Showing papers by "Icahn School of Medicine at Mount Sinai published in 1998"

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease

Abstract: The efficacy and safety of donepezil as a treatment for patients with mild to moderate Alzheimer's disease (AD) was investigated in a multicenter, double-blind study. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg/d donepezil (n = 154), or 10 mg/d donepezil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. The primary efficacy measures were the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus), with the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient rated Quality of Life (QoL) used as secondary measures. Cognitive function, as measured by the ADAS-cog, was significantly improved in the 5- and 10-mg/d donepezil groups as compared with the placebo group at weeks 12, 18, and 24. Clinician's global ratings on the CIBIC plus also improved in both the 5- and 10-mg/d donepezil groups relative to placebo. At the end of the 6-week placebo washout phase, ADAS-cog scores and CIBIC plus ratings were not significantly different for the three groups. Significant treatment benefits were also observed consistently in both the 5- and 10-mg/d groups on the MMSE and the CDR-SB, but there was no consistent effect on the patient-rated QoL. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) were reported more often in the 10-mg/d group than either the 5-mg/d or placebo groups. Side effects were transient and generally mild in severity. These data indicate that donepezil is a well-tolerated drug that improves cognition and global function in patients with mild to moderate AD.

The urgent need to improve health care quality. Institute of Medicine National Roundtable on Health Care Quality.

Abstract: Objective.—To identify issues related to the quality of health care in the United States, including its measurement, assessment, and improvement, requiring action by health care professionals or other constituencies in the public or private sectors.Participants.—The National Roundtable on Health Care Quality, convened by the Institute of Medicine, a component of the National Academy of Sciences, comprised 20 representatives of the private and public sectors, practicing medicine and nursing, representing academia, business, consumer advocacy, and the health media, and including the heads of federal health programs. The roundtable met 6 times between February 1996 and January 1998. It explored ongoing, rapid changes in health care and the implications of these changes for the quality of health and health care in the United States.Evidence.—Roundtable members held discussions with a wide variety of experts, convened conferences, commissioned papers, and drew on their individual professional experience.Consensus Process.—At the end of its deliberations, roundtable members reached consensus on the conclusions described in this article by a series of discussions at committee meetings and reviews of successive draft documents, the first of which was created by the listed authors and the Institute of Medicine project director. The drafts were revised following these discussions, and the final document was approved according to the formal report review procedures of the National Research Council of the National Academy of Sciences.Conclusions.—The quality of health care can be precisely defined and measured with a degree of scientific accuracy comparable with that of most measures used in clinical medicine. Serious and widespread quality problems exist throughout American medicine. These problems, which may be classified as underuse, overuse, or misuse, occur in small and large communities alike, in all parts of the country, and with approximately equal frequency in managed care and fee-for-service systems of care. Very large numbers of Americans are harmed as a direct result. Quality of care is the problem, not managed care. Current efforts to improve will not succeed unless we undertake a major, systematic effort to overhaul how we deliver health care services, educate and train clinicians, and assess and improve quality.

Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein

Abstract: Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA (N-methyl-D-aspartate) receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind a protein known as postsynaptic density-95 (PSD-95), which may regulate the localization of and/or signalling by the receptor. In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift is accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization and synaptic morphology are all unaffected in the mutant mice. PSD-95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.

A Comparison of Four Treatments for Generalized Convulsive Status Epilepticus

Abstract: Background and Methods Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyse...

Understanding cell death in Parkinson's disease

Abstract: Current concepts of the cause of Parkinson's disease (PD) suggest a role for both genetic and environmental influences. Common to a variety of potential causes of nigral cell degeneration in PD is the involvement of oxidative stress. Postmortem analysis shows increased levels of iron, decreased complex I activity, and a decrease in reduced glutathione (GSH) levels. The decrease in GSH levels may be a particularly important component of the cascade of events leading to cell death because it occurs in the presymptomatic stage of PD and may directly induce nigral cell degeneration or render neurons susceptible to the actions of toxins. There is evidence suggesting that oxidative stress might originate in glial cells rather than in neurons, and alterations in glial function may be an important contributor to the pathologic process that occurs in PD. Oxidative damage occurs in the brain in PD, as shown by increased lipid peroxidation and DNA damage in the substantia nigra. Increased protein oxidation is also apparent, but this occurs in many areas of the brain and raises the specter of a more widespread pathologic process occurring in PD to which the substantia nigra is particularly vulnerable. The inability of the substantia nigra to handle damaged or mutant (eg, α-synuclein) proteins may lead to their aggregation and deposition and to the formation of Lewy bodies. Indeed, Lewy bodies stain for both α-synuclein and nitrated proteins. Current evidence enables us to hypothesize that a failure to process structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.

An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines.

Abstract: Parkinson’s disease (PD) is named in honor of James Parkinson, whose classic monograph, “An Essay on the Shaking Palsy,” written in 1817, has provided an enduring description of the clinical features of this disorder.1 PD is an age-related neurodegenerative disorder with an average age at onset of 60 years. An estimated 1 million persons in the United States suffer from PD,2 and there are approximately 60,000 new cases each year. United States Census Bureau projections indicate that there will be a substantial increase in the number of at-risk individuals 60 years of age and older, and therefore the prevalence of PD is likely to increase in the coming decades. The introduction of levodopa in the late 1960s represented a major therapeutic advance in the management of PD,3 providing clinical benefit to virtually all patients and reduced mortality. However, it soon became apparent that long-term treatment with levodopa is complicated by the development of adverse events that include motor fluctuations, dyskinesias, and neuropsychiatric complications.4-6⇓⇓ In addition, with disease progression, patients develop features that do not respond well to levodopa therapy, such as freezing episodes, autonomic dysfunction, falling, and dementia. As a consequence, despite levodopa treatment, most PD patients eventually suffer disabilities that cannot be satisfactorily controlled with existing medical therapies. Therefore, there has been an intensive effort to develop new treatments that reverse disabilities in patients with advanced disease, that provide enhanced clinical benefits with a reduced risk for adverse events, and that slow the rate of disease progression. This has led to an explosion of new laboratory and clinical information and to a variety of new treatment strategies for the management of PD. Physicians who treat PD patients must now assimilate a considerable body of data to optimally manage patients with this complex disorder. …

Prevalence of IgE-mediated food allergy among children with atopic dermatitis.

Abstract: Objective. There is a growing body of clinical and laboratory evidence to support the notion that food allergy plays a role in the pathogenesis of atopic dermatitis (AD). However, the incidence of IgE-mediated food allergy in children with AD is not well established. Design. A prospective study to determine the prevalence of IgE-mediated food hypersensitivity among patients referred to a university-based dermatologist for evaluation of AD. Setting. University hospital pediatric dermatology clinic. Patients. A total of 63 patients with AD were recruited (35 male; 32 white, 24 African-American, 7 Asian). Methods. Patients were assigned an AD symptom score (SCORAD) and were screened for food-specific serum IgE antibodies to six foods (milk, egg, wheat, soy, peanut, fish) known to be the most allergenic in children. The levels of food-specific serum IgE were determined by the CAP System fluoroscein-enzyme immunoassay (CAP); patients with a value ≥0.7 kIUa/L were invited for an additional allergy evaluation. Those with CAP values below the cutoff were considered not food allergic. Patients were considered to be allergic if they met one of the following criteria for at least one food: 1) reaction on food challenge; 2) CAP value more than the 95% confidence interval predictive for a reaction; 3) convincing history of an acute significant (hives, respiratory symptoms) reaction after the isolated ingestion of a food to which there was a positive CAP or prick skin test. Results. A total of 63 patients (median age, 2.8 years; median SCORAD, 41.1) were recruited; 22 had negative CAP values (without a significant difference in age or SCORAD score, compared with the 41 with positive specific IgE values). Further allergy evaluation was offered to the 41 remaining patients; 10 were lost to follow-up and 31 were evaluated further. Of these, 19 underwent a total of 50 food challenges (36 double-blind, placebo-controlled, and 14 open), with 11 patients experiencing 18 positive challenges (94% with skin reactions). Additionally, 6 patients had a convincing history with a predictive level of IgE; 5 had a convincing history with positive, indeterminate levels of IgE; and 1 had predictive levels of IgE (to egg and peanut) without a history of an acute reaction. Overall, 23/63 (37%; 95% confidence interval, 25% to 50%) had clinically significant IgE-mediated food hypersensitivity without a significant difference in age or symptom score between those with or without food allergy. Conclusions. Approximately one third of children with refractory, moderate–severe AD have IgE-mediated clinical reactivity to food proteins. The prevalence of food allergy in this population is significantly higher than that in the general population, and an evaluation for food allergy should be considered in these patients.

Protein Nitration in Parkinson's Disease

Abstract: Oxidative stress has been proposed as a pathogenetic mechanism in Parkinson's disease (PD). One mechanism of oxidative cellular injury is the nitration of protein tyrosine residues, mediated by peroxynitrite, a reaction product of nitric oxide and superoxide radicals. We demonstrate here the presence of nitrotyrosine immunoreactivity in Lewy bodies within melanized neurons and in amorphous deposits associated with intact and degenerating neurons. The core of the Lewy body was frequently intensely immunolabeled, while the rim was lightly labeled or unlabeled. This likely reflects the fact that tyrosine residues of neurofilament proteins are primarily localized to Lewy body cores, and suggests that nitrotyrosine is present in neurofilament protein itself. Although these observations are as yet unable to provide a definitive link between oxidative stress and neuronal dysfunction, they demonstrate that oxidative stress has occurred within the vulnerable neurons of PD, leaving a permanent marker of oxidative modification of neuronal proteins within the target cells of neurodegeneration. In addition, these observations provide a potential link between excitotoxicity and oxidative stress within the vulnerable neurons of PD and represent a pathogenetic mechanism in common with the 2 other major age-related neurodegenerative diseases, Alzheimer disease and amyotrophic lateral sclerosis.

A dose-response study for I-125 prostate implants

Abstract: Purpose: No dose–response study has ever been performed for I-125 prostate implants using modern techniques of implant evaluation and modern treatment outcome end points. The amount of activity per volume implanted was increased over time based on review of postimplant dosimetry. This resulted in different delivered dose levels. This study explores the relationship between dose, biochemical failure, and biopsy results. Materials and Methods: 134 patients with T1–T2 prostate cancer were implanted with I-125 radioactive seeds and followed from 12 to 74 months (median: 32) postimplant. No patient received external beam irradiation or hormonal therapy. All patients implanted with I-125 had Gleason scores ≤6. One month postimplant, a CT-based three-dimensional dosimetric evaluation was performed on all patients. Using TG43 guidelines, dose–volume histograms were calculated. The dose delivered to the gland was defined as the D90 (dose delivered to 90% of prostate tissue as defined by CT). The D90s ranged from 26.8 to 256.3 Gy (median: 140.8 Gy). Biochemical failure was defined as two consecutive rises in prostate specific antigen (PSA) or a nadir level above 1.0 ng/ml. Posttreatment prostate biopsies (six to eight core samples) were routinely performed at 2 years postimplant. Results: Improvements in freedom from biochemical failure (FFBF) rates were seen with increasing D90 levels. The 4-year FFBF rates for patients with D90 values p = 0.02). Patients receiving a D90 p = 0.02). Two-year posttreatment biopsies were negative in 70% (33 of 47) of patients with a D90 p = 0.2). A multivariate analysis using dose, PSA, score, and stage revealed that dose was the most significant predictor of biochemical failure ( p = 0.001). This dose response was more pronounced in patients presenting with PSA levels >10 ng/ml. In these patients, the 4-year FFBF rates were 51 and 100% for the low and high dose groups, respectively ( p = 0.009) and the negative biopsy rates were 64% (14 of 22) and 100% (8 of 8), respectively ( p = 0.05). In patients with presenting PSA p = 0.29). Conclusion: A dose response was observed at a level of 140 Gy. Adequate I -125 implants should deliver a dose of 140–160 Gy using TG43 guidlines.

Hypothalamic Pro-Opiomelanocortin mRNA Is Reduced By Fasting in ob/ob and db/db Mice, but Is Stimulated by Leptin

Abstract: Reduction in the activity of the α-melanocyte-stimulating hormone (α-MSH) system causes obesity, and infusions of α-MSH can produce satiety, raising the possibility that α-MSH may mediate physiological satiety signals. Since α-MSH is coded for by the pro-opiomelanocortin (POMC) gene, we examined if POMC gene expression would be inhibited by fasting in normal mice or in models of obesity characterized by leptin insufficiency ( ob/ob ) or leptin insensitivity ( db/db ). In wild-type mice, hypothalamic POMC mRNA was decreased >60% after a 2-day fast and was positively correlated with leptin mRNA. Similarly, compared with controls, POMC mRNA was decreased by at least 60% in both db/db and ob/ob mice. POMC mRNA was negatively correlated with both neuropeptide Y (NPY) and melanin-concentrating hormone (MCH) mRNA. Finally, treatment of both male and female ob/ob mice with leptin stimulated hypothalamic POMC mRNA by about threefold. These results suggest that impairment in production, processing, or responsiveness to α-MSH may be a common feature of obesity and that hypothalamic POMC neurons, stimulated by leptin, may constitute a link between leptin and the melanocortin system.

MEKK1/JNK signaling stabilizes and activates p53.

Abstract: Activation of the tumor suppressor p53 by stress and damage stimuli often correlates with induction of stress kinases, Jun-NH2 kinase (JNK) As JNK association with p53 plays an important role in p53 stability, in the present study we have elucidated the relationship between the JNK-signaling pathway and p53 stability and activity Expression of a constitutively active form of JNKK upstream kinase, mitogen-activated protein kinase kinase kinase (ΔMEKK1), increased the level of the exogenously transfected form of p53 in p53 null (101) cells as well as of endogenous p53 in MCF7 breast cancer cells Increased p53 level by forced expression of ΔMEKK1 coincided with a decrease in p53 ubiquitination in vivo and with prolonged p53 half-life Computerized modeling of the JNK-binding site (amino acids 97–116; p7 region) enabled us to design mutations of exposed residues within this region Respective mutations (p53101-5-8) and deletion (p53Δp7) forms of p53 did not exhibit the same increase in p53 levels upon ΔMEKK1 expression In vitro phosphorylation of p53 by JNK abolished Mdm2 binding and targeting of p53 ubiquitination Similarly, ΔMEKK1 expression increased p53 phosphorylation by immunopurified JNK and dissociated p53–Mdm2 complexes Transcriptional activity of p53, as measured via mdm2 promoter-driven luciferase, exhibited a substantial increase in ΔMEKK1-expressing cells Cotransfection of p53 and ΔMEKK1 into p53 null cells potentiated p53-dependent apoptosis, suggesting that MEKK1 effectors contribute to the ability of p53 to mediate programmed cell death Our results point to the role of MEKK1-JNK signaling in p53 stability, transcriptional activities, and apoptotic capacity as part of the cellular response to stress

The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins.

Abstract: Nuclear import and export of viral nucleic acids is crucial for the replication cycle of many viruses, and elucidation of the mechanism of these steps may provide a paradigm for understanding general biological processes. Influenza virus replicates its RNA genome in the nucleus of infected cells. The influenza virus NS2 protein, which had no previously assigned function, was shown to mediate the nuclear export of virion RNAs by acting as an adaptor between viral ribonucleoprotein complexes and the nuclear export machinery of the cell. A functional domain on the NS2 with characteristics of a nuclear export signal was mapped: it interacts with cellular nucleoporins, can functionally replace the effector domain of the human immunodeficiency virus type 1 (HIV-1) Rev protein and mediates rapid nuclear export when cross-linked to a reporter protein. Microinjection of anti-NS2 antibodies into infected cells inhibited nuclear export of viral ribonucleoproteins, suggesting that the Rev-like NS2 mediates this process. Therefore, we have renamed this Rev-like factor the influenza virus nuclear export protein or NEP. We propose a model by which NEP acts as a protein adaptor molecule bridging viral ribonucleoproteins and the nuclear pore complex.

Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1.

Abstract: Thyroid hormone, acting through several nuclear hormone receptors, plays important roles in thermogenesis, lipogenesis and maturation of the neonatal brain. The receptor specificity for mediating these effects is largely unknown, and to determine this we developed mice lacking the thyroid hormone receptor TRα1. The mice have an average heart rate 20% lower than that of control animals, both under normal conditions and after thyroid hormone stimulation. Electrocardiograms show that the mice also have prolonged QRS‐ and QT end ‐durations. The mice have a body temperature 0.5°C lower than normal and exhibit a mild hypothyroidism, whereas their overall behavior and reproduction are normal. The results identify specific and important roles for TRα1 in regulation of tightly controlled physiological functions, such as cardiac pacemaking, ventricular repolarisation and control of body temperature.

Nonsurgical factors that influence the outcome of bariatric surgery: a review.

Abstract: Objective Severe obesity (ie, at least 100% overweight or body mass index > or =40 kg/m2) is associated with significant morbidity and increased mortality. It is apparently becoming more common in this country. Conventional weight-loss treatments are usually ineffective for severe obesity and bariatric surgery is recommended as a treatment option. However, longitudinal data on the long-term outcome of bariatric surgery are sparse. Available data indicate that the outcome of bariatric surgery, although usually favorable in the short term, is variable and weight regain sometimes occurs at 2 years after surgery. The objective of this study is to present a review of the outcome of bariatric surgery in three areas: weight loss and improvement in health status, changes in eating behavior, and psychosocial adjustment. The study will also review how eating behavior, energy metabolism, and psychosocial functioning may affect the outcome of bariatric surgery. Suggestions for additional research in these areas are made. Method Literature review. Results On average, most patients lose 60% of excess weight after gastric bypass and 40% after vertical banded gastroplasty. In about 30% of patients, weight regain occurs at 18 months to 2 years after surgery. Binge eating behavior, which is common among the morbidly obese, may recur after surgery and is associated with weight regain. Energy metabolism may affect the outcome of bariatric surgery, but it has not been systematically studied in this population. Presurgery psychosocial functioning does not seem to affect the outcome of surgery, and psychosocial outcome is generally encouraging over the short term, but there are reports of poor adjustment after weight loss, including alcohol abuse and suicide. Conclusions Factors leading to poor outcome of bariatric surgery, such as binge eating and lowered energy metabolism, should be studied to improve patient selection and outcome. Long-term outcome data on psychosocial functioning are lacking. Longitudinal studies to examine the long-term outcome of bariatric surgery and the prognostic indicators are needed.

Clinical Features of Acute Allergic Reactions to Peanut and Tree Nuts in Children

Abstract: Background. Peanut (PN) and tree nut (TN) allergies are potentially life-threatening, rarely outgrown, and appear to be increasing in prevalence. However, there is relatively little reported about the clinical features of acute reactions to these foods and their potential association. Objective. To describe the clinical features of acute reactions during initial and subsequent accidental ingestions of PN and TN among children with a history of at least one acute allergic reaction to these foods. Design. Questionnaire survey, examination, and serologic testing for specific IgE antibody of patients with convincing histories of acute reactions (at least one organ system involved within 60 minutes of ingestion) to PN or TN. Results. A total of 122 patients (63% males; median age, 8 years at time of study) had acute reactions; 68 had reactions only to PN, 20 only to TN, and 34 to both PN and TN. Of those reacting to TN, 34 had reactions to one, 12 to two, and 8 to three or more different TN, the most common being walnut, almond, and pecan. Initial reactions usually occurred at home (median age, 24 months for PN and 62 months for TN) and were considered to result from a first exposure in 72% of cases. Eighty-nine percent of the reactions involved the skin (urticaria, angioedema), 52% the respiratory tract (wheezing, throat tightness, repetitive coughing, dyspnea), and 32% the gastrointestinal tract (vomiting, diarrhea). Two organ systems were affected in 31% of initial reactions, and all three in 21% of reactions. Thirty-eight of 190 first reactions to PN or TN were treated with epinephrine. Accidental ingestions occurred in 55% of PN-allergic children (average of two accidents per patient with an accidental ingestion) and in 30% of TN-allergic children over a median period of 5.5 years. On average, symptoms after accidental exposure were generally similar to those at initial exposure. Accidents occurred commonly in school but also at home and in restaurants. Modes of accidental ingestion included sharing food, hidden ingredients, cross-contamination, and school craft projects using peanut butter. Eighty-three percent of the children were breastfed, with >90% of the mothers ingesting PN and at least one TN during lactation. Among patients reporting no history of exposure (>60% of patients for each TN), IgE antibodies were found to a particular TN in 50% to 82% of patients and to PN in 100% of patients. Conclusions. Acute allergic reactions to PN occur early in life. PN and TN allergic reactions coexist in one third of PN-allergic patients, frequently occur on first known exposure, and may be life-threatening, requiring emergency treatment. Accidental ingestions are common, occur frequently outside of the home, and often require emergency treatment. Consequently, early diagnosis followed by education on avoidance and treatment measures (including self-administered epinephrine) is imperative.

A national survey of physician-assisted suicide and euthanasia in the United States.

Abstract: Background Although there have been many studies of physician-assisted suicide and euthanasia in the United States, national data are lacking. Methods In 1996, we mailed questionnaires to a stratified probability sample of 3102 physicians in the 10 specialties in which doctors are most likely to receive requests from patients for assistance with suicide or euthanasia. We weighted the results to obtain nationally representative data. Results We received 1902 completed questionnaires (response rate, 61 percent). Eleven percent of the physicians said that under current legal constraints, there were circumstances in which they would be willing to hasten a patient's death by prescribing medication, and 7 percent said that they would provide a lethal injection; 36 percent and 24 percent, respectively, said that they would do so if it were legal. Since entering practice, 18.3 percent of the physicians (unweighted number, 320) reported having received a request from a patient for assistance with suicide and 11.1 ...

Asymmetry of Chimpanzee Planum Temporale: Humanlike Pattern of Wernicke's Brain Language Area Homolog

Abstract: The anatomic pattern and left hemisphere size predominance of the planum temporale, a language area of the human brain, are also present in chimpanzees (Pan troglodytes). The left planum temporale was significantly larger in 94 percent (17 of 18) of chimpanzee brains examined. It is widely accepted that the planum temporale is a key component of Wernicke's receptive language area, which is also implicated in human communication-related disorders such as schizophrenia and in normal variations such as musical talent. However, anatomic hemispheric asymmetry of this cerebrocortical site is clearly not unique to humans, as is currently thought. The evolutionary origin of human language may have been founded on this basal anatomic substrate, which was already lateralized to the left hemisphere in the common ancestor of chimpanzees and humans 8 million years ago.

Gating of CaMKII by cAMP-Regulated Protein Phosphatase Activity During LTP

Abstract: Long-term potentiation (LTP) at the Schaffer collateral–CA1 synapse involves interacting signaling components, including calcium (Ca2+)/calmodulin–dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP) pathways. Postsynaptic injection of thiophosphorylated inhibitor-1 protein, a specific inhibitor of protein phosphatase–1 (PP1), substituted for cAMP pathway activation in LTP. Stimulation that induced LTP triggered cAMP-dependent phosphorylation of endogenous inhibitor-1 and a decrease in PP1 activity. This stimulation also increased phosphorylation of CaMKII at Thr286 and Ca2+-independent CaMKII activity in a cAMP-dependent manner. The blockade of LTP by a CaMKII inhibitor was not overcome by thiophosphorylated inhibitor-1. Thus, the cAMP pathway uses PP1 to gate CaMKII signaling in LTP.

Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes

Abstract: Circulating leptin secreted from adipocytes is correlated with fat mass and plasma insulin concentrations in humans and rodents. Plasma leptin, insulin, and glucose decrease during fasting and increase after refeeding; however, the underlying mechanisms regulating the changes of leptin secretion are not known. To investigate the role of insulin-stimulated glucose metabolism in the regulation of leptin secretion, we examined the effects of insulin and inhibitors of glucose transport and metabolism on leptin secretion from rat adipocytes in primary culture. Insulin (0.16-16 nM) increased leptin secretion over 96 h; however, the increase in leptin was more closely related to the amount of glucose taken up by the adipocytes (r = 0.64; P < 0.0001) than to the insulin concentration per se (r = 0.20; P < 0.28), suggesting a role for glucose transport and/or metabolism in regulating leptin secretion. 2-Deoxy-D-glucose (2-DG), a competitive inhibitor of glucose transport and phosphorylation, caused a concentration-dependent (2-50 mg/dl) inhibition of leptin release in the presence of 1.6 nM insulin. The inhibitory effect of 2-DG was reversed by high concentrations of glucose. Two other inhibitors of glucose transport, phloretin (0.05-0.25 mM) and cytochalasin-B (0.5-50 microM), also inhibited leptin secretion. Inhibition of leptin secretion by these agents was proportional to the inhibition of glucose uptake (r = 0.60 to 0.86; all P < 0.01). Two inhibitors of glycolysis, iodoacetate (0.005-1.0 mM) and sodium fluoride (0.1-5 mM), produced concentration-dependent inhibition of leptin secretion in the presence of 1.6 nM insulin. In addition, both 2-DG and sodium fluoride markedly decreased the leptin (ob) messenger RNA content of cultured adipocytes, but did not affect 18S ribosomal RNA content. We conclude that glucose transport and metabolism are important factors in the regulation of leptin expression and secretion and that the effect of insulin to increase adipocyte glucose utilization is likely to contribute to insulin-stimulated leptin secretion. Thus, in vivo, decreased adipose glucose metabolism may be one mechanism by which fasting decreases circulating leptin, whereas increased adipose glucose metabolism would increase leptin after refeeding.