related quality of life. Little information on patient preference was available for UFT/LV, but there was indicated a strong preference for this over 5-FU/LV. The total cost of capecitabine and UFT/LV treatments were estimated at 2111 pounds and 3375 pounds, respectively, compared with the total treatment cost for the Mayo regimen of 3579 pounds. Cost estimates were also presented for the modified de Gramont and inpatient de Gramont regimens. These were 3684 pounds and 6155 pounds, respectively. No survival advantage was shown in the RCTs of the oral drugs against the Mayo regimen. Cost savings of capecitabine and UFT/LV over the Mayo regimen were estimated to be 1461 pounds and 209 pounds, respectively. Drug acquisition costs were higher for the oral therapies than for the Mayo regimen, but were offset by lower administration costs. Adverse event treatment costs were similar across the three regimens. It was inferred that there was no survival difference between the oral drugs and the de Gramont regimens. Cost savings of capecitabine and UFT/LV over the modified de Gramont regimen were estimated to be 1353 pounds and 101 pounds, respectively, and over the inpatient de Gramont regimen were estimated to be 4123 pounds and 2870 pounds, respectively. CONCLUSIONS: The results show that there are cost savings associated with the use of oral therapies. No survival difference has been proven between the oral drugs and the Mayo regimen. In addition, no evidence of a survival difference between the Mayo regimen and the de Gramont regimens has been identified. However, improved progression-free survival and an improved adverse event profile have been shown for the de Gramont regimen over the Mayo regimen. Further research is recommended into the following areas: quality of life data should be included in trials of colorectal cancer treatments; the place of effective oral treatments in the treatment of colorectal cancer, the safety mechanisms needed to ensure compliance and the monitoring of adverse effects; the optimum duration of treatment; the measurement of patient preference; and a phase III comparative trial of capecitabine and UFT/LV versus modified de Gramont treatment to determine whether there was any survival advantage and to collate the necessary economic data.

Antimetabolites, Antineoplastic↗
PubMed2002

Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial.

OBJECTIVES: This phase II study was conducted to evaluate the efficacy and safety of gemcitabine in patients with metastatic breast cancer (MBC). METHODS: Women with histologically or cytologically confirmed bidimensionally measurable MBC not amendable to curative surgery or radiation were eligible. Prior chemotherapy for metastatic disease was not permitted. Patients received gemcitabine 1,200 mg/m(2) on days 1, 8 and 15 for 3 weeks every 28 days for a maximum of 8 cycles. RESULTS: Thirty-nine patients, with a median age of 58 years, were enrolled. The overall response rate for the 35 evaluable patients was 37.1% (95% confidence interval [CI], 21.5-55.1%), with 2 complete responses and 11 partial responses. Median time to progression and survival were 5.1 months (95% CI, 3.5-8.8 months) and 21.1 months (95% CI, 11.0-26.9 months), respectively. Chemotherapy was well tolerated, with a median of 4 cycles completed. Grade 4 toxicities were 1 infection and 1 abnormal pulmonary function. Grade 3 neutropenia and thrombocytopenia occurred in 30.3% and 6.3% of patients, respectively. The most common grade 3 non-hematologic toxicity was nausea/vomiting (10.3%). Five of 21 patients had improved Karnofsky performance status (KPS) scores. CONCLUSION: Single-agent gemcitabine is active and well tolerated as first-line treatment in patients with MBC.

Adolescent↗
PubMed2001

Gene therapy to prevent organophosphate intoxication.

The specific hydrolytic activity of PON1 paraoxonase/arylesterase enzymes in liver and blood provides a natural barrier against the entry of organophosphate toxins into the central and peripheral nervous systems. Inherited differences in PON1 enzyme concentrations may determine levels of susceptibility to organophosphate injury in humans. To test whether boosting serum levels of PON1 enzymes by gene therapy might provide increased protection, we compared the degree of inactivation of whole brain acetylcholinesterase of mice exposed to chlorpyrifos 4 days after intravenous injection of recombinant adenoviruses containing PON1-LQ or PON1-LR genes or no PON1 gene. Both recombinant viruses containing PON1 genes boosted serum arylesterase concentrations by approximately 60% and significantly prevented the inactivation of brain acetylcholinesterase. Some mice were completely protected. These findings indicate that boosting serum levels of PON1 enzymes by a gene delivery vector raises the threshold for organophosphate toxicity by hydrolytic destruction before the chemical can enter the brain.

Acetylcholinesterase↗
PubMed2001

Initiator and upstream elements in the alpha2-tubulin promoter of Giardia lamblia.

Giardia lamblia, one of the earliest diverging eukaryotes and a major cause of diarrhea world-wide, has unusually short intergenic regions, raising questions concerning its regulation of gene expression. We have approached this issue through examination of the alpha2-tubulin promoter and in particular investigated the function of an AT-rich element surrounding the transcription start site. Its placement and the ability of this sequence to direct transcription initiation in the absence of any other promoter elements is similar to the initiator element in higher eukaryotes. However, the sequence diversity of extremely short (8-10 bp) initiator elements is surprising, as is their ability to independently direct substantial levels of transcription. We also identified a large AT-rich element located between -64 and -29 bp upstream of the transcriptional start site and show using both deletions and site-specific mutations of this region that sequences between -60 and the start of transcription are important for promoter strength; interestingly this AT-rich sequence is not highly conserved among different Giardia promoters. These data suggest that while the overall structure of the core promoter has been conserved throughout eukaryotic evolution, significant variation and flexibility is allowed in element consensus sequences and roles in transcription. In particular, the short and diverse sequences that function in transcription initiation in Giardia suggest the potential for relaxed transcriptional regulation.

Animals↗
PubMed2000

Evaluation of a teaching package designed to improve teachers' recognition of depressed pupils-a pilot study.

This pilot study evaluated the impact of a teaching package for school staff on their ability to recognize depressed pupils within a year group in their school. Sixteen teachers were tested before and after training on their ability to identify depressed pupils in that year. The pupils were screened using a 2-stage procedure to determine caseness for Major Depressive Disorder (MDD). After training, teachers felt more confidant about their ability to recognize depressed pupils but this was not able to be statistically verified because of small teachers numbers. This suggests a promising way forward in recognizing depression in the community.

Adolescent↗
PubMed2000

The ion chromatographic separation of high valence metal cations using a neutral polystyrene resin dynamically modified with dipicolinic acid.

A neutral polystyrene resin column, dynamically loaded with dipicolinic acid at a concentration of 0.1 mM in 1 M potassium nitrate eluent, was investigated for the separation characteristics of a number of high valence metal cations over the pH range 0-3. The metal species studied were Th(IV), U(VI), Zr(IV), Hf(IV), Ti(IV), Sn(IV), V(IV) and V(V), Fe(III) and Bi(III), of which Ti(IV), Sn(IV), V(IV) and Fe(III) did not show any retention. For the remaining metal ions, significant retention was obtained with good peak shapes, except for Th(IV), which moved only slightly from the solvent front with some tailing. The retention order at pH 0.3 was Th(IV) < V(V) < Bi(III) < U(VI) < Hf(IV) < Zr(IV). A notable feature of this separation system was the high selectivity shown for uranium, zirconium and hafnium, the last two being nearly resolved in 15 min on the relatively short 10 cm column.

Journal Article↗
PubMed2000

Consent and clinical governance: improving standards and skills.

Obtaining appropriate and informed consent from patients is an integral part of provision of quality health care. Doctors are bound to obtain consent in a manner that is legally and ethically acceptable. The methods employed to train junior doctors in these principles vary from organisation to organisation and the knowledge base of both senior and junior clinicians is far from consistent. This paper raises some of the issues in relation to current practice and teaching and suggests ways in which the process can be improved--largely by introducing some basic standards that should be built on as expertise and skill develop. The author discusses the need for dissemination of information with regard to current national claims experience and the possibility of introducing the subject of consent into postgraduate examinations in a more widespread way.

Humans↗
PubMed2000

Clinical governance and clinical documentation: still a long way to go?

Maintaining good standards of clinical documentation remains a problem in the health service despite continued and consistent advice from protection organisations and professional bodies over many years. This article discusses some of the issues that arise from poor quality note keeping and the need for improvement and the establishment of basic minimum standards for all health records. Requirements are now being placed on NHS bodies to ensure that effective and robust systems are in place to ensure that record management meets Controls Assurance Standards and CNST standards. This article stresses the need to put the current house in order before we lose any opportunities to influence those aspects of electronic systems where appropriate risk management should help reduce the potential for documentation error.

Documentation↗
PubMed2000

Clinical risk--minimising harm in practical procedures and use of equipment.

The article discusses some of the clinical negligence problems and risk management issues arising from training of health professionals (predominantly junior hospital doctors) in practical procedures. There continue to be incidents, claims and complaints in the NHS arising from the clinical practice of doctors or other health professionals who are not perceived to be competent in some of the practical skills they are undertaking. This article addresses some aspects of this training, where it should best be started and who should have responsibility for ensuring that doctors, in particular, continue to work under appropriate supervision. Also acknowledges the current problems facing NHS trusts in trying to ensure that risk management standards are met for training health professionals in the use of medical equipment--a task that has not previously needed to be documented or accounted for on a formal basis. There are considerable resource implications attached to the introduction of systems that can assess and monitor the training provided in the use of medical equipment but the introduction of a baseline assessment is an essential part of sound clinical governance and risk management. It is suggested that risk management exercises of this nature are worthwhile in reducing the potential for harm to patients.

Clinical Competence↗
PubMed1999

Bronchoprotective and bronchodilator effects of single doses of (S)-salbutamol, (R)-salbutamol and racemic salbutamol in patients with bronchial asthma.

OBJECTIVES: The drug salbutamol is used as a 50: 50 racemic mixture of its two enantiomers, (R)- and (S)-salbutamol. Previous studies suggest that the (R)-enantiomer is active, and the (S)-enantiomer is either inert or may be responsible for adverse effects. The aim of the study was to measure the protection given against methacholine (MCh) and adenosine monophosphate (AMP) by (R)-, (S)- and rac-salbutamol and their bronchodilator effects. METHODS: A double-blind, placebo-controlled, four-way cross-over study was performed in subjects with mild to moderate asthma. There were three groups: AMP30 (n = 10), MCh30 (n = 13) and MCh180 (n = 10). The groups received AMP or MCh challenges at either 30 min or 180 min after each of four pretreatments: 100 microg (S)-salbutamol, 100 microg (R)-salbutamol, 200 microg rac-salbutamol or placebo (normal saline), each administered via nebuliser. Spirometry was measured at 30, 60, 90, 120, 150 and 180 min in the MCh180 group. RESULTS: (R)- and rac-salbutamol showed equivalent bronchoprotective effects at 30 min. PC20AMP increased by 3.22 (1.86) and 3.41 (2.15) doubling doses (P < 0.001) and PC20MCh increased by 2.86 (1.09) and 2.75 (0.89) (P < 0.001) respectively. (S)-salbutamol caused no equivalent effect. There was no significant effect at 180 min. No hyper-responsiveness occurred after treatment with (S)-salbutamol. The mean increase in forced expiratory volume in 1 s (FEV1) was 12.4% (6.8%) with (R)- and 12.0%(7.7%) with rac-salbutamol at 90 min. No significant change in FEV1 occurred with (S)-salbutamol. CONCLUSIONS: These results confirm other recent findings that the bronchoprotective and bronchodilator effects of salbutamol are attributable to its (R)-enantiomer. No adverse effects were noted after single doses of (S)-salbutamol.

Adenosine Monophosphate↗
PubMed1998

Discrepant cytogenetic and fluorescence in situ hybridization results in a 26-year-old male with early T-cell acute lymphocytic leukemia.

Analyzable G-banded metaphases were normal in bone marrow from a 26-year-old male having 80% blasts. Fluorescence in situ hybridization (FISH) using the centromeric probe, D7Z1, revealed 85% of interphase cells with one signal for chromosome 7. Chromosome painting revealed a chromosome 7 rearrangement in a few metaphases that were otherwise unanalyzable. A repeat bone marrow confirmed 3 of 20 metaphases, by G-banding, to have multiple rearrangements and aneuploidy, including a large derivative chromosome involving a complex rearrangement of chromosomes 5, 7, and 9; that is, der(5)t(5;9)(q31;q13)ins(5;7)(p15;q?31q?34), with loss of most of chromosome 7 (7 pter-->7q?31); one normal 7 was present. Immunophenotyping characterized the patient's condition as an early T-cell acute lymphocytic leukemia (ALL), with a population of cells suggesting biphenotypic leukemia. He attained a complete clinical remission with chemotherapy. Six months after the initial presentation he received an allogeneic bone marrow transplant. Three months later a CNS relapse was followed by a bone marrow relapse. At this time, eight months after transplant, repeat study of his bone marrow revealed the majority of metaphases had structural and numerical chromosome abnormalities similar to the small clone in the earlier study, including der(5)t(5;9)ins(5;7), but with two normal 7s. FISH showed two 7-centromere signals in interphase. The patient expired one month later.

Adult↗
PubMed1998

Temperature-dependent sex determination in the red-eared slider turtle, Trachemys scripta.

Temperature-dependent sex determination (TSD) in the red-eared slider turtle, Trachemys scripta, has been the subject of a variety of past studies. Incubation temperature appears to affect sex determination in a dose-dependent fashion. This suggests that temperature could be affecting a dosage-sensitive element in the sex-determination cascade. Sex determination in T. scripta is sensitive to estrogen, and data from many studies support the hypothesis that endogenous estrogen production may be involved in female sex determination. However, this hypothesis has not yet been evaluated through aromatase expression studies in this species. Several recent studies have cloned cDNAs for genes that could be involved in sex determination and/or sex differentiation. The cDNAs for SF-1 and MIS have been cloned in T. scripta, indicating that these may represent conserved elements in the sex-determination/sex-differentiation cascade of reptiles. The SOX9 cDNA also has been cloned in T. scripta (Spotila et al., '98), and it shows a sex-specific expression pattern. Future studies targeted at aromatase expression as well as the expression of factors such as SOX9, SF-1, and MIS will begin to provide a more comprehensive picture of the events involved in TSD in T. scripta. Further, such studies could help pinpoint the temperature-sensitive element(s).

Androgens↗
PubMed1998

Identification of de novo chromosomal markers and derivatives by spectral karyotyping.

Despite major advances in molecular cytogenetics during the past decade and the important diagnostic role that fluorescence in situ hybridization (FISH) plays in the characterization of chromosomal abnormalities, the usefulness of this technique remains limited by the number of spectrally distinguishable fluorochromes or fluorochrome combinations. Overcoming this major limitation would allow one to use FISH to screen the whole human genome for chromosomal aberrations which, until recently, was possible only through conventional karyotyping. A recently described molecular cytogenetics technology, 24-color FISH using spectral karyotyping (SKY), permits the simultaneous visualization of all human chromosomes in 24 different colors. Most chromosomal aberrations detected during cytogenetic evaluation can be resolved using routine cytogenetic techniques alone or in combination with single- or dual-color FISH. However, some cases remain unresolved, in particular de novo supernumerary marker chromosomes and de novo unbalanced structural rearrangements. These findings cause particular diagnostic and counseling concerns when detected during prenatal diagnosis. The purpose of this report is to demonstrate the application of SKY in the characterization of these de novo structural chromosomal abnormalities. Eight cases are described in this report. SKY has considerable diagnostic applications in prenatal diagnosis because of its reliability and speed. The identification of the chromosomal origin of markers and unbalanced translocations provides the patient, physician, and genetic counselor with better predictive information on the phenotype of the carrier.

Amniotic Fluid↗
PubMed1997

The effects of inadvertent exposure of mefloquine chemoprophylaxis on pregnancy outcomes and infants of US Army servicewomen.

During US military operations in Somalia, mefloquine, a drug for malaria chemoprophylaxis, was not approved for use in pregnant women. Some female soldiers inadvertently used mefloquine before becoming aware of their pregnancy. A registry was established to follow the outcomes of these pregnancies. Questionnaires were administered at the time the pregnancy was diagnosed, after termination or delivery, and at 1 year after birth. Seventy-two soldiers were eligible for the registry. There were 17 elective abortions, 12 spontaneous abortions, 1 molar pregnancy, and 23 live births. The outcome for 19 soldiers was unknown. An unexpected high rate of spontaneous abortions was observed. All infants were healthy at birth, with no major congenital malformations. One infant died at 4 months of viral pneumonitis. At 1 year of age, 13 infants were reported to be healthy, with normal cognitive and motor development. This study provides additional postmarketing data that mefloquine does not cause gross congenital malformations.

Adult↗
PubMed1996

Negative cooperativity exhibited by the lytic amino-terminal domain of human perforin: implications for perforin-mediated cell lysis.

BACKGROUND: Cytolytic effector cells of the immune system recognize and lyse cells that carry non-self epitopes. One mechanism of cell lysis involves release of a 67-kDa pore-forming protein, perforin. The amino-terminal domain of perforin (>/= 19 residues) can account for most of the lysis activity, by a mechanism that is similar to that of holoperforin. Detailed mechanistic studies of this domain should yield useful insight into the factors underlying perforin activity in vivo. RESULTS: The mechanism of pore formation by the 22-residue amino-terminal domain of perforin was studied by kinetic and thermodynamic methods. Approximately 4 +/- 1 peptide monomers form an active pore by a mechanism that displays negative cooperativity. CONCLUSIONS: A negatively-regulated aggregation mechanism is likely to be common for pore-forming peptides. The positively-charged domain B of perforin (residues 7- 15) may mediate cooperativity through electrostatic interactions. Such a mechanism limits the number of protein molecules that are committed to any particular channel. This data supports smaller pores as the physiologically relevant aggregate, rather than the larger ring sizes identified by electron microscopy at higher, non-biological concentrations.

Humans↗