Intestinal obstruction following blunt abdominal trauma.
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Abdominal Injuries↗
Biomedical subjects
J Gray
Publications and source records attributed to J Gray.
The world-wide telescope.
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Journal Article↗
Glucose-induced toxicity in insulin-producing pituitary cells that coexpress GLUT2 and glucokinase. Implications for metabolic engineering.
We have shown that intermediate lobe (IL) pituitary cells can be engineered to produce sufficient amounts of insulin (ins) to cure diabetes in nonobese diabetic mice but, unlike transplanted islets, ILins cells evade immune attack. To confer glucose-sensing capabilities into these cells, they were further modified with recombinant adenoviruses to express high levels of GLUT2 and the beta-cell isoform of glucokinase (GK). Although expression of GLUT2 alone had negligible effects on glucose usage and lactate production, expression of GK alone resulted in approximately 2-fold increase in glycolytic flux within the physiological (3-20 mm) glucose range. GLUT2/GK coexpression further increased glycolytic flux at 20 mm glucose but disproportionately increased flux at 3 mm glucose. Despite enhanced glycolytic fluxes, GLUT2/GK-coexpressing cells showed glucose dose-dependent accumulation of hexose phosphates, depletion of intracellular ATP, and severe apoptotic cell death. These studies demonstrate that glucose-sensing properties can be introduced into non-islet cells by the single expression of GK and that glucose responsiveness can be augmented by the coexpression of GLUT2. However, in the metabolic engineering of surrogate beta cells, it is critical that the levels of the components be closely optimized to ensure their physiological function and to avoid the deleterious consequences of glucose-induced toxicity.
Adenosine Triphosphate↗
Evidence that inhibition of cathepsin-B contributes to the neuroprotective properties of caspase inhibitor Tyr-Val-Ala-Asp-chloromethyl ketone.
During the use of tetrapeptide and other proprietary caspase inhibitors in the study of neurodegeneration, we had concluded that mechanisms other than the inhibition of caspases contributed to the protective effects of certain caspase inhibitors. Here we report our studies to identify a target for and hence a mechanism by which the tetrapeptide inhibitor tyrosine-valine-alanine-aspartate-chloromethyl ketone (Ac-YVAD-cmk) is able to rescue neuronal cell cultures from cell death. Ac-YVAD-cmk rescued neuronal cells from cell death in response to oxidative stress and oxygen/glucose deprivation. Affinity labeling with biotinylated YVAD-cmk demonstrated distinct binding proteins for the inhibitor in cells from the central nervous system versus Jurkat cells. Binding to the novel target protein was displaced by class-specific protease inhibitors and suggested that the target is a cysteine protease. Affinity purification and sequencing identified the target as cathepsin-B. Cathepsin-B inhibitors competed with biotinylated YVAD-cmk for the target protein. The availability of the target for binding was reduced in cells that had been rescued by unlabeled inhibitor. Cathepsin-B inhibitors rescue hippocampal slices from cell death induced by oxygen/glucose deprivation. These data provide evidence to support a role for cathepsin-B in neuronal cell death, particularly that following ischemia.
Amino Acid Chloromethyl Ketones↗
Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice.
The recent cloning of two GABA(B) receptor subunits, GABA(B1) and GABA(B2), has raised the possibility that differences in GABA(B) receptor subunit composition may give rise to pharmacologically or functionally distinct receptors. If present, such molecular diversity could permit the selective targeting of GABA(B) receptor subtypes specifically involved in pathologies such as drug addiction, spasticity, pain, and epilepsy. To address these issues we have developed a GABA(B1) subunit knockout mouse using gene targeting techniques. In the brains of GABA(B1) null mice, all pre- and postsynaptic GABA(B) receptor function was absent demonstrating that the GABA(B1) subunit is essential for all GABA(B) receptor-mediated mechanisms. Despite this, GABA(B1) null mice appeared normal at birth, although by postnatal week four their growth was retarded and they developed a generalized epilepsy that resulted in premature death. In addition, GABA(B1) heterozygote animals showed enhanced prepulse inhibition responses compared to littermate controls, suggesting that GABA(B1) deficient mice exhibit increased sensorimotor gating mechanisms. These data suggest that GABA(B) receptor antagonists may be of benefit in the treatment of psychiatric and neurological disorders in which attentional processing is impaired.
Action Potentials↗
Lapses of concentration and dyslexic performance on the Ternus task.
Recently, Cestnick and Coltheart (Cognition 71 (1999) 231) have reported evidence of abnormal performance on the Ternus apparent motion task in dyslexics. We demonstrate that some aspects of their data may be accounted for by more frequent lapses of concentration in the dyslexic group than in controls. We then report on a study in which a modification of the Ternus procedure was employed to simplify the task and to control for the effects of inattention. The results suggest that dyslexics do genuinely differ from normal readers in their perceptual processing.
Attention↗
The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy.
Breast and ovarian cancers exhibit similar epidemiologic, genotypic, and phenotypic characteristics. Phosphatidylinositol 3-kinase (PI3K) and the PTEN tumor suppressor gene product phosphorylate and dephosphorylate the same 3' site in the inositol ring of membrane phosphatidylinositols. Germ-line mutations in the PTEN tumor suppressor gene are causative of Cowden's breast cancer predisposition syndrome, and PTEN is frequently mutated in sporadic breast cancers. In contrast, amplification of multiple components of the PI3K pathway is a hallmark of serous epithelial ovarian cancers. The resultant activation of the PI3K pathway in both breast and ovarian cancers contributes to cell-cycle progression, decreased apoptosis, and increased metastatic capabilities. Strikingly, both ovarian and breast cancer cells are selectively sensitive to pharmacologic and genetic manipulation of the PI3K pathway, making molecular therapeutics targeting this pathway particularly attractive approaches for these cancers.
Animals↗
Lay therapy intervention with families at risk for parenting difficulties: The Kempe Community Caring Program.
OBJECTIVE: To determine which areas of family functioning lay therapy intervention can improve in a home visitation program for first time mothers at high risk for parenting difficulties, including the potential for child abuse and neglect. METHODS: Families were assessed for risk of parenting difficulties using the Parent Readiness and Risk Assessment Checklists. Lay therapists completed the Scale of Family Functioning pre- and postintervention with 108 high risk families for whom they provided support, education, and referrals. RESULTS: Paired t tests were done to determine whether the eight categories of the Scale of Family Functioning improved from baseline to termination of the service. Four categories showed statistically significant improvement: social support (p = .001), self-esteem (p < .001), confidence as a parent (p < .001), and affective relationships (p = .003). CONCLUSIONS: Statistically significant improvement occurred in four of the eight categories on the Scale of Family Functioning indicating that home intervention programs can improve some categories of family functioning. Longer intervention and an increased focus on improving parent/infant interactions may be able to increase parental sensitivity and expectations. In this study, the categories of family conflict and stability/meeting basic needs were not amenable to change with lay therapy intervention.
Adult↗
Up-regulation of secretoneurin immunoreactivity and secretogranin II mRNA in rat striatum following 6-hydroxydopamine lesioning and chronic L-DOPA treatment.
Destruction of the nigro-striatal pathway in Parkinson's disease and treatment with L-DOPA lead to persistent alterations in basal ganglia output pathways that are poorly characterised. Differential display mRNA analysis was used to study the effects of 6-hydroxydopamine-induced lesions of the medial forebrain bundle on gene expression in the rat striatum. One up-regulated cDNA identified in two independent groups of 6-hydroxydopamine-lesioned animals was cloned and sequence analysis showed 97% homology to secretogranin II. Differential up-regulation of secretogranin II following 6-hydroxydopamine lesioning was confirmed in a further group of 6-hydroxydopamine-lesioned rats using TaqMan real time quantitative reverse transcription-polymerase chain reaction. Following chronic L-DOPA treatment of 6-hydroxydopamine-lesioned rats, secretogranin II mRNA was further up-regulated to a similar degree to that observed for preproenkephalin A mRNA expression. Immunohistochemical analysis confirmed the increase in secretogranin II peptide levels in striatal neurones in 6-hydroxydopamine-lesioned rats following chronic L-DOPA treatment. The increase in secretogranin II mRNA occurring following destruction of the nigro-striatal pathway and chronic L-DOPA treatment may result in an increase in secretoneurin levels, which could be important for the regulation of striatal output pathways.
Animals↗
Antifungal activities of origanum oil against Candida albicans.
The antimicrobial properties of volatile aromatic oils from medicinal as well as other edible plants has been recognized since antiquity. Origanum oil, which is used as a food flavoring agent, possesses a broad spectrum of in vitro antimicrobial activities attributed to the high content of phenolic derivatives such as carvacrol and thymol. In the present study, antifungal properties of origanum oil were examined both in vitro and in vivo. Using Candida albicans in broth cultures and a micro dilution method, comparative efficacy of origanum oil, carvacrol, nystatin and amphotericin B were examined in vitro. Origanum oil at 0.25 mg/ml was found to completely inhibit the growth of C. albicans in culture. Growth inhibitions of 75% and >50% were observed at 0.125 mg/ml and 0.0625 mg/ml level, respectively. In addition, both the germination and the mycelial growth of C. albicans were found to be inhibited by origanum oil and carvacrol in a dose-dependent manner. Furthermore, the therapeutic efficacy of origanum oil was examined in an experimental murine systemic candidiasis model. Groups of mice (n = 6) infected with C. albicans (5 x LD50) were fed varying amounts of origanum oil in a final vol. of 0.1 ml of olive oil (vehicle). The daily administration of 8.6 mg of origanum oil in 100 microl of olive oil/kg body weight for 30 days resulted in 80% survivability, with no renal burden of C. albicans as opposed to the group of mice fed olive oil alone, who died within 10 days. Similar results were obtained with carvacrol. However, mice fed origanum oil exhibited cosmetically better clinical appearance compared to those cured with carvacrol. The results from our study encourage examination of the efficacy of origanum oil in other forms of systemic and superficial fungal infections and exploration of its broad spectrum effect against other pathogenic manifestations including malignancy.
Animals↗
A genome screen for multiple sclerosis in Italian families.
We have screened the whole genome for linkage in 40 Italian multiplex families with multiple sclerosis using 322 markers. The GENEHUNTER-PLUS program was used to analyse these data and revealed eight regions of potential linkage where the lod score exceeds the nominal 5% significance level (0.7). No region of linkage with genome-wide significance was identified and none of the markers showed evidence of statistically significant transmission disequilibrium. Overall these results have refined the linkage data relating to this disease in Italians modestly supporting some previously identified areas of interest and helping to exclude others.
Genetic Testing↗
Nasal septal surgery: evaluation of symptomatic and general health outcomes.
Although septoplasty and submucous resections are common procedures, there have been very few studies on the outcome of nasal septal surgery. This prospective study of two hundred patients undergoing septal surgery used the Fairley nasal symptom score, the Nottingham health profile, a general health questionnaire and clinical examination of nasal cavities to assess the outcome. A wide range of baseline severity scores was observed. Almost 40% of patients failed to attend for review. Analysis of the outcomes in the remaining 121 patients revealed significant improvement in (a) nasal obstruction in 74%, (b) facial pain in 72%, and (c) catarrh in 64% of patients. There was a lack of correlation between observed postoperative reduction in the number of nasal septal areas deviated and improvement in nasal obstruction. The Nottingham health profile and general health questionnaire scores remained unchanged in a large majority of patients. Postoperative improvement in nasal obstruction was independent of grade of surgeon or concomitant lateral nasal wall surgery. The principal benefits of septal surgery relate to improvement in nasal symptoms. The generic quality-of-life measures such as the Nottingham health profile and general health questionnaire did not show significant improvement in quality of life. Our results support the use of disease-specific instruments to evaluate the outcome of septal surgery.
Adolescent↗
Developing a cancer genetics service in Wales: opinions of gynaecologists on the management of women at risk of familial ovarian cancer.
In Wales, a cancer genetics service has been developing since 1998. Gynaecologists play an integral role in the management of women with a family history of ovarian cancer and we were interested in investigating referral practice and management for relatives of patients with ovarian cancer among gynaecologists in Wales. In 1999, a postal questionnaire was sent to all gynaecologists. The response rate was 51%. The questionnaire contained structured questions about current provision and a number of hypothetical scenarios to explore referral patterns to the cancer genetics service. The results of this study showed that referrals varied widely among specialists, as did the numbers who required onward referral to cancer genetics. The offer of screening to women at high risk of ovarian cancer was consistent, although there were variations in how often it was offered and the age at which it was offered. Most gynaecologists were easily able to establish when it was appropriate to refer onwards to cancer genetics, differentiating between women at high or low risk. There was some confusion about women at moderate risk of ovarian cancer. This study demonstrated the need for clear referral guidelines in Wales. Guidelines have since been distributed to all general practitioners and specialists; however, continued monitoring and further evaluation of referral practices will be necessary.
Family↗
Use of a journal club and letter-writing exercise to teach critical appraisal to medical undergraduates.
INTRODUCTION: There is growing interest in methods of teaching critical appraisal skills at undergraduate and postgraduate levels. We describe an approach using a journal club and subsequent letter writing to teach critical appraisal and writing skills to medical undergraduates. METHODS: The exercise occurs during a 3-week public health medicine attachment in the third year of the undergraduate curriculum. Students work in small groups to appraise a recently published research paper, present their findings to their peers in a journal club, and draft a letter to the journal editor. Evaluation took place through: informal and formal feedback from students; number of letters written, submitted and published, and a comparison of marks obtained by students submitting a literature review assignment with and without critical appraisal teaching during the public health attachment. RESULTS: Feedback from students was overwhelmingly positive. In the first 3(1/2) years, 26 letters have been published or accepted for publication, and 58 letters published on the Internet. There were no significant differences in overall marks or marks for the critical appraisal component of the literature review assignments between the two student groups. DISCUSSION: We believe our approach is an innovative and enjoyable method for teaching critical appraisal and writing skills to medical students. Lack of difference in marks in the literature review between the student groups may reflect its insensitivity as an outcome measure, contamination by other critical appraisal teaching, or true ineffectiveness.
Communication↗
Pseudomonas aeruginosa in cystic fibrosis: cross-infection and the need for segregation.
Evidence-based reasons for segregation of patients colonized with Pseudomonas aerugionsa in the outpatient setting are unclear. To clarify local decisions, Pseudomonas genotyping of the local environment, patients and patient contacts was undertaken in 1993. The hospital environment was re-swabbed in 1997. Pseudomonas genotyping of old and new patients attending the North Staffordshire cystic fibrosis clinic has subsequently been undertaken and more recently been repeated on an annual basis to assess whether the same Pseudomonas genotypes can be found in both the environment and in patients, and whether the same Pseudomonas genotype can be transferred from one patient to another. No Pseudomonas genotype found in the local environment in 1993 or in 1997 has been found in any of our patients. Nine children attending the same special school for many years and sharing the same physiotherapy facilities showed no evidence of cross-infectivity. Except for siblings living in the same household our cross-infectivity rate is very low and where cross-infection has potentially occurred the level of contact between these patients has been minimal. This study does not support the suggestion that patients with cystic fibrosis attending the North Staffordshire clinic and colonized with Pseudomonas aeruginosa should be segregated from non-colonized patients.
Adolescent↗
Using a revised asthma morbidity index to identify varying patterns of morbidity in U.K. general practices.
Both in terms of morbidity and mortality, the therapeutic and organizational management of asthma pose a considerable and continuing challenge to healthcare delivery. One element in attempts to meet this challenge is the recognition of appropriate outcome measures to assess progress in tackling the burden of this disease. This study therefore aimed to assess pragmatically the effectiveness of a revised asthma morbidity index in identifying varying patterns of morbidity in U.K. general practices. A postal survey was conducted of 2,762 patients believed to have or have had asthma from the lists of 12 general practices within the Eden Valley in Cumbria, using a questionnaire which combined the revised Jones morbidity index with questions on age, medication and perception of current asthma. Prescribing data were also recovered for 11 of the practices for the quarter within which the postal survey was conducted. Responses were obtained from 2,123 subjects (77%), of whom 1,474 (70%) believed themselves to be currently asthmatic. In this group, 18% reported low morbidity 34% medium morbidity and 48% high morbidity Age and inhaled steroid use were both positively and significantly associated with high morbidity. Those taking inhaled steroids were 1.4 times more likely to report high morbidity than those nottaking steroids. The prescribed corticosteroid/bronchodilator ratio for cost was both negatively and significantly associated with high morbidity. The revised morbidity index is a simple tool of use in the surveillance of asthma in primary care. It identifies spectra of morbidity which vary between practices, which may be of use in assessing the quality of asthma care provided in the community.
Age Factors↗
Pre-operative estimation of primary breast cancer size: a comparison of clinical assessment, mammography and ultrasound.
This prospective study aimed to determine which is the most precise modality for the pre-operative measurement of primary breast cancers: clinical palpation; mammography; or ultrasound. Analysis of the difference between the measurement of the maximum tumour diameter by these three modalities and by the histological measurement was performed in 210 cases. Clinical palpation tended to overestimate tumour size and gave the largest standard deviation of the difference. Ultrasound and mammography both gave a similar standard deviation of the difference, with ultrasound tending to underestimate tumour size. For all modalities, the standard deviation and the 95% confidence intervals of the difference increased with increasing tumour size. There is little difference between the precision of ultrasound and mammography in measuring tumour size. The wide 95% confidence intervals for any method of pre-operative tumour measurement should be considered when planning patient management.
Journal Article↗
Two-year trends of peripherally inserted central catheter-line complications at a tertiary-care hospital: role of nursing expertise.
We found reductions in peripherally inserted central catheter (PICC) complication rates over 2 years of observation (20.4 vs 13.8/1,000 line-days; relative risk, 0.5-0.9). This difference represents a cost saving due to reduced line reinsertions and reduced use of thrombolytic agents. The presence of a dedicated PICC insertion nursing team and education of ward nurses in PICC maintenance is a plausible explanation for the observed differences.
Adult↗