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Biomedical subjects

Andrew Stewart

Publications and source records attributed to Andrew Stewart.

18 recordsLinked to original sources
PubMed2026

Intestinal infections establish antigen-specific, long-lived memory CD4+ T cells in the brain and meninges.

The meninges form the border between the brain and periphery and house a rich network of immune cells. Here we show that gastrointestinal challenges (intracellular or extracellular bacteria and parasites) reshape the nature of CD4+ T cells in the dura mater, the outer meningeal layer, changing the dominant polarization states to T helper (TH) 1, TH17 and TH2 cells, respectively, with differing cytokine profiles. This occurs via CXCR6-CXCL16-dependent migration of gut-activated CD4+ T cells to the central nervous system, where they establish long-lived memory populations around the dural venous sinuses, within dural lymphoid aggregates and in the brain. Functionally, these orally primed dural CD4+ T were capable of rapid, antigen-specific recall responses, proliferating and producing cytokines upon intravenous rechallenge. Our findings reveal a direct link between intestinal and dural immunity, enabling the central nervous system borders to acquire immunological memory of gut microorganisms, a major source of bloodborne pathogens capable of reaching the brain via fenestrated dural vasculature.

Journal Article↗
PubMed2007

Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets.

Fatty acid amide hydrolase (FAAH) is the primary regulator of several bioactive lipid amides including anandamide. Inhibitors of FAAH are potentially useful for the treatment of pain, anxiety, depression, and other nervous system disorders. However, FAAH inhibitors must display selectivity for this enzyme relative to the numerous other serine hydrolases present in the human proteome in order to be therapeutically acceptable. Here we employed activity-based protein profiling (ABPP) to assess the selectivity of FAAH inhibitors in multiple rat and human tissues. We discovered that some inhibitors, including carbamate compounds SA-47 and SA-72, and AM404 are exceptionally selective while others, like URB597, BMS-1, OL-135, and LY2077855 are less selective, displaying multiple off-targets. Since proteins around 60kDa constitute the major off-targets for URB597 and several other FAAH inhibitors with different chemical structures, we employed the multi-dimensional protein identification technology (MudPIT) approach to analyze their identities. We identified multiple carboxylesterase isozymes as bona fide off-targets of FAAH inhibitors. Consistently, enzymatic assay confirmed inhibition of carboxylesterase activities in rat liver by FAAH inhibitors. Since carboxylesterases hydrolyze a variety of ester-containing drugs and prodrugs, we speculate that certain FAAH inhibitors, by inhibiting carboxylesterases, might have drug-drug interactions with other medicines if developed as therapeutic agents.

Amidohydrolases↗
PubMed2007

Changes in treatment of advanced oropharyngeal cancer, 1985-2001.

OBJECTIVE: The aim of this study is to describe patterns of care of advanced oropharyngeal cancer during 1985 to 2001. METHODS: We extracted oropharyngeal squamous cell cancer cases from the National Cancer Database. Type of initial treatment, type of facility, stage of tumor, payer status, and demographic variables were collected. Fisher exact test was used to compare the patient demographic and clinical characteristics across facility types. Weighted least squares regression analysis was used to analyze treatment trends over time and t-tests were done to test for significance in trends. RESULTS: A total of 54,801 cases were available for analysis. Teaching/research facilities treated a disproportionately higher number of advanced-stage cancers (81%, P < .01). In addition, these facilities treat a higher percentage of uninsured (7%, P < .01) and nonwhite patients (27%, P < .01). The use of organ preservation protocols (chemoradiation) increased from 15% in 1985 to 29% in 2001 (beta1 = 0.0080, P < .05), whereas the use of radiation alone decreased from 42% in 1985 to 27% in 2001 (beta1 = -0.0118, P < .05). The use of cancer-directed surgery remained stable. There was no difference in rates of chemoradiation for advanced oropharyngeal cancer across facility types. CONCLUSIONS: Our results suggest that chemoradiation is increasingly becoming more prevalent at all facility types. The use of radiation alone as primary treatment significantly declined during the study period. In view of the complexity and multidisciplinary nature of treatment for oropharyngeal cancer, it is recommended that care of such patients be discussed at institutional tumor boards and that the recommendations be systematically recorded and documented in hospital cancer registries.

Aged↗
PubMed2006

Developing and validating a diabetes database in a large health system.

BACKGROUND: One component of clinical information systems is a registry of patients. Registries allow providers to identify gaps in care at the population level. Registries also allow for rapid cycle continuous quality improvement, targeted practice change and improved outcomes. Most registries are built based on membership with an insurer or other selection criteria. Little, if any data exist on registries representing demographically heterogeneous populations. METHODS: Administrative and clinical data for the period 1/1/2000-12/30/03 were examined. In total, 46,082,941 lab reports, 233,292,544 medical records, and 9,351,415 medical record abstracts, representing approximately 2 million unique patients were searched. The diabetes source population was identified by presence of any one of the following criteria: ICD-9 code 250 (diabetes) for inpatient, emergency room or outpatient visits; any hemoglobin A1c result; blood glucose >200mg/dl; or diabetes medication. A diagnosis of diabetes was verified by trained chart reviewers on a sample of patients. Single indicators and combinations were examined to determine optimal identification of these cases. RESULTS: In two separate validation studies, using two or more indicators or outpatient diagnosis maximized positive predictive value (PPV) (96 and 97%) and sensitivity (99 and 100%) and identified 55,807 individuals. When all patients with a single indicator of outpatient diagnosis (which had the highest single PPV of 94 and 95%) were included together with those having >or=2 indicators, the final sample size was 65,725. CONCLUSION: Two or more indicators or an out-patient-diagnosis identifies a sizeable and unselective diabetes database which can be used to track processes and outcomes.

Databases, Factual↗
PubMed2006

Changes in treatment of advanced laryngeal cancer 1985-2001.

OBJECTIVE: In 1991, a randomized study was published and demonstrated that use of nonsurgical therapy (chemoradiation) provided similar survival to total laryngectomy (the gold standard) for patients with advanced-stage laryngeal cancer. The purpose of this study was to assess how treatment of advanced laryngeal cancer was influenced by such developments in non-surgical therapy. STUDY DESIGN: Patterns of care study using National Cancer Database (1985-2001). RESULTS: The percentage of advanced-stage patients treated with chemoradiation increased from 8.3% to 20.8% while the proportion treated with radiation alone decreased from 38.9% to 23.0%. Use of chemoradiation increased at a significantly faster rate after the 1991 publication at both community cancer centers and teaching research facilities. The use of total laryngectomy decreased slightly during this period. CONCLUSIONS: The use of chemoradiation increased after the 1991 publication. It was impossible to determine from the NCDB whether additional patients who could benefit from chemo-RT were not offered or did not complete this treatment option. We recommend that treatment recommendations discussed at tumor boards be recorded in cancer registries.

Aged↗
PubMed2006

Laryngeal cancer in the United States: changes in demographics, patterns of care, and survival.

BACKGROUND: Survival has decreased among patients with laryngeal cancer during the past 2 decades in the United States. During this same period, there has been an increase in the nonsurgical treatment of laryngeal cancer. OBJECTIVE: The objectives of this study were to identify trends in the demographics, management, and outcome of laryngeal cancer in the United States and to analyze factors contributing to the decreased survival. STUDY DESIGN: The authors conducted a retrospective, longitudinal study of laryngeal cancer cases. METHODS: Review of the National Cancer Data Base (NCDB) revealed 158,426 cases of laryngeal squamous cell carcinoma (excluding verrucous carcinoma) diagnosed between the years 1985 and 2001. Analysis of these case records addressed demographics, management, and survival for cases grouped according to stage, site, and specific TNM classifications. RESULTS: This review of data from the NCDB analysis confirms the previously identified trend toward decreasing survival among patients with laryngeal cancer from the mid-1980s to mid-1990s. Patterns of initial management across this same period indicated an increase in the use of chemoradiation with a decrease in the use of surgery despite an increase in the use of endoscopic resection. The most notable decline in the 5-year relative survival between the 1985 to 1990 period and the 1994 to 1996 period occurred among advanced-stage glottic cancer, early-stage supraglottic cancers, and supraglottic cancers classified as T3N0M0. Initial treatment of T3N0M0 laryngeal cancer (all sites) in the 1994 to 1996 period resulted in poor 5-year relative survival for those receiving either chemoradiation (59.2%) or irradiation alone (42.7%) when compared with that of patients after surgery with irradiation (65.2%) and surgery alone (63.3%). In contrast, identical 5-year relative survival (65.6%) rates were observed during this same period for the subset of T3N0M0 glottic cancers initially treated with either chemoradiation or surgery with irradiation. CONCLUSIONS: The decreased survival recorded for patients with laryngeal cancer in the mid-1990s may be related to changes in patterns of management. Future studies are warranted to further evaluate these associations.

Antineoplastic Agents↗
PubMed2006

Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database.

BACKGROUND: A recent revision of the American Joint Committee on Cancer (AJCC) staging for gallbladder cancer (6th Edition) involved some major changes. Most notably, T2N0M0 tumors were moved from stage II to stage IB; T3N1M0 disease was moved from stage III to stage IIB; and T4NxM0 (x = any) tumors were moved from stage IVA to stage III. METHODS: In order to determine if these changes were justified by data, an analysis of the 10,705 cases of gallbladder cancer collected between 1989 and 1996 in the NCDB was performed. All patients had >5 year follow-up. RESULTS: The staging according to the 6th Edition provided no discrimination between stage III and IV. Five-year survivals for stage IIA, IIB, III, and IV (6th Edition) were 7%, 9%, 3%, 2% respectively. The data from the National Cancer Database (NCDB) were used to derive a proposed new staging system that builds upon Edition 5 and had improved discrimination of stage groups over previous editions. CONCLUSIONS: Changes in staging systems should be justified by data. Multicenter databases, including the NCDB, represent important resources for verification of evidence-based staging systems.

Databases as Topic↗
PubMed2005

Adjuvant chemotherapy for stage III colon cancer: implications of race/ethnicity, age, and differentiation.

CONTEXT: A 1990 National Institutes of Health Consensus Conference recommended that patients with stage III colon cancer receive adjuvant chemotherapy because survival was improved in clinical trials in patients who received a 5-fluorouracil-based regimen. OBJECTIVE: To determine whether adjuvant chemotherapy is used in the community as a standard of practice that improves outcome and whether it failed to benefit any specific sets of patients. DESIGN, SETTING, AND PARTICIPANTS: Prospective data from 85 934 patients with stage III colon cancer from 560 hospital cancer registries were entered into the National Cancer Data Base between 1990 and 2002 and included standard clinical, pathological, and first course of treatment variables. MAIN OUTCOME MEASURES: Prevalence of adjuvant chemotherapy usage and 5-year survival in patients treated in US hospitals. RESULTS: Adjuvant chemotherapy use increased from 39% in 1991 to 64% in 2002 but was lower in black, female, and elderly patients. It improved 5-year survival from almost 8% in 1991 to more than 16% in 1997 compared with surgery alone. Adjuvant chemotherapy increases survival in elderly patients as much as it does in younger patients. However, the benefit of adjuvant chemotherapy in blacks and those with high-grade cancers is not as great. CONCLUSIONS: Adjuvant chemotherapy use has increased from 1990 to 2002 for patients with stage III colon cancer with an associated increase in 5-year survival of 16%. The benefit of adjuvant chemotherapy seems to be lower in black patients and high-grade cancers. Women have the same benefit but are less often treated. Elderly patients have the same benefit as younger patients but are less frequently treated. New options for adjuvant therapy in 2004-2005 may further improve the outcome of patients with stage III colon cancer.

Adjuvants, Immunologic↗
PubMed2005

The application of a new quantitative assay for the monitoring of integrin-associated protein CD47 on red blood cells during storage and comparison with the expression of CD47 and phosphatidylserine with flow cytometry.

BACKGROUND: After the introduction of universal leukoreduction, the role of factors other than white blood cells in red cell (RBC) storage lesion is attracting increasing attention. These include changes in the levels of CD47 and phosphatidylserine (PS) markers on RBCs during storage. The aim of this study was to monitor these changes with both flow cytometry (FACS) and a newly developed quantitative enzyme-linked immunosorbent assay (ELISA). STUDY DESIGN AND METHODS: A new quantitative ELISA (monoclonal antibody immobilization of RBC antigens [MAIRA]) was developed. The assay yielded consistent linear curves that enabled the measurement of CD47 expression on RBCs. In addition, FACS was used to measure both CD47 expression and PS on RBCs (n = 3 units) during storage (Days 4, 10, 24, and 31). RESULTS: A significant reduction in CD47 expression was observed both by MAIRA assay and by FACS by Days 24 and 31 (p < 0.01), and the correlation between the two assays was significant (p < 0.01). In addition, a significant increase in PS was observed by the same storage days with FACS (p < 0.01). CONCLUSION: The MAIRA assay appears to be suitable for the quantitative measurement of RBC markers during storage. Significant changes in CD47 and PS levels were observed during storage, which may have detrimental immunomodulatory and hemostatic effects on the transfused RBCs.

Antigens, CD↗
PubMed2005

Patient social and economic circumstances--GP perceptions and their influence on management.

BACKGROUND: Socioeconomic status (SES) is a major determinant of health. There is little research on if or how general practitioners assess this in individual patients and use it in their clinical practice. METHODS: An exploratory pilot study was conducted using qualitative methodology. Telephone interviews were conducted with a purposive sample of 11 GPs. RESULTS: The participating GPs commonly assessed SES through observation of patient behaviour and presentation, contextualised with knowledge of the patient's background and the community, rather than direct enquiry. The GPs understood the link between low SES and poor health primarily in terms of a higher prevalence of behavioural risk factors. Participating GPs were generally pessimistic about achieving behaviour change for patients they identified as being of low SES. DISCUSSION: General practitioners' complex understanding of SES is supported by newer theories of health inequalities and social position. However, GP attitudes may potentially play a role in reinforcing inequalities. Further research is needed regarding the relationship between GP perceptions and objective indicators of SES.

Attitude of Health Personnel↗
PubMed2004

ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], a highly potent and selective disubstituted pyridazinone cyclooxgenase-2 inhibitor.

Nonsteriodal anti-inflammatory drugs (NSAIDs) are efficacious for the treatment of pain associated with inflammatory disease. Clinical experience with marketed selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib, and valdecoxib) has confirmed the utility of these agents in the treatment of inflammatory pain with an improved gastrointestinal safety profile relative to NSAID comparators. These COX-2 inhibitors belong to the same structural class. Each contains a core heterocyclic ring with two appropriately substituted phenyl rings appended to adjacent atoms. Here, we report the identification of vicinally disubstituted pyridazinones as potent and selective COX-2 inhibitors. The lead compound in the series, ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], has excellent selectivity (ratio of 276, COX-2/COX-1) in human whole blood, improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency in vivo, and gastric safety in the animal studies. After oral administration, ABT-963 reduced prostaglandin E2 production in the rat carrageenan air pouch model (ED50 of 0.4 mg/kg) and reduced the edema in the carrageenan induced paw edema model with an ED30 of 1.9 mg/kg. ABT-963 dose dependently reduced nociception in the carrageenan hyperalgesia model (ED50 of 3.1 mg/kg). After 14 days of dosing in the adjuvant arthritis model, ABT-963 had an ED(50) of 1.0 mg/kg in reducing the swelling of the hind paws. Magnetic resonance imaging examination of the diseased paws in the adjuvant model showed that ABT-963 significantly reduced bone loss and soft tissue destruction. ABT-963 is a highly selective COX-2 inhibitor that may have utility in the treatment of the pain and inflammation associated with arthritis.

Animals↗
PubMed2004

The portrayal of mental health and illness in Australian non-fiction media.

OBJECTIVE: To provide a detailed picture of the extent, nature and quality of portrayal of mental health/illness in Australian non-fiction media. METHOD: Media items were retrieved from Australian newspaper, television and radio sources over a 1-year period, and identifying/descriptive data extracted from all items. Quality ratings were made on a randomly selected 10% of items, using an instrument based on criteria in Achieving the Balance (a resource designed to promote responsible reporting of mental health/illness). RESULTS: Reporting of mental health/illness was common, with 4351 newspaper, 1237 television and 7801 radio items collected during the study period. Media items most frequently focused on policy/program initiatives in mental health (29.0%), or on causes/symptoms/treatment of mental illnesses (23.9%). Stories about mental health issues in the context of crime were relatively uncommon, accounting for only 5.6% of items. Most media items were of good quality on eight of the nine dimensions; the exception was that details of appropriate help services were only included in 6.4% of items. CONCLUSIONS: In contrast to previous research, the current study found that media reporting of mental health/illness was extensive, generally of good quality and focused less on themes of crime and violence than may have been expected. This is encouraging, since there is evidence that negative media portrayal of mental health/illness can detrimentally affect community attitudes. However, there are still opportunities for improving media reporting of mental health/illness, which should be taken up in future media strategies.

Adolescent↗
PubMed2004

Linguistic focus and good-enough representations: an application of the change-detection paradigm.

A number of lines of study suggest that word meanings are not always fully exploited in comprehension. In two experiments, we used a text-change paradigm to study depth of semantic processing during reading. Participants were instructed to detect words that changed across two consecutive presentations of short texts. The results suggest that the full details of word meanings are not always incorporated into the interpretation and that the degree of semantic detail in the representation is a function of linguistic focus. The results provide evidence for the idea that representations are only good enough for the purpose at hand (Ferreira, Bailey, & Ferraro, 2002).

Humans↗
PubMed2003

Prostate carcinoma presentation, diagnosis, and staging: an update form the National Cancer Data Base.

BACKGROUND: Based on the 1998 Patient Care Evaluation (PCE) from the American College of Surgeons National Cancer Data Base (NCDB), the authors described contemporary nationwide patterns of prostate carcinoma presentation, diagnosis, and staging. METHODS: The authors reviewed 54,212 cases from the 1998 PCE. Demographics, presenting signs and symptoms, tumor characteristics, prostate biopsy techniques, and use of staging modalities were evaluated. RESULTS: The mean age of patients in the sample was 68 years. Among patients with available data, 87.5% had a prostate specific antigen (PSA) level of 4 ng/mL or higher, 83.1% had American Joint Committee on Cancer (AJCC) Stage I-II lesions, 80.2% had well or moderately differentiated cancers, and 68.7% of newly diagnosed patients were asymptomatic. Compared with symptomatic patients, asymptomatic patients were more likely to have localized disease (84.6% vs. 78.2%, P < 0.01) and well or moderately differentiated tumors (82.2% vs. 74.6%, P < 0.01). Transrectal ultrasound-guided prostate biopsy was the most common method of tissue confirmation (45.4%). Radionuclide bone scintigraphy was the most frequently employed staging modality (48.7%). Use of various staging evaluations was more frequent among patients at increased risk for disseminated disease (PSA > 10 ng/mL and/or high-grade tumors) versus patients at lower risk (PSA < or = 10 and low to moderate-grade tumors) for metastatic disease (P < 0.005). CONCLUSIONS: Most newly diagnosed patients with prostate carcinoma are asymptomatic and have moderately differentiated and organ-confined disease. Compared with symptomatic patients, tumors in asymptomatic men are associated with lower pretreatment PSA levels, AJCC stage, and tumor grade. Selective use of staging evaluations, based on risk of metastatic disease, may be relatively uncommon. The NCDB remains a unique and rich source of novel patient care information and serves as a national point of reference for prostate carcinoma presentation, diagnosis, and staging.

Aged↗
PubMed2002

Reporting of suicide in the Australian media.

OBJECTIVE: The media monitoring project aimed to establish a baseline picture of the extent, nature and quality of reporting of suicide by the Australian media, with a view to informing future strategies intended to optimize reporting of suicide. METHOD: Newspaper, television and radio items on suicide were retrieved over 12 months. Identifying and descriptive information were extracted for each item. Approximately 10% of items were rated for quality, using a rating scale based on criteria from Achieving the Balance, a kit designed to promote awareness among media professionals of issues relating to suicide. The scale ranged from 0 (poor quality) to 100 (good quality). RESULTS: Reporting of suicide was extensive (with 4813 items retrieved). The nature of reporting was variable. Items tended to be about completed suicide (rather than attempted suicide or suicidal ideation), and most commonly involved content related to an individual's experiences, policy/programme initiatives and/or suicide statistics, although there were differences across media types. Items showed variability across dimensions of quality. The majority of suicide items did not have examples of inappropriate language, were not inappropriately located, did not use the word 'suicide' in the headline, and did not use explicit photographs/diagrams or footage. However, around half of the suicide items provided a detailed discussion of the method of self-harm and portrayed suicide as merely a social phenomenon. Where items concerned the suicide of a celebrity, reference was commonly made to that person's celebrity status. Most items failed to provide information on help services. The median total quality score was 57.1%. CONCLUSIONS: The reporting of suicide is extensive across all media types, and varies in nature and quality. In general, good items outnumber poorer items. However, there are still opportunities for improving media reporting of suicide.

Adolescent↗
PubMed2002

Perspective in statements of quantity, with implications for consumer psychology.

We demonstrate that presentation of information about quantities, whether expressed in natural language or by using numbers, induces a perspective that influences subsequent processing. Experiment 1 shows this to be true for natural language quantifiers, with negative and positive expressions inducing different perspectives. In Experiment 2, we examined the application of this idea to the specific case of perspectives induced by describing products as containing x% fat or as being x% fat free. We found that the percentage-fat description appears to induce a perspective that is sensitive to the level offat being depicted, with products being judged as less healthy at higher amounts of fat. However, this effect was lessened (Experiment 2) or eliminated (Experiment 3) with the percentage-fat-free description. The experiments suggest the fat-free perspective blocks access to assumptions about healthy fat levels.

Adult↗
PubMedDate not supplied

Deploying the chronic care model to implement and sustain diabetes self-management training programs.

PURPOSE: The purpose of this project was to evaluate the utility of using the 6 elements of the chronic care model (CCM; health system, community, decision support, self-management support, clinical information systems, and delivery system design) to implement and financially sustain an effective diabetes self-management training (DSMT) program. METHODS: The University of Pittsburgh Medical Center (UPMC) uses all elements of the CCM. Partnerships were formed between UPMC and western Pennsylvanian community hospitals and practices; the American Diabetes Association DSMT recognition program provided decision support. A clinical data repository and reorganization of primary care practices aided in supporting DSMT. The following process and patient outcomes were measured: number of recognized programs, reimbursement, patient hemoglobin A1C levels, and the proportion of patients who received DSMT in primary care practices versus hospital-based programs. RESULTS: Using elements of the CCM, the researchers were able to gain administrative support; expand the number of recognized programs from 3 to 21; cover costs through increased reimbursement; reduce hemoglobin A1C levels (P < .0001), and increase the proportion of patients receiving DSMT through delivery in primary care (26.4% suburban; 19.8% urban) versus hospital-based practices (8.3%; P < .0001). CONCLUSIONS: The CCM serves as an effective model for implementing and sustaining DSMT programs.

Chronic Disease↗