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Biomedical subjects

D S Cohen

Publications and source records attributed to D S Cohen.

At least 37 records · Page 2Linked to original sources
PubMed1996

Effect of single-dose rapamycin-based immunosuppression on the development of cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy is the major cause of graft loss more than 1 year after transplantation. Daily rapamycin dosing has been shown to inhibit arterial intimal thickening caused by both alloimmune and mechanical injury. The combination of a single preoperative dose of rapamycin with a short (7 day) course of cyclosporine A has been shown to extend cardiac allograft survival, but its effects on the development of cardiac allograft vasculopathy has not been reported. METHODS: The ACI (RT1(a)) to Lewis (RT1(1)) heterotopic cardiac allograft model was used to assess the development of cardiac allograft vasculopathy and rejection. Treatment groups included nonimmunosuppressed control, cyclosporine A, cyclosporine A/donor-specific transfusion, and rapamycin/cyclosporine A. RESULTS: The addition of a single preoperative dose of rapamycin to a short course of cyclosporine A significantly reduced the prevalence of cardiac allograft vasculopathy in small (1.18 +/- 1.4 versus 0.05 +/- 0.3; p = 0.0001), medium (2.05 +/- 1.09 versus 0.26 +/- 0.62; p = 0.0001), and large (2.57 +/- 0.84 versus 1.43 +/- 1.2; p = 0.0008) vessels when compared with that in allografts treated with a single preoperative donor-specific transfusion and the same cyclosporine A schedule. Cardiac allograft vasculopathy did not develop in the nonimmunosuppressed control grafts or the group treated with cyclosporine A alone, because of the short survival times in these groups. In addition, there was a reduction of the rejection score in the rapamycin-treated allografts compared with that in the other treatment groups (4.0 +/- 0.0 versus 3.25 +/- 0.5; p = 0.0006). CONCLUSIONS: These results suggest that a single preoperative dose of rapamycin is efficacious in preventing the development of cardiac allograft vasculopathy, and continued immunosuppression with rapamycin may be unnecessary.

Animals↗
PubMed1995

Protein thermal denaturation, side-chain models, and evolution: amino acid substitutions at a conserved helix-helix interface.

Random mutant libraries with substitutions at the interface between the N- and C-terminal helices of Saccharomyces cerevisiae iso-1-cytochrome c were screened. All residue combinations that have been identified in naturally occurring cytochrome c sequences are found in the libraries. Mutants with these combinations are biologically functional. Enthalpies, heat capacities, and midpoint temperatures of denaturation are used to determine the entropy and Gibbs free energy of denaturation (delta GD) for the ferri form of the wild-type protein and 13 interface variants. Changes in delta GD cannot be allocated solely to enthalpic or entropic effects, but there is no evidence of enthalpy-entropy compensation. The lack of additivity of delta GD values for single versus multiple amino acid substitutions indicates that the helices interact thermodynamically. Changes in delta GD are not in accord with helix propensities, indicating that interactions between the helices and the rest of the protein outweigh helix propensity. Comparison of delta GD values for the interface variants and nearly 90 non-cytochrome c variants to side-chain model data leads to several conclusions. First, hydrocarbon side chains react to burial-like transfer from water to cyclohexane, but even weakly polar side chains respond differently. Second, despite octanol being a poor model for protein interiors, octanol-to-water transfer free energies are useful stability predictors for changing large hydrocarbon side chains to smaller ones. Third, unlike cyclohexane and octanol, the Dayhoff mutation matrix predicts stability changes for a variety of substitutions, even at interacting sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Effects of coregistration of MR to CT images on MR stereotactic accuracy.

Coregistration of different modality imaging serves to increase the ease and accuracy of stereotactic procedures. In many cases, magnetic resonance (MR) stereotaxis is supplanting computerized tomography (CT). The advantages of increased anatomical detail and multiplanar imaging afforded by MR, however, are offset by its potential inaccuracy as well as the more cumbersome and less available nature of its hardware. A system has been developed by one of the authors by which MR imaging can be performed separately without a stereotactic fiducial headring. Then, immediately prior to surgery, a stereotactic CT scan is obtained and software is used to coregister CT and MR images anatomically by matching cranial landmarks in the two scans. The authors examined this system in six patients as well as with the use of a lucite phantom. After initially coregistering CT and MR images, six separate anatomical (for the patients) and eight artificial (for the phantom) targets were compared. With coregistration, in comparison to CT fiducial scans, errors in each axis are less than or equal to 1 mm using the Cosman-Roberts-Wells system. In fact, the coregistered images are more accurate than MR fiducial images, in the anteroposterior (p = 0.001), lateral (p < 0.05), and vertical (p < 0.03) planes. Three-dimensional error was significantly less in the coregistered scans than the MR fiducial images (p < 0.005). The coregistration procedure therefore not only increases the case of MR stereotaxis but also increases its accuracy.

Brain↗
PubMed1995

Seizure outcome after lesionectomy for cavernous malformations.

Cavernous malformations that are associated with seizures are often treated by surgical resection consisting of lesion removal, "lesionectomy," alone. Through retrospective analysis the authors have examined some factors that may predict failure to eradicate seizures by such a procedure. A group of 51 patients were examined who had been treated for supratentorial cavernous malformations with preoperative seizures and received postoperative follow up lasting at least 1 year. There was one mortality in the group. Of the remaining 50 patients, 15 (30%) had continued postoperative seizures despite therapeutic levels of antiepileptic medications. Variables that were significantly associated with continued seizures postoperatively included increasing duration of preoperative seizure history (p = 0.03), increasing number of preoperative seizures (p < 0.003), and female sex (p < 0.04). One hundred percent of patients with only one preoperative seizure or a seizure history lasting less than 2 months were seizure free following lesionectomy: approximately 75% to 80% of all patients with two to five seizures, or a seizure history lasting 2 to 12 months, were seizure free; and only 50% to 55% of those with more than five seizures or with preoperative seizure histories lasting more than 1 year were seizure free postoperatively. This investigation indicates that patients with shorter seizure histories and fewer preoperative seizures can be effectively treated by lesionectomy alone, whereas those with longer histories and more seizures are not effectively treated by this procedure and may require more extensive resections.

Adolescent↗
PubMed1995

Risk of chromosomal abnormalities, with emphasis on live-born offspring of young mothers.

In a large public urban hospital obstetrics service with > 123,000 deliveries in a 10-year period (1980-89), the frequencies (0.12%) of any type of chromosomal abnormality and of trisomy syndromes were analyzed for maternal age-related risk, by logistic regression. Focusing on very young gravidas, we found that in the study period there were 9,332 births (7.5% of all deliveries) to mothers < or = 16 years old. Estimated risks of chromosomal abnormalities among offspring associated with very young maternal age (9-16 years) were similar to those age-associated risks of mothers 20-29 years old. Risks of chromosomal abnormalities increase with advancing maternal age and are independent of ethnicity.

Adolescent↗
PubMed1994

Stability of yeast iso-1-ferricytochrome c as a function of pH and temperature.

Absorbance-detected thermal denaturation studies of the C102T variant of Saccharomyces cerevisiae iso-1-ferricytochrome c were performed between pH 3 and 5. Thermal denaturation in this pH range is reversible, shows no concentration dependence, and is consistent with a 2-state model. Values for free energy (delta GD), enthalpy (delta HD), and entropy (delta SD) of denaturation were determined as functions of pH and temperature. The value of delta GD at 300 K, pH 4.6, is 5.1 +/- 0.3 kcal mol-1. The change in molar heat capacity upon denaturation (delta Cp), determined by the temperature dependence of delta HD as a function of pH (1.37 +/- 0.06 kcal mol-1 K-1), agrees with the value determined by differential scanning calorimetry. pH-dependent changes in the Soret region indicate that a group or groups in the heme environment of the denatured protein, probably 1 or both heme propionates, ionize with a pK near 4. The C102T variant exhibits both enthalpy and entropy convergence with a delta HD of 1.30 kcal mol-1 residue-1 at 373.6 K and a delta SD of 4.24 cal mol-1 K-1 residue-1 at 385.2 K. These values agree with those for other single-domain, globular proteins.

Calorimetry, Differential Scanning↗
PubMed1994

Pediatric cancer: predicting sibling adjustment.

Within the context of a coping model, the present study attempted to determine variables associated with good and poor adjustment for siblings (N = 129) of pediatric cancer patients. Family cohesion and adaptability were found to mediate the impact of pediatric cancer on the healthy sibling. Specifically, high levels of family cohesion and adaptability were associated with better adaptation for siblings. Some support also was found for Folkman, Schaefer, and Lazarus' (1979) coping model, as the following variables, proposed by the model, predicted sibling adjustment to pediatric cancer: health/energy/morale, social support, and utilitarian resources. Results from this study stress the need to examine the child in a variety of ecological contexts (e.g., parental and familial functioning; neighborhood/community support).

Adaptation, Psychological↗
PubMed1993

A biomechanical evaluation of magnetic resonance imaging-compatible wire in cervical spine fixation.

In a bovine cervical spine model, the ultimate and fatigue strengths as well as relative magnetic resonance imaging artifact produced by titanium, cobalt chrome, and stainless-steel wires in various gauges were assessed. Single-cycle and fatigue strength of wire constructs were measured. Although larger wires generally had greater static strength, fatigue strength was mixed. Sixteen-gauge titanium, and all stainless-steel models (22-gauge braided, 18-gauge, and Songer cable) withstood 10,000 cycles without failure, whereas all other constructs rarely could withstand a similar 10,000 cycles. Magnetic resonance imaging was performed on calf cervical spines instrumented with the various materials. Titanium exhibited the least artifact, stainless-steel showed the greatest artifact, and cobalt chrome an intermediate amount. Although titanium wire produces the least amount of magnetic resonance imaging artifact, it remains a poor choice for implant fixation because its notch sensitivity reduces its fatigue resistance compared with stainless steel, which remains the more dependable choice.

Animals↗
PubMed1993

Beneficial effects of combined thromboxane synthase inhibition/receptor blockade with CGS 22652 in a canine model of coronary thrombosis.

Various antiplatelet agents were examined for their effectiveness as adjuncts to thrombolytic therapy in a canine model of thrombin-induced coronary thrombosis. Aspirin (5 mg/kg i.v. bolus), CGS 15435A (thromboxane synthase inhibitor (TxSI), 0.1 mg/kg i.v. bolus +0.04 mg/kg per h) and BM 13.505 (thromboxane receptor antagonist (TxRA), 0.5 mg/kg i.v. bolus +0.2 mg/kg per h) administered concurrently with streptokinase (750,000 units/h) were examined for their effects on reperfusion and reocclusion, as were a combination therapy with CGS 15435A + BM 13.505 or the dual TxRA/TxSI inhibitor, CGS 22652 (1 mg/kg i.v. bolus +0.4 mg/kg per h). All dogs received heparin (150 U/kg bolus + 50 U/kg per h) throughout the experimental protocol. Survival analysis at reperfusion indicated that thrombolysis was significantly improved in dogs treated with CGS 15435A, BM 13.505, CGS 15435A+BM 13.505 or CGS 22652 over that of vehicle-treated animals. Both dual inhibitor groups and the BM 13.505 group were significantly different from aspirin. Aspirin-treated dogs were not different from vehicle. Otherwise, all treatments differed from the vehicle-treated group at reocclusion. Time and incidence of reocclusion for CGS 22652 was significantly improved over that of BM 13.505. Residual thrombus weight was significantly reduced in the CGS 22652-treated and BM 13.505 + CGS 15435A-treated animals. These findings demonstrate that streptokinase-induced thrombolysis is accompanied by TxA2/prostaglandin H2 synthesis and platelet activation and suggest a role for platelet activation during reocclusion following clot lysis. These studies also show it is possible to combine the beneficial effects of both a TxRA and TxSI into a single chemical entity, CGS 22652, which, when administered as adjunctive therapy to streptokinase, results in an apparent synergistic antithrombotic effect.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 5. Synthesis and evaluation of enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylalkyl)octanoic acid.

The enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylpropyl)octanoic acid (1) and its pyridinyl ether analog (2) were synthesized using the highly diastereoselective method of alkylation of acyloxazolidinone. These enantiomerically pure compounds were compared with the corresponding racemic compounds 1 and 2 for their in vitro activity. Compounds 1, 1R, and 1S and 2,2S, and 2R were equipotent as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) (IC50 = 2-30 nM). Upon oral administration to guinea pigs, the enantiomers inhibited the ex vivo U 46619-induced platelet aggregation with potency similar to that of the corresponding racemic compound. This indicates that the enantiomers have pharmacologic profile and bioavailability similar to that of the corresponding racemic compound.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Traumatic brain injury, hemorrhagic shock, and fluid resuscitation: effects on intracranial pressure and brain compliance.

Intracranial hypertension following traumatic brain injury is associated with considerable morbidity and mortality. Hemorrhagic hypovolemia commonly coexists with head injury in this population of patients. Therapy directed at correcting hypovolemic shock includes vigorous volume expansion with crystalloid solutions. It is hypothesized that, following traumatic brain injury, cerebrovascular dysfunction results in rapid loss of brain compliance, resulting in increased sensitivity to cerebrovascular venous pressure. Increased central venous pressure (CVP) occurring with vigorous crystalloid resuscitation may therefore contribute to the loss of brain compliance and the development of intracranial hypertension. The authors tested this hypothesis in miniature swine subjected to traumatic brain injury, hemorrhage, and resuscitation. Elevated CVP following resuscitation from hemorrhage to a high CVP significantly worsened intracranial hypertension in animals with concurrent traumatic brain injury, as compared to animals subjected to traumatic brain injury alone (mean +/- standard error of the mean: 33.0 +/- 2.0 vs. 20.0 +/- 2.0 mm Hg, p < 0.05) or to animals subjected to the combination of traumatic brain injury, hemorrhage, and resuscitation to a low CVP (33.0 +/- 2.0 vs. 24.0 +/- 2.0 mm Hg, p < 0.05). These data support the hypothesis that reduction in brain compliance can occur secondary to elevation of CVP following resuscitation from hemorrhagic shock. This may worsen intracranial hypertension in patients with traumatic brain injury and hemorrhagic shock.

Animals↗
PubMed1992

Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 2. Synthesis and biological activity of 8-(benzenesulfonamido)-7-(3-pyridinyl)octaonic acid and related compounds.

A series of arylsulfonamide alkanoic acids substituted with a 3-pyridinyl group along the aliphatic chain were synthesized and tested in vitro for their ability to antagonize thromboxane A2 (TxA2) receptors and inhibit thromboxane synthase. These compounds were found to potently inhibit the U 46619-induced aggregation of human platelets and to also inhibit TxA2 biosynthesis in a human microsomal platelet preparation. However, some members of the series, notably compound 21, were found to display agonist activity on the rabbit aorta TxA2 receptor. This unwanted agonist activity appeared to be related to the presence of a substituent beta to the arylsulfonamido group.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 3. Pyridinylalkyl-substituted 8-[(arylsulfonyl)amino]octanoic acids.

A series of 8-[(arylsulfonyl)amino]octanoic acids substituted with a pyridinylalkyl group along the chain were synthesized and tested in vitro for their ability to both antagonize the binding of thromboxane A2 to its receptors and to inhibit the thromboxane synthase enzyme. This series of compounds were found to inhibit the U 46619-induced aggregation of human platelets and the U 46619-induced contraction of dog saphenous vein. The compounds also inhibited TxA2 biosynthesis in a human microsomal platelet preparation. The relative position of the pyridinylalkyl and arylsulfonamide groups had significant effects on the thromboxane receptor antagonist (TxRA) activity and thromboxane synthase inhibitor (TxSI) activity. Compounds with the pyridine ring at the 7- or 8-position of the octanoic acid side chain were weakly active as TxSI but behaved as potent TxRA at the platelet receptor for TxA2. However, these compounds were agonists at the vascular receptor. Substitution of the pyridinylalkyl group at the 2- or 3-position resulted in compounds with potent TxSI activity and weak TxRA activity. The activity profile of the compounds with the pyridinylalkyl substitution at the 4-, 5-, or 6-position was very desirable. Compound 22 with a pyridinylpropyl substituent at the 4-position was found to display extremely potent TxRA and TxSI properties.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 4. 8-[[(4-Chlorophenyl)sulfonyl]amino]-4-(3-(3-pyridinyl) propyl)octanoic acid and analogs.

The title compound (10a) and its analogs were synthesized and found to possess two activities, the inhibition of the biosynthesis of thromboxane A2 and antagonism of its receptors. The in vitro and in vivo profile of these compounds as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) is described. 10a and its analogs displayed very potent TxRA activity in human washed platelets (IC50 approximately 10(-7)-10(-9) M) and dog saphenous vein (pA2 approximately 9) and also potent TxSI activity (IC50 approximately 10(-9) M). The good bioavailability and the long duration of action of some of these compounds was demonstrated using ex vivo measurement of the TxRA activity upon oral administration to guinea pigs. Compounds 10a, 20, and 33 potently inhibited arachidonic acid induced bronchoconstriction in guinea pigs.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Transforming growth factor beta differentially regulates expression of integrin subunits in guinea pig airway epithelial cells.

The integrin family is composed of a large number of heterodimers, each one mediating distinct interactions with extracellular matrix and/or cell surface ligands. The expression of integrins appears to be tightly regulated in vivo, but the mechanisms by which cells control the formation and surface expression of specific pairs of subunits have not been well characterized. Two integrin subunits, the alpha subunit alpha v, and the beta subunit beta 1, could pose special problems in regulation because of their capacity to associate with multiple partners. In the present study, we have examined the effects of the cytokine transforming growth factor beta 1 (TGF-beta 1) on the expression of alpha v- and beta 1-containing integrins in primary cultures of guinea pig airway epithelial cells, e.g. cells that we have previously found to express multiple potential partners for both alpha v and beta 1. TGF-beta 1 increased the surface expression of both alpha v- and beta 1-containing heterodimers after periods of stimulation from 24 to 72 h. These increases in surface expression were associated with significant increases in the concentrations of mRNA encoding each of the partners of alpha v and beta 1, but with only minimal increases in mRNA encoding alpha v and beta 1 themselves. Airway epithelial cells metabolically labeled with [35S]methionine during stimulation with TGF-beta 1 demonstrated only a minimal increase in the synthesis of new alpha v protein at a time when synthesis of alpha v's beta subunit partners and surface expression of alpha v-containing heterodimers were dramatically increased. These data suggest that, at least in some cells, promiscuous integrin subunits (both alpha and beta) may normally be synthesized in excess. Thus, the surface expression of specific integrin heterodimers can be regulated primarily through regulation of the synthesis of the specific partners of these subunits.

Animals↗