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Biomedical subjects

G S Francis

Publications and source records attributed to G S Francis.

At least 19 recordsLinked to original sources
PubMed2001

Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability.

OBJECTIVE: To assess axonal damage and its contribution to disability at different stages of multiple sclerosis (MS). BACKGROUND: Recent in vivo imaging and in situ pathologic studies have demonstrated that substantial axonal damage accompanies the inflammatory lesions of MS. However, the relation of axonal damage to the duration of MS and its contribution to disability at different stages of the disease remain poorly defined. DESIGN: We performed proton magnetic resonance spectroscopic imaging in 88 patients with a wide range of clinical disability and disease duration to measure N-acetylaspartate (NAA, an index of axonal integrity) relative to creatine (Cr) in a large central brain volume that included mostly normal-appearing white matter on magnetic resonance imaging. RESULTS: We observed that the NAA/Cr values were abnormally low in the early stages of MS, even before significant disability (measured using the Expanded Disability Status Scale [EDSS]) was evident clinically, and declined more rapidly with respect to EDSS at lower than at higher EDSS scores (P<.001). The correlation of NAA/Cr values with EDSS score was significantly (P<.03) stronger in patients with mild disability (EDSS score <5, Spearman rank order correlation = -0.54, P<.001) than in patients with more severe disability (EDSS score >/=5, Spearman rank order correlation = -0.1, P<.9). When similar analyses were performed in patients with MS grouped for duration of disease, the subgroup with early disease duration (<5 years) also showed central brain NAA/Cr resonance intensity ratios significantly lower than healthy controls (P<.001). CONCLUSION: Cerebral axonal damage begins and contributes to disability from the earliest stages of the disease.

Adult↗
PubMed2000

Decreased SLIM1 expression and increased gelsolin expression in failing human hearts measured by high-density oligonucleotide arrays.

BACKGROUND: Failing human hearts are characterized by altered cytoskeletal and myofibrillar organization, impaired signal transduction, abnormal protein turnover, and impaired energy metabolism. Thus, expression of multiple classes of genes is likely to be altered in human heart failure. METHODS AND RESULTS: We used high-density oligonucleotide arrays to explore changes in expression of approximately 7000 genes in 2 nonfailing and 2 failing human hearts with diagnoses of end-stage ischemic and dilated cardiomyopathy, respectively. We report altered expression of (1) cytoskeletal and myofibrillar genes (striated muscle LIM protein-1 [SLIM1], myomesin, nonsarcomeric myosin regulatory light chain-2 [MLC(2)], and ss-actin); (2) genes responsible for degradation and disassembly of myocardial proteins (alpha(1)-antichymotrypsin, ubiquitin, and gelsolin); (3) genes involved in metabolism (ATP synthase alpha-subunit, succinate dehydrogenase flavoprotein [SDH Fp] subunit, aldose reductase, and TIM17 preprotein translocase); (4) genes responsible for protein synthesis (elongation factor-2 [EF-2], eukaryotic initiation factor-4AII, and transcription factor homologue-HBZ17); and (5) genes encoding stress proteins (alphaB-crystallin and mu-crystallin). In 5 additional failing hearts and 4 additional nonfailing controls, we then compared expression of proteins encoded by the differentially expressed genes, alphaB-crystallin, SLIM1, gelsolin, alpha(1)-antichymotrypsin, and ubiquitin. In each case, changes in protein expression were consistent with changes in transcript measured by microarray analysis. Gelsolin protein expression was also increased in cardiomyopathic hearts from tropomodulin-overexpressing (TOT) mice and rac1-expressing (racET) mice. CONCLUSIONS: Altered expression of the genes identified in this study may contribute to development of the heart failure phenotype and/or represent compensatory mechanisms to sustain cardiac function in failing human hearts.

Adolescent↗
PubMed2000

Multiple sclerosis: magnetization transfer MR imaging of white matter before lesion appearance on T2-weighted images.

PURPOSE: To determine the evolution of magnetization transfer (MT) in white matter regions before and after plaque development in patients with multiple sclerosis (MS). MATERIALS AND METHODS: In a 5-year longitudinal evaluation, 30 patients with MS underwent conventional magnetic resonance (MR) imaging, MT MR imaging, and clinical assessment. Cross-sectional data in 12 healthy subjects were also collected. Semiautomated lesion classification with use of T2-weighted MR images was used to measure the time course of the MT ratio (calculated with MR data acquired without and with MT saturation) in every voxel and to help analyze the relationship with the status of lesions depicted on T2-weighted images. RESULTS: There was a significant (P <.001) temporal decline in lesion MT ratio after lesion appearance on T2-weighted images. A significant (P <. 001) progressive decline in MT ratio was also present in voxels that later became lesions, prior to initial detection on T2-weighted images. Even 1(1/2) years prior to lesion appearance, the MT ratio (33.3%) in regions destined to become such lesions was significantly (P <.001) lower than that in both white matter in healthy subjects (41.3%) and other normal-appearing white matter in patients with MS (38.1%). CONCLUSION: The MT ratio reveals progressive focal abnormalities in MS that antedate by up to 2 years the appearance of lesions on T2-weighted MR images.

Adult↗
PubMed2000

Adjunctive medical therapy for acute coronary syndromes.

Adjunctive therapy is critical in treating acute coronary syndromes. Aspirin, nitrates, beta-blockers, ACE inhibitors, HMG-CoA reductase inhibitors (statins), and intra-aortic balloon pumps all have important roles and should be considered on a case-by-case basis.

Coronary Disease↗
PubMed1999

Impaired chronotropic response to exercise stress testing as a predictor of mortality.

CONTEXT: Chronotropic incompetence, an attenuated heart rate response to exercise, is a predictor of all-cause mortality in healthy populations. This association may be independent of exercise-induced myocardial perfusion defects. OBJECTIVE: To examine the prognostic significance of chronotropic incompetence in a low-risk cohort of patients referred for treadmill stress testing with thallium imaging. DESIGN: Prospective cohort study conducted between September 1990 and December 1993. SETTING: Tertiary care academic medical center. PATIENTS: Consecutive patients (1877 men and 1076 women; mean age, 58 years) who were not taking beta-blockers and who were referred for symptom-limited treadmill thallium testing. MAIN OUTCOME MEASURES: Association of chronotropic incompetence, defined as either failure to achieve 85% of the age-predicted maximum heart rate or a low chronotropic index, a heart rate response measure that accounts for effects of age, resting heart rate, and physical fitness, with all-cause mortality during 2 years of follow-up. RESULTS: Three hundred sixteen patients (11%) failed to reach 85% of the age-adjusted maximum heart rate, 762 (26%) had a low chronotropic index, and 612 (21%) had thallium perfusion defects. Ninety-one patients died during the follow-up period. After adjustment for age, sex, thallium perfusion defects, and other confounders, failure to reach 85% of the age-predicted maximum heart rate was associated with increased risk of death (adjusted relative risk [RR], 1.84; 95% confidence interval [CI], 1.13-3.00; P=.01), as was a low chronotropic index (adjusted RR, 2.19; 95% CI, 1.43-3.44; P<.001). CONCLUSION: Among patients with known or suspected coronary disease, chronotropic incompetence is independently predictive of all-cause mortality, even after considering thallium perfusion defects. Incorporation of chronotropic response into the routine interpretation of stress thallium studies may improve the prognostic power of this test.

Cardiovascular Diseases↗
PubMed1999

Migratory behavior of lymphocytes isolated from multiple sclerosis patients: effects of interferon beta-1b therapy.

Previous reports by our group and by others have shown that in vitro treatment of T cells derived from healthy, normal subjects with interferon beta-1b (IFN-beta1b) reduces metalloproteinase (metalloproteinase type 9 [MMP-9]) activity with a consequent reduction in lymphocyte migration. In this study, we used a Boyden chamber assay to assess the migratory capacity of T cells derived from multiple sclerosis patients who either did or did not receive IFN-beta1b. Lymphocytes derived from patients treated for less than 2 years with IFN-beta migrated at a low rate that was indistinguishable from that of cells isolated from healthy donors. However, longer term treatment with IFN (>3.5 years) was associated with a reversion of the migration to a high level that did not differ statistically from that of cells isolated from untreated multiple sclerosis patients. For both high-migratory groups, migration could be reduced to control levels after the exogenous addition of TIMP-1, a relatively specific inhibitor of the MMP-9, implicating this protease in the process of T-cell migration. Our findings suggest that one of the mechanisms by which IFN-beta exerts its action is by reducing MMP-9 activity and thus the entry of inflammatory cells into the nervous system and, as such, MMPs may constitute potential therapeutic targets in inflammatory diseases such as multiple sclerosis.

Adult↗
PubMed1999

Cardiac complications in the intensive care unit.

Advances in the care of critically ill patients has been startling, especially in patients with acute coronary syndromes. With new therapies and procedures, however, have come new complications. On balance, our patients are better off, but the stakes are now higher and the complications more serious. The need for constant vigilance has never been greater.

Adult↗
PubMed1999

Apoptosis, Bcl-2, and proliferating cell nuclear antigen in the failing human heart: observations made after implantation of left ventricular assist device.

BACKGROUND: Heart failure is characterized by progressive left ventricular remodeling, a complex process that results from cell growth and cell death. The quantitative contribution of apoptotic cells toward left ventricular remodeling has varied widely in tissue removed from cardiomyopathic hearts. Apoptosis has been responsive to angiotensin-converting enzyme inhibition in experimental heart failure, but the dynamics and responsiveness to chronic left ventricular unloading have not been studied. METHODS AND RESULTS: We studied 8 patients with severe heart failure before and after chronic left ventricular unloading with a left ventricular assist device (LVAD). Tissue from the left ventricular apex removed at the time of LVAD implantation was examined for apoptosis using the technique of terminal deoxynucleotidyl transferase deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) in 10 patients. These same hearts explanted at the time of cardiac transplantation were then examined for apoptosis after patients had been on the LVAD for 99 +/- 20 (SEM) days. An additional 10 patients with equally severe heart failure who underwent heart transplantation without the use of an LVAD served as controls. Eight hearts obtained at autopsy approximately 6 hours after death from patients who died of non-cardiovascular disease causes served as non-heart failure controls. Additionally, 6 hearts were examined by immunohistochemistry for the antiapoptotic protein, Bcl-2, and for the repair and/or proliferation marker, proliferating cell nuclear antigen (PCNA), before and after LVAD. Apoptosis was not detected in the tissue sections from the hearts of 8 patients at the time of LVAD implantation. Only 1 of these patients had limited apoptosis (< 1 apoptotic cell/1,000 myocytes) after LVAD insertion. Three of 10 patients with severe heart failure who did not receive an LVAD but underwent transplantation showed limited apoptosis (< 1 apoptotic cell/1,000 myocytes). Likewise, none of the control hearts from patients who died of noncardiovascular disease manifested apoptosis. Six of 6 patients overexpressed Bcl-2 at the time of LVAD insertion. In all these patients, Bcl-2 returned to negligible levels after chronic unloading of the heart. Likewise, PCNA was abundantly expressed in 5 of 6 failing hearts at the time of LVAD implantation and was reduced in 4 of 5 hearts after chronic unloading by LVAD. CONCLUSION: Apoptosis is a rare or inconsistent finding in the failing human heart. Overexpression of such indicators of cellular stress and DNA replication and/or repair as Bcl-2 and PNCA in heart failure may be altered by optimizing left ventricular loading conditions by such mechanical devices as the LVAD.

Adult↗
PubMed1999

Treatment with interferon beta-1b improves quality of life in multiple sclerosis.

BACKGROUND: The Canadian Burden of Illness Study Group reported that the quality of life (QoL) of multiple sclerosis (MS) patients falls drastically, early in the disease. With disability progression, the physical functioning scales of the Short Form 36 (SF-36) showed further decreases in QoL. The objective of this study is to describe the QoL of MS patients treated with interferon beta-1b (IFNB-1b) and to compare it to the QoL observed in a group of patients who had not been treated with IFNB-1b. METHODS: Treated patients were prospectively recruited and were seen at their regular visit to the MS clinic. They self-completed the SF-36 questionnaire and their QoL was described and retrospectively compared to that of historical controls. RESULTS: When IFNB-1b treated patients were compared to historical control patients with the same relapsing forms of MS, the treated patients with an Expanded Disability Status Scale (EDSS) score lower than 3.0 had a significantly better QoL. This was significant for four of the eight SF-36 domains: Physical Function (+22%, p = 0.0102), Role-Physical (+100%, p = 0.0022), General Health (+27%, p = 0.0070) and Social Function (+19%, p = 0.0287). The average QoL difference was 8% in the EDSS 3.0-6.0 group and 10% in the EDSS > 6 group. CONCLUSION: Patients with relapsing forms of MS treated with IFNB-1b have better QoL than patients who are not treated, especially those with an EDSS < 3.0.

Adolescent↗