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Biomedical subjects

Elizabeth Allen

Publications and source records attributed to Elizabeth Allen.

13 recordsLinked to original sources
PubMed2006

Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport.

Mutations in gigaxonin were identified in giant axonal neuropathy (GAN), an autosomal recessive disorder. To understand how disruption of gigaxonin's function leads to neurodegeneration, we ablated the gene expression in mice using traditional gene targeting approach. Progressive neurological phenotypes and pathological lesions that developed in the GAN null mice recapitulate characteristic human GAN features. The disruption of gigaxonin results in an impaired ubiquitin-proteasome system leading to a substantial accumulation of a novel microtubule-associated protein, MAP8, in the null mutants. Accumulated MAP8 alters the microtubule network, traps dynein motor protein in insoluble structures and leads to neuronal death in cultured wild-type neurons, which replicates the process occurring in GAN null mutants. Defective axonal transport is evidenced by the in vitro assays and is supported by vesicular accumulation in the GAN null neurons. We propose that the axonal transport impairment may be a deleterious consequence of accumulated, toxic MAP8 protein.

Animals↗
PubMed2006

Revised British Isles Lupus Assessment Group 2004 index: a reliable tool for assessment of systemic lupus erythematosus activity.

OBJECTIVE: To test the interrater reliability of the revised British Isles Lupus Assessment Group 2004 (BILAG-2004) index for the assessment of systemic lupus erythematosus (SLE) activity. METHODS: Patients with SLE were recruited from 11 centers. Two physician raters separately assessed the patients' disease activity using the BILAG-2004 index in routine clinical practice. Scores ranged from A (for very active disease) to E (for inactivity). Two reliability exercises were performed. Changes were made to the index after the first exercise (E1), and additional training was provided to the raters before the second exercise (E2). E1 and E2 involved 12 and 14 raters, respectively. Interrater reliability was assessed using kappa statistics and intraclass correlation coefficients. Levels of agreement and the extent of major disagreement were also examined. Major disagreement was defined as a score difference between raters of A versus C, D, or E or B versus D or E. RESULTS: For each exercise, 97 patients were recruited. In E1, the mean age of the patients was 42.3 years (range 18.5-82.2 years), 89.7% were women, and 74.2% were white, 8.2% were Afro-Caribbean, and 13.4% were South Asian, and in E2, the mean age was 43.7 years (range 17.7-75 years), 90.7% were women, and 68% were white, 15.5% were Afro-Caribbean, and 11.3% were South Asian. The mean disease duration was 9.4 years (range 0-32.1 years) for patients in E1 and 10 years (range 0-34.8 years) in E2. There was improvement in the interrater reliability and the level of agreement from E1 to E2. Further improvement was achieved after removal of poorly performing items. CONCLUSION: The BILAG-2004 index is a reliable tool to assess SLE activity. The use of a well-defined glossary and training of raters are essential to ensure the optimal performance of the index.

Activities of Daily Living↗
PubMed2006

Teaching internal medicine residents in the new era. Inpatient attending with duty-hour regulations.

BACKGROUND: Little is known about the impact of resident duty-hour regulations on the inpatient teaching experience. OBJECTIVE: Provide descriptive information on the effect of resident duty-hour regulations on attendings and the educational environment. DESIGN: Qualitative analysis of attending focus groups and e-mail survey of residents in Internal Medicine. PARTICIPANTS: Inpatient attending physicians at 2 academic centers and residents at the affiliated university-based Internal Medicine residency program in Portland, OR. RESULTS: Seventy-two percent of eligible attendings participated in 2 focus groups. Three themes were generated: increased clinical role, altered time management, and altered teaching. Attending physicians report performing more clinical work, teaching less, using more focused teaching methods, and experiencing an increased perception of intensity. Forty percent of eligible residents completed our e-mail survey. We organized residents data using the same 3 themes as attending physician data. Residents observed attending physicians performing increased clinical work, being more time aware, delivering more focused teaching, and having less time to teach. Participants noted changes in autonomy and professionalism. Strategies to enhance teaching effectiveness in the new environment were described. CONCLUSION: Duty-hour regulations have increased attending clinical responsibility and decreased teaching time in 1 residency program, leading to the perception of a more intense attending experience. Duty-hour regulations encourage educators to determine what is critical to preserve in the educational experiences of learners and challenge us to reexamine autonomy and professionalism in training.

Attitude of Health Personnel↗
PubMed2005

Gigaxonin interacts with tubulin folding cofactor B and controls its degradation through the ubiquitin-proteasome pathway.

Gigaxonin is mutated in human giant axonal neuropathy (GAN), an autosomal recessive neurodegenerative disorder. The presence of generalized cytoskeletal abnormalities , including few microtubules and accumulated intermediate filaments (IFs), in GAN suggests an essential role of gigaxonin in cytoskeletal organization and dynamics. However, the molecular mechanisms underlying the cytoskeletal pathology remain to be elucidated. Over the years, the ubiquitin-proteasome system (UPS) of intracellular protein degradation has been implicated in the control of many fundamental cellular processes. Defects in this system seem to be directly linked to the development of human diseases, including cancers and neurodegenerative diseases . Here, we show that gigaxonin controls protein degradation of tubulin folding cofactor B (TBCB) , a function disrupted by GAN-associated mutations. The substantial TBCB protein accumulation caused by impaired UPS may be a causative factor of cytoskeletal pathology in GAN. Our study provides important insight into pathogenesis of neurodegenerative diseases associated with cytoskeletal abnormalities.

Animals↗
PubMed2005

Microtubule-associated protein 8 contains two microtubule binding sites.

Microtubule-associated proteins (MAPs) are critical regulators of microtubule dynamics and functions, and have long been proposed to be essential for many cellular events including neuronal morphogenesis and functional maintenance. In this study, we report the characterization of a new microtubule-associated protein, we named MAP8. The protein of MAP8 is mainly restricted to the nervous system postnatally in mouse. Its expression could first be detected as early as at embryonic day 10, levels plateau during late embryonic and neonatal periods, and subsequently decrease moderately to remain constant into adulthood. In addition to its carboxyl terminal binding site, the MAP8 polyprotein also contains a functional microtubule-binding domain at its N-terminal segment. The association of the carboxyl terminal of the light chain with actin microfilaments could also be detected. Our findings define MAP8 as a novel microtubule associated protein containing two microtubule binding domains.

Actin Cytoskeleton↗
PubMed2005

Gigaxonin-controlled degradation of MAP1B light chain is critical to neuronal survival.

Giant axonal neuropathy (GAN) is a devastating sensory and motor neuropathy caused by mutations in the GAN gene, which encodes the ubiquitously expressed protein gigaxonin. Cytopathological features of GAN include axonal degeneration, with accumulation and aggregation of cytoskeletal components. Little is currently known about the molecular mechanisms underlying this recessive disorder. Here we show that gigaxonin controls protein degradation, and is essential for neuronal function and survival. We present evidence that gigaxonin binds to the ubiquitin-activating enzyme E1 through its amino-terminal BTB domain, while the carboxy-terminal kelch repeat domain interacts directly with the light chain (LC) of microtubule-associated protein 1B (MAP1B). Overexpression of gigaxonin leads to enhanced degradation of MAP1B-LC, which can be antagonized by proteasome inhibitors. Ablation of gigaxonin causes a substantial accumulation of MAP1B-LC in GAN-null neurons. Moreover, we show that overexpression of MAP1B in wild-type cortical neurons leads to cell death characteristic of GAN-null neurons, whereas reducing MAP1B levels significantly improves the survival rate of null neurons. Our results identify gigaxonin as a ubiquitin scaffolding protein that controls MAP1B-LC degradation, and provide insight into the molecular mechanisms underlying human neurodegenerative disorders.

Animals↗
PubMed2005

Effect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa.

BACKGROUND: Between 1995 and 2000, KwaZulu-Natal province, South Africa, experienced a marked increase in Plasmodium falciparum malaria, fuelled by pyrethroid and sulfadoxine-pyrimethamine resistance. In response, vector control was strengthened and artemether-lumefantrine (AL) was deployed in the first Ministry of Health artemisinin-based combination treatment policy in Africa. In South Africa, effective vector and parasite control had historically ensured low-intensity malaria transmission. Malaria is diagnosed definitively and treatment is provided free of charge in reasonably accessible public-sector health-care facilities. METHODS AND FINDINGS: We reviewed four years of malaria morbidity and mortality data at four sentinel health-care facilities within KwaZulu-Natal's malaria-endemic area. In the year following improved vector control and implementation of AL treatment, malaria-related admissions and deaths both declined by 89%, and outpatient visits decreased by 85% at the sentinel facilities. By 2003, malaria-related outpatient cases and admissions had fallen by 99%, and malaria-related deaths had decreased by 97%. There was a concomitant marked and sustained decline in notified malaria throughout the province. No serious adverse events were associated causally with AL treatment in an active sentinel pharmacovigilance survey. In a prospective study with 42 d follow up, AL cured 97/98 (99%) and prevented gametocyte developing in all patients. Consistent with the findings of focus group discussions, a household survey found self-reported adherence to the six-dose AL regimen was 96%. CONCLUSION: Together with concurrent strengthening of vector control measures, the antimalarial treatment policy change to AL in KwaZulu-Natal contributed to a marked and sustained decrease in malaria cases, admissions, and deaths, by greatly improving clinical and parasitological cure rates and reducing gametocyte carriage.

Adolescent↗
PubMed2005

Teaching systems-based practice to residents by using independent study projects.

The changing health care marketplace requires new graduates to be familiar with complex health systems. Since 1999 the Oregon Health & Science University internal medicine residency program has offered a seminar-based health systems curriculum, but residents lacked an opportunity to actively apply learned concepts. To achieve this goal, the authors developed a second curricular component, the Health Systems Independent Study Project (HSISP). The HSISP is a self-directed assessment of a health care system or delivery issue residents complete in their third year. The curriculum was implemented in 2001 with goals of gaining a focused understanding of a health systems concept and building related skills. Residents present their study projects to all curriculum participants. Topics addressed so far include adherence to coronary artery disease guidelines in a defined population, screening strategies for lung cancer, resident burnout, and many others. Residents have found that these projects enhance their systems knowledge, help them link systems-based-practice concepts to clinical practice, and foster opportunities for networking and early career development.

Curriculum↗
PubMed2005

The evaluation of rectal bleeding in adults. A cost-effectiveness analysis comparing four diagnostic strategies.

BACKGROUND: Though primary care patients commonly present with rectal bleeding, the optimal evaluation strategy remains unknown. OBJECTIVE: To compare the cost-effectiveness of four diagnostic strategies in the evaluation of rectal bleeding. DESIGN: Cost-effectiveness analysis using a Markov decision model. DATA SOURCES: Systematic review of the literature, Medicare reimbursement data, Surveillance, Epidemiology, and End Results (SEER) Cancer Registry. TARGET POPULATION: Patients over age 40 with otherwise asymptomatic rectal bleeding. TIME HORIZON: The patient's lifetime. PERSPECTIVE: Modified societal perspective. INTERVENTIONS: Watchful waiting, flexible sigmoidoscopy, flexible sigmoidoscopy followed by air contrast barium enema (FS+ACBE), and colonoscopy. OUTCOME MEASURES: Incremental cost-effectiveness ratio. RESULTS OF BASE-CASE ANALYSIS: The incremental cost-effectiveness ratio for colonoscopy compared with flexible sigmoidoscopy was 5,480 dollars per quality-adjusted year of life saved (QALY). Watchful waiting and FS+ACBE were more expensive and less effective than colonoscopy. RESULTS OF SENSITIVITY ANALYSES: The cost of colonoscopy was reduced to 1,686 dollars per QALY when age at entry was changed to 45. Watchful waiting became the least expensive strategy when community procedure charges replaced Medicare costs, when age at entry was maximized to 80, or when the prevalence of polyps was lowered to 7%, but the remaining strategies provided greater life expectancy at relatively low cost. The strategy of FS+ACBE remained more expensive and less effective in all analyses. In the remaining sensitivity analyses, the incremental cost-effectiveness of colonoscopy compared with flexible sigmoidoscopy never rose above 34,000 dollars. CONCLUSIONS: Colonoscopy is a cost-effective method to evaluate otherwise asymptomatic rectal bleeding, with a low cost per QALY compared to other strategies.

Adult↗
PubMed2004

Short- and long-term effects of highly active antiretroviral therapy on Kaposi sarcoma-associated herpesvirus immune responses and viraemia.

OBJECTIVE: To investigate the effect of highly active antiretroviral therapy (HAART) on Kaposi sarcoma-associated herpesvirus (KSHV) DNA load, anti-KSHV antibody responses and KSHV-specific CD8 T cell responses in HIV-infected individuals over a 2 year period. DESIGN: Prospective study of 27 HIV-infected antiretroviral therapy-naive individuals, with (n = 4) and without KS (n = 23), before HAART and at 3-month intervals, during treatment with HAART. METHODS: Sequential blood samples were collected for anti-KSHV antibody detection, KSHV DNA load in peripheral blood mononuclear cells (PBMC) and plasma, HIV Gag-specific and KSHV-specific CD8 T cell responses, HIV-1 plasma RNA load and CD4 and CD8 T cell counts. RESULTS: KSHV DNA in PBMC and plasma became less detectable over time during HAART, in particular after 12 months. KSHV DNA was undetectable in plasma after 24 months on HAART. Anti-KSHV lytic, but not latent, antibody levels increased within 12 months of treatment. KSHV-specific CD8 T cell responses were absent prior to HAART but became detectable in some patients within 6 months of starting treatment, and continued to increase thereafter. CONCLUSIONS: HAART (both protease inhibitor-based and non-nucleoside reverse transcriptase inhibitor-based antiretroviral combinations) is associated with immune reconstitution to KSHV and with undetectable KSHV viraemia. However, this restoration is apparent (in particular) only after a relatively long (> 24 months) period of treatment. These immune responses could contribute to the decreased incidence of KS during HAART, but it is unlikely to be a complete explanation for the often rapid resolution of KS when HAART is started.

Adult↗
PubMed2003

BPAG1n4 is essential for retrograde axonal transport in sensory neurons.

Disruption of the BPAG1 (bullous pemphigoid antigen 1) gene results in progressive deterioration in motor function and devastating sensory neurodegeneration in the null mice. We have previously demonstrated that BPAG1n1 and BPAG1n3 play important roles in organizing cytoskeletal networks in vivo. Here, we characterize functions of a novel BPAG1 neuronal isoform, BPAG1n4. Results obtained from yeast two-hybrid screening, blot overlay binding assays, and coimmunoprecipitations demonstrate that BPAG1n4 interacts directly with dynactin p150Glued through its unique ezrin/radixin/moesin domain. Studies using double immunofluorescent microscopy and ultrastructural analysis reveal physiological colocalization of BPAG1n4 with dynactin/dynein. Disruption of the interaction between BPAG1n4 and dynactin results in severe defects in retrograde axonal transport. We conclude that BPAG1n4 plays an essential role in retrograde axonal transport in sensory neurons. These findings might advance our understanding of pathogenesis of axonal degeneration and neuronal death.

Animals↗
PubMed2002

Discovery of gene families and alternatively spliced variants by RecA-mediated cloning.

Probing the functional complexity of the human genome will require new gene cloning techniques, not only to discover intraspecies gene homologs and interspecies gene orthologs, but also to identify alternatively spliced gene variants. We report homologous cDNA cloning methods that allow cloning of gene family members, genes from different species, and alternatively spliced gene variants. We cloned human 14-3-3 gene family members using DNA probes with as much as 35% sequence divergence, cloned alternatively spliced gene forms of Rad51D, and cloned a novel splice form of the human 14-3-3 theta gene with a unique expression pattern. Interspecies gene cloning was demonstrated for the mouse Rad51C and mouse beta-actin genes using human gene probes. The gene family cloning method is fast, efficient, and free from PCR errors; moreover, it exploits the abilities of RecA protein to pair homologous or partially homologous DNA sequences stably in kinetically trapped, multistranded DNA hybrids that can be used for subsequent gene clone enrichment.

14-3-3 Proteins↗