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Biomedical subjects

E Fisher

Publications and source records attributed to E Fisher.

At least 19 recordsLinked to original sources
PubMed2006

Preliminary evidence of FABP2 A54T polymorphism associated with reduced risk of type 2 diabetes and obesity in women from a German cohort.

The T54 variant of the FABP2 gene has shown an association with the insulin resistance syndrome in some, but not all, studies. Here, we tested the hypothesis that the association between FABP2 A54T genotype and type 2 diabetes (T2DM) is confounded by body mass index (BMI) and is different between the two genders. 192 incident cases of T2DM and 384 sex- and age-matched controls were taken from the EPIC-Potsdam study cohort. Logistic regression analyses revealed that BMI was a strong confounder for diabetes risk association among women. When adjusted for BMI, the homozygous T54 variant was significantly associated with reduced risk of T2DM in women (OR = 0.24, 95 %CI: 0.07 - 0.82), but not in men in the co-dominant inheritance model. Accordingly, HbA (1c) values were significantly lower in women carrying two T54 alleles with BMI regarded as covariate. While accounting for potentially confounding effects, linear trends of increased BMI and leptin values were observed in women according to the presence of T54 alleles. The interaction term (p = 0.04) of continuous BMI and T54-coding genotypes suggested that the T54 variant is an effect-modifier for BMI in females. We conclude that the T54 allele of FABP2 A54T is associated both with higher BMI and reduced risk of T2DM in women from the German EPIC-Potsdam study.

Adult↗
PubMed2006

Association between functional FABP2 promoter haplotype and type 2 diabetes.

Fatty acid-binding protein 2 (FABP2) is a cytosolic protein expressed exclusively in epithelial cells of the small intestine. Some, albeit not conclusive, evidence indicates that the Thr-allele of FABP2 Ala54Thr polymorphism is associated with type 2 diabetes. More recently, common FABP2 promoter polymorphisms have shown association with postprandial increase of triglycerides, body composition and plasma lipid levels. Therefore, we reasoned that variants in the FABP2 promoter may also predispose to type 2 diabetes mellitus. In our Caucasian study population, we found three SNPs and three insertion-deletion polymorphisms that are in complete linkage disequilibrium defining promoter haplotype A and B within 1kb 5' of the FABP2 initiation codon. Haplotype calculations indicated that the FABP2 promoter and Ala54Thr variants were strongly linked. Functional analysis of promoter fragments demonstrated that haplotype difference is caused by polymorphisms within 260 bp downstream of the FABP2 initiation codon. Using a prospective case-control study nested within the EPIC-Potsdam cohort of 192 incident type 2 diabetes cases and 384 sex-/age-matched controls, male subjects carrying the FABP2 haplotype B allele showed significantly decreased risk of type 2 diabetes when adjusted for BMI (OR = 0.50, 95 % CI = 0.28 - 0.87, p < 0.05) and additional covariates (OR = 0.42, 95 % CI 0.22 - 0.81, p < 0.01). Further adjustment for the Ala54Thr polymorphism revealed an OR of 0.18 (95 % CI 0.06 - 0.49, p < 0.001). Similarly, Ala/Ala homozygote males carrying the promoter haplotype B had decreased risk (0.33, 0.11 - 0.94, p < 0.05) of type 2 diabetes after stratification for the Ala54Thr polymorphism. FABP2 promoter haplotypes or genotype combinations defined by the promoter and Ala54Thr polymorphism were not associated with BMI, body fat, leptin, HbA (1c), total cholesterol or HDL. In conclusion, our findings suggest that the functional FABP2 promoter haplotype may contribute to type 2 diabetes in a sex-specific manner.

Adult↗
PubMed2005

MRI as a marker for disease heterogeneity in multiple sclerosis.

BACKGROUND: Whereas recent data from imaging studies challenge the prevailing notion that multiple sclerosis (MS) is purely an inflammatory disease, pathologic studies suggest differences in the disease processes between individual patients with MS. The ability to dissect the pathophysiologic disease heterogeneity, if it indeed exists, by methodologies that can be applied in vivo is important both for the development of new therapeutics and for the ability to identify the optimal therapy for an individual patient. OBJECTIVE: To design a stratification algorithm for patients with MS based on accepted MRI measurements reflective of inflammation and axonal damage/tissue loss and to assess if such MS subgroups retain their intergroup differences long term. METHODS: Mathematical modeling was used to select three discriminatory MRI measures for clinical outcome based on the cross-sectional analysis of 71 patients with untreated MS and tested general applicability of the stratification scheme on the independent longitudinal cohort of 71 MS patients. RESULTS: By consecutive employment of MRI measures reflective of inflammation and tissue loss, the authors were able to separate MS patients into four clinically meaningful subgroups. The analysis of the longitudinal confirmatory cohort demonstrated persistence of the intergroup differences in selected MRI measures for 8 years. CONCLUSIONS: The inflammatory activity and destructiveness of the multiple sclerosis process are to some degree independent of each other, and the successive evaluation of both of these variables can strengthen prediction of clinical outcome in individual patients.

Adult↗
PubMed2005

Rate of brain atrophy in relapsing MS decreases during treatment with IFNbeta-1a.

OBJECTIVE: To determine the time course of brain atrophy during treatment with once-weekly IM interferon beta-1a (IFNbeta-1a). METHODS: The MRI cohort (n = 386) of the European IFNbeta-1a dose comparison study in relapsing multiple sclerosis (MS) was analyzed. In addition to baseline and three annual scans, a frequent subgroup (n = 138) had two scans before treatment initiation and scans at months 4, 5, 6, 10, and 11. Brain parenchymal fraction (BPF), a normalized measure of whole-brain atrophy, and volume of Gd-enhancing lesions (T1Gd) and T2 hyperintense lesions (T2LL) were evaluated. RESULTS: BPF decrease was -0.686% (first year), -0.377% (second year), and -0.378% (third year). Analysis of the frequent subgroup showed that 68% of the first-year BPF decrease occurred during the first 4 months of treatment. This change was paralleled by a drop in T1Gd and T2LL. In the frequent subgroup, an annualized atrophy rate was determined by a regression slope for the pretreatment period and from month 4 of treatment onward. Annualized pretreatment rate (-1.06%) was significantly higher than the under-treatment rate (-0.33%). CONCLUSIONS: In the first year of treatment with anti-inflammatory agents, atrophy measurements are possibly confounded by resolution of inflammatory edema or more remote effects of previous damage to the CNS. The atrophy rate reduction observed after treatment month 4 may reflect a beneficial but partial effect of interferon beta-1a and was sustained over the 3-year study period.

Adult↗
PubMed2005

Estimating long-term effects of disease-modifying drug therapy in multiple sclerosis patients.

Two methods were used to estimate the long-term impact of disease-modifying drug therapy (DMDT) in patients with relapsing multiple sclerosis (MS) who completed a placebo-controlled, randomized clinical trial of interferon beta-1a (IFNbeta-1a). The study cohort consisted of patients with ambulatory relapsing MS who had previously participated in a placebo-controlled clinical trial for two years. At its end, patients were managed in an unstructured fashion by their neurologists and re-evaluated at an average of 6.1 years after the end of the trial. Follow-up evaluation was obtained for 93% of the 172 eligible patients. Because study inclusion criteria required that all patients have an Expanded Disability Status Scale (EDSS) score of < or = 3.5 at entry, disability progression at follow-up was defined as EDSS > or = 6.0. Two methods were used to estimate the expected proportions that reached EDSS > or = 6.0 at follow-up. Estimates were compared with observed proportions. Method 1 used progression rates observed during the two-year phase III clinical trial and the percentage of time that patients were on DMDT during the follow-up period. Method 2 used progression rates from a natural history comparison group of relapsing-remitting MS patients. At the eight-year follow-up, 42.0% of the original placebo patients and 29.1% of the original IFNbeta-1a patients reached an EDSS > or = 6.0, an observed treatment effect of approximately 30%. Using method 1, it was estimated that 36.3% of the original placebo patients and 27.6% of the original IFNbeta-1a patients should have reached an EDSS > or = 6.0. Use of the natural history control group (method 2) predicted less plausible outcomes. Estimated proportions of patients reaching the endpoint were 63.3% for the original placebo group and 55.8% for the original IFNbeta-1a group. Treatment effect sizes of 75-90% would be required to match estimates from method 2 with the observed outcome. The paucity of data on the long-term treatment of patients with MS may be aided by applying these or similar methods to vigorously followed cohorts of patients.

Adjuvants, Immunologic↗
PubMed2005

Precaution, law and principles of good administration.

The precautionary principle is a legal principle concerned with the process of how decisions are made. In implementing and interpreting it regard must be had to the surrounding legal culture and in particular the principles of good administration in operation. Highlighting those principles emphasises that within a particular jurisdiction there is often very little agreement over their nature. Within the European Union contradictory principles are the product of: assumptions about risk problem-solving, the ambiguous nature of European administration, a concern with accountability in the face of recent food controversies, and the impact of international trade rules. These contradictory principles present a number of challenges for implementing the precautionary principle.

Decision Making↗
PubMed2003

Pattern reversal visual evoked potentials as a measure of visual pathway pathology in multiple sclerosis.

BACKGROUND: Pattern reversal visual evoked potentials (PRVEPs) have a well-documented role in diagnosis of multiple sclerosis (MS), but their value as a visual function surrogate remains controversial. METHODS: We evaluated PRVEP in 37 patients with MS who were participating in a long-term follow-up study following a phase III trial of interferon beta-1a (Avonex). Patients were examined to determine the Kurtzke Extended Disability Status Score (EDSS), multiple sclerosis functional composite (MSFC), contrast letter acuity (CLA), and had cranial MRI scans to determine whole brain atrophy (BPF). PRVEP was evaluated for P100 latency, amplitude, and waveform morphology. Two summary scores were created: for Score A, abnormal latencies, morphologies, and amplitudes of each individual eye were added; for Score B, abnormal latencies, morphologies, and amplitude ratio between eyes was determined. Sixteen patients in this group also had PRVEP at the time they enrolled in the clinical trial, eight years previously. RESULTS: At the follow-up exam, over 75% of patients had abnormal PVEP parameters while visual acuity (VA) was abnormal only in 59%. Increased PRVEP latency over the eight-year period correlated with deterioration assessed by EDSS (P = 0.006), BPF (P = 0.0001), and MSFC (P = 0.0041). Score A was significantly correlated with EDSS, BPF, CLA, cognitive function, and quality of life assessed with the Sickness Impact profile. No correlation was seen with the MSFC. CONCLUSIONS: The results indicate that PRVEP measures MS-related pathology, and can provide not only diagnostic but also prognostic information during evaluation of MS patients.

Evoked Potentials, Visual↗
PubMed2002

Eight-year follow-up study of brain atrophy in patients with MS.

OBJECTIVE: To characterize whole-brain atrophy in relapsing-remitting MS (RRMS) patients over an 8-year period. The specific goals of this study were to determine if brain atrophy is related to subsequent disability status and to identify MRI correlates of atrophy progression. METHODS: A follow-up study was conducted to reassess patients from a phase III trial of interferon beta-1a (IFNbeta-1a) 8 years after randomization. Clinical and MRI data from 172 patients followed over 2 years in the original trial were used as baseline data. Follow-up data were obtained on 160 patients, including 134 patients with follow-up MRI examinations. Brain atrophy was estimated by automated calculation of brain parenchymal fraction. The relation between atrophy during the original trial and disability status at follow-up was determined. Correlations were also determined between lesion measurements from the original trial and the brain parenchymal fraction at follow-up. RESULTS: Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial. CONCLUSIONS: The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.

Adjuvants, Immunologic↗
PubMed2001

Sporadic--but not variant--Creutzfeldt-Jakob disease is associated with polymorphisms upstream of PRNP exon 1.

Human prion diseases have inherited, sporadic, and acquired etiologies. The appearance of the novel acquired prion disease, variant Creutzfeldt-Jakob disease (vCJD), and the demonstration that it is caused by the same prion strain as that causing bovine spongiform encephalopathy, has led to fears of a major human epidemic. The etiology of classical (sporadic) CJD, which has a worldwide incidence, remains obscure. A common human prion-protein-gene (PRNP) polymorphism (encoding either methionine or valine at codon 129) is a strong susceptibility factor for sporadic and acquired prion disease. However, a quantitative-trait-locus study of prion incubation periods in mice has demonstrated an important factor that is close to Prnp but is independent of its coding sequence or that of the nearby prion-like doppel gene (Prnd). We have analyzed the PRNP locus for such tightly linked susceptibility factors. Fifty-six polymorphic sites have been identified within 25 kb of the PRNP open reading frame, including sites within the PRNP promoter and the PRNP 3' untranslated region. These have been characterized in 61 Centre d'Etude du Polymorphisme Humain (CEPH) families, demonstrating extensive linkage disequilibrium around PRNP and the existence of 11 major European PRNP haplotypes. Haplotype frequencies estimated in healthy U.K. control individuals were very similar to those deduced in the CEPH families. A common haplotype was overrepresented in patients with sporadic CJD (sCJD). Through use of a log-linear modeling approach to simultaneously model Hardy-Weinberg and linkage disequilibria, a significant independent association was found between sCJD and a polymorphism upstream of PRNP exon 1 (P=.005), in addition to the strong susceptibility conferred by codon 129 (P=2x10(-8)). However, although our sample size was necessarily small, no association was found between these polymorphisms and vCJD or iatrogenic CJD, in keeping with their having distinct disease mechanisms. In addition, there was no evidence of a PRNP founder effect in the first reported geographical cluster of vCJD.

3' Untranslated Regions↗
PubMed2001

Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS.

OBJECTIVE: To determine whether the MS Functional Composite (MSFC) can predict future disease progression in patients with relapsing remitting MS (RR-MS). BACKGROUND: The MSFC was recommended by the Clinical Outcomes Assessment Task Force of the National MS Society as a new clinical outcome measure for clinical trials. The MSFC, which contains a test of walking speed, arm dexterity, and cognitive function, is expressed as a single score on a continuous scale. It was thought to offer improved reliability and responsiveness compared with traditional clinical MS outcome measures. The predictive value of MSFC scores in RR-MS has not been determined. METHODS: The authors conducted a follow-up study of patients with RR-MS who participated in a phase III study of interferon beta-1a (AVONEX) to determine the predictive value of MSFC scores. MSFC scores were constructed from data obtained during the phase III trial. Patients were evaluated by neurologic and MRI examinations after an average interval of 8.1 years from the start of the clinical trial. The relationships between MSFC scores during the clinical trial and follow-up status were determined. RESULTS: MSFC scores from the phase III clinical trial strongly predicted clinical and MRI status at the follow-up visit. Baseline MSFC scores, and change in MSFC score over 2 years correlated with both disability status and the severity of whole brain atrophy at follow-up. There were also significant correlations between MSFC scores during the clinical trial and patient-reported quality of life at follow-up. The correlation with whole brain atrophy at follow-up was stronger for baseline MSFC than for baseline EDSS. CONCLUSION: MSFC scores in patients with RR-MS predict the level of disability and extent of brain atrophy 6 to 8 years later. MSFC scores may prove useful to assign prognosis, monitor patients during early stages of MS, and to assess treatment effects.

Adult↗
PubMed2001

The use of tat and env sequences from human immunodeficiency virus 1 in phylogenetic epidemiological studies.

Using nucleotide sequences from the first exon of the tat gene of the human immunodeficiency virus 1 (HIV-1), we tested the hypothesis that a Florida dentist (a common source) infected five of his patients in the course of dental procedures against the null hypothesis that the dentist and each individual of the dental group independently acquired the virus within the local community. This novel approach of analyzing the tat gene region was used because it may, in some circumstances, be more informative for phylogenetic epidemiology than the more commonly used C2-V3 envelope gene region. The first exon of the tat gene was polymerase chain reaction (PCR)-amplified and directly sequenced from uncultured peripheral blood mononuclear cells. Patient's sequences were compared with sequences from six HIV-1 infected heterosexual couples unrelated to the dentist or the five patients, but from the same general geographic area. In addition, a sixth infected dental patient, previously inferred to have acquired HIV-1 from a source other than the dentist, was included. Multiple phylogenetic analyses demonstrated that the sequences of the five patients were significantly more closely related to each other than to sequences of the controls. Our results using tat sequences, combined with envelope sequence data, strongly support a common phylogenetic epidemiological relationship among these five patients, and the HIV-1 infected dentist who treated them. Correct recovery of known epidemiological relationships among couples included in the analysis further strengthens this conclusion.

Base Sequence↗
PubMed2001

Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a Southwest Oncology Group study (SWOG 9235).

OBJECTIVES: To determine the efficacy and tolerability of bicalutamide in patients with advanced prostate cancer with progression after conventional hormonal therapy. METHODS: Fifty-two patients received bicalutamide, 150 mg once daily, as second-line therapy after progressing following treatment with orchiectomy or luteinizing hormone-releasing hormone analogue or diethylstilbestrol, alone or in combination. Patients had measurable (n = 8) or assessable (n = 44) disease, a Southwest Oncology Group performance status of 0 to 2, and no prior antiandrogen therapy or chemotherapy. The objective response to treatment was assessed every 12 weeks; symptoms and pain were assessed monthly with questionnaires for 6 months. RESULTS: There was evidence of palliation with three measures of pain and, to a lesser extent, with a measure of overall symptom status after 3 months of taking bicalutamide. No complete or partial responses occurred. However, 9 (20%) of 44 subjects with adequate prostate-specific antigen data had a 50% or higher decrease in their prostate-specific antigen levels, which did not correlate with symptom improvement. The median survival time was 15 months. The most common side effects were hot flashes (23%) and nausea (21%). CONCLUSIONS: These data suggest that bicalutamide decreases pain and improves symptom status in patients with prostate cancer in whom first-line hormonal therapy failed.

Adenocarcinoma↗
PubMed2001

Postictal diffusion-weighted imaging for the localization of focal epileptic areas in temporal lobe epilepsy.

PURPOSE: Diffusion-weighted MR imaging (DWI) is a novel technique to delineate focal areas of cytotoxic edema of various etiologies. We hypothesized that DWI may also detect the epileptogenic region and adjacent areas during the ictal and early postictal periods in patients with temporal lobe epilepsy (TLE). METHODS: We studied patients with intractable TLE (n = 9), due to hippocampal sclerosis (HS, n = 7), left mesial temporal lobe tumor (n = 1), and of unknown etiology (n = 1). Informed consent was obtained before inclusion in the study. All patients with single short seizures were scanned immediately after EEG-documented seizures (between 45 and 150 min); one of two patients in status was scanned 14 h after cessation of seizures. DWI results were analyzed visually and by calculating apparent diffusion coefficient (ADC) maps. RESULTS: We found significant decreases in ADC postictally in one of six patients with TLE due to HS and single short seizures. One patient with an incompletely resected temporal lobe tumor also exhibited ADC abnormalities. One patient in focal status epilepticus revealed a decrease in ADC, and one patient with a continuous aura had no DWI abnormality. CONCLUSIONS: Postictal DWI technique may occasionally help delineate epileptic areas in some patients with TLE. Yield is low in patients with HS and single short seizures: it may be higher in patients with tumor or status epilepticus.

Adolescent↗
PubMed2000

Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer.

PURPOSE: To evaluate preoperative dendritic cell (DC) mobilization and tumor infiltration after administration of Flt3 ligand (Flt3L) to patients with metastatic colon cancer. PATIENTS AND METHODS: Twelve patients with colon cancer metastatic to the liver or lung received Flt3L (20 microg/kg/d subcutaneously for 14 days for one to three cycles at monthly intervals) before attempted metastasectomy. The number and phenotype of DCs mobilized into peripheral-blood mononuclear cells (PBMCs) were evaluated by flow cytometry. After surgical resection, metastatic tumor tissue was evaluated for DC infiltration. In vivo immune responses to recall antigens were measured. RESULTS: After Flt3L administration, on average, the total number of leukocytes in the peripheral blood increased from 5.9 +/- 1.0 x 10(3)/mm(3) to 11.2 +/- 3.8 x 10(3)/mm(3) (mean +/- SD, P: =. 0001). The percentage of CD11c(+)CD14(-) DCs in PBMCs increased from 2.4% +/- 1.8% to 8.8% +/- 4.7% (P: =.004). Delayed-type hypersensitivity (DTH) responses to recall antigens (CANDIDA:, mumps, and tetanus) showed marginally significant increases in reactivity after Flt3L administration (P: =.06, P: =.03, and P: =.08, respectively). An increase in the number of DCs was observed at the periphery of the tumors of patients who received Flt3L compared with those of patients who had not. CONCLUSION: Flt3L is capable of mobilizing DCs into the peripheral blood of patients with metastatic colon cancer and may be associated with increases in DC infiltration in the peritumoral regions. Flt3L mobilization is associated with a trend toward increased DTH responses to recall antigens in vivo. The use of Flt3L to increase circulating DCs for cancer immunotherapy should be considered.

Adjuvants, Immunologic↗
PubMed2000

Topical negative pressure in wound management.

OBJECTIVE: To investigate the role of topical negative pressure (TNP) therapy in the management of difficult wounds. DESIGN: Prospective consecutive patient series. PATIENTS AND SETTING: 30 patients referred to our tertiary plastic and reconstructive surgical service with wounds deemed unsuitable for reconstructive surgery were treated between November 1997 and the end of December 1998. The mean pretreatment duration of the wounds was 418 days (range, 8-1650 days). All wounds were at least Grade III pressure sores. INTERVENTION: Topical negative pressure therapy (TNP) using the VAC device (KCI Medical, San Antonio, USA). Suction (75-125 mmHg) was continuous for the first 48 hours, then intermittent (2 min on, 5 min off). MAIN OUTCOME MEASURES: Achievement of wound healing endpoints: (1) complete healing of the wound; (2) obliteration of the wound cavity to allow surface dressings; or (3) closure of the wound by suture or skin graft. RESULTS: TNP was successful in 26 out of 30 patients with mean therapy time of 35 days (range, 3-124 days). Healing was more rapid in acute (less than six weeks old) wounds. A reduction in the number of bacterial species and colonies was also observed during therapy. CONCLUSION: TNP can, in some circumstances, promote rapid secondary wound healing. A further randomised trial of TNP versus more traditional wound management modalities is justified.

Bandages↗
PubMed2000

Implementation of a large-scale ENU mutagenesis program: towards increasing the mouse mutant resource.

Systematic approaches to mouse mutagenesis will be vital for future studies of gene function. We have begun a major ENU mutagenesis program incorporating a large genome-wide screen for dominant mutations. Progeny of ENU-mutagenized mice are screened for visible defects at birth and weaning, and at 5 weeks of age by using a systematic and semi-quantitative screening protocol-SHIRPA. Following this, mice are screened for abnormal locomotor activity and for deficits in prepulse inhibition of the acoustic startle response. Moreover, in the primary screen, blood is collected from mice and subjected to a comprehensive clinical biochemical analysis. Subsequently, secondary and tertiary screens of increasing complexity can be used on animals demonstrating deficits in the primary screen. Frozen sperm is archived from all the male mice passing through the screen. In addition, tail tips are stored for DNA. Overall, the program will provide an extensive new resource of mutant and phenotype data to the mouse and human genetics communities at large. The challenge now is to employ the expanding mouse mutant resource to improve the mutant map of the mouse. An improved mutant map of the mouse will be an important asset in exploiting the growing gene map of the mouse and assisting with the identification of genes underlying novel mutations-with consequent benefits for the analysis of gene function and the identification of novel pathways.

Animals↗