Biomedical subjects
Publications and source records attributed to S Brown.
Multi-Link coronary stents, both 15 and 25 mm, can be used from the radial artery approach with a high degree of efficacy. The complexity of coronary artery stenting is greatly diminished by using the Multi-Link stent delivery system, which eliminates the need for "bare stenting."
We have cloned and characterized a novel isoform of the skeletal muscle LIM protein 1 (SLIM1), designated SLIMMER. SLIM1 contains an N-terminal single zinc finger followed by four LIM domains. SLIMMER is identical to SLIM1 over the first three LIM domains but contains a novel C-terminal 96 amino acids with three potential bipartite nuclear localization signals, a putative nuclear export sequence, and 27 amino acids identical to the RBP-J binding region of KyoT2, a murine isoform of SLIM1. SLIM1 localized to the cytosol of Sol8 myoblasts and myotubes. SLIMMER was detected in the nucleus of myoblasts and, following differentiation into myotubes, was exclusively cytosolic. Recombinant green fluorescent protein-SLIM1 localized to the cytoplasm and associated with focal adhesions and actin filaments in COS-7 cells, while green fluorescent protein-SLIMMER was predominantly nuclear. SLIMMER truncation mutants revealed that the first nuclear localization signal mediates nuclear localization. The addition of the proposed nuclear export sequence decreased the level of exclusively nuclear expression and increased cytosolic SLIMMER expression in COS-7 cells. The leucine-rich nuclear export signal was required for the export of SLIMMER from the nucleus of myoblasts to the cytoplasm of myotubes. Collectively, these results suggest distinct roles for SLIM1 and SLIMMER in focal adhesions and nuclear-cytoplasmic communication.
Sex hormones are involved in the physiological regulation of several aspects of behavior and neuroendocrine events. It has been accepted that such effects are mediated directly by steroid actions on neurons; however, new studies have shown that the glial cells are also affected by gonadal steroids. The microglia are one specialized brain glial cell type, which is a target for estrogen actions. In fact, we believe that many of the immune and nonimmune regulatory functions of microglia in the brain are influenced directly by estrogen via expression and secretion of cytokines, and growth factors by the microglia. The present review details only a section of the known aspects of microglial function, focusing mainly on nonimmune regulatory actions in the brain and their functional relationship with sex hormones. Moreover, we present evidence for the presence of estrogen receptor-beta (ERbeta) in rat microglial cells.
OBJECTIVES: To re-evaluate the cost effectiveness of treating hepatitis C virus (HCV) infection with interferon alfa (IF alpha) in Australia, taking into account changes in clinical practice. DESIGN: A decision-analytic method (Markov model) was used to simulate the costs and effects of 6 months and 12 months of treatment with IF alpha versus no treatment (conventional management). Both costs and effects were modelled over 30 years. DATA SOURCES: Published meta-analysis of the effectiveness of treatment, professional judgement about treatment protocols, scheduled medical fees, diagnosis-related costs for hospital admission, and a literature search for quality-of-life weights. PATIENTS: A hypothetical cohort of 1000 patients with chronic HCV infection aged 40 years at the start of treatment. MAIN OUTCOME MEASURES: Incremental costs per life-year gained and per quality-adjusted life-year (QALY) gained. RESULTS: Compared with no treatment, IF alpha treatment for 6 months results in an extra 94.2 life-years or 320.1 QALYs at an extra cost of $1.8 million (after discounting at 3%) in a cohort of 1000 patients. Discounted cost per life-year gained is $19,110, which is about a quarter of the cost reported in 1994. The discounted cost per QALY gained is $5625. Extended treatment for another 6 months results in an additional 89.0 life-years saved or 170.8 QALYs gained at an incremental discounted cost of $15,835 per life-year gained and $8250 per QALY gained. CONCLUSIONS: The cost effectiveness of IF alpha treatment for HCV infection has improved as a result of better patient selection, cost reductions and enhanced effectiveness of extended treatment. The results are sensitive to assumptions made about quality of life and the discount rate.
Desensitization of cannabinoid receptor signaling by a G-protein coupled receptor kinase (GRK) was examined using the Xenopus oocyte expression system. Application of a CB1 agonist, WIN 55,212-2, evoked a concentration-dependent increase in K+ conductance (Kir3) in oocytes coexpressing rat CB1 with the G-protein-gated, inwardly rectifying K+ channels Kir3.1 and Kir3.4. Desensitization was slight during continuous agonist application in the absence of GRK and arrestin. However, coexpression of GRK3 and beta-arrestin 2 (beta-arr2) caused profound homologous CB1 receptor desensitization, supporting the hypothesis that GRK3 and beta-arr2 effectively produce CB1 receptor desensitization. To identify the regions of the CB1 receptor responsible for GRK3- and beta-arr2-mediated desensitization, we constructed several CB1 receptor mutants. Truncation of the C-terminal tail of CB1 receptor at residue 418 (Delta418) almost completely abolished desensitization but did not affect agonist activation of Kir3. In contrast, truncation at residues 439 and 460 did not significantly affect GRK3- and beta-arr2-dependent desensitization. A deletion mutant (Delta418-439) did not desensitize, indicating that residues within this region are important for GRK3- and beta-arr2-mediated desensitization. Phosphorylation in this region was likely involved in desensitization, because mutation of either of two putative phosphorylation sites (S426A or S430A) significantly attenuated desensitization. CB1 receptors rapidly internalize after activation by agonist. Phosphorylation of S426 or S430 was not necessary for internalization, because the S426A/S430A CB1 mutant internalized when stably expressed in AtT20 cells. These studies establish that CB1 desensitization can be regulated by a GRK and that different receptor domains are involved in GRK- and beta-arrestin-dependent desensitization and CB1 internalization.
Inositol polyphosphate 4-phosphatase (4-phosphatase) is an enzyme that catalyses the hydrolysis of the 4-position phosphate from phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P2]. In human platelets the formation of this phosphatidylinositol, by the actions of phosphatidylinositol 3-kinase (PI 3-kinase), correlates with irreversible platelet aggregation. We have shown previously that a phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase forms a complex with the p85 subunit of PI 3-kinase. In this study we investigated whether PI 3-kinase also forms a complex with the 4-phosphatase in human platelets. Immunoprecipitates of the p85 subunit of PI 3-kinase from human platelet cytosol contained 4-phosphatase enzyme activity and a 104-kDa polypeptide recognized by specific 4-phosphatase antibodies. Similarly, immunoprecipitates made using 4-phosphatase-specific antibodies contained PI 3-kinase enzyme activity and an 85-kDa polypeptide recognized by antibodies to the p85 adapter subunit of PI 3-kinase. After thrombin activation, the 4-phosphatase translocated to the actin cytoskeleton along with PI 3-kinase in an integrin- and aggregation-dependent manner. The majority of the PI 3-kinase/4-phosphatase complex (75%) remained in the cytosolic fraction. We propose that the complex formed between the two enzymes serves to localize the 4-phosphatase to sites of PtdIns(3,4)P2 production.
Trisomy 12 is the most frequent numerical chromosomal abnormality reported in chronic lymphocytic leukemia (CLL). Its significance in other cancers, however, has not been extensively investigated until recently. Less than 20 cases of polysomy for chromosome 12 have been studied thus far. The most recent data in the literature suggest that gain of chromosome 12 may be a recurrent and sometimes early event in breast carcinogenesis. To test the hypothesis that a subset of breast cancer may be characterized by chromosome 12 trisomy, we conducted a retrospective study of 40 specimens. Of these, ten were stage I, ten were stage II, ten were stage III, and ten were stage IV. Out of the total sample, 12 cases (30%) were found to be presumably trisomic, if a conservative cutoff point of greater than or equal to 15% cells with three signals is adopted. Furthermore, some, but not all, of the 12 cases were found to be likely triploid, when data from a control chromosome 17 probe were taken into account. Thus, our data support the hypothesis that a subset of breast cancer exists which is characterized by an abnormal copy of chromosome 12, in either a diploid or a triploid background.
To test the hypothesis that the frequency of abnormal chromosome 8 copy number increases with the severity of the disease as defined by an increase in clinical stage, we conducted a fluorescence in situ hybridization (FISH) study of a sample of 42 breast cancer specimens utilizing a protocol that was optimized by our laboratory. Cytogenetic results, obtained from blinded analyses of archival specimens, demonstrated that the higher clinical stages (i.e., stages III and IV) yield higher frequencies of abnormal chromosome 8 copy number. Specifically, 45.45% and 50% of the stage I and stage II cases, respectively, were abnormal, whereas 63.64% and 60% of the stage III and stage IV cases, respectively, were abnormal for chromosome 8 copy number. The overall frequency of abnormal chromosome 8 copy number was 54.76% (23 of 42 tumors studied). When the results of a control probe were taken into account, 34.78% (8 of 23) of the abnormal cases were trisomic, whereas the remaining cases were likely triploid. Thus, the present data not only established that chromosome 8 trisomy is a recurrent finding in breast cancer, but also confirmed a higher frequency of occurrence of abnormal chromosome 8 copy number with the higher clinical stages. Future experiments utilizing additional specimens in this laboratory and from other laboratories are necessary to confirm and extend the findings of the present study.
BACKGROUND: Prognosis in patients with syndrome X (chest pain and normal coronary arteriograms) is good; however, persistent chest pain and functional disability are common in these patients. Accurate assessment of quality of life may be useful for patient management. AIM: The quality of life status in patients with syndrome X was assessed using a specific questionnaire. This questionnaire was developed and validated for the assessment of quality of life in patients with typical chest pain despite normal coronary arteriograms. METHODS: Ninety consecutive patients were invited to complete both the questionnaire (on two occasions within 2 weeks) and a standardized angina dairy. Fully completed questionnaires were received from 66 (73%) patients (mean age 58 +/- 8 years, 55 women). RESULTS: Answers were scored according to a grading system where higher scores indicate worse quality of life. We observed that total scores increased with severity of angina (Canadian Class I, 38 +/- 16, II: 93 +/- 29, III-IV, 119 +/- 23; p < 0.001) and correlated with both the number and the severity of chest pain episodes (r = 0.50-0.66: p < 0.001). In patients who remained clinically stable (n = 37) during the 2-week assessment, test-retest analysis showed no score differences (87 +/- 30 vs. 81 +/- 30; p = 0.1), while total score increased in patients (n = 24) whose symptoms worsened (108 +/- 31 vs. 116 +/- 31; p < 0.02) and was reduced in those (n = 5) whose symptoms improved (55 +/- 37 vs. 39 +/- 28; p < 0.04). CONCLUSION: Our study shows that quality of life is significantly impaired in patients with syndrome X and that the specific questionnaire used for assessment is a reliable and sensitive tool for the evaluation of quality of life in patients with chest pain and normal coronary arteriograms.
LIM proteins perform critical roles in development and tissue differentiation. The skeletal muscle LIM protein 1 (SLIM1) comprises four and a half LIM domains. Northern blot analysis demonstrated high level expression of SLIM1 mRNA in adult human skeletal muscle with intermediate expression in adult heart and lower expression in other tissues. Western blot analysis using specific affinity-purified anti-SLIM1 antipeptide antibodies demonstrated a 32 kDa polypeptide in the aorta and atria of rabbit heart, but not in vena cava, interventricular septum or ventricular muscle. SLIM1 was also demonstrated in rabbit skeletal muscle. In situ hybridization of whole mouse embryos confirmed the cardiac expression of SLIM1 was restricted to the cardiac outflow tract from embryonic day 8.5-11. No expression was seen in atrial or ventricular muscle. SLIM1 mRNA was also demonstrated in the hindbrain, neural tube and somites. The localized expression of SLIM1 to the outflow tract of the embryonic heart implies an important role for the protein in the development of this region and possibly in congenital heart anomalies involving the separation and formation of the aortic and pulmonary trunks.
PURPOSE: To present a case of Freeman-Sheldon syndrome (FSS) with a previously unreported technique of anesthetic management, consisting of a malignant hyperthermia free anesthetic and laryngeal mask airway. CLINICAL FEATURES: Freeman-Sheldon syndrome (also known as whistling face syndrome, Windmill-Vane-Hand syndrome, cranio-carpo-tarsal dysplasia and distal arthrogryposis type 2) is a rare congenital disorder defined by facial and skeletal abnormalities. The three basic abnormalities are microstomia with pouting lips, camptodactyly with ulnar deviation of the fingers and talipes equinovarus. Patients with FSS frequently present for surgical correction of musculoskeletal or facial abnormalities. There are several anesthetic challenges including difficult airway, intravenous cannulation and regional technique. They may be at increased risk for malignant hyperthermia and postoperative pulmonary complications. We present a case of a two-year-old child with FSS undergoing elective unilateral inguinal hernia repair. A non-triggering anesthetic technique was used, consisting of 2 mg x kg(-1) propofol followed by a continuous infusion, nitrous oxide 50%/oxygen, and 3 microg x kg(-1) fentanyl. Intraoperative and postoperative analgesia was provided by an ilioinguinal nerve block with 10 ml bupivacaine 0.25% with epinephrine 1:200,000. The airway was maintained with a #2 laryngeal mask airway. The anesthetic was uneventful and there were no signs or symptoms of malignant hyperthermia. The patient was discharged home later the same day in good health. CONCLUSION: The use of a laryngeal mask airway and non-triggering anesthetic technique should be considered as options for anesthetic management in patients with FSS for short procedures that do not require neuromuscular blockade.
We have analyzed the Tribolium castaneum ortholog of the Drosophila homeotic gene Deformed (Dfd) and determined its expression pattern during embryogenesis in this beetle. Tc Deformed (Tc Dfd) is expressed in the blastoderm and the condensing germ rudiment in a region that gives rise to gnathal segments. During germ band extension Tc Dfd is expressed in the mandibular and maxillary segments, their appendages, and the dorsal ridge. Comparison of insect Dfd protein sequences reveals several highly conserved regions. To determine whether common molecular features reflect conserved regulatory functions we used the Gal4 system to express the Tribolium protein in Drosophila embryos. When Tc Dfd is expressed throughout embryonic ectoderm under the control of P69B, the beetle protein autoregulates the endogenous Dfd gene. In addition, the Drosophila proboscipedia gene (a normal target of Dfd) is ectopically activated in the antennal and thoracic segments. We also compared the ability of the beetle and fly proteins to rescue defects in Dfd- mutants by expressing each throughout the embryonic during embryogenesis. Both proteins rescued Dfd- defects to the same extent in that they each restore the development of mouth hooks and cirri, as well as cause gain-of-function abnormalities of posterior mouth parts. As before, pb was ectopically activated in the antennal segment. This is the first demonstration of the ability of a heterologous homeotic selector protein to directly regulate a target gene independent of an endogenous Drosophila autoregulatory loop.
Ambulatory surgery centers are flourishing in the United States. Accreditation of these unique facilities by the Accreditation Association for Ambulatory Health Care reflects a commitment to quality, patient-centered care and to excellence in this specialty area. The accreditation process is complex and lengthy; the benefits, however, outweigh the disadvantages. By successfully completing the accreditation process, a facility demonstrates to the public, its patients, and other health care professionals that it provides exemplary ambulatory surgical care. Successfully accredited facilities also have competitive advantages over nonaccredited surgical centers.
OBJECTIVES: The objectives of the study were: (1) to evaluate effectiveness of photodynamic therapy (PDT) for symptom palliation in patients with inoperable lung cancer; (2) to determine survival benefit in a subset of patients. METHODS: One hundred patients, 68 male, 32 female, aged 44-81 years (mean 62.5) with advanced inoperable bronchogenic cancer and endobronchial luminal obstruction were prospectively studied. Eighty-two percent had previous chemo/radiotherapy. The pre-treatment protocol consisted of: clinical, radiological and bronchoscopic examination, pulmonary function testing, assessment of WHO performance status and clinical staging. Treatment protocol was: intravenous injection of 2 mg/kg body weight of photofrin/polyhaematoporphyrin and interstitial illumination using 630 nm laser light 24-72 h later. Follow-up was at 6-8 weeks for 1 year. Then every 3-6 months if applicable. Repeat PDT as necessary. RESULTS: All patients were stage IIIa-IV. The histology of the tumour was: non small cell in 90 and small cell in 10. There was no treatment related mortality. Mean endoluminal obstruction fell from 85.8% to 17.5%, mean forced vital capacity (FVC) and forced expiratory volume in 1s (FEVI) improvement was 430 ml and 280 ml, respectively. Ninety patients died from 6 weeks to 37 months, mean and median survival: 9 months and 5 months, respectively. Ten patients are alive from 13 to 72 months, mean 36 months, median 29 months. Overall 2-year survival was 19%. Multivariant analysis indicated that age, sex, histology and stage of disease did not influence survival significantly but performance status did. Patients with WHO < 2 had mean and median survival of 17.8 and 14 months versus WHO > 2, 6.9 mean and 4 months median survival (log-rank P < 0.0001). CONCLUSIONS: (1) PDT is effective in palliation of inoperable advanced lung cancer. (2) Subset of patients with a better performance status have added survival benefit.
BACKGROUND: Schizophrenia has a high natural mortality of a largely environmental aetiology. There is, however, little research about possible risk factors. This study measured the diet, cigarette and alcohol use, exercise and obesity of a cohort of people with schizophrenia and compared results to general population rates. METHODS: Semi-structured interview using validated research instruments on 102 middle-aged subjects with a diagnosis of schizophrenia, living in the community. Results were compared to general population norms using standard statistical tests. RESULTS: The subjects ate a diet higher in fat and lower in fibre than the general population. They look little exercise but were not significantly more obese. They smoked heavily but drank less alcohol. Most differences remained significant after controlling for social class. CONCLUSIONS: People with schizophrenia have an unhealthy lifestyle, which probably contributes to the excess mortality of the disease. They are therefore an appropriate target group for health promotion interventions.
Environmental managers are increasingly charged with involving the public in the development and modification of policies regarding risks to human health and the environment. Involving the public in environmental decision making first requires a broad understanding of how and why the public perceives various risks. The Savannah River Stakeholder Study was conducted with the purpose of investigating individual, economic, and social characteristics of risk perceptions among those living near the Savannah River Nuclear Weapons Site. A number of factors were found to impact risk perceptions among those living near the site. One's estimated proximity to the site and relative river location surfaced as strong determinants of risk perceptions among SRS residents. Additionally, living in a quality neighborhood and demonstrating a willingness to accept health risks for economic gain strongly abated heightened risk perceptions.
BACKGROUND: To date only eight US studies have simultaneously examined cancer incidence in relation to social class and race/ethnicity; all but one included only black and white Americans. To address gaps in knowledge we thus investigated socioeconomic gradients in cancer incidence among four mutually exclusive US racial/ethnic groups-- Asian and Pacific Islander, black, Hispanic, and white-- for five major cancer sites: breast, cervix, colon, lung, and prostate cancer. METHODS: We generated age-adjusted cancer incidence rates stratified by socioeconomic position using: (a) geocoded cancer registry records, (b) census population counts, and (c) 1990 census block-group socioeconomic measures. Cases (n = 70,899) were diagnosed between 1988 and 1992 and lived in seven counties located in California's San Francisco Bay Area. RESULTS: Incidence rates varied as much if not more by socioeconomic position than by race/ethnicity, and for each site the magnitude - and in some cases direction - of the socioeconomic gradient differed by race/ethnicity and, where applicable, by gender. Breast cancer incidence increased with affluence only among Hispanic women. Incidence of cervical cancer increased with socioeconomic deprivation among all four racial/ethnic groups, with trends strongest among white women. Lung cancer incidence increased with socioeconomic deprivation among all but Hispanics, for whom incidence increased with affluence. Colon and prostate cancer incidence were inconsistently associated with socioeconomic position. CONCLUSIONS: These complex patterns defy easy generalization and illustrate why US cancer data should be stratified by socioeconomic position, along with race/ethnicity and gender, so as to improve cancer surveillance, research, and control.
Achalasia is the best described motor disorder of the esophagus. Associations with familial glucocorticoid deficiency and alacrima (triple A syndrome) have been described in the pediatric population, but no attention has been paid to the possibility of this association in adults. Tear production was assessed in 20 patients with achalasia and 20 age- and sex-matched controls. Deficient tears were found in four achalasics compared with none among the controls (P < 0.05). This suggests that some variant of the triple A Syndrome (achalasia, alacrima, and adrenocortical insufficiency) may exist in adult patients with achalasia as well.