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Biomedical subjects

G Phillips

Publications and source records attributed to G Phillips.

At least 19 recordsLinked to original sources

Ceramide regulation of the tumor suppressor phosphatase PTEN in rafts isolated from neurotumor cell lines.

The neutral sphingolipid ceramide has been implicated in the apoptotic death of cells by a number of different mechanisms, including activation of protein kinase B (Akt) phosphatase. Here we present evidence that ceramide recruits the tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10) into membrane microdomains (rafts), where it could act to reduce the levels of polyphosphoinositides necessary for the activation of Akt. A PTEN construct with a red-fluorescent protein (RFP) tag was overexpressed in both a human cell line derived from oligodendroglioma (HOG) and a rat pheochromocytoma cell line (PC12) by means of an inducible promoter system (Tet-Off). Induction of PTEN by removal of doxycycline enhanced both capsase-3 and cell death with staurosporine, wortmannin, or C2-ceramide, whereas antisense PTEN had the reverse effect. Overexpression of PTEN also increased acid sphingomyelinase (ASMase) activity. PTEN normally has a generalized (cytosolic/membrane) distribution, but treatment with C2-ceramide translocated a fraction of the PTEN to the plasma membrane, showing a plasma membrane distribution similar to that observed for a prenylated green-fluorescent (GFP) construct. PTEN was then shown to translocate to the detergent-resistant membrane microdomain fraction (raft) of the plasma membrane. The colocalization of sphingomyelinases, ceramide, polyphosphoinositides, and PTEN in the raft fraction further suggests that the association of these lipids is critical for regulating cell death.

Androstadienes↗

A tiered risk-based approach for predicting diffuse and point source phosphorus losses in agricultural areas.

Implementation of the European Union Water Framework Directive requires an assessment of the pressures from human activity, which, combined with information on the sensitivity of the receiving waterbody to the pressures, will identify those water bodies at risk of failing to meet the Directive's environmental objectives. Part of the process of undertaking the risk assessment for lakes is an assessment of diffuse agricultural phosphorus (P) pressures. Three approaches of increasing sophistication were developed for this purpose: a basic 'risk screening' approach (tier 1) applicable to all lakes in Great Britain (GB) and based on export coefficients for different land cover classes and animal types; the Pressure Delivery Risk Screening Matrix approach (tier 2) that differentiated between pressures in surface water and groundwater river basins; and the Phosphorus Indicators Tool (PIT), a simple model of locational risk and P delivery potential (tier 3). Application of the three approaches to a range of lake catchments in England demonstrated that a tiered risk assessment approach was appropriate which was tailored to the quality of the available data. A step-wise procedure was developed whereby if the tier 1 and 2 approaches showed a catchment to be at high risk of failing to meet the Directive's environmental objectives with regard to P, it was justifiable to undertake a more detailed assessment using the tier 3 approach. The tier 1 approach was applied to all lakes in GB greater than 1 ha in size on the assumption that the boundary between the good/moderate status classes under the Water Framework Directive guidelines represented a doubling of the total P (TP) reference conditions. The initial outputs suggested that 51% of lakes in GB are predicted to not meet the TP targets identified for high or good status and must, therefore, be considered at risk. There were regional differences in numbers of lakes at risk. Scotland appeared to have the fewest sites at risk (18%); England the most (88%), with Wales having an intermediate percentage (56%). A comparison of P pressures on freshwaters using the tier 2 approach with other pressures on waterbodies (e.g. nitrate, sediment) in GB is shown as risk maps on the Environment Agency website at: . The tier 3 approach was applied to data-rich catchments and identified at the 1 km(2) areas of relatively high risk of P delivery to water.

Agriculture↗

A study of telephone screening and direct observation of surgical wound infections after discharge from hospital.

Post-discharge surveillance of surgical site infection is necessary if accurate rates of infection following surgery are to be available. We undertook a prospective study of 376 knee and hip replacements in 366 patients in order to estimate the rate of orthopaedic surgical site infection in the community. The inpatient infection was 3.1% and the post-discharge infection rate was 2.1%. We concluded that the use of telephone interviews of patients to identify the group at highest risk of having a surgical site infection (those who think they have an infection) with rapid follow-up by a professional trained to diagnose infection according to agreed criteria is an effective method of identifying infection after discharge from hospital.

Adult↗

Haplotype block and superblock structures of the alpha1-adrenergic receptor genes reveal echoes from the chromosomal past.

A significant proportion of the human genome is contained within haplotype blocks across which pairwise linkage disequilibrium (LD) is very high. However, LD is also often high between markers at more remote distances, and within different haplotype blocks. Here, we evaluate the origins of haplotype block structure in the three genes for alpha1 adrenergic receptors (alpha1-AR) in the human genome ( ADRA1A, ADRA1B and ADRA1D) by genotyping dense single-nucleotide polymorphism (SNP) marker maps, and show that LD signals between distant markers are due to the presence of extended haplotype superblocks in individuals with ancient chromosomes which have escaped historic recombination. ARs mediate the physiological effects of epinephrine and norepinephrine, and are targets of many therapeutic drugs. This work has identified haplotype backgrounds of alpha1-AR missense variants, haplotype block structures in US Caucasians and African Americans, and haplotype tag SNPs for each block, and we present strong evidence for ancient haplotype block superstructure at these genes which has been partially disrupted by recombination, and evidence for reinstatement of linkage disequilibrium by subsequent recombination events. ADRA1A is comprised of four haplotype blocks in US Caucasians, while in African Americans Block 1 is split. ADRA1B has four blocks in US Caucasians, but in African Americans only the first two blocks are present. ADRA1D has two blocks in US Caucasians, and the first block is replaced by two smaller blocks in African Americans. For both ADRA1A and ADRA1B, haplotype superstructures may represent a novel, higher-level hierarchy in the human genome, which may reduce redundancy of testing by further aggregation of genotype data.

Black or African American↗

Presence of bacteriuria caused by trimethoprim resistant bacteria in patients prescribed antibiotics: multilevel model with practice and individual patient data.

OBJECTIVE: To look for evidence of a relation between antibiotic resistance and prescribing by general practitioners by analysis of prescribing at both practice and individual patient level. DESIGN: Repeated cross-sectional study in 1995 and 1996. SETTING: 28 general practices in the Ninewells Hospital laboratory catchment area, Tayside, Scotland. SUBJECTS REVIEWED: 8833 patients registered with the 28 practices who submitted urine samples for analysis. MAIN OUTCOME MEASURES: Resistance to trimethoprim in bacteria isolated from urine samples at practice and individual level simultaneously in a multilevel model. RESULTS: Practices showed considerable variation in both the prevalence of trimethoprim resistance (26-50% of bacteria isolated) and trimethoprim prescribing (67-357 prescriptions per 100 practice patients). Although variation in prescribing showed no association with resistance at the practice level after adjustment for other factors (P = 0.101), in the multilevel model resistance to trimethoprim was significantly associated with age, sex, and individual-level exposure to trimethoprim (P < 0.001) or to other antibiotics (P = 0.002). The association with trimethoprim resistance was strongest for people recently exposed to trimethoprim, and there was no association for people with trimethoprim exposure more than six months before the date of the urine sample. DISCUSSION: Analysis of practice level data obscured important associations between antibiotic prescribing and resistance. The results support efforts to reduce unnecessary prescribing of antibiotics in the community and show the added value of individual patient data for research on the outcomes of prescribing.

Adolescent↗

Telepathology on the Solomon Islands--two years' experience with a hybrid Web- and email-based telepathology system.

The National Referral Hospital in Honiara, Solomon Islands, has used an Internet-based system in Switzerland for telepathology consultations since September 2001. Due to the limited bandwidth of Internet connections on the Solomon Islands, an email interface was developed that allows users in Honiara to submit cases and receive reports by email. At the other end, consultants can use a more sophisticated Web-based interface that allows discussion of cases among an expert panel. The result is a hybrid email- and Web-based telepathology system. Over two years, 333 consultations were performed, in which 94% of cases could be diagnosed by a remote pathologist. A computer-assisted 'virtual institute' of pathologists was established. This form of organization helped to reduce the median time from submission of the request to a report from 28 h to 8.5 h for a preliminary diagnosis and 13 h for a final report. A final report was possible in 77% of all submitted cases.

Electronic Mail↗

Autotransplantation for advanced lymphoma and Hodgkin's disease followed by post-transplant rituxan/GM-CSF or radiotherapy and consolidation chemotherapy.

Disease relapse occurs in 50% or more of patients who are autografted for relapsed or refractory lymphoma (NHL) or Hodgkin's disease (HD). The administration of non-cross-resistant therapies during the post-transplant phase could possibly control residual disease and delay or prevent its progression. To test this approach, 55 patients with relapsed/refractory or high-risk NHL or relapsed/refractory HD were enrolled in the following protocol: stem cell mobilization: cyclophosphamide (4.5 g/m(2)) + etoposide (2.0 g/m(2)) followed by GM-CSF or G-CSF; high-dose therapy: gemcitabine (1.0 g/m(2)) on day -5, BCNU (300 mg/m(2)) + gemcitabine (1.0 g/m(2)) on day -2, melphalan (140 mg/m(2)) on day -1, blood stem cell infusion on day 0; post-transplant immunotherapy (B cell NHL): rituxan (375 mg/m(2)) weekly for 4 weeks + GM-CSF (250 microg thrice weekly) (weeks 4-8); post-transplant involved-field radiotherapy (HD): 30-40 Gy to pre-transplant areas of disease (weeks 4-8); post-transplant consolidation chemotherapy (all patients): dexamethasone (40 mg daily)/cyclophosphamide (300 mg/m(2)/day)/etoposide (30 mg/m(2)/day)/cisplatin (15 mg/m(2)/day) by continuous intravenous infusion for 4 days + gemcitabine (1.0 g/m(2), day 3) (months 3 + 9) alternating with dexamethasone/paclitaxel (135 mg/m(2))/cisplatin (75 mg/m(2)) (months 6 + 12). Of the 33 patients with B cell lymphoma, 14 had primary refractory disease (42%), 12 had relapsed disease (36%) and seven had high-risk disease in first CR (21%). For the entire group, the 2-year Kaplan-Meier event-free survival (EFS) and overall survival (OS) were 30% and 35%, respectively, while six of 33 patients (18%) died before day 100 from transplant-related complications. The rituxan/GM-CSF phase was well-tolerated by the 26 patients who were treated and led to radiographic responses in seven patients; an eighth patient with a blastic variant of mantle-cell lymphoma had clearance of marrow involvement after rituxan/GM-CSF. Of the 22 patients with relapsed/refractory HD (21 patients) or high-risk T cell lymphoblastic lymphoma (one patient), the 2-year Kaplan-Meier EFS and OS were 70% and 85%, respectively, while two of 22 patients (9%) died before day 100 from transplant-related complications. Eight patients received involved field radiation and seven had radiographic responses within the treatment fields. A total of 72 courses of post-transplant consolidation chemotherapy were administered to 26 of the 55 total patients. Transient grade 3-4 myelosuppression was common and one patient died from neutropenic sepsis, but no patients required an infusion of backup stem cells. After adjustment for known prognostic factors, the EFS for the cohort of HD patients was significantly better than the EFS for an historical cohort of HD patients autografted after BEAC (BCNU/etoposide/cytarabine/cyclophosphamide) without consolidation chemotherapy (P = 0.015). In conclusion, post-transplant consolidation therapy is feasible and well-tolerated for patients autografted for aggressive NHL and HD and may be associated with improved progression-free survival particularly for patients with HD.

Adult↗

Laparoscopic management of ectopic pregnancy: a 5-year experience.

The objective of this study was to review our management of ectopic pregnancy with the introduction of a laparoscopic service to the obstetrics and gynaecology department at South Cleveland Hospital. A retrospective analysis of 210 cases of ectopic pregnancy managed from May 1995 to May 2000 including operative findings and surgical data were collected prospectively over the past 5 years. All our women with an ectopic pregnancy were treated surgically. One hundred and seventy-seven (84.3%) patients were managed successfully laparoscopically with no major intraoperative or postoperative complications. Thirty-three (15.7%) women were managed by laparotomy for various reasons. Salpingectomy was the main (80%) procedure performed either by laparoscopy or by laparotomy. Thirty-five (16.7%) women were treated conservatively by salpingostomy. Of these 22.9% achieved a successful pregnancy and delivery. Half of our patients were managed by senior registrars. The estimated blood loss, the need for blood transfusion and the length of hospital stay following laparoscopic treatment were significantly less than those in laparotomy group. This study demonstrated that laparoscopic management of ectopic pregnancy is the most beneficial procedure with maximum safety and efficiency when the laparoscopic service is added to the unit.

Adult↗

Prior trimethoprim use and trimethoprim-resistant urinary tract infection: a nested case-control study with multivariate analysis for other risk factors.

Trimethoprim resistance is increasingly prevalent in community-acquired urinary infections. The objective of this study was to evaluate the association between exposure to community-prescribed trimethoprim and other risk factors in subjects and subsequent trimethoprim-resistant urinary tract infection. The design was a nested case-control study using a record-linkage database. Study subjects submitted a urine sample to the Ninewells Hospital Laboratory between July 1993 and December 1995. Antibiotic exposure in subjects with trimethoprim-resistant isolates (cases) was compared with antibiotic exposure in subjects with trimethoprim-susceptible isolates (controls). Study subjects were drawn from the catchment area of a large teaching hospital in Tayside, Scotland. There were 13765 males and females aged 1-106 years who submitted their first urine sample for culture during the study period. After adjustment for significant risk factors and confounding variables, logistic regression analysis showed exposure to trimethoprim [odds ratio (OR) 4.35] or any antibiotic other than trimethoprim (OR 1.32) to be predictive of resistance. The growth of Proteus spp. (OR 115.14) and bacterial growth other than Escherichia coli and Proteus spp. (OR 2.83) were also predictor variables. Hospitalization in the previous 6 months was not independently associated with trimethoprim resistance. In conclusion, trimethoprim resistance was independently associated with exposure to trimethoprim and to antibiotics other than trimethoprim. Reduction in trimethoprim prescribing alone may not reduce the prevalence of trimethoprim resistance.

Anti-Infective Agents, Urinary↗

Functional analysis of genes for biosynthesis of pyocyanin and phenazine-1-carboxamide from Pseudomonas aeruginosa PAO1.

Two seven-gene phenazine biosynthetic loci were cloned from Pseudomonas aeruginosa PAO1. The operons, designated phzA1B1C1D1E1F1G1 and phzA2B2C2D2E2F2G2, are homologous to previously studied phenazine biosynthetic operons from Pseudomonas fluorescens and Pseudomonas aureofaciens. Functional studies of phenazine-nonproducing strains of fluorescent pseudomonads indicated that each of the biosynthetic operons from P. aeruginosa is sufficient for production of a single compound, phenazine-1-carboxylic acid (PCA). Subsequent conversion of PCA to pyocyanin is mediated in P. aeruginosa by two novel phenazine-modifying genes, phzM and phzS, which encode putative phenazine-specific methyltransferase and flavin-containing monooxygenase, respectively. Expression of phzS alone in Escherichia coli or in enzymes, pyocyanin-nonproducing P. fluorescens resulted in conversion of PCA to 1-hydroxyphenazine. P. aeruginosa with insertionally inactivated phzM or phzS developed pyocyanin-deficient phenotypes. A third phenazine-modifying gene, phzH, which has a homologue in Pseudomonas chlororaphis, also was identified and was shown to control synthesis of phenazine-1-carboxamide from PCA in P. aeruginosa PAO1. Our results suggest that there is a complex pyocyanin biosynthetic pathway in P. aeruginosa consisting of two core loci responsible for synthesis of PCA and three additional genes encoding unique enzymes involved in the conversion of PCA to pyocyanin, 1-hydroxyphenazine, and phenazine-1-carboxamide.

Bacterial Proteins↗

Synthesis of hepatic secretory proteins in normal adults consuming a diet marginally adequate in protein.

The plasma concentration and hepatic synthesis rates of albumin, transthyretin, very low-density lipoprotein apolipoprotein B-100 (VLDL-apoB-100), high-density lipoprotein apolipoprotein A-1, fibrinogen, alpha1-antitrypsin, and haptoglobin were measured in six normal adults before and after consuming a protein intake of 0.6 g. kg body wt(-1). day(-1) for 7 days. The synthesis of hepatic proteins was measured from the incorporation of [(2)H(5)]- phenylalanine, following prime/continuous infusion, using plasma VLDL-apoB-100 isotopic enrichment to represent the precursor pool. Synthesis of albumin declined by 50% (P < 0.001) following the lower-protein diet, VLDL-apoB-100 declined by 20% (P < 0.001), and apoA-1 declined by 16% (P < 0.05). By contrast, synthesis increased for fibrinogen (50%, P < 0.05) and haptoglobin (90%, P < 0.001). This pattern of change, with decreased synthesis of nutrient transport proteins and increased formation of acute-phase proteins, suggestive of a low-grade inflammatory response, was accompanied by increased plasma concentration of the inflammatory cytokine interleukin 6 (30%, P < 0.05). The pattern of change in the synthesis of hepatic secretory proteins following 7 days on the low-protein diet may be of functional relevance for lipid transport and the capacity to cope with stress.

Acute-Phase Proteins↗

The effects of psychological therapies under clinically representative conditions: a meta-analysis.

Recently, concern has arisen that meta-analyses overestimate the effects of psychological therapies and that those therapies may not work under clinically representative conditions. This meta-analysis of 90 studies found that therapies are effective over a range of clinical representativeness. The projected effects of an ideal study of clinically representative therapy are similar to effect sizes in past meta-analyses. Effects increase with larger dose and when outcome measures are specific to treatment. Some clinically representative studies used self-selected treatment clients who were more distressed than available controls, and these quasi-experiments underestimated therapy effects. This study illustrates the joint use of fixed and random effects models, use of pretest effect sizes to study selection bias in quasi-experiments, and use of regression analysis to project results to an ideal study in the spirit of response surface modeling.

Humans↗

Community antibiotic therapy, hospitalization and subsequent respiratory tract isolation of Haemophilus influenzae resistant to amoxycillin: a nested case-control study.

The study objective was to determine whether recent community antibiotic prescribing and hospitalization are associated with beta-lactam resistance in respiratory isolates of Haemophilus influenzae. Data obtained for hospitalization and community prescribing (in the previous 3 months) from 412 adults (>15 years) in whom an episode of respiratory tract infection had been described, during which H. influenzae was isolated, were analysed. Seventy-three (17.7%) isolates of H. influenzae were resistant to amoxycillin. Resistance was associated with recent hospitalization [odds ratio (OR) 3.2, 1.8-5.6] and antibiotic exposure in the community (2.1, 1.2-3.6). These variables were independently associated with amoxycillin resistance [hospitalization (OR 4.5, 1. 7-12.5) and community beta-lactam antibiotic exposure (3.9, 1.6-9. 8)]. Hospitalized patients probably received antibiotics during their admission although aquisition of the organism or the beta-lactamase via plasmids from other Gram-negative organisms in the hospital could also be a factor. Control measures to reduce the inappropriate use of antimicrobials in the community and in hospital need to be reinforced.

Adolescent↗

An outbreak of skin sepsis in abattoir workers caused by an 'unusual' strain of Streptococcus pyogenes.

An outbreak of indolent skin infections due to an 'unusual' serological type of Streptococcus pyogenes that lasted for 3 months and affected eight workers in an abattoir is described. The group A streptococcal (GAS) isolates were serotyped as M-type 59; however, they possessed a T-protein pattern (T5/27/44) that is not commonly associated with M-type 59. Further genotypic characterisation studies revealed that all eight isolates were indistinguishable by pulsed-field gel electrophoresis (PFGE) and possessed the emm gene encoding for the M-type 59. Once identified, and after a combination of penicillin treatment, exclusion of workers with lesions and reinforcement of standard hygiene precautions, no further cases developed. Although common in the 1970s and 1980s, streptococcal infections in this situation are now reported infrequently. This report serves to highlight the issues surrounding working practices in abattoirs.

Abattoirs↗