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D M Cohen

Publications and source records attributed to D M Cohen.

At least 19 recordsLinked to original sources
PubMed1997

Aging, metabolism, and Alzheimer disease: review and hypotheses.

Relationships are considered among aging, metabolism, and Alzheimer disease (AD). In particular, after 60 years, human populations show progressive age-related trends for increased blood glucose that are concurrent with the accelerating incidence of AD. The accumulation of glycated products in the AD brain, such as is also found in peripheral tissues during diabetes, suggests interactions of AD with age-related changes in metabolism. A review of 13 recent studies on AD and diabetes shows no consensus, although most studies indicate an apparent exclusion of AD and diabetes. We argue that longitudinal studies are needed to evaluate the possibility that an initial age-related hyperglycemic state is reversed by the cachexia and weight loss common to later stages of AD. A review of literature on chronic food restriction in rodents shows the slowing of some aspects of aging in the nervous system and generally supports interactions of peripheral metabolism with brain aging. Finally, we discuss aspects of intermediary metabolism that could ensue from oxidative damage to enzymes by glycation or oxidative stress which include excess production of ammonia from the inhibition of glutamine synthetase and the production of glyceraldehyde-3-phosphate, a glycating agent that could contribute to damage in addition to the hyperglycemic trends during aging.

Aging↗
PubMed1996

Urea-inducible Egr-1 transcription in renal inner medullary collecting duct (mIMCD3) cells is mediated by extracellular signal-regulated kinase activation.

Urea (200-400 milliosmolar) activates transcription, translation of, and trans-activation by the immediate-early gene transcription factor Egr-1 in a renal epithelial cell-specific fashion. The effect at the transcriptional level has been attributed to multiple serum response elements and their adjacent Ets motifs located within the Egr-1 promoter. Elk-1, a principal ternary complex factor and Ets domain-containing protein, is a substrate of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases. In the renal medullary mIMCD3 cell line, urea (200-400 milliosmolar) activated both ERK1 and ERK2 as determined by in-gel kinase assay and immune-complex kinase assay of epitope-tagged] ERK1 and ERK2. Importantly, urea did not affect abundance of either ERK. Urea-inducible Egr-1 transcription was a consequence of ERK activation because the ERK-specific inhibitor, PD98059, abrogated transcription from the murine Egr-1 promoter in a luciferase reported gene assay. In addition, activators of protein kinase A, including forskolin and 8-Br-cAMP, which are known to inhibit ERK-mediated events, also inhibited urea-inducible Egr-1 transcription. Furthermore, urea-inducible activation of the physiological ERK substrate and transcription factor, Elk-1, was demonstrated through transient cotransfection of a chimeric Elk-1/GAL4 expression plasmid and a GAL4-driven luciferase reporter plasmid. Taken together, these data indicate that, in mIMCD3 cells, urea activates ERKs and the ERK substrate, Elk-1, and that ERK inhibition abrogates urea-inducible Egr-1 transcription. These data are consistent with a model of urea-inducible renal medullary gene expression wherein sequential activation of ERKs and Elk-1 results in increased transcription of Egr-1 through serum response element/Ets motifs.

Animals↗
PubMed1996

Urea inducibility of egr-1 in murine inner medullary collecting duct cells is mediated by the serum response element and adjacent Ets motifs.

The renal medullary solute urea increases transcription and protein expression of the zinc finger-containing transcription factor Egr-1 in a renal epithelial cell-specific fashion. Transient transfection of mIMCD3 cells with a luciferase reporter gene driven by 1.2 kilobases of the murine egr-1 5'-flanking sequence showed 4-fold increase in reporter gene activity with 200 mM urea treatment. The effect of impermeant solutes such as NaCl was much less pronounced, whereas the permeant solute glycerol had no effect. In addition, this same sequence, minus the egr-1 minimal promoter, conferred urea responsiveness to a heterologous (thymidine kinase) promoter. Whereas deletion of two putative AP-1 sites from the sequence had no effect upon urea inducibility, elimination of the five putative serum response elements (SREs) abolished the urea effect. Progressive deletion of the SREs caused a corresponding diminution in urea effect. Two key tandem SREs (SRE-3 and SRE-4), in conjunction with their two adjacent clusters of Ets motifs, were sufficient to confer urea responsiveness to a reporter gene. This response was markedly attenuated in the absence of either cluster of Ets motifs and was abolished if both clusters were deleted. By electrophoretic mobility shift assay, formation of the ternary complex was constitutive and was demonstrable in vitro despite the presence of 200 mosm urea or NaCl. Therefore urea-inducible egr-1 transcription in renal medullary cells is mediated through the SRE and adjacent Ets motifs; ternary complex formation is not inhibited even in the presence of physiological hyperosmolality.

Animals↗
PubMed1996

Urea signaling in cultured murine inner medullary collecting duct (mIMCD3) cells involves protein kinase C, inositol 1,4,5-trisphosphate (IP3), and a putative receptor tyrosine kinase.

Urea, in concentrations unique to the renal medulla, increases transcription and protein expression of several immediate-early genes (IEGs) including the zinc finger-containing transcription factor, Egr-1. In the present study, the proximal 1.2 kb of the murine Egr-1 5' -flanking sequence conferred urea-responsiveness to a heterologous luciferase reporter gene when transiently transfected into renal medullary mIMCD3 cells,and this effect was comparable with that of the extremely potent immediate-early gene inducer, O-tetradecanoylphorbol 13-acetate (TPA). Urea inducibility of Egr-1 expression was protein kinase C (PKC)-dependent because staurosporine and calphostin C abrogated the urea effect, and down-regulation of PHC through chronic TPa treatment inhibited both urea-inducible Egr-1 protein expression and gene transcription. In addition, hyperosmotic urea increased inositol 1,4,5-trisphosphate (IP3) release from mIMCD3 cells and induced tyrosine phosphorylation of the receptor tyrosine kinase-specific phospholipase C (PLC) isoform, PLC-gamma. Importantly, urea-inducible Egr-1 expression was strongly genistein-sensitive, to a much greater extent than the comparable TPA-inducible Egr-1 expression. These data suggest that urea-inducible Egr-1 expression is a consequence of sequential PLC-gamma activation, IP3 release, and PKC activation. Urea-inducible PLC-gamma activation, in conjunction with the genistein-sensitivity of urea-inducible Egr-1 expression suggest the possibility of a cell surface or cytoplasmic urea-sensing receptor tyrosine kinase.

Alkaloids↗
PubMed1996

Population requirements for capitation planning in pediatric cardiac surgery.

OBJECTIVE: To determine the population number necessary to generate a sufficient volume of pediatric cardiac surgeries to allow accurate prediction of resource utilization. DESIGN: All pediatric cardiac surgical patients receive care in our institution by means of only four clinical pathways that are based on acuity, not diagnosis or procedure. This allows accurate tracking of resource utilization. Based on available information, 750 consecutive surgically treated patients were retrospectively assigned to a pathway. They were subsequently subdivided into study groups of decreasing sizes from 150 to 35. Variability of pathway distribution from group to group was examined as a measure of the ability to predict resource utilization based on group size. Pediatric cardiac statistics from the state of Ohio were then used to extrapolate to the population base necessary to generate each group size. SETTING: A regional pediatric cardiac referral center. PATIENTS: All sequential patients who underwent pediatric cardiac surgery between July 1991 and January 1994. RESULTS: Statewide statistics showed that a population base of 1 million people generates 100 pediatric cardiac operations. Groups of 100 patients or greater had minimal variation in pathway distribution from group to group, allowing accurate prediction of hospital charges. This was not true for groups of 50 patients or less. CONCLUSIONS: Resource utilization for pediatric cardiac surgery can be accurately predicted in a capitated setting for populations of 1 million covered lives (100 procedures) or greater. For populations of 500 000 covered lives or less, variability of case mix is great enough to suggest the need for a more individualized payment mechanism.

Capitation Fee↗
PubMed1996

Anomalous course of the left main coronary artery in tetralogy of Fallot.

An extremely rare coronary artery anomaly where the left main coronary artery arose anteriorly from the right coronary sinus and coursed in front of the right ventricular outflow tract was present in a patient with tetralogy of Fallot. Preoperative angiocardiography was interpreted as normal. Operative recognition was prevented by dense adhesions and a partial intramural course. Division of the vessel at repair resulted in death of the patient. The angiographic pattern associated with this anomaly is very unusual, and in many views looks deceptively normal. Details are presented.

Coronary Angiography↗
PubMed1996

Intrathoracic cystic hygroma: a report of three cases.

Cystic hygromas are relatively uncommon benign tumors of the lymphatic system. The lesions frequently are apparent at birth, and more than 90% are detected before the end of the second year of life. Most commonly, cystic hygroma presents as a soft tissue mass in the posterior triangle of the neck, and only rarely does it extend into the mediastinum. Isolated intrathoracic hygromas are exceedingly rare and have been reported infrequently among children. Herein the authors review three cases of intrathoracic cystic hygroma, spanning a period of 30 years at their institution.

Child, Preschool↗
PubMed1996

Transcriptional responses to tubule challenges.

Adaptation to physiological stimuli often involves changes in gene transcription. Studies of hyperosmolar stress in renal epithelial cells have provided an ideal paradigm for understanding regulation of gene expression. Renal epithelial cells respond very differently to hyperosmolar NaCl and urea and several strategies including cloning based on known biological function, candidate gene analysis, and differential display analysis have successfully identified many genes induced by these hyperosmolar challenges. Hyperosmolar NaCl produces adverse effects on cellular biosynthetic processes and compensatory increases are observed in transcription of transporters, stress proteins, and metabolic enzymes. In contrast, hyperosmolar urea fails to inhibit biosynthetic processes but, nonetheless, initiates a very specific program of gene expression in renal epithelial cells. This program appears to involve a urea sensor/receptor system which activates transcription and translation of the zinc-finger transcription factor Egr-1. This work highlights the concept that rapid analysis of differential gene expression will enable one to define cellular programs of gene expression involving up- and down-regulation of functionally-related gene families.

Animals↗
PubMed1996

Transfusion patterns in pediatric open heart surgery.

BACKGROUND: Transfusions in pediatric open heart surgery were analyzed to determine the percentage of patients transfused, the types and volumes of blood components used, and the relationships among transfusions, patient characteristics, surgeon, and surgical procedure. STUDY DESIGN AND METHODS: In a 9-month period, 122 patients, aged 12 or less (median, 1 year; 31% <4 months old), underwent 126 procedures (37 routine, 60 complex, 29 repeat operations). Bypass circuit size and priming solution, target intraoperative hematocrit, heparinization, protamine reversal, and transfusion indications and doses were standardized. The number of full "adult" units of packed red cells (RBCs), units of fresh-frozen plasma (FFP), and platelet concentrates (PCs) transfused in the operating room through postoperative Day 3 were tabulated. RESULTS: RBCs, FFPs, and PCs were transfused in 98, 54, and 58 percent of cases, respectively. Twenty-two percent of components were transfused postoperatively. The average numbers of components transfused for complex procedures (3.4 RBCs, 6.1 total) and repeat operations (4.0 RBCs, 8.1 total) were greater than those for routine procedures (1.8 RBCs, 2.1 total) (p<0.01). The average total number of components transfused did not correlate with surgeon or patient age; patients <4 months old used the largest mean numbers of RBCs and total components of all types. For four procedures, preoperative crossmatch and directed-donation collection orders that would be expected to produce acceptable utilization rates and a <15-percent chance of needing additional components were determined. CONCLUSION: Blood order protocols for pediatric open heart surgery can be procedure-specific, should address the use of non-red cell components, and should cover early postoperative transfusions.

Blood Transfusion↗
PubMed1996

Intraosseous needle: use of the miniature C-arm imaging device to confirm placement.

Intraosseous infusions are commonly used in pediatric emergencies. Although this technique is often lifesaving, significant complications can develop from incorrect needle placement. Current methods of evaluating needle position rely on the operator's experience with the procedure. We describe the use of a miniature C-arm imaging device to accurately confirm proper needle placement.

Cardiopulmonary Resuscitation↗
PubMed1996

NaCl but not urea activates p38 and jun kinase in mIMCD3 murine inner medullary cells.

The mitogen-activated protein kinases (MAPKs), p38 and jun kinase (JNK), are activated by diverse stressors in cells of nonrenal medullary origin. Epithelial cells of the renal medulla are among the very few cells of higher eukaryotes routinely subjected to hyperosmotic stress, composed of principally NaCl and urea. Hyperosmotic NaCl activated p38 and JNK in a time- and dose-dependent fashion in cells of the murine terminal inner medullary collecting duct cell line (mIMCD3) as determined by immune complex kinase assay. Hyperosmotic urea exerted a minimal effect upon only p38 activation, which was evident only at 5 min. The NaCl effect was dose dependent to 800 mosmol/kgH2O; 800 mosmol/kgH2O urea, in contrast, exerted no effect. Consistent with these observations, NaCl (800 mosmol/kgH2O) but not urea (800 mosmol/kgH2O) increased tyrosine phosphorylation of p38 and JNK at 10 min. Therefore, even in the extremely osmotolerant renal medullary mIMCD3 cell line, derived from a tissue adapted for routine exposure to elevated osmolality, hypertonic NaCl activated two stress-responsive MAPKs. Urea, in contrast, exerted virtually no effect; therefore, cellular protection from urea stress operates through a mechanism distinct from the stress-responsive MAPKs.

Animals↗
PubMed1995

Clinical pathways can be based on acuity, not diagnosis.

The standardization of medical practice is gaining acceptance as a technique for controlling length of stay and hospital charges, while maintaining quality. Most clinical pathways address specific diagnoses or procedures, but we have developed a new approach in which pathways for cardiac care are based on acuity. All congenital cardiac surgical care rendered at Columbus Children's Hospital now falls within one of four such clinical pathways. This simplified approach is easy to use and has been well accepted. Our experience in a group of 107 consecutive patients treated in this fashion is described. The results of variance analyses, along with length of stay and charge data, are presented to demonstrate the degree to which resource utilization can be standardized in this widely variable group of patients whose problems were made cohesive by classification according to acuity level. We conclude that the resultant standardization offers considerable advantages for the managed care environment.

Cardiac Surgical Procedures↗
PubMed1995

Electrical injuries in a pediatric emergency department.

STUDY OBJECTIVE: To examine the spectrum of electrical injuries and develop guidelines for management. DESIGN: Retrospective review of charts compiled during a 6-year period (1988 through 1993). SETTING: Pediatric emergency department. PARTICIPANTS: Seventy-eight patients seen for electrical injuries. RESULTS: Fifty-four percent of patients were boys, and the mean age of the patients was 5.3 years. Eighty-two percent sustained burns. We divided patients into those who were involved in major electrical current events (n = 8) (water contact and high voltage) and minor electrical current events (n = 70) (injury sustained while placing an object in an outlet or touching/plugging in a cord or during oral contact with a cord). Of the minor events, all burns (n = 61) involved less than 1% of body surface area. Eighteen patients sustained second-degree burns, and 19 sustained third-degree burns. Of the eight major-event patients, one had abnormal ECG/rhythm strip findings, two had abnormal urinalysis results, and six had abnormal levels of creatine phosphokinase. All eight were admitted. Of the 70 minor-event patients, 2 of 53 had abnormal ECG/rhythm strip findings, 1 of 48 had abnormal urinalysis results, and 2 of 40 had abnormal creatine phosphokinase levels. Thirty-six of the 70 minor-event patients were admitted. Patients involved in major events were more likely to undergo studies (P = .002), to have an abnormal result (P = .000008), and to be hospitalized (P = .008). In minor-event patients, hospitalization was limited to observation and the fitting of oral appliances. CONCLUSION: Children involved in electrical events are usually exposed to low-voltage household current resulting in minor injury. Asymptomatic children with minor electrical injuries do not require laboratory evaluation or hospitalization.

Accidents, Home↗
PubMed1995

Pediatric patients requiring CPR in the prehospital setting.

STUDY OBJECTIVE: To determine the outcome of pediatric patients with prehospital cardiopulmonary arrest. DESIGN: Chart review of all patients with prehospital cardiopulmonary arrest who were subsequently admitted to a pediatric emergency department from January 1988 to January 1993. Cardiopulmonary arrest was considered to have been present if assisted ventilation and chest compressions were performed on an apneic, pulseless patient. SETTING: Pediatric ED. PARTICIPANTS: Pediatric patients in prehospital cardiac arrest. RESULTS: In all, 95 patients were identified. Fifty-six had initial hospital care at the pediatric ED (primary patients). The remaining 39 were transported to the pediatric ED after initial care of another institution (secondary patients). Forty-one percent of patients were younger than 1 year. Most arrests were respiratory in origin; asystole was the most common dysrhythmia. Fifteen patients (27%) survived to discharge. Fourteen of the survivors had return of spontaneous circulation before ED arrival. Thirty-three patients were in arrest on ED arrival; in 16 (48%) of these, return of spontaneous circulation subsequently developed in the ED, and 1 survived to discharge. Two survivors, including the survivor with return of spontaneous circulation in the ED, had severe neurologic sequelae. Ten (26%) of the secondary patients survived. All survivors had return of spontaneous circulation before arrival in the ED. Two survivors had severe neurologic sequelae. CONCLUSION: Most successfully resuscitated pediatric arrest victims are resuscitated in the prehospital setting and do not suffer severe neurologic injury. Most patients who present to the ED in continued arrest and survive to discharge have severe neurologic injury.

Age Factors↗
PubMed1995

Protection of human polymorphonuclear leukocyte function from the deleterious effects of isolation, irradiation, and storage by interferon-gamma and granulocyte-colony-stimulating factor.

BACKGROUND: Fungal infections represent a difficult challenge to clinicians caring for neutropenic patients with hematologic malignancies, as antifungal therapy often has limited success in that setting. One promising yet problematic alternative approach is leukocyte transfusion. The isolation of polymorphonuclear leukocytes (PMNs) induces apoptosis and functional deterioration, and irradiation to prevent transfusion-associated graft-versus-host disease causes further functional deterioration. STUDY DESIGN AND METHODS: The ability of interferon-gamma and granulocyte-colony-stimulating factor (G-CSF), used both alone and in combination, to protect PMNs after 0 or 20 hours' storage in cell culture (as a model for function after transfusion) and irradiation with 0, 5, or 30 Gy was studied. RESULTS: Without cytokine treatment, 20-hour-old PMNs showed marked apoptosis, no appreciable chemotaxis, and no ability to kill Candida albicans. In contrast, cytokine treatment significantly reduced apoptosis and protected chemotaxis, C. albicans killing, and surface-receptor expression from both storage and irradiation. Although the majority of the benefit appeared to be due to G-CSF, consistent trends suggested better function of PMNs after combined treatment with interferon-gamma and G-CSF. CONCLUSION: Judicious use of cytokines may preserve PMN function. These findings have important implications for the transfusion of PMNs to cytopenic patients.

Apoptosis↗
PubMed1995

Estimation of TCA cycle flux, aminotransferase flux, and anaplerosis in heart: validation with syntactic model.

Weiss et al. (Circ. Res. 70: 392-408, 1992) proposed a model of the citric acid cycle (CAC) in myocytes and a system of 17 differential equations that can be used to describe the changes over time in enrichment of carbons C-2 and C-4 of glutamate under conditions of metabolic steady state. They also proposed an empirical measure (KT) of flux through the CAC, which has been shown to be correlated to O2 consumption in rat hearts perfused with acetate or a mixture of glucose and acetate. We report a new method for estimation of the absolute rate of the flux through the CAC in heart (vTCA), without the numerical solution of differential equations. Unlike KT, our estimate is equal to the rate of flux catalyzed by the alpha-ketoglutarate dehydrogenase complex (vTCA), not merely correlated with it. We also estimate the rate of flux catalyzed by aspartate aminotransferase (vTA) and by NADP(+)-dependent malic enzyme (an anaplerotic reaction). The formula for vTCA during administration of [2-13C]acetate is as follows: vTCA = M[(C-2ssLC-4)/[C-4ss(LC-4-LC-2)]], where C-2ss and C-4ss represent steady-state fractional enrichment, LC-2 and LC-4 represent dominant rate constants of C-2 and C-4 of glutamate, respectively, and M is the sum of concentrations of aspartate, glutamate, and intermediates of the CAC. The assumptions underlying our formula are as follows: 1) metabolic steady state is maintained, 2) exchange of molecules between cytosolic and mitochondrial compartments is rapid, 3) 13C enters pools of the CAC only from acetyl CoA via citrate synthase, 4) [citrate]/[glutamate] < 1 + (vTCA/vTA), and 5) (m-[glutamate])/M < C-2ss/C-4ss.

Aspartate Aminotransferases↗