Showing papers by "Icahn School of Medicine at Mount Sinai published in 1989"

The consortium to establish a registry for alzheimer’s disease (CERAD). Part I. Clinical and neuropsychological assessment of alzheimer’s disease

Abstract: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed brief, comprehensive, and reliable batteries of clinical and neuropsychological tests for assessment of patients with the clinical diagnosis of Alzheimer's disease (AD). We administered these batteries in a standardized manner to more than 350 subjects with a diagnosis of AD and 275 control subjects who were enrolled in a nationwide registry by a consortium of 16 university medical centers. The tests selected for this study measured the primary cognitive manifestations of AD across a range of severity of the disorder, and discriminated between normal subjects and those with mild and moderate dementia. The batteries also detected deterioration of language, memory, praxis, and general intellectual status in subjects returning for reassessment 1 year later. Interrater and test-retest reliabilities were substantial. Long-term observations of this cohort are in progress in an effort to validate the clinical and neuropsychological assessments and to confirm the diagnosis by postmortem examinations. Although information on validation is limited thus far, the CERAD batteries appear to fill a need for a standardized, easily administered, and reliable instrument for evaluating persons with AD in multicenter research studies as well as in clinical practice.

Profound Peripheral Insulin Resistance, Independent of Obesity, in Polycystic Ovary Syndrome

Abstract: Hyperinsulinemia secondary to a poorly characterized disorder of insulin action is a feature of the polycystic ovary syndrome (PCO). However, controversy exists as to whether insulin resistance results from PCO or the obesity that is frequently associated with it. Thus, we determined in vivo insulin action on peripheral glucose utilization (M) and hepatic glucose production (HGP) with the euglycemic glucose-clamp technique in obese ( n = 19) and nonobese ( n = 10) PCO women and age- and body-composition-matched normal ovulatory women ( n = 11 obese and n = 8 nonobese women). None had fasting hyperglycemia. Two obese PCO women had diabetes mellitus, established with an oral glucose tolerance test; no other women had impairment of glucose tolerance. However, the obese PCO women had significantly increased fasting and 2-h glucose levels after an oral glucose load and increased basal HGP compared with their body-composition-matched control group. There were statistically significant interactions between obesity and PCO in fasting glucose levels and basal HGP ( P < .05). Steady-state insulin levels of ∼100 μU/ml were achieved during the clamp. Insulin-stimulated glucose utilization was significantly decreased in both PCO groups whether expressed per kilogram total weight ( P < .001) or per kilogram fat free mass ( P < .001) or when divided by the steady-state plasma insulin (I) level (M/I, P < .001). There was residual HGP in 4 of 15 obese PCO, 0 of 11 obese normal, 2 of 10 nonobese PCO, and 0 of 8 nonobese normal women. The metabolic clearance rate of insulin did not differ in the four groups. We conclude that 1 ) PCO women have significant insulin resistance that is independent of obesity, changes in body composition, and impairment of glucose tolerance, 2 ) PCO and obesity have a synergistic deleterious effect on glucose tolerance, 3 ) hyperinsulinemia in PCO is not the result of decreased insulin clearance, and 4 ) PCO is associated with a unique disorder of insulin action.

The nature and course of depression following myocardial infarction.

Abstract: • Two hundred eighty-three patients admitted to cardiac care units for myocardial infarction at two urban teaching hospitals were interviewed 8 to 10 days after infarction and 171 were reinterviewed 3 to 4 months later Initially, 45% met diagnostic criteria for minor or major depression, including 18% with major depressive syndromes Depression was not associated with the severity of cardiac illness but was associated with the presence of noncardiac medical illnesses Three to 4 months after infarction, 33% of patients met criteria for minor or major depression The large majority of patients who initially met criteria for major but not minor depression showed evidence of depression at 3 months and most patients with major depression had not returned to work by 3 months Treatment of major depressive syndromes after myocardial infarction may reduce chronicity and disability, while minor depressive syndromes may be similar to normal grief and tend to be self-limited ( Arch Intern Med 1989;149:1785-1789)

Coarctation of the aorta. Long-term follow-up and prediction of outcome after surgical correction.

Abstract: The long-term clinical course was studied in 646 patients, who underwent isolated operative repair of coarctation of the aorta at the Mayo Clinic from 1946 to 1981. There were 17 perioperative deaths, and 58 patients were lost to follow-up. Of the 571 patients with long-term follow-up, 11% required subsequent cardiovascular surgery, and 25% developed hypertension. There were 87 late deaths. The mean age at death was 38 years (range, 0-67 years). Estimated survival analysis revealed 91% of patients alive at 10, 84% at 20, and 72% at 30 years after operative repair. The most common cause of late death was coronary artery disease in 32 patients, followed by sudden death, heart failure, cerebrovascular accidents, and ruptured aortic aneurysm. Age, sex, and postoperative systolic blood pressure were found to be independently predictive of survival. For patients less than 14 years of age at the time of initial coarctectomy, survival to 20 years was 91%, and for patients 14 years or older at the time of operation, survival was 79%. The best survivorship was observed in patients operated on at 9 years of age or less. The higher the postoperative systolic pressure, the higher the probability of death. This study has the largest population undergoing repair of coarctation of the aorta with a median follow-up of as long as 20 years. Four main points emerged. 1) Age at the time of initial repair is the most important predictor of long-term survival. Surgery should be offered to patients after age 1 year or sooner if hypertension is severe. 2) Coronary artery disease is the most common cause of late death.(ABSTRACT TRUNCATED AT 250 WORDS)

A Prospective Study of Human Immunodeficiency Virus Type 1 Infection and the Development of AIDS in Subjects with Hemophilia

Abstract: We evaluated a multicenter cohort of 1219 subjects with hemophilia or related disorders prospectively, focusing on 319 subjects with documented dates of seroconversion to human immunodeficiency virus type 1 (HIV-1). The incidence rate of the acquired immunodeficiency syndrome (AIDS) after seroconversion was 2.67 per 100 person-years and was directly related to age (from 0.83 in persons 1 to 11 years old up to 5.66 in persons 35 to 70 years old; Ptrend = 0.00003). The annual incidence of AIDS ranged from zero during the first year after seroconversion to 7 percent during the eighth year, with eight-year cumulative rates (±SE) of 13.3±5.3 percent for ages 1 to 17, 26.8±6.4 percent for ages 18 to 34, and 43.7±16.4 percent for ages 35 to 70. Serial immunologic and virologic markers (total numbers of CD4 lymphocytes, presence of serum interferon or HIV-1 p24 antigen, and low or absent serum levels of anti-p24 or anti-gp120) predicted a high risk for the subsequent development of AIDS. Adults 35 to 70 ...

Liquid diet technique of ethanol administration: 1989 update

Abstract: A technique of feeding alcohol as part of a liquid diet is reviewed that achieves an alcohol consumption of clinical relevance, while maintaining dietary control and providing adequate nutrition. With this procedure, blood alcohol levels are obtained which mimic clinical conditions and allow experimental duplications of many pathological complications caused by alcohol. In the rat, the liquid diet technique provides a model for the alcoholic fatty liver, various alcohol-induced metabolic, endocrine and central nervous system abnormalities (including tolerance and dependence) and the interaction of ethanol with industrial solvents, many commonly used drugs, analgesics, carcinogens and nutrients. This technique also resulted in the discovery of a new pathway of ethanol metabolism in the microsomes involving an ethanol-specific cytochrome P-450 (P450IIE1), which has now been confirmed in man. P450IIE1 contributes not only to the metabolic tolerance to ethanol, but also explains the enhanced susceptibility of the alcoholic to many ubiquitous xenobiotic agents. The liquid diet technique provides the flexibility to adjust to special experimental or physiological needs by allowing for various substitutions including changes in lipids, proteins or other dietary constituents. This procedure is thereby ideally suited for the study of the interactions of alcohol with deficiency or excess of various nutrients. The technique also facilitates the comparison with controls by simplifying pair feeding procedures. Although the flexibility of the liquid diet technique is one of its key advantages, a standard 'all purpose' liquid diet is described which is appropriate for most experimental applications. In addition, two other general formulae are given, namely a low fat diet (that allows the study of the effects of ethanol in the presence of minimal hepatic lipid accumulation) and a high protein diet (to meet increased needs, e.g. during pregnancy and lactation). The optimal amount of ethanol for the rat liquid diet was found to be 5 g/dl or 36% of total energy. With lesser amounts of alcohol, intake falls below a critical threshold; blood levels of alcohol then become negligible and the model becomes irrelevant to clinical conditions. In the rat, amounts of ethanol above 5 g/dl were not found to be associated with any further gain in alcohol ingestion. By contrast, in the baboon, the ethanol content could be raised profitably to 7 g/dl or 50% of total energy and resulted in the development of cirrhosis. This higher alcohol intake, together with species difference, may explain the greater severity of liver lesions produced by alcohol in the baboon.(ABSTRACT TRUNCATED AT 400 WORDS)

Dopamine turnover and glutathione oxidation: implications for Parkinson disease.

Abstract: Parkinson disease is characterized by a major loss (approximately 80% or more) of dopaminergic nigrostriatal neurons and by an increased turnover of neurotransmitter by surviving neurons of the nigrostriatal tract. In theory, increased turnover of dopamine should be associated with an oxidative stress derived from increased production of hydrogen peroxide. The peroxide is formed during the oxidative deamination of dopamine by monoamine oxidase. In experiments with mice, increased presynaptic turnover of dopamine was evoked by injection of reserpine, which interferes with the storage of dopamine in synaptic vesicles. Loss of dopamine and formation of deaminated metabolites were accompanied by a significant rise (87.8%) in the level of oxidized glutathione in brain. This change was observed in the striatum, which is richly innervated by dopamine terminals, but not in the frontal cortex, which receives a much sparser innervation by catecholamine nerve terminals. The rise in oxidized glutathione was seen even though dopamine terminals constitute only 1% or less of the mass of the striatum. Clorgyline, an inhibitor of monoamine oxidase type A, blocked the formation of oxidized glutathione. These observations confirm that a selective increase in neurotransmitter turnover within nigrostriatal nerve terminals can evoke a change in cellular redox status. We suggest that an oxidative stress may play a role in the natural history of Parkinson disease.

Controlled Study of Haloperidol, Pimozide, and Placebo for the Treatment of Gilles de la Tourette's Syndrome

Abstract: • The results of this controlled study of the treatment of 57 patients with Gilles de la Tourette's syndrome suggested that both haloperidol and pimozide were more effective than placebo, but that haloperidol was slightly more effective than pimozide. Adverse effects occurred more frequently with haloperidol vs placebo than with pimozide vs placebo, but the frequency was not significantly different for haloperidol compared with pimozide. Clinically significant cardiac effects did not occur at a maximum dosage of 0.3 mg/kg or 20 mg/d for pimozide and 10 mg/d for haloperidol. However, the QTc interval was prolonged during pimozide treatment compared with that during haloperidol treatment, although the values for both medications were not in an abnormal range.

Major Depressive Disorder and Immunity: Role of Age, Sex, Severity, and Hospitalization

Abstract: • An association between depression and altered immunity has been suggested but has not been consistently demonstrated. We have studied 91 patients with unipolar major depressive disorder, and no mean differences were found between the patients and concurrently studied matched controls in mitogen-induced lymphocyte proliferation, lymphocyte subsets, and natural killer cell activity. There were, however, significant age-related differences between the depressed patients and controls in mitogen responses and in the number of T4 lymphocytes. In contrast to age-related increases in mitogen response and in T4 cells in controls, depressed patients did not show increased lymphocyte responses or numbers of T4 lymphocytes with advancing age. Severity of depression and hospitalization status were also associated with immune system changes. Altered immunity does not appear to be a specific biologic correlate of major depressive disorder but may occur in subgroups of depressed patients.

The affective lability scales: development, reliability, and validity.

Abstract: A self-report measure of changeable affect was developed, with a goal of identification of patterns of instability in mood. Scales measuring lability in anxiety, depression, anger, and hypomania, and labile shifts between anxiety and depression and hypomania and depression were constructed. These scales were then evaluated for internal consistency, retest reliability, score stability across samples, and for discriminant validity through assessment of association with measures of dysphoria and intensity of affect. The final versions of the scales are short scales that yield highly stable estimates of affect lability. It was noted that these scales are highly correlated in unselected students and it is believed that ongoing research with clinical populations will better allow for determination of the independence of these scales.

Age of alcoholism onset. I. Relationship to psychopathology

Abstract: • Numerous attempts have been made to subdivide populations of alcoholics into homogeneous subgroups. Although no consensus has been reached about the characteristics of these subgroups, a number of classification schemes have identified a subgroup of patients with a high genetic loading for alcoholism, an early onset of alcoholism, a severe course, and coexisting psychiatric problems consisting of aggressive tendencies or criminality. In a recent typology proposed by Cloninger on the basis of adoption studies, this subgroup has been classified as type 2. Another group of patients who were found to differ in their mode of inheritance and clinical characteristics was classified as type 1. The identification of etiologically homogeneous subgroups is easier in studies of adoptees than in studies of individuals who were not adopted. In an attempt to divide alcoholics into two groups of individuals presenting type 1 and type 2 characteristics, we used as a criterion the age of alcoholism onset because type 2 alcoholics as well as their fathers had been found to abuse alcohol at a younger age than type 1 patients. Patients with an onset of alcoholism before their 20th birthday were found to have a significantly higher incidence of paternal alcoholism and were twice as likely to have been incarcerated for crimes involving physical violence. We also observed other features not previously described in this patient subgroup. Patients who started abusing alcohol in their teens were three times as likely to be depressed and four times as likely to have attempted suicide as patients with a later onset of alcohol abuse.

Release of endogenous dopamine by stimulation of 5-hydroxytryptamine3 receptors in rat striatum.

Abstract: 5-Hydroxytryptamine (5-HT) caused a persistent, concentration-dependent increase of spontaneous release of endogenous dopamine (DA) from superfused rat striatal slices. 2-Methyl-5-HT, a selective 5-HT3 agonist, mimicked the 5-HT response with a potency only slightly less than that of 5-HT. A highly selective 5-HT3 antagonist, ICS 205-930 [(3-alpha-tropanyl)1H-indole-3-carboxylic acid ester], inhibited the effect of both agonists with a pKB value characteristic of 5-HT3 receptors. 5-HT-evoked DA release was resistant to antagonism by methiothepin and methysergide, antagonists at 5-HT 1-like and 5-HT2 receptors. Neither (2,5-dimethoxy-4-iodophenyl)-2-aminopropane, the selective 5-HT2 receptor agonist, nor 5-carboxamidotryptamine, the selective 5-HT 1-like receptor agonist, altered DA release. The release of DA by 5-HT3 stimulation was Ca++-dependent and partially sensitive to tetrodotoxin. 5-HT and 2-methyl-5-HT also increased K+-evoked DA release. These observations constitute direct, unambiguous evidence that in rat striatum 5-HT3 receptors modulate release of DA.

Similarity transformation approach to identifiability analysis of nonlinear compartmental models.

Abstract: Through use of the local state isomorphism theorem instead of the algebraic equivalence theorem of linear systems theory, the similarity transformation approach is extended to nonlinear models, resulting in finitely verifiable sufficient and necessary conditions for global and local identifiability. The approach requires testing of certain controllability and observability conditions, but in many practical examples these conditions prove very easy to verify. In principle the method also involves nonlinear state variable transformations, but in all of the examples presented in the paper the transformations turn out to be linear. The method is applied to an unidentifiable nonlinear model and a locally identifiable nonlinear model, and these are the first nonlinear models other than bilinear models where the reason for lack of global identifiability is nontrivial. The method is also applied to two models with Michaelis-Menten elimination kinetics, both of considerable importance in pharmacokinetics, and for both of which the complicated nature of the algebraic equations arising from the Taylor series approach has hitherto defeated attempts to establish identifiability results for specific input functions.

Purified influenza virus hemagglutinin and neuraminidase are equivalent in stimulation of antibody response but induce contrasting types of immunity to infection.

Abstract: BALB/c mice immunized with graded doses of chromatographically purified hemagglutinin (HA) and neuraminidase (NA) antigens derived from A/Hong Kong/1/68 (H3N2) influenza virus demonstrated equivalent responses when HA-specific and NA-specific serum antibodies were measured by enzyme-linked immunosorbent assays (ELISAs). Antibody responses measured by hemagglutination inhibition or neuraminidase inhibition titrations showed similar kinetic patterns, except for more rapid decline in hemagglutination inhibition antibody. Injection of mice with either purified HA or NA resulted in immunity manifested by reduction in pulmonary virus following challenge with virus containing homologous antigens. However, the nature of the immunity induced by the two antigens differed markedly. While HA immunization with all but the lowest doses of antigen prevented manifest infection, immunization with NA was infection-permissive at all antigen doses, although reduction in pulmonary virus was proportional to the amount of antigen administered. The immunizing but infection-permissive effect of NA immunization over a wide range of doses is in accord with results of earlier studies with mice in which single doses of NA and antigenically hybrid viruses were used. The demonstrable immunogenicity of highly purified NA as a single glycoprotein without adjuvant offers a novel infection-permissive approach with potentially low toxicity for human immunization against influenza virus.

Mechanisms of arterial thrombosis in nonparallel streamlines: platelet thrombi grow on the apex of stenotic severely injured vessel wall. Experimental study in the pig model.

Abstract: The role of thrombosis in various acute coronary syndromes has been established. However, the basic mechanism by which plaque rupture leads to a growing thrombus in the vicinity of stenotic lesions is not well understood. Using a characterized flow chamber in a rheologically controlled system, we have mimicked stenotic vessels and studied for the first time cell-vessel wall interaction in nonparallel streamlines. Stenoses ranging from 0 to 80% were produced with stripped tunica media to mimic severe vessel wall damage, and perfused with heparinized flowing blood. This perfusion device was placed within an extracorporeal system in swine, and blood was perfused for selected times from 1 to 30 min. Platelet deposition on the surface was evaluated by 111Indium-labeled platelets. As percent stenosis increased, platelet deposition significantly increased (P less than 0.001), indicating a shear-induced cell activation. Analysis of the axial distribution of platelet deposition indicated that the apex, and not the flow recirculation zone distal to the apex, was the segment of greater platelet accumulation within 30 min of blood perfusion (P less than 0.001). These results also indicate that the severity of the acute platelet response to plaque rupture probably depends on the location of the rupture with relation to the apex of the plaque.

Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome.

Abstract: We have investigated the hypothesis that hyperinsulinemia may cause the polycystic ovary syndrome (PCO) by directly stimulating gonadal steroidogenesis and/or gonadotropin secretion. 10 insulin-resistant women with PCO and 5 age- and weight-matched ovulatory normal women had pulsatile gonadotropin release, gonadotrope sensitivity to gonadotropin-releasing hormone, and sex hormone levels studied on two consecutive study days, basally and during the infusion of insulin (mean +/- SEM steady state insulin levels, 1,254 +/- 63 microU/ml PCO vs. 907 +/- 92 microU/ml normal, P less than or equal to 0.01). Insulin acutely increased mean delta (6 h minus prestudy) levels of androstenedione (A) (P less than or equal to 0.001) and estradiol (E2) (P less than or equal to 0.05) and decreased mean plasma pool (0-6 h) levels of testosterone (T) (P less than 0.05), nonsex hormone binding globulin-bound T (P less than 0.05), and dihydrotestosterone (P less than or equal to 0.01) in the PCO women. Insulin also decreased mean plasma 6 h A to estrone (E1) ratios and increased 6 h E1 levels (both P less than or equal to 0.05) in the PCO women. There were significant sequence effects (insulin + day) in the PCO women on T/E2 ratios, indicating a carryover action of insulin. Insulin had no effects on gonadotropin release in the PCO women. In the normal women, the only significant change was an insulin or study day effect that increased mean 6 h E2 levels (P less than or equal to 0.01). There were significant spontaneous decreases in mean luteinizing hormone (p less than 0.05) and follicle-stimulating hormone levels (p less than or equal to 0.01) in the PCO but not the normal women on the second day of study. This study indicates that insulin can directly alter peripheral sex hormone levels independent of changes in gonadotropin release in insulin-resistent PCO women. Insulin decreased the levels of potent androgens in PCO women and did not increase androgen levels in normal women, arguing against a simple, direct causal relationship between hyperinsulinemia and hyperandrogenism in PCO.

Promoter analysis of influenza virus RNA polymerase.

Abstract: Influenza virus polymerase, which was prepared depleted of viral RNA, was used to copy small RNA templates prepared from plasmid-encoded sequences. Template constructions containing only the 3' end of genomic RNA were shown to be efficiently copied, indicating that the promoter lay solely within the 15-nucleotide 3' terminus. Sequences not specific for the influenza virus termini were not copied, and, surprisingly, RNAs containing termini identical to those from plus-sense cRNA were copied at low levels. The specificity for recognition of the virus sense promoter was further defined by site-specific mutagenesis. It was also found that increased levels of viral protein were required in order to catalyze both the cap endonuclease-primed and primer-free RNA synthesis from these model templates, as well as from genomic-length RNAs. This finding indicates that the reconstituted system has catalytic properties very similar to those of native viral ribonucleoprotein complexes.

A network of influences on adolescent drug involvement: Neighborhood, school, peer, and family.

Abstract: The interrelationship of neighborhood, school, peer, and family factors and adolescent drug involvement was investigated. Data were collected separately from 518 adolescents and their mothers when the children were between 9 and 18 years of age and again two years later. Neighborhood and school effects were not directly related to adolescent drug use. Neighborhood effects were mediated through the domains of school, peer, and family; school effects were mediated through the peer domain. Family and peer variables had a direct impact on adolescent drug involvement. Risk factors in the adolescents' peer environment can be ameliorated by protective factors in their school environment. Implications for the prevention of drug use are discussed.

A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B.

Abstract: The Cancer and Leukemia Group B (CALGB) conducted a prospective randomized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer (SCCL). After stratification for sex and performance status, patients were randomly assigned to receive chemotherapy with methotrexate, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (CCNU) (MACC), or MACC plus warfarin (MACC + W), or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC (MEPH/MACC). Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values. A total of 328 patients were enrolled, and 294 were evaluable. There was a statistically significant advantage in objective response rates (complete [CR] and partial responses [PR], respectively) for MACC + W (17% and 50%) as compared with MACC alone (8% and 43%) or MEPH/MACC (10% and 38%) (P = .012). Both failure-free survival (P = .054 Wilcoxon test) and...

The medical school as a social organization: the sources of resistance to change

Abstract: Medical schools vary by nation and by culture but, for students, the experience appears to be very similar. Also, despite a half-century of radical changes in medical practice, education as a process of socialization for the profession is relatively unchanged. At the same time, medical educators have frequently instituted curricular reforms. To analyse this history of reform without change, this paper first establishes what the content and structure of medical education is, and how it came to be that way; second it traces a process whereby the scientific mission of academic medicine has crowded out its social responsibility to train for society's most basic health-care delivery needs. The main argument is that medical education's manifest humanistic mission is little more than a screen for the research mission that is the major thrust of the institution's social structure.