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Biomedical subjects

S Gershon

Publications and source records attributed to S Gershon.

At least 19 recordsLinked to original sources
PubMed2003

Effects of acetyl-L-carnitine and myo-inositol on high-energy phosphate and membrane phospholipid metabolism in zebra fish: a 31P-NMR-spectroscopy study.

Acetyl-L-carnitine (ALCAR) and myo-inositol are reported to enhance motor activity in animal models; modulate membrane phospholipid metabolism (ALCAR and myo-inositol) and high-energy phosphate metabolism (ALCAR) back to normal; and be effective treatments of major depression in humans. Fish in general and zebra fish in particular present unique animal models for the in vivo study of high-energy phosphate and membrane phospholipid metabolism by noninvasive in vivo 31P NMR. This 31P NMR study of free-swimming zebra fish showed that both ALCAR and myo-inositol decreased levels of phosphodiesters and inorganic orthophosphate and increased levels of PCr in the fish. These findings demonstrate both ALCAR and myo-inositol modulate membrane phospholipid and high-energy phosphate metabolism in free-swimming zebra fish.

Acetylcarnitine↗
PubMed2001

Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.

BACKGROUND: Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis. METHODS: We analyzed all reports of tuberculosis after infliximab therapy that had been received as of May 29, 2001, through the MedWatch spontaneous reporting system of the Food and Drug Administration. RESULTS: There were 70 reported cases of tuberculosis after treatment with infliximab, for a median of 12 weeks. In 48 patients, tuberculosis developed after three or fewer infusions. Forty of the patients had extrapulmonary disease (17 had disseminated disease, 11 lymph node disease, 4 peritoneal disease, 2 pleural disease, and 1 each meningeal, enteric, paravertebral, bone, genital, and bladder disease). The diagnosis was confirmed by a biopsy in 33 patients. Of the 70 reports, 64 were from countries with a low incidence of tuberculosis. The reported frequency of tuberculosis in association with infliximab therapy was much higher than the reported frequency of other opportunistic infections associated with this drug. In addition, the rate of reported cases of tuberculosis among patients treated with infliximab was higher than the available background rates. CONCLUSIONS: Active tuberculosis may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent tuberculosis infection or disease.

Adolescent↗
PubMed2001

Chronic myo-inositol increases rat brain phosphatidylethanolamine plasmalogen.

BACKGROUND: Oral myo-inositol (12--18 g/day) has shown beneficial effect in placebo-controlled studies of major depression, panic disorder, and obsessive compulsive disorder, and preliminary data suggest it also may be effective in bipolar depression. Evidence linking antidepressant activity to membrane phospholipid alterations suggested the examination of acute and chronic myo-inositol effects on rat brain membrane phospholipid metabolism. METHODS: With both (31)P nuclear magnetic resonance (NMR) and quantitative high-performance thin-layer chromatography (HPTLC; hydrolysis) methods, rat brain phospholipid levels were measured after acute (n = 20, each group) and chronic myo-inositol administration (n = 10, each group). With (31)P NMR, we measured myo-inositol rat brain levels after acute and chronic myo-inositol administration. RESULTS: Brain myo-inositol increased by 17% after acute myo-inositol administration and by 5% after chronic administration, as compared with the control groups. Chronic myo-inositol administration increased brain phosphatidylethanolamine (PtdEtn) plasmalogen by 10% and decreased brain PtdEtn by 5%, thus increasing the ratio PtdEtn plasmalogen (PtdEtn-Plas)/PtdEtn by 15%. Phosphatidylethanolamine plasmalogen levels quantified by (31)P NMR and HPTLC were highly correlated. The validity and reliability of the (31)P NMR method for phospholipid analysis were demonstrated with phospholipid standards. CONCLUSIONS: The observed alteration in the PtdEtn-Plas/PtdEtn ratio could provide insights into the therapeutic effect of myo-inositol in affective disorders.

Animals↗
PubMed2001

Brain lithium concentrations in bipolar disorder patients: preliminary (7)Li magnetic resonance studies at 3 T.

BACKGROUND: This study was conducted to investigate the feasibility of human brain (7)Li MRS investigations at a high magnetic field (3 T), and to further explore the relationship between brain and serum lithium measures in lithium-treated bipolar patients. METHODS: Eight bipolar disorder type I patients (5 males, 3 females; mean age +/- SD = 33 +/- 9 years) were studied. A 3-T scanner, using a dual-tuned ((1)H and (7)Li) echoplanar imaging (EPI) compatible radiofrequency (RF) birdcage coil was used. (7)Li magnetic resonance spectroscopy (MRS) signal was acquired at the frequency of 49.64 MHz using an imaging selective in vivo spectroscopy (ISIS) sequence (TR = 15 sec, 128 averages), and quantitation was obtained in reference to an external standard. RESULTS: The mean +/- SD oral lithium dose was 1265 +/- 442 mg/day, and the mean +/- SD 12-hour serum level was 0.69 +/- 0.19 mEq/L. The measured brain lithium concentrations varied from 0.23 to 0.55 mEq/L (mean +/- SD = 0.35 +/- 0.11 mEq/L). The brain-serum ratios varied from 0.30 to 0.80 (mean +/- SD = 0.52 +/- 0.16). Subjects on single daily doses of lithium at bedtime (n = 5) had higher brain-serum lithium ratios compared with those on twice-a-day schedules (n = 3) (0.61 +/- 0.12 and 0.37 +/- 0.07, respectively; Mann--Whitney U test, Z = -2.24, p =.03). CONCLUSIONS: This study demonstrated for the first time the feasibility of (7)Li MRS human studies at 3 T. Future studies should examine a possible role for this methodology in investigations of lithium refractoriness and prediction of treatment outcome in bipolar patients.

Adult↗
PubMed2001

Anxiety disorders and major depression, together or apart.

This paper will discuss the relationship between anxiety and depression. We will begin with a brief historical perspective. We will then move into the twentieth century, with a focus on the 1950s, at which time the introduction of pharmacological treatment options revolutionized the field of psychiatry. The use of psychiatric medications and the observation of treatment response provided an additional means of understanding the relationship between anxiety and depression. From the late 1970s to the 1990s, it became apparent that various medications possessed wider therapeutic profiles than were previously recognized. For example, many medications were found to be efficacious in both anxiety and depressive disorders. These expanded therapeutic profiles provided additional clues to fuel our thinking about the relationship between anxiety and depression. The two major objectives of this paper are, first, to describe and formalize a process of pharmacological dissection and, second, to consider how this process might contribute to our search for a better understanding of the relationship between anxiety and depression.

Anti-Anxiety Agents↗
PubMed2001

Differentiating primary pathophysiologic from secondary adaptational processes.

The following manuscript is mainly conceptual in nature. It should be read with reservation since the relevance of its suggestions have yet to be proven. Basically it proposes two rules for the differentiation between primary illness-related pathophysiological vs. secondary adaptational processes. These rules may guide hypotheses generation for further research that is aimed at understanding psychiatric disorders and their shared and unshared mechanisms. For example, in the case of anxiety disorders and depression, it may be of interest to learn if their shared properties are of primary pathophysiological or secondary adaptational significance. We first present some historical observations on the development of the concept of "secondary adaptational processes." We assume such adaptational processes are generated by the organism in order to compensate for primary pathophysiological malfunction or impairment. Next, we propose rules that may enable the dissection of secondary adaptational from primary pathophysiological processes. We also discuss the possible implications of designing studies to sort out these processes, suggesting that the understanding of adaptational processes, may explain the effects of "placebo treatment." Finally we illustrate the application of these rules by two examples: a) amygdala activation, a biological alteration shared by anxiety disorders and major depression and b) elevated plasma soluble interleukin 2 receptor, an unshared property by anxiety disorders and major depression. Also, the first example relates to a biological perturbation associated with a primary pathophysiological mechanism, while the second represents a biological alteration associated with secondary adaptational processes.

Adaptation, Psychological↗
PubMed2001

Illness characteristics and their association with prescription patterns for bipolar I disorder.

INTRODUCTION: The present study explores the relationships among psychotropic medications, illness-related parameters, patient demography, suicidality, and levels of functioning in a voluntary bipolar case registry. METHODS: Four hundred and fifty-seven subjects with bipolar I disorder were selected from a voluntary registry for subjects with bipolar illness. Demographic characteristics, psychotropic medications, age at onset of illness, duration of illness, number of hospitalizations, the ability to live independently, employment and driving status as well as the history of suicidal attempts were obtained through a structured phone interview. RESULTS: Subjects treated with antidepressants had a shorter duration of illness, while patients treated with antipsychotic drugs had an earlier onset of illness. The number of hospitalizations for mania was fewer among patients taking a combination of lithium and carbamazepine as compared to patients not receiving them, while subjects taking neuroleptics had more hospitalizations as compared to subjects not receiving them. The number of psychotropic agents prescribed correlated positively with the number of hospitalizations for depressive episodes. Curiously, no correlations were found between the types of psychotropic agents prescribed and the levels of functioning or a history of suicidal attempts. Interestingly, our results suggest that more than half of the subjects were unable to live independently or to work due to their illness. Also, more than 50% of the subjects had at least one suicidal attempt, the majority occurred during depressive episodes. CONCLUSIONS: Our results suggest that subjects with bipolar I disorder have high rate of suicidal attempts and may have serious functional impairments.

Adolescent↗
PubMed2001

Tumor-induced insufficiency in T cell activity and hyperproduction of interleukin-2 in rat giant hepatomas.

The roles of lymphoid elements and apoptosis-related proteins in the development of extremely large hepatomas were studied in rats. Hepatoma cells were inoculated subcutaneously into 6-week-old rats, and 4 months later the quantities of T and B cells, macrophages, and cells positive for Fas, Fas ligand (FasL) and interleukin-2 (IL-2) were immunochemically evaluated in tumors. Grafting of hepatoma cells caused the development of giant tumors that could reach one-third of the rat's body weight. Within the hepatomas, almost all CD8(+) T cells were destroyed as they passed from the tumoral stroma into the parenchyma and came in contact with tumor epithelial cells. This could be the consequence of IL-2 production, since about 90% of tumor cells were CD25(+). The tumoral mass increased despite the significant increase in tumor necrosis. Cells with Ki67 or in mitosis, and cells positive for Fas and FasL were found only among tumor epithelial cells that were necrotic and never among viable cells. We suggest that progress in tumorigenesis is facilitated by inhibition of T helper cells, and the extensive death of T killer cells is caused by the high levels of the tumor produced IL-2.

Animals↗
PubMed2001

Effects of chronic lithium administration on rat brain phosphatidylinositol cycle constituents, membrane phospholipids and amino acids.

OBJECTIVE: There is evidence linking affective disorders and their treatment to alterations in membrane phospholipid metabolism, the phosphatidylinositol (PtdIns) second messenger cycle and brain excitatory and inhibitory amino acids. This study examines lithium effects on rat brain metabolites associated with the above systems and their reversal by myo-inositol. METHODS: Thirty rats were treated for 14 days with i.p. lithium, saline or lithium plus myo-inositol. 1H, 31P and 7Li NMR were used to measure brain metabolites. RESULTS: Lithium, administered alone or with myo-inositol, resulted in brain lithium concentrations of approximately 0.6 microM/gram brain tissue. Brain myo-inositol was unchanged when lithium was co-administered with myo-inositol. Lithium increased brain inositol-1-phosphate (I1P) by 98% compared with saline and this effect was not attenuated by the addition of myo-inositol. Lithium treatment decreased phosphatidylserine (PtdSer) and PtdIns by 3% and 8%, respectively. Lithium also decreased taurine levels by 8% and increased aspartate levels by 9%. The above effects of lithium on PtdSer, PtdIns and taurine were attenuated or abolished by the co-administration of myo-inositol. CONCLUSIONS: Lithium alters levels of key membrane phospholipids and appears to affect the balance between inhibitory and excitatory amino acids in rat brain. Co-administration of myo-inositol attenuates some of these lithium effects on brain metabolites.

Amino Acids↗
PubMed2001

The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder.

OBJECTIVES: Topiramate, a structurally novel anticonvulsant, is being evaluated for other neurological conditions such as migraine, neuropathic pain, and essential tremor, and also for psychiatric conditions such as bipolar disorder, bulimia, post-traumatic stress disorder, and schizoaffective disorder, in addition to obesity. This article will focus on the use of topiramate for bipolar disorder. METHODS: The pharmacological profile of topiramate is compared to other established and putative mood stabilizers, and a rationale for its use in bipolar disorder is presented. Data from open clinical trials of topiramate for depression, mania, and rapid-cycling bipolar disorder are summarized. Preliminary data from one pilot dose-finding, double-blind, random-assignment, placebo-controlled, 3-week parallel group study of two doses of topiramate for acute bipolar I mania is reported. Safety data regarding topiramate was reviewed. Finally, the potential place of this agent in bipolar illness is considered. RESULTS: The pharmacological advantages for topiramate are low protein binding, minimal hepatic metabolism and mainly unchanged renal excretion, a 24-h half-life, and minimal drug interactions. Open clinical studies suggest a 50-65% response for refractory bipolar mania, and a 40-56% response for refractory bipolar depression in mainly add-on treatment. Open clinical studies of topiramate for rapid-cycling subjects and those for comorbid bulimia, substance abuse, post-traumatic stress, migraine, and obesity report effectiveness. The primary efficacy endpoint data (change from baseline Y-MRS total scores) of the placebo-controlled, random assignment parallel group phase II dose-finding study were not statistically significant. However, once the antidepressant-associated manias (28 of the sample, of 97 subjects) were excluded from the controlled study, the post-hoc analyses indicated the higher dose (512 mg/day) topiramate treatment group showed a statistically significant reduction in endpoint Y-MRS change scores as compared to placebo (p < 0.03). Adverse effects of topiramate in bipolar subjects include attention, concentration and memory problems, fatigue, sedation, transient paraesthesias, nausea, and anorexia. Some subjects experience word-finding difficulty. Weight loss may be seen in several topiramate-treated subjects with bipolar disorder. CONCLUSIONS: Topiramate appears to show promise as an addition to the agents available to treat bipolar disorder. More definitive controlled data on the efficacy of topiramate in the acute and continuation phases as well as for the prophylaxis either as monotherapy or as combination treatment of bipolar disorder are ongoing, and the results are awaited.

Acetates↗
PubMed2000

Increased cerebrospinal fluid glutamine levels in depressed patients.

BACKGROUND: There is increasing evidence for an association between alterations of brain glutamatergic neurotransmission and the pathophysiology of affective disorders. METHODS: We studied the association between cerebrospinal fluid (CSF) metabolites, including glutamine, in unipolar and bipolar depressed patients versus control subjects using a proton magnetic resonance spectroscopy technique. Cerebrospinal fluid samples were obtained from 18 hospitalized patients with acute unmedicated severe depression without medical problems and compared with those of 22 control subjects. RESULTS: Compared with the control group, the depressed patient group had significantly higher CSF glutamine concentrations, which correlated positively with CSF magnesium levels. CONCLUSIONS: These findings suggest an abnormality of the brain glial-neuronal glutamine/glutamate cycle associated with N-methyl-D-aspartate receptor systems in patients with depression.

Adolescent↗
PubMed2000

Long-term oscillation of corticosterone following intermittent cocaine.

We have shown that repeated administration of cocaine, as well as other drugs and nondrug stressors, can induce alternating increases and decreases in several neurotransmitter and endocrine endpoints, which we call oscillation. Oscillation studies have typically used 3-4 pretreatments with cocaine or other agents, raising the question of whether oscillation lasts beyond this point. Using plasma corticosterone as our endpoint measure, we therefore inquired whether oscillation would persist across eight administrations of cocaine over a 28-day period. We report oscillation of corticosterone levels persisting across all eight cocaine groups. Our data also indicate that the degree of oscillation increases with the intertreatment interval.

Animals↗
PubMed2000

Stability of CSF metabolites measured by proton NMR.

Analysis of cerebrospinal fluid (CSF) metabolites can provide data regarding CNS involvement in neurologic and psychiatric illness. However, there is lack of research into the effect of processing and storage of CSF specimens on the levels of metabolites analyzed. CSF specimens from 10 depressed patients were analyzed by proton NMR before and after 72 hours exposure to room temperature. No effect of exposure was found on myoinositol, glucose, acetate, and alanine CSF levels and there was a substantial decrease of citrate (>50%) and increase in lactate, glutamine, creatine, and creatinine levels.

Amino Acids↗
PubMed2000

Inositol as an add-on treatment for bipolar depression.

OBJECTIVE: Inositol is a constituent of the intracellular phosphatidyl inositol (PI) second messenger system, which is linked to various neurotransmitter receptors. Inositol crosses the blood-brain barrier in pharmacological doses, and has shown efficacy in a small double-blind study of unipolar depression. This pilot study evaluated its potential efficacy and safety in bipolar depression. METHODS: Twenty-four consenting adult men and women with DSM-IV bipolar depression (bipolar I = 21; bipolar II = 3) were randomly assigned to receive either 12 g of inositol or D-glucose as placebo for 6 weeks. Efficacy and safety ratings were done weekly. Thymoleptic medications (lithium, valproate, carbamazepine) in stable doses and at therapeutic levels at study entry were continued unchanged. RESULTS: Two subjects receiving placebo dropped out early due to worsening or non-adherence to the protocol. Among the 22 subjects who completed the trial, six (50%) of the inositol-treated subjects responded with a 50% or greater decrease in the baseline Hamilton Depression Rating Scale (HAM-D) score and a Clinical Global Improvement (CGI) scale score change of 'much' or 'very much' improved, as compared to three (30%) subjects assigned to placebo, a statistically nonsignificant difference. On the Montgomery-Asberg Depression Rating Scale (MADRS), eight (67%) of twelve inositol-treated subjects had a 50% or greater decrease in the baseline MADRS scores compared to four (33%) of twelve subjects assigned to placebo (p = 0.10). Inositol was well tolerated with minimal side effects, and thymoleptic blood levels were unaltered. CONCLUSIONS: These pilot data suggest a controlled study with an adequate sample size, and the appropriate rating scale may demonstrate efficacy for inositol in bipolar depression. The tolerability and the 'natural substance' aspect of inositol may be particularly appealing to subjects with bipolar depression.

Adult↗
PubMed2000

Psychotropic drug prescription patterns among patients with bipolar I disorder.

INTRODUCTION: Combination treatment, rather than monotherapy, is prevalent in the treatment of subjects with bipolar disorder, probably due to the complex and phasic nature of the illness. In general, prescription patterns may be influenced by the demographic characteristics of patients as well. We evaluated prescription patterns and the influence of demographic variables on these patterns in a voluntary registry of subjects with bipolar disorder. METHODS: A subset of data from a larger voluntary registry was extracted for demographic variables and psychotropic medication use that had been reported in the month prior to registration by ambulatory, non-hospitalized subjects with bipolar I disorder in 1995/96 (n = 457). RESULTS: Among the thymoleptic agents, lithium was prescribed in over 50% of subjects, valproate in approximately 40%, and carbamazepine in 11% of subjects. Eighteen percent of subjects had no prescription for thymoleptic agents. Nearly one-third of all subjects were receiving antipsychotic agents, of whom two-thirds were receiving the traditional neuroleptic agents. More than half of all subjects were receiving concomitant antidepressants, of whom nearly 50% received the SSRI antidepressants and nearly 25% received buproprion. Approximately 40% of subjects received benzodiazepines. Only 18% of subjects received monotherapy, and nearly 50% received three or more psychotropic agents. In general, no associations were noted between demographic parameters including age, gender, marital or educational status, and psychotropic prescriptions. CONCLUSION: Consistent with the anecdotal reports, these data confirm that combination treatment is far more common than monotherapy. Demography appears to have a minimal impact on cross-sectional prescription patterns in subjects with bipolar disorder. Given that combination treatments are the rule rather than the exception, we should strive to achieve rational, yet pragmatic, treatment guidelines and algorithms to minimize the risks while maximizing the benefits of these combination treatments for patients with bipolar disorder.

Adult↗