Biomedical subjects

J Schoenfeld

Publications and source records attributed to J Schoenfeld.

17 recordsLinked to original sources

PubMed2001

Generation of a humanized, high affinity anti-tissue factor antibody for use as a novel antithrombotic therapeutic.

Blocking the cofactor function of human tissue factor may be beneficial in various coagulation-mediated diseases. The murine antibody D3 binds to the membrane proximal substrate interaction region of human tissue factor and blocks tissue factor function even in the presence of bound factor VIIa. The cloned murine D3 antibody was humanized and affinity matured by exchanging amino acids in the complementarity determining regions as well as in the antibody framework. The humanized antibody, D3H44, bound to tissue factor with a 100-fold increased affinity (KD 0.1 nM) as compared to the original murine and chimeric versions. Depending on the particular disease, different pharmacokinetic properties of the antibody may be required and, therefore, several antibody variants-- F(ab), F(ab')2, IgG2, IgG4 and IgG4b-were generated. In vitro, the humanized D3 antibodies displayed potent inhibition of plasma clotting and tissue factor: factor VIIa-mediated activation of factors IX and X (e.g. D3H44-F(ab')2, IC50(F.X) 47 pM). In addition, D3H44-F(ab')2 completely prevented fibrin deposition in a human ex vivo thrombosis model under venous blood flow conditions (IC50 37 nM). The humanized D3 antibodies may be utilized for treatment of cardiovascular diseases which involve tissue factor activity, e.g. acute coronary syndrome and venous thrombosis.

Amino Acid Sequence↗

PubMed2000

Effects of growth hormone on cardiac dysfunction and gene expression in genetic murine dilated cardiomyopathy.

Beneficial cardiac effects of growth hormone (GH) have been shown in heart failure in several settings, but studies are lacking on this and other forms of treatment in the cardiomyopathic (CM) mouse heart. In mice with dilated cardiomyopathy due to disruption of the muscle LIM protein (MLP) gene [MLP null mice (MLP-/-)], natural history was first assessed by an initial echocardiogram at 8 weeks and a later follow-up study (n = 31). In most mice, left ventricular (LV) dilation increased and/or function decreased by 5 months, and 3 of 12 mice followed for 9 months died. At the end of follow-up, 22 MLP-/- mice (average age 10.2 months) had both LV dilation and reduced LV function and were selected for studies of GH effects on cardiac function and gene expression; mice were randomized to vehicle (controls) or recombinant human (rh) GH and restudied after 2 weeks. In the GH-treated group compared to the control group, LV % fractional shortening and LV wall thickness (echocardiography) were increased, the LV dP/dtmax (catheter-tip micromanometry) was enhanced, and LV relaxation (tau) improved; however, the LV weight was not significantly increased. The LV expression of many genes was altered in MLP-/- mice, and several were influenced by GH. Thus, short-term RhGH treatment improved LV function in a setting of chronic cardiac deterioration and significantly reduced elevated LV mRNA expression of some (ANP, BNP) but not other members of the embryonic gene program. The MLP null cardiomyopathic mouse can be useful for exploring altered signaling and therapeutic interventions in heart failure.

Animals↗

PubMed2000

Gene expression profiling in an in vitro model of angiogenesis.

In the present study we have used a novel, comprehensive mRNA profiling technique (GeneCalling) for determining differential gene expression profiles of human endothelial cells undergoing differentiation into tubelike structures. One hundred fifteen cDNA fragments were identified and shown to represent 90 distinct genes. Although some of the genes identified have previously been implicated in angiogenesis, potential roles for many new genes, including OX-40, white protein homolog, KIAA0188, a homolog of angiopoietin-2, ADAMTS-4 (aggrecanase-1), and stanniocalcin were revealed. Support for the biological significance was confirmed by the abrogation of the changes in the expression of angiogenesis inhibitors and in situ hybridization studies. This study has significantly extends the molecular fingerprint of the changes in gene expression that occur during endothelial differentiation and provides new insights into the potential role of a number of new molecules in angiogenesis.

Cells, Cultured↗

PubMed1999

Neuropsychological and behavioral status of children with complex partial seizures.

Neuropsychological and behavioral status were examined in 57 children aged 7 to 16 years with complex partial seizures (CPS) and compared with 27 sibling control children of the same age. Epilepsy had a significant effect on both cognitive and behavioral adjustment measures. Children with CPS had significant impairment across all seven cognitive domains assessed, reflective of a profile of relatively diffuse and generalized cognitive dysfunction. Age at onset of recurrent seizures was the strongest and most consistent predictor of adequacy of cognitive functioning; earlier age at onset was associated with poorer cognitive status. Children with CPS also had more problems compared with sibling control children on measures of social and school competence and internalizing behavior problems, but not externalizing behaviors. Further, frequency of seizure activity in the past year, rather than age at seizure onset, emerged as the strongest predictor of these behavioral difficulties. These findings are discussed in the context of understanding the impact of CPS on cognition and behavioral adjustment, and identifying the contribution of various aspects of the neurodevelopmental course of CPS to these issues.

Achievement↗

PubMed1997

Neuropsychological characteristics of the syndrome of mesial temporal lobe epilepsy.

OBJECTIVE: To identify the neuropsychological features of the syndrome of mesial temporal lobe epilepsy (MTLE), a surgically remediable epileptic syndrome defined by the presence of hippocampal sclerosis, using a broad and comprehensive neuropsychological test battery. SETTING: Epilepsy surgery center. PATIENTS: After scalp adn invasive electroencephalographic monitoring, a consecutive series of 107 adults were found to have intractable complex partial seizures of unilateral left (n = 62) or right (n = 45) temporal lobe origin. Patients were included if they were not retarded and had left hemisphere dominance for speech but no magnetic resonance imaging abnormalities other than hipocampal sclerosis. Histopathological analyses of resected hippocamppi showed that 66 patients had hippocampal sclerosis (MTLE+), and 41 did not have evidence of significant hippocampal sclerosis (MTLE-). INTERVENTIONS: None. MAIN DEPENDENT MEASURES: A comprehensive battery of neuropsychological tests that included measures of intelligence, academic achievement, language, visuoperceptual or visuospatial function, memory and learning, attention, and problem-solving abilities. RESULTS: The syndrome of MTLE was associated with considerable generalized cognitive impairment (in intelligence, academic achievement, language, and visuospatial functions), but not related to adequacy of performances in other selected cognitive domains (attention or concentration, executive functions). Material-specific memory effects were obtained-primarily for verbal memory in association with left-sided MTLE. CONCLUSIONS: Distinct neuropsychological features of spared, compromised, and laterality-specific cognitive impairments characterize the syndrome of MTLE. This information needs to be incorporated into formal syndrome criteria.

Adult↗

PubMed1997

Reorganization of verbal memory function in early onset left temporal lobe epilepsy.

The purpose of this investigation was to examine the issue of reorganization of verbal memory function following early insult to the left mesial temporal region. It was hypothesized that reorganization of memory function was most likely to occur in those patients with an early age of seizure onset who have a more limited degree of extra-hippocampal neuropathology. Fifty-four patients with epilepsy of unequivocal left temporal lobe origin were classified into four groups on the basis of the presence/absence of hippocampal sclerosis and degree of postoperative seizure relief. Measures of verbal learning and memory as well as nonmemory measures were administered both before and 6 to 8 months after anterior temporal lobectomy. Findings were consistent with the reorganization proposal. The clinical and theoretical significance of the findings are discussed.

Adult↗

PubMed1996

Hippocampal sclerosis and verbal encoding ability following anterior temporal lobectomy.

Previous research has shown that the degree of verbal memory decline following left anterior temporal lobectomy (ATL) is inversely related to the extent of neuronal dropout in resected left hippocampus. The goal of this investigation was to clarify further the nature of the free recall impairment and to determine the relative contribution of verbal retrieval and encoding processes. Seventy-six patients who underwent left (n = 46) or right (n = 30) ATL were classified according to the presence or absence of hippocampal sclerosis and pre- to postoperative changes in free recall, cued recall and recognition memory for verbal material were examined. Surgically induced free recall impairments were selectively associated with resection of nonsclerotic left hippocampus and represented a 29-35% decline in verbal learning ability. These free recall deficits were due to postoperative impairment in verbal encoding efficiency, not retrieval difficulties. Assessment of false positive recognition errors indicated that resection of nonsclerotic left hippocampus selectively impaired the ability to encode stimulus uniqueness within correct semantic fields. The clinical and theoretical significance of these results are discussed.

Adult↗

PubMed1996

Empirical techniques for determining the reliability, magnitude, and pattern of neuropsychological change after epilepsy surgery.

PURPOSE: We assessed test-retest neuropsychological performance in patients with complex partial seizures to derive reliable change indices (RCIs) and regression-based norms for change, indices that may be helpful in assessing cognitive outcome after anterior temporal lobectomy. METHODS: Forty patients with complex partial seizures (CPS) who did not undergo epilepsy surgery were administered a comprehensive neuropsychological battery on two occasions. Their test-retest data were used to compute both RCIs and regression-based norms for change for each neuropsychological index. RCIs corrected for practice effects provide a confidence interval (CI) indicating the degree of performance change required to exceed the variability attributable to sources of error (e.g., practice, test-retest reliability). Regression-based norms for change also correct for several sources of measurement error and examine observed versus expected test-retest changes on a common metric, thereby facilitating determination of the degree and relative magnitude of change across cognitive domains. RESULTS: Mean changes in test-retest performance were generally modest, but were evident across several test measures. Our data indicate a considerable degree of individual variability in test-retest performance. CONCLUSIONS: RCIs and regression-based norms are complementary indexes and can be particularly useful in examining the test-retest performance of individual patients who undergo epilepsy surgery as well as in the more general investigation of cognitive outcome after epilepsy surgery.

Adult↗

PubMed1991

L-threonine in the treatment of spasticity.

Preclinical data indicate that the administration of the amino acid L-threonine increases glycine levels in rat spinal cord. In order to investigate glycinergic mechanisms in spasticity, and other signs of the upper motor syndrome, we gave 4.5 and 6.0 g/day of L-threonine to 18 patients with familial spastic paraparesis (FSP) according to a double-blind, crossover protocol. The response to treatment at the end of each 2-week period was based upon three measures: the physician's global impressions; the patients' global impressions; and semiquantitative ratings of strength, muscle tone, DTRs, walking, hopping, and running. Blood and CSF were collected during each treatment period for amino acid analyses. Based upon the severity rating scales, there was a statistically significant (p less than 0.02) decrease in motor impairment and spasticity during L-threonine administration compared to placebo treatment; significant treatment effects were not found on the physician's and patients' global impressions. Plasma and CSF levels of threonine increased significantly during L-threonine treatment but glycine levels did not change. These data indicate that L-threonine significantly suppressed the signs of spasticity even though the benefits were not clinically valuable.

Adult↗

PubMed1982