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Biomedical subjects

J A Cohen

Publications and source records attributed to J A Cohen.

At least 19 recordsLinked to original sources
PubMed2000

Murine macrophages stimulated with central and peripheral nervous system myelin or purified myelin proteins release inflammatory products.

Macrophage inflammatory products including tumor necrosis factor (TNF) and interleukin-12/p40 are implicated in demyelinating diseases such as multiple sclerosis (MS), Guillain-Barré syndrome, and animal models experimental autoimmune encephalomyelitis and neuritis. The macrophage product angiotensin converting enzyme (ACE) is released during inflammation. ACE can also be elevated in MS. We investigated the ability of central (CNS) and peripheral nervous system (PNS) myelin to stimulate TNF, interleukin-12, and ACE production by murine macrophages. Both CNS and PNS myelin and purified myelin basic protein and P2 protein induced release of these products. Direct stimulation by myelin may represent a mechanism of inducing release of macrophage products in inflammatory demyelination or neural injury.

Animals↗
PubMed2000

Intrarater and interrater reliability of the MS functional composite outcome measure.

OBJECTIVE: To assess practice effects, and intrarater and interrater reliability of the MS functional composite (MSFC) outcome measure. BACKGROUND: To address the poor reliability and insensitivity to change of available MS clinical rating scales, the National MS Society's Clinical Outcomes Assessment Task Force developed the MSFC, a multidimensional quantitative clinical outcome measure that includes tests of leg function/ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). METHODS: Ten patients with secondary progressive MS underwent six testing sessions over a 2-week period. The MSFC was administered by the same examining technician in the first five sessions and by the other technician in the sixth. Patients were reassessed by both technicians after 6 months (sessions 7 and 8). The MSFC score was calculated as the mean of the Z scores of the three components. A pooled dataset derived from secondary progressive MS patients in the placebo arms of previous clinical trials and natural history studies served as the reference population to standardize scores. RESULTS: Practice effects were evident initially but stabilized by the fourth administration. The intraclass correlation coefficient (ICC) was 0.97 for the MSFC for session 4 versus session 5 (intrarater reliability). The ICC was 0.95 for session 5 versus session 6 (interrater reliability), and was 0.96 for session 7 versus session 8 when patients were reassessed 6 months later. CONCLUSIONS: The MS functional composite (MSFC) outcome measure had excellent intrarater and interrater reliability when standardized procedures were used to train examining technicians and to assess patients. Prebaseline testing sessions should be included in clinical trials employing the MSFC to compensate for practice effects.

Humans↗
PubMed2000

Glatiramer acetate (Copaxone) treatment in relapsing-remitting MS: quantitative MR assessment.

OBJECTIVE: To evaluate the efficacy of glatiramer acetate (GA, Copaxone; Teva Pharmaceutical Industries, Ltd., Petah Tiqva, Israel) by MRI-based measures in patients with relapsing-remitting (RR) MS. METHODS: Twenty-seven patients with clinically definite RR-MS were treated with either 20 mg of GA by daily subcutaneous self-injection (n = 14) or placebo (n = 13) for approximately 24 months. Axial dual-echo fast-spin-echo T2-weighted images and T1-weighted images before and after gadolinium (Gd) were acquired at 1.5 tesla and transferred into an image processing computer system. The main outcome measures were the number of Gd-enhanced T1 and T2 lesions and their volume as well as brain parenchyma volume. RESULTS: The values of age, disease duration, Expanded Disability Status Scale (EDSS) score, the number of T1- and T2-weighted lesions, and their volume were similar between GA- and placebo-receiving groups at the entry of this study. There was a decrease in the number of T1-enhanced lesions (p = 0.03) and a significant percent annual decrease of their volume in GA recipients compared with those of placebo recipients. There were no significant differences between changes in the two groups in the number of T2 lesions and their volume. The loss of brain tissue was significantly smaller in the GA group compared with that of the placebo group. CONCLUSIONS: These results show that GA treatment may decrease both lesion inflammation and the rate of brain atrophy in RR-MS.

Adult↗
PubMed2000

The potential for vigabatrin-induced intramyelinic edema in humans.

PURPOSE: Vigabatrin (Sabril, Hoechst Marion Roussel) is an antiepilepsy drug (AED) presently marketed in 64 countries for the treatment of partial and secondarily generalized seizures. Vigabatrin (VGB) is marketed in a subset of these countries for the treatment of infantile spasms. Clinical experience in humans has shown that VGB provides effective seizure control with a wide margin of safety. However, animal toxicity studies raised concern when prolonged administration of VGB was shown to induce intramyelinic edema (IME) in some laboratory animal species. METHODS: Animal and human data were reviewed with respect to the potential for VGB-induced IME. Surveillance of patients receiving VGB in clinical trials or by prescription has been conducted for >15 years to identify patients developing clinical abnormalities that might be IME related. RESULTS: The histologic lesions of VGB-induced IME in animals are reliably reproduced and correlate with changes in multimodality evoked potentials (EPs) and magnetic resonance imaging (MRI). Numerous studies of the effects of VGB on EP and MRI in epilepsy patients have demonstrated no clear-cut IME-related changes in these modalities. Additionally, autopsy and surgical brain samples from VGB-treated patients have been scrutinized for potential IME histopathology. In an estimated 350,000 patient-years of VGB exposure (approximately 175,000 patients exposed for 2 years at an average dose of 2 g/day), no definite case of VGB-induced IME has been identified. CONCLUSIONS: Comprehensive review of a variety of sources of data failed to identify any definite case of IME in humans treated with VGB.

Animals↗
PubMed1999

Therapy of relapsing multiple sclerosis. Treatment approaches for nonresponders.

There is increasing impetus to begin disease-modifying therapy for relapsing multiple (R-MS) early, before the development of irreversible tissue damage and resultant permanent disability. However, all of the currently-approved therapies for relapsing multiple sclerosis are only partially effective for patients as a group. Treatment failure can be due to noncompliance with therapy, intolerable adverse effects, the development of neutralizing antibodies, or non-responsive disease. Neurologists managing patients on disease-modifying therapy for R-MS must remain vigilant for these issues and take appropriate action when necessary.

Anti-Inflammatory Agents↗
PubMed1999

Suture loop to aid in ganciclovir implant removal.

BACKGROUND: The ganciclovir implant (Vitrasert; Bausch & Lomb Inc, Claremont, Calif) has been a useful device in the management of cytomegalovirus retinitis. Seven months after placement, implant exchange is often considered. However, removal may be difficult and may result in vitreous hemorrhage or intraocular dislocation. OBJECTIVE: To describe a suture loop attached to the implant strut and left in the sub-Tenon space to aid in implant removal. METHODS: Twenty-five eyes of 17 patients received a ganciclovir implant with an 8-0 nylon suture loop left beneath the Tenon capsule and underwent at least 6 months of follow-up. Two of these eyes subsequently had a similarly modified ganciclovir implant placed at a separate site (inferonasally) with at least 6 additional months of follow-up. Six eyes of 3 patients had the implant removed as part of an exchange and underwent at least 4 months of follow-up. RESULTS: In the 25 eyes, there were no cases of endophthalmitis, wound leak, suture exposure, or other complications. At implant removal in the 6 eyes previously mentioned, the loop was used for traction on the implant and aided in localization of the implant strut. In these 6 eyes, there were no cases of retinal or choroidal detachment, visually significant vitreous hemorrhage, implant dislocation, or other complications. CONCLUSION: A sub-Tenon capsule suture loop is well tolerated and can assist in ganciclovir implant removal.

Adult↗
PubMed1999

Total homocysteine is associated with nephropathy in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) and hyperhomocysteinemia are both associated with premature vascular disease. We tested the hypothesis that homocysteine is associated with vascular disease and other diabetic complications in patients with NIDDM. The current investigation is a cross-sectional analysis of baseline variables for participants in the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial. Men and women aged 40 to 74 years with NIDDM and a mean diastolic blood pressure (BP) of 80 mm Hg or higher were eligible. We measured serum levels of total homocysteine (tHcy), cystathionine, and methylmalonic acid (MMA) and correlated these values with clinical and other laboratory measures of the complications of diabetes mellitus in 452 subjects. tHcy was higher in males than in females and correlated with the duration of hypertension and systolic BP. tHcy was significantly correlated with MMA (r = .35, P < .0001) and cystathionine (r = .53, P < .0001) levels and inversely correlated with serum B12 (r = -.23, P < .0001) and folate (r = -.18, P < .0001). It was significantly correlated with serum creatinine (r = .28, P < .0001 for males and r = .39, P < .0001 for females) and inversely correlated with creatinine clearance (r = -.19, P < .005 for males and r = -.30, P < .0001 for females). tHcy was not increased in subjects with cardiovascular disease or retinopathy, but it was increased in those with neuropathy (10.3 v 9.3 micromol/L, P < .05) and macroalbuminuria (11.0 v 9.2 micromol/L, P < .005). Of these subjects, 2.2% met the criteria for vitamin B12 deficiency and 1% met the criteria for folate deficiency. We conclude that elevations of tHcy in this population appear to be the result of a combination of vitamin deficiency and decreased renal function and do not appear to be a predictor of cardiovascular disease.

Adult↗
PubMed1999

Sumatriptan treatment for migraine in a health maintenance organization: economic, humanistic, and clinical outcomes.

This study was undertaken to assess the impact of 12 months of sumatriptan therapy (6 mg subcutaneously) for migraine on health care use, health-related quality of life, productivity, patient satisfaction with the medication, and clinical efficacy in a health maintenance organization (HMO). One hundred forty-eight patients received open-label sumatriptan for 12 months for the treatment of migraine. Medical records were reviewed to obtain information on the frequency of migraine-related health care use during the 12 months before and during sumatriptan treatment. Patients completed questionnaires on their productivity at work, health-related quality of life, and satisfaction with medication at baseline and after 3, 6, and 12 months of sumatriptan treatment. For each migraine, patients recorded pain severity scores before and after taking sumatriptan and the time between dosing and onset of meaningful relief. Sumatriptan was associated with significant reductions in migraine-related use of general outpatient services, telephone calls, urgent care services, and emergency department visits (P < 0.05); a significant increase in the use of pharmacy services (P < 0.05); and significant and sustained improvements in health-related quality-of-life scores compared with baseline (P < 0.001). Patients lost significantly less time from work and were significantly more satisfied with sumatriptan compared with their usual therapy (P < 0.05). Two hours after dosing, 81% of patients experienced reduction of moderate or severe pain to mild or no pain, and 90% of all patients experienced meaningful relief of pain. The use of sumatriptan for 12 months in an HMO was associated with reductions in health care use and improved health-related quality of life, productivity, and patient satisfaction with medication.

Adult↗
PubMed1999

Quantification of axonal damage in traumatic brain injury: affinity purification and characterization of cerebrospinal fluid tau proteins.

Diffuse axonal injury is a primary feature of head trauma and is one of the most frequent causes of mortality and morbidity. Diffuse axonal injury is microscopic in nature and difficult or impossible to detect with imaging techniques. The objective of the present study was to determine whether axonal injury in head trauma patients could be quantified by measuring levels of CSF tau proteins. Tau proteins are structural microtubule binding proteins primarily localized in the axonal compartment of neurons. Monoclonal antibodies recognizing the form of tau found in the CSF of head trauma patients were developed by differential CSF hybridoma screening using CSF from head trauma and control patients. Clones positive for head trauma CSF tau proteins were used to characterize this form of tau and for ELISA development. Using the developed ELISA, CSF tau levels were elevated >1,000-fold in head trauma patients (mean, 1,519 ng/ml of CSF) when compared with patients with multiple sclerosis (mean, 0.014 ng/ml of CSF; p < 0.001), normal pressure hydrocephalus (nondetectable CSF tau), neurologic controls (mean, 0.031 ng/ml of CSF; p < 0.001), or nonneurologic controls (nondetectable CSF tau; p < 0.001). In head trauma, a relationship between clinical improvement and decreased CSF tau levels was observed. These data suggest that CSF tau levels may prove a clinically useful assay for quantifying the axonal injury associated with head trauma and monitoring efficacy of neuroprotective agents. Affinity purification of CSF tau from head trauma patients indicated a uniform cleavage of approximately 18 kDa from all six tau isoforms, reducing their apparent molecular sizes to 30-50 kDa. These cleaved forms of CSF tau consisted of the interior portion of the tau sequence, including the microtubule binding domain, as judged by cyanogen bromide digestion. Consistent with these data, CSF cleaved tau bound taxol-polymerized microtubules, indicating a functionally intact microtubule binding domain. Furthermore, epitope mapping studies suggested that CSF cleaved tau proteins consist of the interior portion of the tau sequence with cleavage at both N and C terminals.

Alzheimer Disease↗
PubMed1999

Glycated albumin stimulation of PKC-beta activity is linked to increased collagen IV in mesangial cells.

Albumin modified by Amadori-glucose adducts induces coordinate increases in the expression of extracellular matrix proteins, transforming growth factor (TGF)-beta1, and the TGF-beta type II receptor in glomerular mesangial cells. Because activation of protein kinase C (PKC) accompanies the increased mesangial cell expression of matrix proteins and TGF-beta1 induced by high ambient glucose, we postulated that glycated albumin (GA) modulates PKC activity and that PKC participates in mediating the GA-induced stimulation of matrix production. To test this hypothesis, we examined the effects of PKC inhibitors on collagen type IV production by mouse or rat mesangial cells incubated with GA, and the influence of GA on PKC activity in these cells. Increased collagen type IV production evoked by GA in 5.5 and 25 mM glucose in mouse mesangial cells was prevented by both general (GF-109203X) and beta-specific (LY-379196) PKC inhibitors. Total PKC activity, measured by phosphorylation of a PKC-specific substrate, increased with time after exposure of rat mesangial cells to GA compared with the nonglycated, glucose-free counterpart. GA caused an increase in PKC-beta1 membrane-bound fraction and in total PKC activity in media containing physiological (5.5 mM) glucose concentrations in rat mesangial cells, confirming that the glucose-modified protein, and not a "hyperglycemic" milieu, was responsible. The findings indicate that Amadori-modified albumin stimulates mesangial cell PKC activity, and that activation of the PKC-beta isoform is linked to the stimulation of collagen type IV production.

Animals↗
PubMed1999

Identification of the A-band localization domain of myosin binding proteins C and H (MyBP-C, MyBP-H) in skeletal muscle.

Although major constituents of the thick filaments of vertebrate striated muscles, the myosin binding proteins (MyBP-C and MyBP-H) are still of uncertain function. Distributed in the cross-bridge bearing zone of the A-bands of myofibrils, in a series of transverse 43 nm stripes, the proteins are constructed of a tandem series of small globular domains, each composed of approximately 90-100 amino acids, which have sequence similarities to either the C2-set of immunoglobulins (IgC2) and the fibronectin type III (FnIII) motifs. MyBP-C is composed of ten globular domains ( approximately 130 kDa) whereas MyBP-H is smaller ( approximately 58 kDa) and consists of a unique N-terminal segment followed by four globular domains, the order of which is identical to that of MyBP-C (FnIII-IgC2-FnIII-IgC2). To improve our understanding of this protein family we have characterized the domains in each of these two proteins which are required for targeting the proteins to their native site(s) in the sarcomere during myogenesis. Cultures of skeletal muscle myoblasts were transfected with expression plasmids encoding mutant constructs of the MyBPs bearing an N-terminal myc epitope, and their localization to the A-band examined by immunofluorescence microscopy. Based on the clarity and intensity of the myc A-band signals we concluded that constructs encoding the four C-terminal motifs of MyBP-C and MyBP-H ( approximately 360 amino acids) were all that was necessary to efficiently localize each of these peptides to the A-band. Truncation mutants lacking one of these 4 domains were less efficiently targeted to the C-zone of the sarcomere. Deletion of the last C-terminal motif of MyBP-H, its myosin binding domain, abolished all localization to the A-band. A chimeric construct, HU-3C10, in which the C-terminal motif of MyBP-H was replaced by the myosin binding domain of MyBP-C, efficiently localized to the A-band. Taken together, these observations indicate that MyBP-C and MyBP-H are localized to the A-band by the same C-terminal domain, composed of two IgC2 and two FnIII motifs. A model has been proposed for the interaction and positioning of the MyBPs in the thick filament through a ternary complex of the four C-terminal motifs with the myosin rods and titin.

Animals↗
PubMed1998

Risks for sensorimotor peripheral neuropathy and autonomic neuropathy in non-insulin-dependent diabetes mellitus (NIDDM).

Identification of risk factors for development of diabetic sensorimotor peripheral neuropathy (DSPN) and diabetic autonomic neuropathy (DNA) may help to prevent or modify these complications. The ABCD Trial, a prospective study of diabetic complications, has identified risk factors of the presence and staging of peripheral neuropathy based on neurological symptom scores, neurological disability scores, autonomic function testing and quantitative sensory examination. DSPN is independently associated with diabetes duration [odds ratio (OR) = 1.5 per 10 years], body weight (OR = 1.1 per 5 kg), age (OR = 1.8 per 10 years), retinopathy (OR = 2.3), overt albuminuria (OR = 2.5), height (OR = 1.2 per 10 cm), duration of hypertension (OR = 1.1 per 10 years), insulin use (OR = 1.4), and race/ethnicity [African American vs. non-Hispanic white (OR = 0.4) and Hispanic vs. non-Hispanic white (OR = 0.8)]. DAN is independently associated with diabetes duration (OR = 1.2 per 10 years), body weight (OR = 1.1 per 5 kg), glycosylated hemoglobin (OR = 1.1 per 2.5%), overt albuminuria (OR = 1.6), and retinopathy (OR = 1.8).

Adult↗
PubMed1998

Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura.

Elevated serum lactate dehydrogenase (LDH) is a characteristic finding in patients with thrombotic thrombocytopenic purpura (TTP). It is widely accepted that total serum LDH principally rises due to the release of red blood cell LDH as a consequence of intravascular hemolysis. To identify the cellular source of serum LDH in TTP, we prospectively analyzed total serum LDH and LDH isoenzyme profiles in 10 consecutive patients with classic, acute idiopathic TTP within 5 days of clinical presentation. Total LDH was quantitated on a Hitachi 911 Analyzer (Indianapolis, IN), using the lactate to pyruvate reaction. LDH isoenzymes were measured by serum protein electrophoresis, using the Beckman LDH Isoenzyme Kit (Anaheim, CA). Isoenzymes attributable to erythrocytes (LDH1, LDH2) were not disproportionately elevated in 9 of 10 patients. LDH3 was below or within normal limits for all 10 patients, and one patient showed a slightly increased LDH4. Serum LDH5, the isoenzyme derived primarily from liver and skeletal muscle, was elevated 1-2 times normal in all patients. Evidence supporting hemolysis as the major contribution to the elevated total serum LDH frequently encountered in acute TTP was not identified in this study. The isoenzyme fractions LDH and LDH2 elevated by erythrocyte injury were not disproportionately elevated in this series. LDH 5, the isoenzyme found in skeletal muscle and liver, was consistently 1- to 2-fold greater than normal in all patients. We propose that the elevation of serum LDH seen in patients with TTP is due to release of LDH from a variety of tissues damaged as a result of systemic ischemia.

Erythrocytes↗
PubMed1998

Glycated albumin stimulates fibronectin gene expression in glomerular mesangial cells: involvement of the transforming growth factor-beta system.

Albumin modified by Amadori glucose adducts, formed in increased amounts in diabetes, stimulates collagen IV production and gene expression in renal glomerular mesangial cells, and induces mesangial matrix accumulation accompanied by increased mRNA encoding alpha 1 (IV) collagen and fibronectin in diabetic animals. These effects contribute to the pathogenesis of diabetic nephropathy, and resemble biologic activities of the cytokine TGF-beta 1, which also has been causally implicated in diabetic renal disease. We postulated that Amadori-modified glycated albumin modulates TGF-beta 1 expression in mesangial cells, and that TGF-beta 1 participates in mediating the glycated albumin-induced increases in mesangial cell matrix production. To test this hypothesis, we measured mRNA encoding TGF-beta 1, the TGF-beta Type II receptor and fibronectin, a key matrix component of the TGF-beta 1 tissue response, after incubation of mesangial cells with glycated albumin. Steady state levels of the mRNAs encoding for these proteins were stimulated when mesangial cells were cultured in the presence of albumin containing Amadori glucose adducts compared with levels in cells cultured with the nonglycated, glucose-free counterpart. The glycated protein-induced changes in mRNA expression were observed with concentrations of glycated albumin encompassing those found in clinical specimens and in media containing physiologic (5.5 mM) glucose concentrations, indicating that they were due to the glucose-modified protein and not to a hyperglycemic milieu. Further, they were accompanied by increased translated fibronectin protein, which was prevented with TGF-beta neutralizing antibody, as was the glycated albumin-induced increase in fibronectin mRNA. The findings indicate that Amadori-modified glycated albumin stimulates mesangial cell TGF-beta 1 gene expression by mechanisms that are operative under normoglycemic conditions. These data provide the first link between elevated glycated serum albumin concentrations and increased TGF-beta 1 bioactivity in the pathogenesis of mesangial matrix accumulation in diabetes.

Animals↗
PubMed1998

Factors that mediate treatment outcome of sexually abused preschool children: six- and 12-month follow-up.

OBJECTIVE: The role of familial, demographic, developmental, and treatment-mediating factors on treatment outcome of sexually abused preschool children was evaluated 6 and 12 months after treatment. METHOD: Forty-three sexually abused preschool children and their parents who were evaluated shortly after disclosure of sexual abuse and then were provided with one of two treatment interventions were reevaluated at the completion of treatment and 6 and 12 months after treatment. Parents completed the Child Behavior Checklist, the Child Sexual Behavior Inventory, and the Weekly Behavior Report to measure a variety of emotional and behavioral symptoms in children. Parents also completed the Beck Depression Inventory, the Family Adaptability and Cohesion Evaluation Scales-III, the Parent Emotional Reaction Questionnaire, the Parental Support Questionnaire, and the Maternal Social Support Index. Children completed the Battelle Developmental Inventory and the Peabody Picture Vocabulary Test at pretreatment to assess developmental levels. RESULTS: Correlational and stepwise multiple regression analyses were conducted to analyze the role of the hypothesized mediating variables in predicting scores on outcome measures across the two treatment groups. While the Parent Emotional Reaction Questionnaire was the strongest familial predictor of treatment outcome at posttreatment, parental support became a stronger predictor of outcome at the 6- and 12-month follow-up points. Treatment group was the strongest overall predictor of outcome at posttreatment and at 12-month follow-up. Demographic and developmental factors did not strongly predict outcome. CONCLUSIONS: Findings indicate the strong impact of parental support on treatment outcome in sexually abused preschool children over the course of a 12-month follow-up and emphasize the importance of including parental interventions in treating sexually abused preschool children. They also support the superior effectiveness of cognitive-behavioral therapy over supportive counseling for this population.

Analysis of Variance↗