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Biomedical subjects

C Cohen

Publications and source records attributed to C Cohen.

At least 145 records · Page 8Linked to original sources
PubMed1997

Molecular polarity in tropomyosin-troponin T co-crystals.

New features of the structure and interactions of troponin T and tropomyosin have been revealed by electron microscopy of so-called double-diamond co-crystals. These co-crystals were formed using rabbit alpha2 tropomyosin complexed with troponin T from either skeletal or cardiac muscle, which have different lengths in the amino-terminal region, as well as a bacterially expressed skeletal muscle troponin T fragment of 190 residues that lacks the amino-terminal region. Differences in the images of the co-crystals have allowed us to establish the polarities of both the troponin T subunit and tropomyosin in the projected lattice. Moreover, in agreement with their sequences, the amino-terminal region of a bovine cardiac muscle troponin T isoform appears to be longer than that from the rabbit skeletal muscle troponin T isoform and to span more of the amino terminus of tropomyosin at the head-to-tail filament joints. Images of crystals tilted relative to the electron beam also reveal the supercoiling of the tropomyosin filaments in this lattice. Based on these results, a three-dimensional model of the double-diamond lattice has been constructed.

Animals↗
PubMed1997

Evidence for the involvement of dopamine receptors in ethanol-induced hyperactivity in mice.

Based on the hypothesis that drugs of abuse increase locomotor activity through mechanisms related to reinforcement, i.e. the mesolimbic dopamine (DA) system, ethanol-induced hyperactivity might provide a screening model to investigate the effect of ethanol on reward pathways. In the present study, ethanol had bidirectional effects on locomotion in mice: hyperactivity at low doses (2-3 g/kg) and sedation at high doses (4-5 g/kg). Such high doses induced a loss of righting reflex (LRR). The stimulant effect of ethanol was blocked by the D2/D3 antagonists, haloperidol (0.2 mg/kg) and tiapride (30-60 mg/kg), and by the D1 antagonist, SCH 23390 (0.03 mg/kg) whereas the non selective DA antagonist, clozapine decreased ethanol-induced hyperactivity at a dose (1 mg/kg) which also decreased activity in control animals. Unlike haloperidol and clozapine which potentiated LRR induced by ethanol, the selective DA antagonists, tiapride and SCH 23390, had no effect. Pretreatment with the D2/D3 agonist, quinpirole (0.1-0.3 mg/kg), reduced hyperactivity induced by ethanol presumably by stimulation of pre-synaptic receptors but did not change LRR. The D1 full agonist, SKF 81297 which produced hyperactivity by itself and the D1 partial agonist, SKF 38393, did not specifically affect ethanol-induced activities. The results indicate that activation of D1 and D2/D3 DA receptors is implicated in ethanol-induced hyperactivity whereas other mechanisms might mediate the sedative effects of ethanol. Tiapride and haloperidol, both used in the management of alcohol dependence, might exert beneficial effects by counteracting the reinforcing effects of ethanol. Tiapride's lack of interaction with the depressant effects of ethanol may account for its better tolerance in alcoholic patients.

Animals↗
PubMed1997

Complementary medicine and HIV infection.

The social role of alternative medicine is critical in empowering the large proportion of HIV-positive patients who choose to use nontraditionally prescribed medicines. Working toward an open scientific dialogue with HIV-related complementary therapies is a worthy goal for all providers.

Complementary Therapies↗
PubMed1997

Calcitonin inhibits phospholipase A2 and collagenase activity of human osteoarthritic chondrocytes.

Calcitonin (CT) is a known potent inhibitor of bone resorption but its effect on cartilage enzymatic degradation has been incompletely studied. Salmon CT, at a concentration of 0, 0.1, 0.25, 0.5, 2.5 and 50 ng/ml, was added at 24 or 72 h to the culture medium of chondrocytes from human osteoarthritic hips and knees. The spontaneous collagenolytic activity, measured using a radiolabeled type II collagen, was inhibited by CT in a dose-dependent manner. However, CT had no effect on the total collagenolytic activity assayed after APMA activation. Stromelysin and plasmin activity, measured by degradation of casein and a synthetic substrate, were also unaffected by CT. Chondrocyte phospholipase A2 activity, assayed using a labeled specific substrate, was decreased by CT. Chondrocyte pre-incubation with CT significantly decreased the cell binding of labeled TNF alpha, but did not affect IL-1 beta cell binding. Attachment of chondrocytes on fibronectin was markedly stimulated by CT, while attachment to type II collagen was not. Significant effects were obtained using at least 2 or 5 ng/ml of CT. CT appears to decrease collagenolytic activity by decreasing its activation and/or increasing its inhibition by tissue inhibitors of metalloproteinases (TIMP). CT might act on osteoarthritic chondrocyte activation via mechanisms such as phospholipase A2 activity, human necrosis factor-alpha or fibronectin receptor expression.

Calcitonin↗
PubMed1997

Epidermal growth factor (EGF) and EGF receptor in hypospadias.

OBJECTIVE: To determine whether alterations in epidermal growth factor (EGF), which plays a major role both in the masculinization of the genitourinary tract and in wound healing, or EGF receptor (EGFR) expression are associated with hypospadias. PATIENTS AND METHODS: The prepuces from 22 children undergoing circumcision (median age 27 months, range 5-87) and skin biopsies from 16 children undergoing surgery for hypospadias (median age 12 months, range 3-57) were studied. Fourteen patients had distal, one had mid-shaft and one had penoscrotal hypospadias. Immunoperoxidase staining was carried out for EGF and EGFR and the density of the staining quantified using image cytometry by an operator unaware of the diagnosis. RESULTS: The median EGF density in foreskins obtained by circumcision was 75% (mean 73, SE 2.1) compared with 54% (mean 52, SE 3.9) for tissue samples from patients with hypospadias (P < 0.001); the mean EGFR was similar in both materials. CONCLUSION: The mean EGF value was deficient in skin adjacent to hypospadias defects compared to normal phallic skin, suggesting that the inadequate expression of EGF may be related to the aetiology of hypospadias and to possible wound complications following surgery for hypospadias.

Child↗
PubMed1997

Assessment of the antidepressant-like effects of L-type voltage-dependent channel modulators.

L-type voltage-dependent calcium channel blockers acting at different sites were tested in animal models of depression. Their effects on locomotion were studied in separate experiments. Nifedipine, a drug which interacts selectively with dihydropyridine (DHP) binding sites, reduced immobility time in the mouse forced swimming test and tail suspension test, but lacked activity in the differential-reinforcement-of-low-rate schedule in rats (DRL 72 s). The effects of nifedipine in the tail suspension test was partly antagonized by Bay K 8644, a DHP channel activator, indicating that its effect involved L-type calcium channel. Several other DHP drugs (nicardipine, nitrendipine, isradipine, felodipine and nimodipine) also showed antidepressant-like properties in the tail suspension test, whereas amlodipine, a less selective compound, lacked activity. In contrast to the DHP drugs, verapamil and (-)emopamil (which act at the phenylalkylamine binding sites), diltiazem and clentiazem (benzothiazepine binding sites), and the non-selective drug, flunarizine, were inactive in the tail suspension test. Negative results were also obtained with verapamil, diltiazem and flunarizine in the forced swimming test and with flunarizine on DRL 72 s responding. The present results show that DHP channel blockers displayed 'antidepressant-like' properties in mice. There was little dissociation, however, between the doses that produced antidepressant effects and those that decreased locomotor activity.

Animals↗
PubMed1997

Social problem solving in hyperactive-aggressive children: how and what they think in conditions of automatic and controlled processing.

Examined how and what children think under conditions of automatic and controlled processing within the context of social problem solving. In a condition that elicited automatic processing, hyperactive-aggressive children did not differ in being able to identify the components of a problem or in the number of solutions generated to solve a problem, but were more aggressive in the types of solutions generated, as compared to nonhyperactive-nonaggressive children. Furthermore, in a condition eliciting controlled processing, hyperactive-aggressive children did not differ in identifying problem components, generating solutions, or in anticipating outcomes for solutions, but were less able to anticipate consequences, and were more aggressive in choosing a best solution to solve a problem, as compared to nonhyperactive-nonaggressive children. The study demonstrated a relation between problem-solving codes that discriminated between groups, and overall child adjustment. Implications for social problem-solving interventions are discussed.

Adult↗
PubMed1997

Social and community resources and long-term recovery from treated and untreated alcoholism.

OBJECTIVE: Long-term studies of the course of alcoholism suggest that a variety of factors other than professional treatment influence the process of recovery. This study evaluated the role of demographic factors, baseline alcohol-related problems and depression, professional treatment, Alcoholics Anonymous (AA) and other social and community resources in predicting remission and psychosocial outcome over 8 years. METHOD: A sample of 628 previously untreated alcoholic individuals was recruited at detoxification units and alcoholism information and referral services. Of these participants, 395 (68.2%) were followed 3 and 8 years later. Most (83.3%) were white (n = 329) and 50.1% (n = 198) were men. At each contact point, participants completed a self-administered inventory that assessed their current problems, treatment utilization, AA participation and quality of relationships. RESULTS: Number of inpatient treatment days received in the 3 years after baseline were not independently related to 8-year remission or psychosocial outcomes. More outpatient treatment in the first 3 years increased the likelihood of 8-year remission, but was not related to psychosocial outcomes. The number of AA meetings attended in the first 3 years predicted remission, lower depression, and higher quality relationships with friends and spouse/partner at 8 years. Extended family quality at baseline also predicted remission and higher quality friendships and family relationships at 8 years. CONCLUSIONS: Given that alcoholism is a chronic, context-dependent disorder, it is not surprising that short-term interventions have little long-term impact. Social and community resources that are readily available for long periods are more likely to have a lasting influence on the course of alcoholism.

Adult↗
PubMed1997

Characterization of the discriminative stimulus produced by the dopamine antagonist tiapride.

The ability of tiapride, a selective D2/D3 dopamine receptor antagonist, to exert discriminative stimulus control of responding was investigated by training rats to discriminate this drug (30 mg/kg) from saline in a two-lever, food-reinforcement procedure. Acquisition of tiapride discrimination required a relatively lengthy training period (mean of 76 sessions) but stable performance was maintained throughout the 18- month study. The dose of tiapride eliciting 50% tiapride-lever choice (ED50) was 2.2 mg/kg. After determination of the dose-effect curve with tiapride, substitution tests with several dopamine antagonists and other reference compounds were performed. All dopamine antagonists, including amisulpride (ED50 4 mg/kg), sulpiride (18 mg/kg), sultopride (1.5 mg/kg), clebopride (0.13 mg/kg), raclopride (0.16 mg/kg), metoclopramide (1.4 mg/kg), remoxipride (4.8 mg/kg), pimozide (2.7 mg/kg), thioridazine (3.4 mg/kg), olanzapine (0.97 mg/kg), chlorpromazine (1.9 mg/kg), risperidone (0.22 mg/kg) and haloperidol (0.14 mg/kg), except clozapine (>10 mg/kg), produced dose-dependent substitution for tiapride. Tiapride-like stimulus effects were observed at doses that decreased response rates. However, ED50 values for substitution by tiapride, amisulpride, sulpiride, sultopride, pimozide, clebopride and thioridazine were lower than ED50 values for decreasing responding. Additional studies were conducted to evaluate the ability of direct and indirect dopamine agonists to attenuate the tiapride discriminative stimulus. Pretreatment with d-amphetamine and nomifensine antagonized the discriminative stimulus effects of tiapride. Quinpirole, 7-OH-DPAT, bromocriptine and apomorphine partially blocked the stimulus effects of tiapride whereas SKF 38393 did not affect the discrimination. These results from substitution and antagonism tests indicated that the discriminative effects of tiapride are mediated by activity at D2/D3 dopamine receptors.

Animals↗
PubMed1997

A pragmatic cost-effectiveness study of routine epidural corticosteroid injections for lumbosciatic syndrome requiring inhospital management.

A multicenter randomized study was conducted using a pragmatic approach to evaluate the benefits and costs of routine epidural corticosteroid injections for the treatment of lumbosciatic syndrome requiring inhospital management. The primary evaluation criterion was whether other treatments were required after one to three injections. The 108 patients were randomly allocated to treatment with or without routine epidural corticosteroids. Rest and a nonsteroidal antiinflammatory drug were used in all patients. The two groups were comparable at baseline except for a larger proportion of males in the routine epidural corticosteroid group. Patients in the routine epidural corticosteroid group were more likely to require other treatments, but the difference was only of borderline significance after adjustment for gender. Results showed that physicians based their treatment decisions primarily on whether an improvement in the clinical status of the patient was apparent at the second visit. None of the other factors studied influenced treatment decisions. Clinical efficacy criteria were identical in the two groups. Hospital costs contributed most of the total cost, and the mean cost was higher in the routine epidural corticosteroid group. These data suggest that adding an epidural injection as a first-line treatment to rest and a nonsteroidal antiinflammatory drug for the treatment of lumbosciatic syndrome requiring inhospital management results in additional costs and no gain in efficacy.

Adolescent↗
PubMed1997

Image cytometric nuclear DNA quantitation of paragangliomas in tissue sections. Prognostic significance.

OBJECTIVE: Image cytometric quantitation of nuclear DNA of paragangliomas may provide prognostic information that cannot be obtained from histopathologic study. Flow cytometry has demonstrated DNA aneuploid tumors to have a higher risk of progression than diploid neoplasms. STUDY DESIGN: DNA ploidy of 56 paragangliomas was assessed by image cytometry of 5-micron, Feulgen-stained, formalin-fixed, paraffin-embedded tissue sections. RESULTS: Thirty-three (59%) paragangliomas were diploid and 23 (41%) aneuploid. Of the 30 adrenal pheochromocytomas, 15 (50%) were diploid. Thirteen (93%) of the 14 carotid body tumors were diploid. Five of seven (71%) glomus jugulare tumors and two of five (40%) extraadrenal paragangliomas were aneuploid. During a mean follow-up of 57 months (range, 1 month to 36 years) of 44 patients with 47 paragangliomas, 33 (75%) were alive and without disease; 7 (16%), including 1 glomus jugulare, 2 carotid body and 4 pheochromocytoma patients, developed recurrences/metastases. By multivariate analysis, image cytometric DNA ploidy was predictive of disease-free survival for adrenal pheochromocytomas. No significant differences in overall survival, disease-free survival or recurrence/metastasis rate were noted between other diploid and aneuploid tumors. CONCLUSION: Aneuploidy suggests a risk of early recurrence for adrenal pheochromocytomas.

Adrenal Gland Neoplasms↗
PubMed1996

A model of Ca(2+)-free calmodulin binding to unconventional myosins reveals how calmodulin acts as a regulatory switch.

BACKGROUND: In contrast to conventional muscle myosins, where two different light chains (LCs) stabilize the elongated regulatory domain (RD) region of the head portion of the molecule, unconventional myosins are a diverse group of motors in which from one to six calmodulin (CaM) subunits are bound tandemly to the RD. In both cases, the heavy chains of the RDs have special sequences called "IQ motifs' to which the LCs or CaM bind. A previously puzzling aspect of certain unconventional myosins is their unusual mode of regulation, where activation of motility occurs at low levels of Ca2+. Although the atomic structure of the conventional muscle myosin RD has been determined, no crystallographic structure of the RD of an unconventional myosin is yet available. RESULTS: We have constructed a model of vertebrate CaM bound to the first IQ motif present in the neck region of an unconventional myosin (chicken brush border myosin I), using strict binding rules derived from the crystal structure of the scallop RD. The model accounts for aspects of the regulation of many unconventional myosins where CaM is bound at low levels of Ca2+ and released or changed in conformation at high levels of Ca2+. The conformational changes as a function of Ca2+ depend not only on the precise sequence of the IQ motifs but also on the interactions between CaM molecules bound to adjacent sites on the myosin heavy chain. CONCLUSIONS: According to our model, the full versatility of CaM binding to target peptides is displayed in the regulation of unconventional myosins. At low concentrations of Ca2+, CaM binds in a manner similar to the LCs of conventional myosins. At higher Ca2+ concentrations, CaM changes conformation and acts as a switch to regulate the activity of the unconventional myosin molecules.

Amino Acid Sequence↗
PubMed1996

Image cytometric comparison of proliferating cell nuclear antigen and MIB-1 staining in hepatocellular carcinoma and adjacent liver tissue.

Studies of cellular proliferation may aid in elucidation of mechanisms of hepatocarcinogenesis and provide potential prognostic information in cases of hepatocellular carcinoma. Increased proliferation has been reported in the liver tissue adjacent to hepatocellular carcinoma and may be a risk factor for recurrence after tumor resection. We quantitated proliferating cell nuclear antigen (PCNA) clone PC10 and MIB-1 nuclear immunostain by image cytometry in fixed, paraffin-embedded tissue sections of normal, cirrhotic, and dysplastic livers with and without co-existent hepatocellular carcinoma and in the hepatocellular carcinoma. Fifteen high power fields were analyzed in each case using the CAS 200 image analyzer and results were expressed as the percent positive nuclear area. Cirrhotic liver showed significantly less proliferation adjacent to hepatocellular carcinoma than without hepatocellular carcinoma. There was a similar, but not significant, tendency for dysplastic liver. Increasing mean proliferation was noted from normal to cirrhotic to dysplastic liver to low grade to high grade hepatocellular carcinoma. These findings were similar using both PC10 and MIB-1. There tended to be slightly more staining with PC10 than with MIB-1, but the mean percent positive nuclear area was significantly greater with PC10 only in high grade hepatocellular carcinoma. Comparison of individual cases, however, yielded significant correlation between the two antibodies in the low grade and high grade hepatocellular carcinomas, but not in the benign livers. These findings demonstrate that image cytometric quantitation of PC10 and MIB-1 immunostain may be comparable measures of cellular proliferation and that there is no increase in proliferation in the hepatic tissue adjacent to hepatocellular carcinoma.

Antibodies, Monoclonal↗
PubMed1996

Structure of the regulatory domain of scallop myosin at 2 A resolution: implications for regulation.

BACKGROUND: In contrast to the myosins of vertebrate skeletal muscle, molluscan myosins are regulated molecules whose enzymatic activity is switched on by the direct binding of Ca2+. The head portion (S1) of the molecule consists of a motor domain and a regulatory domain (RD) containing a 'regulatory' and an 'essential' light chain (RLC and ELC, respectively). The structures of scallop myosin RD with bound Ca2+, as well as the S1 fragment of chicken skeletal muscle myosin, have been determined previously to 2.8 A resolution. RESULTS: We have determined the structure at 2.0 A resolution of scallop myosin RD with bound Ca2+. The unusual coordination at the specific Ca(2+)-binding site in the ELC has now been clarified, as has the structural basis for Mg2+ binding to the RLC. A comparison of the scallop RD structure with that in the chicken S1 structure shows differences in the bending of the two RDs in two different places. CONCLUSIONS: Based on these structural results, a model for regulation is proposed in which the Ca(2+)-bound RD is a rigid structure, and transient flexibility of the Ca(2+)-free RD allows the myosin heads to make stabilizing intramolecular linkage which shut off the motor.

Adenosine Triphosphatases↗
PubMed1996

Heptad breaks in alpha-helical coiled coils: stutters and stammers.

The discontinuities found in heptad repeats of alpha-helical coiled-coil proteins have been characterized. A survey of 40 alpha-fibrous proteins reveals that only two classes of heptad breaks are prevalent: the stutter, corresponding to a deletion of three residues, and the newly identified "stammer," corresponding to a deletion of four residues. This restriction on the variety of insertions/deletions encountered gives support to a unifying structural model, where different degrees of supercoiling accommodate the observed breaks. Stutters in the hemagglutinin coiled-coil region have previously been shown to produce an underwinding of the supercoil, and we show here how, in other cases, stammers would lead to overwinding. An analysis of main-chain structure also indicates that the mannose-binding protein, as well as hemagglutinin, contains an underwound coiled-coil region. In contrast to knobs-into-holes packing, these models give rise to non-close-packed cores at the sites of the heptad phase shifts. We suggest that such non-close-packed cores may function to terminate certain coiled-coil regions, and may also account for the flexibility observed in such long alpha-fibrous molecules as myosin. The local underwinding or overwinding caused by these specific breaks in the heptad repeat has a global effect on the structure and can modify both the assembly of the protein and its interaction properties.

Protein Conformation↗