Search PubMed⌕ Search

Biomedical subjects

A Brooks

Publications and source records attributed to A Brooks.

At least 55 records · Page 3Linked to original sources
PubMed1999

The 37-amino-acid interdomain of dengue virus NS5 protein contains a functional NLS and inhibitory CK2 site.

The dengue virus NS5 RNA-dependent RNA polymerase has been detected in the nucleus of virus-infected mammalian cells. We demonstrate here for the first time using in vitro and in vivo assay systems that the 37-amino-acid linker interdomain of NS5 (residues 369 to 405) contains a nuclear localization sequence (NLS) which is capable of targeting b-galactosidase to the nucleus. Further, we show that the linker is recognized by subunits of the NLS-binding importin complex with an affinity similar to that of the bipartite NLS of the retinoblastoma protein and, in analogous fashion to proteins such as the SV40 large tumor antigen, contains a functional protein kinase CK2 phosphorylation site (threonine 395). Interestingly, this site appears to inhibit NS5 nuclear targeting, probably through a cytoplasmic retention mechanism. The linker may have an important role in targeting NS5 to the nucleus in a regulated manner during the dengue virus infectious cycle.

Adenosine Triphosphate↗
PubMed1999

Redesigning the surgery clerkship at MCP Hahnemann School of Medicine to address the educational needs of generalists.

This article describes how the surgery clerkship at MCP Hahnemann School of Medicine was redesigned to provide all students a well-rounded general professional education and to address the specific educational needs of generalists. During the 12-week clerkship, students spend eight weeks on two different general surgery rotations, which include significant experiences in outpatient settings. The evaluation and management of common general surgical problems, as well as the holistic approach to patient care, are emphasized. A nurse educator, recruited through funding obtained from The Robert Wood Johnson Foundation's Generalist Physician Initiative, provides formal instruction in holistic care and teaches bedside procedures. Two weeks are devoted to focused surgical subspecialty experiences addressing common conditions and are conducted primarily in outpatient settings. The remaining two weeks include an integrated musculoskeletal disease rotation, including orthopaedic surgery, rheumatology, physiatry, and radiology. Didactic teaching includes criteria for referral of patients from generalists to specialists. The new clerkship model has been well received by the students. Review of student logs for the first six months indicates the breadth of surgical experience has been maintained and appropriate balance achieved between simple and complex surgical cases. Further evaluation of the model will continue through longitudinal follow-up.

Clinical Clerkship↗
PubMed1999

Incidence and management of gynaecological-related ureteric injuries.

We report a 5-year review of all ureteric injuries at a major Sydney teaching hospital as a result of gynecological procedures. A retrospective analysis was made of all hospital medical records and consultant follow-up notes from January,1990 to May, 1995. Injuries were recorded in 22 patients with a mean age 52 years (range 31-88). Of these, 17 occurred at our institution, while 5 were referred from peripheral hospitals. Two injuries were bilateral, and 6 were discovered intraoperatively. Patients were managed acutely where possible. Treatment options included cystoscopy and retrograde stenting, deligation, neoureterocystostomy, transureteroureterostomy or nephrectomy. Follow-up imaging was available in 16 patients, of those, 15 were normal, and 1 showed bilateral obstruction secondary to radiotherapy. The overall risk of ureteric injury for all methods of hysterectomy was 0.44% (0.24% for total abdominal hysterectomy).

Adult↗
PubMed1998

Overexpression of nerve growth factor in the heart alters ion channel activity and beta-adrenergic signalling in an adult transgenic mouse.

1. The electrophysiological and pharmacological properties of cardiac myocytes from the hearts of adult transgenic mice engineered to overexpress nerve growth factor (NGF) in the heart were studied. 2. There was a 12% increase in the ventricular myocyte capacitance in NGF myocytes consistent with cardiac hypertrophy, and action potential duration at 90% repolarization (APD90) was prolonged by 142 % compared with wild-type (WT) myocytes. This was due, at least in part, to a decrease in the density of two K+ currents, Ito and IK(ur), which were significantly reduced in NGF mice with no change in their electrophysiological characteristics. We found no change in the current density or electrophysiological properties of the L-type Ca2+ current. 3. The effect on Ito and IK(ur) of TEA and 4-aminopyridine (4-AP) was not different in cells isolated from WT and NGF mice. The prolongation of APD observed in NGF cells was mimicked in WT cells by exposure to 1 mM 4-AP, which partially blocked Ito, completely blocked IK(ur) and increased APD90 by 157%. 4. The isoprenaline-induced increase in ICa was significantly smaller in NGF myocytes than in WT myocytes. This was not due to a decrease in beta-adrenergic receptor (beta-AR) density, as this was increased in NGF tissue by 55%. Analysis of beta-AR subtypes showed that this increase was entirely due to an increase in beta2-AR density with no change in beta1-ARs. 5. The response of the beta-AR-coupled adenylyl cyclase system to isoprenaline, Gpp(NH)p and forskolin was studied by measuring cAMP production. In NGF tissue, isoprenaline elicited a significantly smaller response than in WT myoyctes and this was not due to reduced adenylyl cyclase activity as the responses of NGF tissue to guanylylimidodiphosphate (Gpp(NH)p) and forskolin were unaffected. 6. In conclusion, the overexpression of NGF in the mouse heart resulted in a decrease in the current density of two K+ channels, which contributed to the prolongation of the cardiac action potential. Despite an increase in beta2-AR density in the hearts of the NGF mice, the response to isoprenaline was diminished, and this was due to an uncoupling of the beta-ARs from the intracellular signalling cascade. These potentially pathological changes may be involved in the occurrence of ventricular arrhythmias in cardiac hypertrophy and failure, and this mouse provides a novel model in which to study such changes.

Action Potentials↗
PubMed1998

Accounts of experiences of bulimia: a discourse analytic study.

OBJECTIVES: To identify the variety of versions of bulimia constructed by participants, to suggest functions and consequences of these constructions, and to examine the sociocultural ideologies evident in participants' discourse. METHODS: Ten women and one man were interviewed about their experiences of bulimia. Transcribed interviews were analyzed using a discourse analytic approach. RESULTS: Five dominant ways of talking about bulimia were identified: Individuals were constructed as victims of bulimia, women were constructed as victims of social stereotypes, bulimia was constructed as a damaging action one performs on oneself, bulimia was constructed as a personality trait of individuals, and bulimia was marginalized as abnormal and disgusting. DISCUSSION: Sociocultural ideologies evident in participants' accounts included the valuing of individual will-power and self-mastery and the construction of a mind-body dichotomy entailing the need to control the latter. The analysis emphasizes the importance of considering the sociocultural context within which psychological problems occur.

Adult↗
PubMed1998

Erosive oesophagitis: outcome of repeated long term maintenance treatment with low dose omeprazole 10 mg or placebo.

AIMS: To investigate the efficacy of daily maintenance treatment with omeprazole 10 mg in reducing the relapse rate of healed erosive oesophagitis. METHODS: Three hundred patients with erosive oesophagitis (grade 2 or greater) received omeprazole 20 mg daily for 12 weeks, followed by 40 mg daily for a further 12 weeks if required. After healing, patients were randomised to double blind treatment with omeprazole 10 mg daily or placebo for up to 18 months. On relapse the treatment cycle was repeated. RESULTS: The cumulative healing rate at 12 weeks in the initial healing period was 95%, and 96% and 98% on rehealing courses after relapse in the first and second maintenance periods respectively. After 12 weeks of treatment, 98% of patients were free from heartburn and 97% were free of all reflux related symptoms. Relapse in the subgroup of patients who relapsed in both maintenance periods was infrequent on omeprazole 20 mg daily: only 9% at two years. Gastrin concentrations rose above normal in one third of patients. One patient had linear hyperplasia of endocrine cells and another had micronodular hyperplasia. There were no side effects definitely attributable to omeprazole. CONCLUSION: Maintenance treatment with omeprazole 10 mg daily keeps about 60% of patients with erosive oesophagitis in prolonged remission. Patients relapsing once are likely to do so again; they can subsequently be treated effectively with omeprazole 20 mg daily.

Anti-Ulcer Agents↗
PubMed1998

Prolonged air leak following radical upper lobectomy: an analysis of incidence and possible risk factors.

STUDY OBJECTIVES: To examine the incidence and clinical significance of prolonged air leak (PAL) in patients undergoing radical upper lobectomy and to determine potential risk factors for PAL in this group of patients. DESIGN: Retrospective review of a prospective database. SETTING: Experience of one thoracic surgeon at a tertiary care cancer center. PATIENTS: One hundred consecutive patients undergoing right upper lobectomy and mediastinal lymph node dissection for non-small cell lung cancer over an 11-year period. MEASUREMENTS: PAL was defined as an air leak lasting >7 days. Preoperative, intraoperative, and postoperative clinical data were collected and analyzed to determine the factors associated with PAL. RESULTS: PAL was the most prevalent postoperative complication, comprising 25.5% of all complications seen, and lasting an average of 12.1+/-5.3 days. In 21 of the 26 patients with PAL, this complication was the only morbidity identified. There was no statistically significant difference in patient age, gender, preoperative FEV1 and diffusion of carbon monoxide, exposure to neoadjuvant chemotherapy, status of pulmonary fissures, or pathologic stage between the PAL group vs the remaining 74 patients without this complication. A significantly greater proportion of patients with PAL had FEV1/FVC ratio < or =50% (6/26 vs 5/74; p=0.02). Patients with PAL had significantly longer median length of hospital stay (11 vs 7 days; p=0.0001). Moreover, PAL was the single most common reason for an extended length of hospitalization (21/58, 36% of all causes). CONCLUSION: PAL is an alarmingly common postoperative complication and is the most frequent cause of an extended length of hospital stay in patients undergoing radical upper lobectomy. Severe obstructive pulmonary disease predisposes patients to the development of this complication.

Adult↗
PubMed1997

Functional requirement of the hypoxia-responsive element in the activation of the inducible nitric oxide synthase promoter by the iron chelator desferrioxamine.

We have previously reported that a 19-base pair element of the 5'-flanking region of the inducible nitric oxide synthase (iNOS) gene containing a sequence homology to a hypoxia-responsive enhancer (iNOS-HRE) mediates picolinic acid (PA)- or hypoxia-induced activation of the iNOS promoter in interferon-gamma (IFN-gamma)-treated murine macrophages. The iron chelator desferrioxamine (DFX) induces the activity of the human erythropoietin enhancer in Hep3B cells. We have investigated the influence of DFX on the activation of the iNOS promoter and iNOS gene expression in ANA-1 macrophages. We have found that DFX induced DNA-binding activity to the hypoxia-inducible factor 1 (HIF-1) consensus sequence of the iNOS promoter and activated the iNOS-HRE in murine macrophages. These activities of DFX were associated with a synergistic induction of iNOS mRNA expression and iNOS transcription in IFN-gamma-treated ANA-1 macrophages. Functional analysis of the 5'-flanking region of the iNOS gene demonstrated that IFN-gamma plus DFX activated the full-length iNOS promoter and that the iNOS-HRE was required for DFX-induced iNOS transcriptional activity. We also investigated the role of iron metabolism in the DFX- or PA-dependent induction of HIF-1 activity and iNOS expression. We demonstrate that addition of iron sulfate completely abolished DFX or PA induction of HIF-1 binding and iNOS-HRE activation and abrogated IFN-gamma plus either DFX- or PA-induced iNOS expression. These data establish that DFX is a co-stimulus for the transcriptional activation of the iNOS gene in IFN-gamma-treated macrophages, and they provide evidence that the iNOS-HRE is required for the DFX-dependent activation of the iNOS promoter. Furthermore, our results indicate that the iNOS-HRE is a regulatory element of the iNOS promoter responsive to iron chelation.

Animals↗
PubMed1997

Sequential bilateral isolated lung perfusion in the rat: an experimental model.

BACKGROUND: A model of isolated single-lung perfusion in the rat has been established in our laboratory to study the chemotherapeutic treatment of pulmonary metastases. A sequential bilateral isolated lung perfusion model was designed to investigate the feasibility of staged perfusions in the rat. METHODS: Twenty-four Fischer rats were randomized into three experimental groups of 8 rats each. All rats underwent left isolated lung perfusion. One, 2, or 3 weeks later, the rats in groups I, II, and III, respectively, underwent contralateral (right) perfusion. Five control animals (group IV) underwent sequential bilateral sham thoracotomies 1 week apart. Arterial blood gas analysis was performed 1 week after the second operation in the rats in groups I and IV. RESULTS: All animals survived the first operation, with 100% (8/8), 75% (6/8), and 100% (8/8) of the animals in perfusion groups I, II, and III, respectively, surviving the second operation. All control animals (group IV) survived the second sham thoracotomy. Arterial blood gas analysis did not show a significant difference in the oxygen or carbon dioxide partial pressure or the pH between group I and IV (p = 0.32, 0.96, and 0.76, respectively). CONCLUSIONS: Our experiments demonstrate that sequential bilateral isolated lung perfusion is safe in and well tolerated by the rat. This model can be used to investigate the safety and efficacy of staged perfusions with chemotherapeutic agents in the treatment of bilateral pulmonary metastases in the rat.

Animals↗
PubMed1997

Isolated lung perfusion with doxorubicin prolongs survival in a rodent model of pulmonary metastases.

BACKGROUND: We developed a rodent model of unilateral pulmonary metastases to evaluate long-term survival after isolated lung perfusion with doxorubicin. METHODS: In the model development study, on day 0, two groups of F344 rats (n = 15) underwent transient right pulmonary artery occlusion for either 5 or 10 minutes at the time of intravenous injection of methylcholantrene-induced sarcoma cells. On day 14, all animals were sacrificed and lung nodules counted. In the survival study, on day 0, 21 rats received intravenous injection of sarcoma cells with concomitant 10-minute right pulmonary artery occlusion. On day 7, eight rats underwent left isolated lung perfusion with doxorubicin (6.4 mg/kg); five rats underwent perfusion with buffered Hespan; six untreated rats were studied as controls. RESULTS: Ten of fifteen animals (67%) in the model study with 5-minute pulmonary artery occlusion had right-sided tumor nodules. Ten-minute occlusion resulted in a tumor-free right lung in all animals. In the survival study, all animals in the Hespan and control groups died of massive tumor replacement of the left lung, with median survival times of 20 and 18 days, respectively. The median survival time of 36 days for the animals undergoing isolated lung perfusion with doxorubicin was significantly longer (p < 0.00001). The left lung of two of the doxorubicin perfused rats was tumor-free at 6 weeks. CONCLUSIONS: Isolated lung perfusion with doxorubicin results in a durable response and prolongs survival in the treatment of experimental sarcoma pulmonary metastases.

Animals↗
PubMed1997

Somatic gene transfer approaches to manipulate neural networks.

Gene transfer methods can be exploited to create somatic mosaic tissues to elucidate gene product action in cells comprising a network. This article describes the evolution of approaches beginning from herpes amplicon vectors with constitutive gene expression to herpes vectors with regulated gene expression and concludes with the development of a combined germline/somatic gene transfer method that allows for highly versatile spatial and temporal control of in vivo gene expression. Where possible examples of each approach are provided. In addition, the advantages and limitations of the approaches are discussed.

Animals↗
PubMed1997

Emergency admissions for upper gastrointestinal disease and their relation to NSAID use.

BACKGROUND: There are considerable variations in estimates of the number of emergency upper gastrointestinal admissions per annum which are attributable to nonsteroidal anti-inflammatory drug (NSAID) use. AIM: To obtain a more accurate estimate of the number of these emergency admissions per annum in UK. METHODS: A retrospective survey of the case notes of all emergency admissions for upper gastrointestinal disease ('Cases') to two English District General Hospitals with a combined catchment population of 550,000. Records of all community deaths attributed to upper gastrointestinal diagnoses (with the same ICD codes) were also surveyed. Matched controls were identified from emergency admissions not caused by upper gastrointestinal diagnoses. The proportions of patients taking NSAIDs on admission to hospital (or at the time of death at home) and the outcome following admission to hospital were analysed. RESULTS: 620 emergency upper gastrointestinal admissions were identified and matched with 460 controls. Cases were more likely to be NSAID users than Controls (31% vs. 16%, OR 2.4, 95% CI: 1.8, 3.3: P < 0.001). Case NSAID use was higher in females and with increasing age. As severity of mode of presentation worsened, the probability of NSAID use increased (e.g. OR relative to controls for peptic pain 1.9, for perforation 5.9). Blood transfusion requirements were significantly higher (P < 0.0001) in Cases taking NSAIDs, although NSAID use did not influence mortality. Extrapolation from these data indicate that there are 65,000 emergency upper gastrointestinal admissions per annum in UK; 12,000 of these admissions (including 2230 deaths) are attributable to NSAID use. A further 330 attributable deaths occur in the community. CONCLUSIONS: There is a strong association between NSAID use and propensity for upper gastrointestinal emergency admission; NSAID use is associated with significant morbidity and mortality each year in UK.

Adolescent↗