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Biomedical subjects

D L Rosenstein

Publications and source records attributed to D L Rosenstein.

At least 19 recordsLinked to original sources
PubMed2005

Psychiatric and neuropsychological characterization of Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS) is a rare, single-gene, malformation syndrome that includes central polydactyly, hypothalamic hamartoma, bifid epiglottis, endocrine dysfunction, and other anomalies. The syndrome has variable clinical manifestations and is inherited in an autosomal dominant pattern. We sought to determine whether psychiatric disorders and/or neuropsychological impairment were characteristic of PHS. We prospectively conducted systematic neuropsychiatric evaluations with 19 PHS subjects ranging in age from 7 to 75 years. The evaluation included detailed clinical interviews, clinician-rated and self-report instruments, and a battery of neuropsychological tests. Seven of 14 adult PHS subjects met diagnostic criteria for at least one DSM-IV Axis I disorder. Three additional subjects demonstrated developmental delays and/or neuropsychological deficits on formal neuropsychological testing. However, we found no characteristic psychiatric phenotype associated with PHS, and the frequency of each of the diagnoses observed in these subjects was not different from that expected in this size sample. The overall frequency of psychiatric findings among all patients with PHS cannot be compared to point prevalence estimates of psychiatric disease in the general population because of biased ascertainment. This limitation is inherent to the study of behavioral phenotypes in rare disorders. The general issue of psychiatric evaluation of rare genetic syndromes is discussed in light of this negative result.

Abnormalities, Multiple↗
PubMed2001

A curriculum for teaching psychiatric research bioethics.

Psychiatric research has received intense ethical scrutiny during the past decade. Changes in how studies are designed, reviewed by ethics boards, conducted, and reported in the literature have created a need for a systematic approach to teaching psychiatric research ethics to clinical researchers in training. The purpose of this article is to describe a model curriculum and comprehensive background reading list for training in psychiatric research bioethics. The curriculum was designed as an interactive seminar in a research fellowship program but can be adapted and incorporated into existing medical school and psychiatry residency training curricula. Participants in the seminar provide formal and informal evaluations of each session and the seminar as a whole. The seminar, now in it's third year, has been regularly attended and highly regarded by the NIMH research fellows who have participated. In response to recommendations by the participants, the content and organization of the seminar has been modified. Clinical research is both scientifically and ethically complex. Our initial experience with a formal curriculum in psychiatric research bioethics suggests that this educational activity has been both meaningful and relevant for psychiatrists training to be clinical investigators.

Curriculum↗
PubMed2000

Neuroimaging in delirium and related conditions.

Delirium is one of the most fascinating and poorly understood syndromes in medicine. To a large extent, attempts to study the pathophysiology of delirium have been hampered by the many different types of delirium and their variable symptom expression. The emergence of sophisticated brain imaging methodologies has made it possible to move beyond diagnostic considerations and investigate the neurobiology of specific symptom clusters observed in delirium and related conditions. In this review, neuroimaging findings of relevance to delirium are interpreted in relation to phenomenologically similar symptom states as well as clinical diagnoses. A promising approach in this regard is to combine neuroimaging techniques with symptom-provoking pharmacologic challenge paradigms. Such symptom-oriented neuroimaging studies hold particular promise for improving our understanding of the pathophysiology of delirium and its treatment.

Brain↗
PubMed1999

IRB review of psychiatric medication discontinuation and symptom-provoking studies.

Federal regulations governing human subjects research call for additional protections for the "mentally disabled." However, there is currently no consensus definition of mental disability or guidelines for how these research subjects should be protected. This ambiguity complicates the work of institutional review boards (IRBs) charged with the review and approval of protocols involving psychiatric medication discontinuation and symptom provocation. It is particularly important for these studies to be reviewed within the larger context of the research program in which they are conducted. The author proposes a process for IRB review of these studies, which includes the implementation of additional safeguards for subjects determined by the IRB to be vulnerable. Recommendations also are made for training psychiatric clinical investigators in issues related to research bioethics.

Bioethics↗
PubMed1999

Conditioned immune response to interferon-gamma in humans.

We determined whether a classical conditioning paradigm may be used to condition immunologic responses in normal human subjects receiving an optimal immunostimulating dose of recombinant human interferon-gamma (rhIFN-gamma). We conducted a placebo-controlled, double-blind study of 31 normal volunteers in order to determine whether an initially immune-neutral stimulus, oral propylene glycol (PG), could eventually elicit an immune response as a consequence of its being paired with a known immunostimulatory dose and schedule of rhIFN-gamma. Subjects were randomly assigned to one of three groups: (A) rhIFN-gamma injections paired with PG; (B) normal saline injections paired with PG; (C) rhIFN-gamma injections alone. During the 4-week study, subjects received progressively fewer injections so that, by the final week of the study, no injections were given and groups A and B received only PG. The principal outcome measures were serum concentrations of quinolinic acid (QUIN) and neopterin, two nonspecific but sensitive markers of immune activation, and expression of Fc receptors (CD64) on peripheral blood mononuclear cells. RhIFN-gamma injections produced significant and predictable alterations in each of the measured immune parameters. No group B subject made an immune response. Mean serum QUIN levels were significantly higher at the end of week three for subjects in the experimental condition (group A) than for subjects receiving rhIFN-gamma alone (group C) despite receiving identical doses of rhIFN-gamma. Similarly, the predicted decay in mean serum neopterin levels from the end of week 1 to the end of week 2 was seen in group C but not in group A. The exposure of group A to PG blunted the decline of CD64 expression in week four. The data suggest that the pairing of an unconditioned stimulus (rhIFN-gamma) and a conditioned stimulus (PG) permits the conditioned stimulus alone to prolong a cytokine-induced response in normal humans.

Adjuvants, Immunologic↗
PubMed1998

Professional integrity in clinical research.

In response to public concern over abuses in human medical experimentation, the dominant approach to the ethics of clinical research during the past 30 years has been regulation, particularly via institutional review board review and approval of scientific protocols and written consent forms. However, the effectiveness of regulatory mechanisms in ensuring the ethical conduct of clinical research is limited. Little attention has been devoted to the nature and role of professional integrity of physician investigators, a conscientious framework for guiding investigators in the socially important but morally complex activity of clinical research. Professional integrity is vital in forging an ethically sound relationship between investigators and patient volunteers, a relationship that differs in important ways from the patient-physician relationship in standard clinical practice. We examine critically 2 models of the moral identity of physician investigators, the investigator as clinician and the investigator as scientist; in neither of these 2 models can the physician investigator eliminate completely the moral conflicts posed by clinical research. The professional integrity of physician investigators depends on a coherent moral identity that is proper to the enterprise of clinical research. The roles of clinician and scientist must be integrated to manage conscientiously the ethical complexity, ambiguity, and tensions between the potentially competing loyalties of science and care of volunteer patients.

Beneficence↗
PubMed1997

Fluoxetine in the treatment of premenstrual dysphoria.

We performed a double-blind, placebo-controlled, crossover trial of fluoxetine in 17 women with prospectively confirmed PMS who also met criteria for premenstrual dysphoric disorder (PMDD). A subset of 10 women with PMDD and an additional 10 controls participated in a single-dose m-chlorophenylpiperazine (m-CPP) challenge during the follicular and luteal phases of the menstrual cycle. We evaluated the ability of the acute behavioral response to luteal phase m-CPP administration to predict therapeutic response to fluoxetine. compared with baseline, fluoxetine, but not placebo, treatment significantly improved both emotional and physical symptoms. We identified 11 (65%) fluoxetine responders who no longer met diagnostic criteria for PMDD during fluoxetine but remained symptomatic during placebo treatment. In addition, acute symptomatic improvement also occurred following m-CPP administration in 7 of 10 women with PMDD. The small number of m-CPP nonresponders did not respond to fluoxetine either. Our findings confirm that fluoxetine is an effective treatment of PMDD.

Adult↗
PubMed1996

Peripheral measures of arginine vasopressin, atrial natriuretic peptide and adrenocorticotropic hormone in premenstrual syndrome.

Because of the unique combination of physical (e.g. bloating, water retention) and psychological (e.g. mood, memory) symptoms associated with premenstrual syndrome (PMS), various hypothalamic and pituitary hormones have been implicated in the pathophysiology of PMS. We measured plasma adrenocorticotropic hormone (ACTH), arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) across the menstrual cycle in 19 women with PMS and 12 normal women. AVP concentrations were lower throughout the menstrual cycle in symptomatic PMS patients compared with PMS patients during asymptomatic cycles and normal women. No differences in ACTH and ANP were observed between patients and controls. However, ACTH and ANP were positively and significantly correlated with each other in women with PMS but not in controls. These findings contribute to a growing list of menstrual cycle-independent findings in women with PMS and suggest that there may be an underlying neurobiological vulnerability that predisposes some women to experience somatic and mood dysregulation in the luteal phase of the menstrual cycle.

Adrenocorticotropic Hormone↗
PubMed1996

Relationship between skeletal muscle intracellular ionized magnesium and measurements of blood magnesium.

The current laboratory approach to assessing magnesium status is based on determining the concentration of total Mg ((Mg)) in serum or plasma. This strategy is problematic in that the amount of Mg in blood is less than 1% of total body Mg and does not accurately reflect (Mg) in other tissues. Furthermore, the (Mg) of blood does not distinguish biologically active, ionized Mg from the bound fraction. The goal of this study was to determine intracellular ionized Mg ((Mg++)i) of skeletal muscle in vivo and to compare results with the (Mg) of blood constituents. (Mg++)i was determined in resting skeletal muscle by using phosphorus 31 magnetic resonance (31P-MR) spectroscopy. (Mg) was measured in serum (S(Mg)), serum ultrafiltrate (UF(Mg)), mononuclear blood cells (MBC(Mg)), and red blood cells (RBC(Mg)) by using atomic absorption spectroscopy or a colorimetric assay. In a sample of 60 healthy adult subjects, skeletal muscle (Mg++)i = 557 +/- 97 mumol/L (mean +/- SD); S(Mg) = 0.78 +/- 0.09 mmol/L; UF(Mg) = 0.60 +/- 0.12 mmol/L; MBC(Mg) = 13.8 +/- 2.3 mmol/L; and, RBC(Mg) = 1.92 +/- 0.33 mmol/L. A significant negative correlation was found between (Mg++)i and S(Mg) (r = -0.43, p < 0.05). S(Mg) was significantly lower (p < 0.05) and (Mg++)i significantly higher (p < 0.05) in women than in men, but neither was related to age. These findings provide new insight into the relationship between blood Mg measures and (Mg++)i of the largest soft tissue mass of the human body.

Adult↗
PubMed1995

Skeletal muscle intracellular ionized magnesium measured by 31P-NMR spectroscopy across the menstrual cycle.

OBJECTIVE: The hormonal regulation of magnesium (Mg) metabolism is poorly understood. Preliminary evidence suggests that reproductive hormones may influence Mg concentrations in various tissues. The purpose of this study was to determine if Mg concentrations in blood and muscle are affected by the phase of the menstrual cycle. METHODS: Magnesium measures were obtained from 16 women over the course of one complete menstrual cycle. The principal outcome measure was intracellular ionized Mg ([Mg++]i) in skeletal muscle as measured by 31P nuclear magnetic resonance spectroscopy. Three blood measures (serum, red blood cell, and mononuclear blood cell) of total Mg ([Mg]) were also obtained. RESULTS: Mean Mg concentrations were stable across the menstrual cycle with no evidence of a menstrual cycle phase effect for any of the measures. Furthermore, skeletal muscle [Mg++]i was not correlated with any blood measure of [Mg]. CONCLUSION: These results suggest that physiologic fluctuations in reproductive hormones do not influence either blood [Mg] or skeletal muscle [Mg++]i in healthy, regularly cycling women.

Adult↗
PubMed1994

Magnesium measures across the menstrual cycle in premenstrual syndrome.

The purpose of this study was to evaluate blood magnesium (Mg) measures across the menstrual cycle in women with premenstrual syndrome (PMS) and control women. Longitudinal determinations of plasma, red blood cell (RBC) and mononuclear blood cell (MBC) Mg were made in 26 women with prospectively confirmed PMS and in a control group of 19 women. Data were analyzed using analysis of variance with repeated measures and Spearman rank correlations. Significant diagnostic group effects were observed for RBC and MBC Mg concentrations (p < 0.05). These effects reflected lower Mg concentrations in PMS patients at each sampling time. No significant effects were observed for either plasma Mg or MBC Mg content, nor were there significant time by diagnosis effects for any of the measures. Consistent with earlier studies, we found decreased RBC Mg concentrations and additionally observed decreased MBC Mg concentrations in women with PMS. However, neither of these relative deficits were confined to the luteal phase.

Adult↗
PubMed1993

Seizures associated with antidepressants: a review.

BACKGROUND: Seizures are uncommon, but serious, adverse effects of antidepressant drugs. A better understanding of drug-related seizure risk, its predictors, and its neurophysiologic basis might help clinicians avoid this adverse event. A better understanding of the factors involved in the determination of seizure risk would be helpful for interpretation of seizure rates reported. METHOD: The authors review case reports, series of cases, and information from clinical trials of antidepressants to determine antidepressant-related seizure risk. Predisposing factors are identified. Effects of dose, blood levels, and duration of treatment on seizure risk are examined. Electrophysiologic and in vitro models of drug-related seizure induction are discussed. RESULTS: A significant proportion of drug-related seizures occurs in individuals with an identifiable predisposition, such as previous seizures, sedative or alcohol withdrawal, and multiple concomitant medications. Seizure risk for most antidepressants increases with dose (or blood level), and comparisons between drugs should consider seizure rates at the effective dose (or blood level) for each drug. For imipramine, the most frequently studied tricyclic, the literature indicates a seizure rate between 0.3% and 0.6% at effective doses. In unselected patients and at higher doses, these rates may be higher. Fluoxetine, sertraline, fluvoxamine, trazodone, nomifensine, and the monoamine oxidase inhibitors have a lower seizure risk. Estimates for recently marketed antidepressants with intermediate seizure risk are complicated by the fact that effective doses and blood levels are not well established. CONCLUSION: Assessment of seizure risk in individuals involves consideration of predisposing factors, the antidepressant selected, and the bioavailability of the drug. Future studies of seizure risk would benefit from the use of specified criteria for determination of probable seizure events, a priori definition of predisposing exclusions, samples sufficiently large to provide adequate power, blood level monitoring, and inclusion of duration of drug treatment in the calculation of risk.

Antidepressive Agents↗