Inhibition of glutamine synthetase induces critical energy threshold for neuronal survival.
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Alzheimer Disease↗
Biomedical subjects
D M Cohen
Publications and source records attributed to D M Cohen.
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↗
Mitogen-activated protein kinase cascades and the signaling of hyperosmotic stress to immediate early genes.
Among prokaryotes and lower eukaryotes, the threat of exposure to hyperosmotic stress is ubiquitous. Among higher eukaryotes, in contrast, only specific tissues are routinely exposed to marked hypertonicity. The mammalian renal medulla, the prototypical example, is continually subjected to an elevated solute concentration as a consequence of the renal concentrating mechanism. Until recently, the investigative focus has concerned the effects of diverse solutes on the regulation of genes essential for the adaptive accumulation of osmotically active organic solutes. Recent and sweeping developments elucidating the molecular mechanisms underlying stress signaling to the nucleus have focused interest on earlier events in the response to hyperosmotic stress. Such events include the transcriptional activation and post-translational modification of transcriptional activating proteins, a large subset of which represent the protein products of so-called immediate early genes. This review highlights developments in the understanding of stress signaling in general and hypertonic stress signaling in particular in both yeast and higher eukaryotic models. The relationship between hyperosmotic stress signaling and the transcription and activation of immediate-early gene transcription factors is explored.
Animals↗
Effects of in vitro and in vivo cytokine treatment, leucapheresis and irradiation on the function of human neutrophils: implications for white blood cell transfusion therapy.
Treatment of human polymorphonuclear leucocytes (PMNL) separated by density sedimentation (DS) from normal donors (PMNL-NL-DS) with interferon-gamma (IFN-gamma) + granulocyte colony-stimulating factor (G-CSF) lessens the damage caused by isolation and irradiation. We have studied granulocyte-macrophage colony-stimulating factor (GM-CSF) in this system, as well as the behaviour of PMNL collected by continuous flow leucapheresis (CFL) from donors treated with G-CSF (PMNL-GCSF-CFL). After isolation, PMNLs were treated with IFN-gamma + G-CSF, GM-CSF or IFN-gamma + G-CSF + GM-CSF, irradiated with 0 or 30 Gy and studied after 0 and 20 h in cell culture. All regimens reduced apoptosis of PMNL-NL-DS. Killing of Candida albicans by 20-h-old PMNL-NL-DS was best preserved by IFN-gamma + G-CSF treatment. A similar pattern of results was obtained for assays of PMNL-NL-DS chemotaxis and superoxide production. There was a consistent trend toward reduced function after irradiation in all assays. PMNL-GCSF-CFL less often demonstrated the morphological features of apoptosis, and this was further reduced by cytokine regimens containing IFN-gamma + G-CSF. In assays of C. albicans killing and chemotaxis, 20-h-old untreated PMNL-GCSF-CFL performed as well as freshly isolated PMNL-GCSF-CFL. PMNL-GCSF-CFL showed decay in CD11b (CR3), CD16 (Fc gamma III) and CD64 (Fc gamma R1) expression after 20 h in cell culture, but treatment with IFN-gamma + G-CSF preserved expression. There was a trend toward reduced function after radiation. Comparison of PMNL-GCSF separated by CFL and DS demonstrated that CFL itself is a strong inducer of the morphological features of apoptosis. This study shows that while separation by CFL, and irradiation are damaging to PMNLs, damage may be reduced by use of cytokines.
Antigens, Surface↗
New developments in the treatment of hypoplastic left heart syndrome.
Progress has been made in the treatment of children born with hypoplastic left heart syndrome. From a mortality of more than 95% at 1 month of age in an era prior to surgical intervention, an actuarial survival of 58% at 5 years of age for staged surgical palliation is now being achieved. The short-term results with cardiac transplantation also appear to be excellent. Efforts are being directed at identifying potential risk factors, and fetal ultrasonography is capable of monitoring the progression of this malformation in utero. Refinements in surgical technique and postoperative care have been achieved, reducing the overall risk of the Norwood operation and sudden hemodynamic instability in the intensive care unit. Practice patterns and perceptions of outcome vary widely. Presently there is no unanimity of opinion that surgical therapy should be offered to all patients, and comfort care continues to be a family option.
Cardiac Surgical Procedures↗
Hypotonicity increases transcription, expression, and action of Egr-1 in murine renal medullary mIMCD3 cells.
In cells of the murine renal inner medullary collecting duct (mIMCD3) cell line, acute hypotonic shock (50% dilution of medium with sterile water but not with sterile 150 mM NaCl) increased Egr-1 mRNA abundance 2.5-fold at 6 h, as determined by Northern analysis. This increase was accompanied by increased Egr-1 transcription, as quantitated by luciferase reporter gene assay. Increased transcription was dose dependent, additive with other Egr-1 transcriptional activators, and occurred in the absence of overt cytotoxicity, as quantitated via a fluorometric viability assay. In addition, hypotonic stress increased Egr-1 protein abundance, which was accompanied by augmented Egr-1-specific DNA binding ability, as measured via electrophoretic mobility shift assay. Increased DNA binding was further associated with increased transactivation by Egr-1, demonstrated through transient transfection of mIMCD3 cells with a luciferase reporter gene driven by tandem repeats of the Egr-1 DNA consensus sequence. Taken together, these data indicate that hypotonic stress activates Egr-1 transcription, translation, DNA binding, and transactivation in renal medullary cells. This phenomenon might play a role in the acquisition of the adaptive phenotype in response to hypotonic stress in cells of the renal medulla in vivo.
Animals↗
New non-cocaine-containing topical anesthetics compared with tetracaine-adrenaline-cocaine during repair of lacerations.
OBJECTIVE: To compare the effectiveness of three new topical anesthetics that do not contain cocaine (prilocaine-phenylephrine, tetracaine-phenylephrine [tetraphen], and tetracaine-lidocaine-phenylephrine) to that of tetracaine-adrenaline-cocaine (TAC) during laceration repair in children. DESIGN: Prospective, randomized, double-blind clinical trial. SETTING: The emergency department of an urban children's hospital. PARTICIPANTS: Children 1 year of age or older with a laceration </= 5 cm in length that required suturing. Intervention. A total of 240 children were randomly assigned to one of four treatment groups. OUTCOME MEASURES: Pain felt during suturing was scored by suture technicians, research assistants, parents, and patients >/= 5 years of age using a visual analogue scale (VAS). Suture technicians, research assistants, and parents also scored pain using a seven-point Likert scale. In addition, suture technicians completed an anesthetic effectiveness scale. RESULTS: There was consistently no difference demonstrated between the effectiveness of tetraphen and that of TAC for each outcome measure of each observer group. A statistically significant difference was seen among anesthetics when comparing VAS and Likert scale scores of suture technicians and Likert scale scores of research assistants. Based on post hoc analyses, these statistically significant differences were between TAC and prilocaine-phenylephrine (suture technician VAS and Likert scale) and between TAC and tetracaine-lidocaine-phenyl-ephrine (suture technician Likert scale), but not between TAC and tetraphen. When power analyses were performed using alpha = 0.05 and beta = 0.20, it was possible to detect a difference of 1.2 VAS units for each of the observer groups. Based on anesthetic effectiveness scale scores, the three new topical preparations collectively performed significantly better on the face and scalp than on the extremities (relative risk = 1.83; 95% confidence interval 1.20 < relative risk < 2.79). CONCLUSION: This study demonstrated the effectiveness and safety of three new non-cocaine-containing topical anesthetics. Consistently, there was no statistical difference demonstrated between the effectiveness of tetraphen and that of TAC for each outcome measure of each observer group. Tetraphen offers an effective alternative to TAC during laceration repair in children.
Adolescent↗
Miniature C-arm imaging: an in vitro study of detecting foreign bodies in the emergency department.
STUDY OBJECTIVE: Recently, we have had clinical success detecting foreign bodies (FBs) using a mobile C-arm fluoroscopic device. This study tests its utility to detect FBs of differing densities in soft tissue. DESIGN: Blinded, randomized, controlled in vitro study. METHODS: Two physicians used the Xi-scan mini C-arm to image FBs. Five FBs of differing densities were studied: metal, gravel, glass, wood, and plastic. The FBs were placed into the deep muscles of chicken legs. One hundred observations were made: 50 legs with FBs and 50 legs without FBs. The blinded investigators imaged the legs and determined the presence or absence of FBs. RESULTS: Imaging located 100% of metal, gravel and glass FBs. Plastic and wood could not be consistently detected (sensitivity 0.4, specificity 0.6). CONCLUSIONS: This device accurately detects metal, gravel and glass. Radiolucent (wood) and semiradiopaque (plastic) FBs could not be located reliably. Clinical trials would define utility of this device in saving time, money and radiation exposure.
Animals↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗