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Biomedical subjects

E Hoffman

Publications and source records attributed to E Hoffman.

At least 19 recordsLinked to original sources
PubMed2003

Transcriptomal analysis of failing and nonfailing human hearts.

Heart failure is a multifactorial disease that may result from different initiating events. To contribute to an improved comprehension of normal cardiac function and the molecular events leading to heart failure, we performed large-scale gene expression analysis of failing and nonfailing human ventricle. Our aim was to define and compare expression profiles of 4 specific pathophysiological cardiac situations: 1) left ventricle (LV) from nonfailing heart; 2) LV from failing hearts affected by dilated cardiomyopathy (DCM); 3) LV from failing hearts affected by ischemic CM (ICM); 4) right ventricle (RV) from failing hearts affected by DCM or ICM. We used oligonucleotide arrays representing approximately 12,000 human genes. After stringent numerical analyses using several statistical tests, we identified 1,306 genes with a similar expression profile in all 4 cardiac situations, therefore representative of part of the human cardiac expression profile. A total of 95 genes displayed differential expression between failing and nonfailing heart samples, reflecting a reversal to developmental gene expression, dedifferentiation of failing cardiomyocytes, and involvement of apoptosis. Twenty genes were differentially expressed between failing LV and failing RV, identifying possible candidates for different functioning of both ventricles. Finally, no genes were found to be significantly differentially expressed between failing DCM and failing ICM LV, emphasizing that transcriptomal analysis of explanted hearts results mainly in identification of expression profiles of end-stage heart failure and less in determination of expression profiles of the underlying etiology. Taken together, our data resulted in identification of putative transcriptomal landmarks for normal and disturbed cardiac function.

Adolescent↗
PubMed2001

Longitudinal study of brain morphology in first episode schizophrenia.

BACKGROUND: Beginning with Kraepelin, schizophrenia has been viewed as a progressive disorder. Although numerous studies of the longitudinal course of schizophrenia have demonstrated the clinical deterioration that occurs predominantly in the early stages of the illness, the pathophysiology of this clinical phenomenon has not been established. This aspect of the illness may be of critical importance to understanding the pathogenesis of schizophrenia and determining preventive therapeutic strategies. Abnormalities in brain morphology have been consistently described in schizophrenia, but it is not known when in the natural history of the illness they arise and whether they are progressive. Previous studies of brain morphology have been inconclusive, in part because of the variability of methods for image acquisition and analysis, assessment of patients already at chronic stages of their illness with extensive prior treatment exposure, and inadequate periods of follow-up. METHODS: To address these questions we examined 107 patients in their first episode of schizophrenia or schizoaffective disorder and 20 healthy volunteers using high resolution magnetic resonance imaging (MRI) and clinical assessments of psychopathology and treatment outcome for periods of up to 6 years. Fifty-one patients and 13 control subjects had MRIs after at least 12 months of follow-up. RESULTS: Results confirm the findings of ventricular enlargement and anterior hippocampal volume reductions in first episode schizophrenia patients that have been previously reported. In addition, we found changes in selected structures over time in relation to treatment outcome, including increases in ventricular volume that were associated with poor outcome patients. Contrary to our hypothesis, there were no significant reductions in cortical and hippocampal volumes over time. CONCLUSIONS: The finding of progressive ventricular enlargement in patients with poor outcome schizophrenia is consistent with the hypothesis that persistent positive and negative symptoms result in progressive brain changes in the form of ventricular enlargement, possibly due to neurodegeneration rather than the confounding effects of treatment. Future studies of first episodes of schizophrenia should utilize higher resolution imaging techniques that compare clinically well characterized patients with and without poor outcome and recurrent symptoms to control subjects who are well matched to patients for age and gender. There is also a need to control for treatment effects of typical antipsychotic medication on brain structure.

Adolescent↗
PubMed2001

Refining the risk assessment of metal-contaminated soils.

Determining the bioavailability of toxic metals (Pb, As, and Cd) in a diverse range of soils, allows scientifically derived data to dictate site-specific remedies to reduce the risk for sensitive human populations. Based on a series of dosing trials in a juvenile swine model, site-specific estimates of relative bioavailability of Pb in soil ranged from 3% to 86% compared to soluble lead acetate. Another experiment using a pregnant swine model revealed: 1) Pb accumulation in fetal tissues was 50% or more of maternal and; 2) pregnant females accumulated 2-to-4 times more lead in tissues than unbred females. Relative bioavailability results for arsenic- and cadmium-contaminated soils further support the view that soil metals are not always as well absorbed as soluble forms, therefore use of default toxicity factors for assessing human health risk may overestimate the hazard.

Animals↗
PubMed2001

Social facilitation of object-oriented hand use in a Rett syndrome variant girl: implications for partial preservation of an hypothesized specialized cerebral network.

Partial preservation of object-oriented hand use (OOHU) was studied behaviorally in a 6-1/2-year-old girl with the preserved speech variant (PSV) of Rett syndrome (RS), associated with a T 158 missense MeCP2 mutation and favorably skewed X-inactivation. At home, OOHU was limited except for self-feeding. When examined, overall time invested in toy play was only 38% of that of healthy subjects, and also, by comparison with healthy subjects, less when autonomous than when socially-facilitated (13% vs 63%). Good interest in and responsiveness to people translated into better motivation for OOHU. She responded to others' requests for grasping and handling objects and used them to reinforce affiliations with people. Results were discussed in terms of a disruption of the formation of a specialized OOHU cerebral network in RS, partially compensated for by the favorably skewed X-inactivation, which among other effects permitted functional retention of the network segment incorporating social influence and motivation.

Child↗
PubMed2001

Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials.

OBJECTIVE: The authors conducted a review and meta-analysis of studies that compared the efficacy and tolerability of typical and second-generation antipsychotics for patients with treatment-resistant schizophrenia. METHOD: A systematic search revealed 12 controlled studies (involving 1,916 independent patients), which were included in the review. For the seven studies that compared clozapine to a typical antipsychotic, a meta-analysis was performed to examine clozapine's effects on overall psychopathology, response rate, extrapyramidal symptoms, and tardive dyskinesia. RESULTS: The meta-analysis confirmed that treatment-resistant schizophrenic patients have more favorable outcomes when treated with clozapine rather than a typical antipsychotic, as reflected by Brief Psychiatric Rating Scale total score, categorical response rate, Scale for the Assessment of Negative Symptoms score, Simpson-Angus Rating Scale score, and compliance rate. Clozapine also conferred benefits on the sickest treatment-resistant schizophrenic patients. Patients treated with olanzapine also had more favorable outcomes with regard to categorical response and compliance rates. CONCLUSIONS: In the aggregate, the results of a meta-analysis indicated that clozapine exhibits superiority over typical antipsychotics in terms of both efficacy (as measured by improvement in overall psychopathology) and safety (in terms of reduced extrapyramidal side effects). However, the magnitude of the clozapine treatment effect was not consistently robust. Efficacy data for other second-generation antipsychotics in the treatment of patients with refractory schizophrenia were inconclusive. There is, therefore, a growing need to consider new and different treatment strategies, whether they be adjunctive or monotherapeutic, for schizophrenia that continues to be resistant or only partially responsive to treatment.

Adolescent↗
PubMed2000

Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers.

Cancer-testis antigen NY-ESO-1 is one of the most immunogenic tumor antigens defined to date. Spontaneous humoral and CD8+ T-cell responses to NY-ESO-1 are detected in 40-50% of patients with advanced NY-ESO-1-expressing tumors. A clinical trial was initiated to study the immunological effects of intradermal vaccination with 3 HLA-A2-binding NY-ESO-1 peptides in 12 patients with metastatic NY-ESO-1-expressing cancers. Seven patients were NY-ESO-1 serum antibody negative, and five patients were NY-ESO-1 serum antibody positive at the outset of the study. Primary peptide-specific CD8+ T-cell reactions and delayed-type hypersensitivity responses were generated in four of seven NY-ESO-1 antibody-negative patients. Induction of a specific CD8+ T-cell response to NY-ESO-1 in immunized antibody-negative patients was associated with disease stabilization and objective regression of single metastases. NY-ESO-1 antibody-positive patients did not develop significant changes in baseline NY-ESO-1-specific T-cell reactivity. However, stabilization of disease and regression of individual metastases were observed in three of five immunized patients. These results demonstrate that primary NY-ESO-1-specific CD8+ T-cell responses can be induced by intradermal immunization with NY-ESO-1 peptides, and that immunization with NY-ESO-1 may have the potential to alter the natural course of NY-ESO-1-expressing tumors.

Amino Acid Sequence↗
PubMed2000

Construction, production, and characterization of humanized anti-Lewis Y monoclonal antibody 3S193 for targeted immunotherapy of solid tumors.

The Lewis Y (Ley) antigen is a blood group-related antigen that is expressed in a high proportion of epithelial cancers (including breast, colon, ovary, and lung cancer) and is an attractive target for monoclonal antibody-directed therapy. The murine monoclonal 3S193 (IgG3) was generated in BALB/c mice by immunization with Ley-expressing cells of the MCF-7 breast carcinoma cell-line. The murine 3S193 showed high specificity for Ley in ELISA tests with synthetic Ley and Ley-containing glycoproteins and glycolipids and also reacted strongly in rosetting assays and cytotoxic tests with Ley-expressing cells. We generated a humanized form of the murine 3S193 antibody by linking cDNA sequences encoding the variable region of murine 3S913 with frameworks of the human KOL heavy chain and REI K chain. The genes for the humanized 3S193 monoclonal antibody IgG1 were transfected into mouse myeloma NS0 cells and cloned for the establishment of high antibody-producing colonies. Humanized 3S193 antibody was subsequently produced through in vitro culture and under good manufacturing practice conditions using hollow-fiber bioreactors. The purified humanized 3S193 (hu3S193) was subsequently characterized and validated for use in preliminary immunotherapy investigations. hu3S193 reacted specifically with Ley antigen, with similar avidity to the murine form. hu3S193 demonstrated potent immune effector function, with higher antibody-dependent cell-mediated cytotoxicity than its murine counterpart and potent complement-dependent cytotoxicity (ED50, 1.0 microg/ml). The in vivo immunotherapeutic potential of hu3S193 was assessed in a human breast xenograft model using MCF-7, Ley-positive cells. Six i.v. doses of up to 1 mg of hu3S193 were administered to animals bearing established tumors (120-130 mm3) with no significant effect on tumor growth. In contrast, in an MCF-7 xenograft preventive model, a 1-mg hu3S193 dosage schedule was able to significantly slow tumor growth compared with placebo and isotype-matched control IgG1 antibody. hu3S193 has promise for immunotherapy of Ley-positive tumors and is currently entering Phase I clinical trials.

Amino Acid Sequence↗
PubMed2000

Women's health and complexity science.

Conceptual frameworks in science have shifted from reductionism and its focus on ever-smaller parts to complexity, an outgrowth of chaos theory that views those parts in relation to one another, to the larger entity they form and to the environment in which that entity exists. Examples of this conceptual shift are occurring in many areas of science, but nowhere is it more germane than in the medical sciences that serve women. After a historical focus on reproduction and the development of obstetrics-gynecology, medicine has now gained a broader view of the woman using sex- and gender-based science, and a new field called "women's health" is evolving. Complexity science does not invalidate or eliminate the need for reductionist science, it simply makes a wider array of phenomena understandable. Its method allows going beyond the metaphor of the body as a machine and challenges the user to re-examine how health and illness are understood. This article explores how these changes in science must inform the development of an academic discipline in women's health. The conceptual framework of complexity science also advances the discussions about women's health from reproduction to a totally new and exciting exploration of the interactions between reproduction and all other organ functioning that occurs in women in the contexts of their lives.

Curriculum↗
PubMed2000

Thirty-six-month outcome of prenatal cocaine exposure for term or near-term infants: impact of early case management.

Gestational cocaine use is associated with serious pregnancy complications having fetal and neonatal implications. However, many cocaine-abusing women deliver uneventfully at term. The purpose of this study was to assess the neurodevelopmental outcome for term or near-term infants after prenatal cocaine exposure and to determine whether that outcome would be modified by early, intensive family case management. Cocaine-exposed infants identified after delivery at an urban hospital were alternately assigned to receive case management (n = 70) or routine follow-up (n = 48). A matched, non-drug-exposed group of infants was identified for comparison (n = 41). Infants aged up to 36 months were serially evaluated in a multidisciplinary clinic with cognitive, psychomotor, and language testing. Group comparisons were performed using one-way analysis of variance. There were no statistical differences in mean cognitive, psychomotor, or language quotients between cocaine-exposed and non-drug-exposed infant groups aged up to 36 months. At 6 months of age, case-managed cocaine-exposed infants had a significantly higher mean Bayley Mental Developmental Index score than those who were routinely managed. However, no differences were present at subsequent assessments. Among cocaine-exposed infants who remained with their mothers at 36 months, verbal scores were significantly higher for case-managed compared with routine-managed infants. The negative effects of urban, low socioeconomic status may overshadow the impact of prenatal cocaine exposure on early childhood outcome for those infants born without prenatal complications.

Adult↗
PubMed2000

Quality in women's health: the organizing principles for the NAWH (National Association for Women's Health) trade association.

Quality in women's health care has been assessed with preventive measures such as mammograms and pap smears, and obstetrical measures, such as prenatal care. Although awareness about sex and gender differences among researchers, health professionals, and women themselves has grown dramatically over the last 10 years, health care policy and medical education have not been influenced to any significant degree. Sex and gender differences have not been developed for a wider range of services, such as diagnosis and treatment of acute or chronic conditions, outside of reproductive health. This article reviews contemporary women's health issues and discusses the need for collaboration among multiple stakeholder groups within the health care industry to address quality in women's health care.

Consumer Organizations↗
PubMed1999

A randomized controlled clinical trial comparing ventricular fibrillation detection time between two transvenous defibrillator models. The Acute Ventak AV investigator group.

The Ventak AV is an implantable cardioverter defibrillator with dual chamber pacing capability. Features include detection and treatment of ventricular arrhythmias, detection of atrial arrhythmias, as well as dual chamber pacing. The objective of the investigation was to verify the efficacy of the Ventak AV in detecting ventricular fibrillation in the presence of dual chamber pacing. Thirty-three patients, who were to receive an implantable defibrillator were randomized (1:1) in a paired comparison study to the Ventak AV (study device) and the Ventak Mini (control) during defibrillation threshold testing. In order to create a "worst case scenario" for sensing of ventricular fibrillation, pacing was performed at high lower rate limit values (Ventak AV DDD pacing at 150/min, Ventak Mini at VVI 100/min). Ventricularfibrillation was induced and the randomized device was allowed to detect and treat the arrhythmia. This test was repeated for each patient using the alternate device in a randomized order, such that all patients were tested with both devices. The mean ventricular fibrillation detection time for the Ventak AV was 2.0+/-0.11 seconds and for the control device the detection time was 1.8+/-0.11 seconds (P = 0.26). Appropriate tachyarrhythmia therapy decision was documented in all episodes for both devices. The study patient population demonstrated equivalent ventricular fibrillation detection time between the Ventak AV and the Ventak Mini. The Ventak AV demonstrated effectiveness in detecting ventricular fibrillation in the presence of high rate dual chamber pacing.

Adult↗
PubMed1999

MR imaging findings in children with merosin-deficient congenital muscular dystrophy.

BACKGROUND AND PURPOSE: Our purpose was to determine the brain MR imaging characteristics of merosin-deficient congenital muscular dystrophy in children. METHODS: We reviewed the MR imaging findings of the brain in three children with known merosin-deficient congenital muscular dystrophy to determine the presence of any cerebral or cerebellar abnormalities of development or abnormalities of the white matter. RESULTS: In all three patients, there was normal formation of the cerebrum, the cerebellum, and no evidence of neuronal migration anomalies. All three patients had abnormal white matter in the cerebrum, with sparing of the corpus callosum, internal capsule, cerebellum, and brain stem. CONCLUSION: MR imaging of the brain in children with merosin-deficient congenital muscular dystrophy reveals a consistent pattern of white matter abnormality. We postulate that disruption of the blood-brain barrier associated with merosin deficiency leads to increased water content, resulting in abnormal white matter signal intensity.

Brain↗
PubMed1999

Does lesion size affect the outcome in avascular necrosis?

The size of the necrotic lesion may be a significant factor in predicting outcome and determining treatment in hips with avascular necrosis. However, to date most reports on the treatment of this condition have not attempted to correlate outcome with lesion size. Seventy-three hips with avascular necrosis were evaluated, 11 in Stage I and 62 in Stage II. All were treated with core decompression and bone grafting. Patients were followed up 2 to 6 years (mean, 39 months). The results were determined by change in Harris hip score, degree of radiographic progression, and the need for total hip replacement. Outcome was correlated with the lesion size, stage, etiology, and other factors. In Stage I, the true three-dimensional size of the lesion was measured with a new technique of quantitative magnetic resonance imaging. In Stage II, measurements were obtained from radiographs using a modular system for quantitative digital analysis. Hips were divided into three groups based on lesion size: Group A, less than 15% of femoral head involvement; Group B, 15% to 30%; and Group C, greater than 30%. There were no significant differences in outcome between Stages I and II and no relationship to etiology or other demographic factors. When correlated with lesion size, radiographs on a 21-point scale showed progression by 1.1, 4.2, and 4.3 points; the Harris hip score showed an improvement of 10.6 and 3.3 points and a loss of 3.6 points; and total hip replacement was required in 7%, 31%, and 33% of Group A, B, and C lesions, respectively. The difference in outcome between small lesions and large or medium lesions was statistically significant, but no significant differences were seen between medium and large lesions. These observations emphasize the importance of lesion size in predicting outcome after core decompression and grafting and possibly after other surgical and nonsurgical methods of managing hips with avascular necrosis. They also encourage the use of methods of evaluation and staging that include a determination of lesion size and stage.

Arthroplasty, Replacement, Hip↗
PubMed1998

Myotonic dystrophy: molecular windows on a complex etiology.

Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, with an incidence of approximately 1 in 8500 adults. DM is caused by an expanded number of trinucleotide repeats in the 3'-untranslated region (UTR) of a cAMP-dependent protein kinase (DM protein kinase, DMPK). Although a large number of transgenic animals have been generated with different gene constructions and knock-outs, none of them faithfully recapitulates the multisystemic and often severe phenotype seen in human patients. The transgenic data suggest that myotonic dystrophy is not caused simply by a biochemical deficiency or abnormality in the DM kinase gene product. Emerging studies suggest that two novel pathogenetic mechanisms may play a role in the disease: the expanded repeats appear to cause haploinsufficiency of a neighboring homeobox gene and also abnormal DMPK RNA appears to have a detrimental effect on RNA homeostasis. The complex, multisystemic phenotype may reflect an underlying multifaceted molecular pathophysiology: the facial dysmorphology may be due to pattern defects caused by haploinsufficiency of the homeobox gene, while the muscle disease and endocrine abnormalities may be due to both altered RNA metabolism and deficiency of the cAMP DMPK protein.

Adult↗
PubMed1998

An Experimental Investigation of the Incentives to Form Agricultural Marketing Pools.

This paper presents theoretical extensions and laboratory tests of Hoffman and Libecap's (1994) model of individual firms' incentives to form agricultural marketing pools. The key incentives are lower variance in output prices and economies in scale in marketing. This paper extends the model by formulating the pooling problem as a game of incomplete information in which firms have heterogeneous and private risk attitudes. An experiment is conducted to test the theoretical implications of this model. Statistical analysis of the experimental data supports the model predictions of pooling rates, but also reveals that subjects form systematic probability biases and do not behave as strategically as the model suggests. Copyright 1998 Academic Press.

Journal Article↗