p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases.

Cdc25A, a phosphatase essential for G1-S transition, associates with, dephosphorylates, and activates the cell cycle kinase cyclin E-cdk2. p21CIP1 and p27 are cyclin-dependent kinase (cdk) inhibitors induced by growth-suppressive signals such as p53 and transforming growth factor beta (TGF-beta). We have identified a cyclin binding motif near the N terminus of Cdc25A that is similar to the cyclin binding Cy (or RR LFG) motif of the p21CIP1 family of cdk inhibitors and separate from the catalytic domain. Mutations in this motif disrupt the association of Cdc25A with cyclin E- or cyclin A-cdk2 in vitro and in vivo and selectively interfere with the dephosphorylation of cyclin E-cdk2. A peptide based on the Cy motif of p21 competitively disrupts the association of Cdc25A with cyclin-cdks and inhibits the dephosphorylation of the kinase. p21 inhibits Cdc25A-cyclin-cdk2 association and the dephosphorylation of cdk2. Conversely, Cdc25A, which is itself an oncogene up-regulated by the Myc oncogene, associates with cyclin-cdk and protects it from inhibition by p21. Cdc25A also protects DNA replication in Xenopus egg extracts from inhibition by p21. These results describe a mechanism by which the Myc- or Cdc25A-induced oncogenic and p53- or TGF-beta-induced growth-suppressive pathways counterbalance each other by competing for cyclin-cdks.

Thinking disorder in depression.

This experiment demonstrated abstract reasoning deficits in depressed patients and detailed some of the components of cognition that may determine such deficits. Subjects were given a discrimination learning problem in which possible solutions had to be formulated and tested against new information. Depressed subjects performed more poorly on the task than controls. Two types of errors--inability to narrow down the set of possible solutions (poor "focusing") and perseveration on disconfirmed hypotheses--hampered the performance of depressed but not control subjects. While logic, memory, and attention were intact at an elementary level, the inability to coordinate these functions in a complex task appeared to be an important feature of the depressive impairment.

Laparoscopy After Liver Transplant: Result of an Initial Series.

UNLABELLED: There are few reports about laparoscopic approach after liver transplantation (LT). The aim of this paper is to analyze in terms of feasibility and therapeutic effectiveness an initial experience with laparoscopy in patients who have had a liver transplantation. METHODS: Laparoscopic procedures were divided into "early" and "late" laparoscopy. RESULTS: A total of 10 laparoscopic procedures after LT were performed in 9 patients: 3 early and 7 late. The early laparoscopic procedures were performed in 3 patients who had a torpid evolution in their liver transplant: 2 were diagnostic only and 1 was also therapeutic. There were no intraoperative events or conversions. We recorded 2 complications. In 7 patients a late laparoscopy was performed: 4 in the upper abdomen and 3 in the lower abdomen. Of the 4 in the upper abdomen, 3 were liver procedures and 1 was in the transverse colon, on the other side; in addition, 2 laparoscopic inguinal hernia repairs and 1 laparoscopic appendectomy also were performed. None of these 7 cases was converted, and there were no intraoperative events. CONCLUSIONS: The early postoperative period, in critically ill patients diagnostic and eventually therapeutic laparoscopy was feasible and effective in our cases. Late laparoscopy in the upper abdomen is difficult due to adhesions and adds to the risk of poor graft function, but was feasible for both diagnostic and therapeutic purposes. Late laparoscopy in the lower abdomen with good graft function has the same safety and efficacy as those performed on nontransplanted patients.

Atypicality in primary depressive illness: a preliminary survey.

Primary depressive illness comprises a wide variety of clinical presentations which may represent disorders with different underlying biology, life course, and treatment response. In order to explore possible correlates of such clinical heterogeneity, we have constructed a rating scale for atypical depressive illness. Forty-four patients, all meeting Research Diagnostic Criteria for primary major depressive disorder were evaluated for atypicality using the scale. Within this group, atypicality was found to be characterized by lack of clearly encapsulated episodes of depression, a high degree of character pathology, prominent anxiety, somatization, and neurotic symptoms, and a past history of diagnostic confusion. Atypical patients were younger than typicals, more likely to be unipolar or bipolar II, and more often hospitalized, despite lower frequency of depressive episodes. While both typical and atypical groups showed decreased REM latency and increased urinary-free cortisol, they differed in measures related to noradrenergic metabolism, monoamine oxidase activity, and slow wave sleep. Preliminary results also raised the question of possible differences in treatment response between typical and atypical patients.

d-Amphetamine: effects on memory in a depressed population.

The effect of intravenous d-amphetamine on memory functions in a group of depressed patients was examined in a double-blind placebo-controlled study. Active drug administration resulted in an increase in verbal free recall but no change in cued recall, suggesting specific effects on memory processes. The level of psychological processing of the presented stimulus was shown to interact with drug-induced facilitation of recall. Improvement in memory of more shallowly processed material under amphetamine related significantly to subjects' base-line indices of noradrenergic function. Drug-induced changes in mood did not correlate with improvement in cognitive functioning. The interrelationships between biochemical determinants of mood and memory are discussed in light of these findings.

Cognitive functioning in biological subtypes of depression.

This study describes a method for investigating clinical correlates of biological subtypes of depression, using cognitive functioning as the principal behavioral variable. Dexamethasone Suppression Test (DST) escapers were compared to DST suppressors and healthy controls on a battery of learning and memory procedures designed to investigate cognitive functioning in detail. DST suppressors, but not escapers, were cognitively impaired on our tasks. The performance of controls and DST escapers was related to depth of semantic processing, whereas performance of DST suppressors varied inversely with degree of felt hopelessness. Examination of cognitive functioning in future studies may provide useful insights into the clinical significance of biological markers of depression.

Research without external funding in North American psychiatry.

OBJECTIVE: The authors investigated the extent and characteristics of published psychiatric research from U.S. and Canadian medical schools that was carried out without external funding. METHOD: They reviewed reports of unfunded research in 14 psychiatric journals, tabulating methodological factors and topics of study. They surveyed first authors about their academic duties and resources used in the studies. RESULTS: Unfunded studies represented 26% of research reports, were usually prospective, most commonly dealt with phenomenology/epidemiology or psychopharmacology, used low levels of technology, and were accomplished on a modest budget of time and money. CONCLUSIONS: Unfunded studies make a substantial and economically efficient contribution to psychiatric research. Future investigations should detail the institutional conditions necessary to sustain this type of research productivity.

Altered lateralization of cognitive processes in depressed women.

Eighteen normal men and women had a left hemisphere advantage for processing a verbal task, but depressed women showed a trend toward right hemisphere superiority. In depression the right hemisphere may share functions performed exclusively by the left hemisphere in normal subjects. Altered laterality may be a trait of depression-prone people or a change related to depressive episodes themselves. In the latter case, the right hemisphere may be compensating for relative deactivation of the dominant left hemisphere.

Heterogeneity of amphetamine response in depressed patients.

There is considerable diversity of opinion as to the nature of the response of depressed patients to amphetamine infusion. The authors report on the clinical response of 18 endogenously depressed patients to double-blind, intravenous administration of amphetamine or saline. Although the drug produced activation, mood elevation, and recall of emotionally charged material in the group as a whole, there was considerable heterogeneity of response as well as a tendency for response dimensions to vary independently of one another. The heterogeneity of clinical response may be associated with differences in underlying clinical, biological, and genetic variables in affectively ill patients.

Differential inhibitory noradrenergic responses to clonidine in 25 depressed patients and 25 normal control subjects.

The authors measured plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma norepinephrine, blood pressure, and heart rate responses to the alpha 2-adrenergic agonist clonidine in 25 depressed patients and 25 normal control subjects. In the control subjects clonidine reduced plasma norepinephrine, blood pressure, and heart rate significantly more than placebo. In the depressed patients clonidine reduced blood pressure and the percent fall in plasma norepinephrine but not plasma MHPG or heart rate significantly more than placebo. The absolute and percent reductions in plasma MHPG and heart rate following clonidine were significantly less than in control subjects. These results raise the possibility that the sensitivity of the alpha 2-adrenergic receptors inhibitory to noradrenergic output may be reduced in depression.

Multiple personality disorder in a hospital setting.

Multiple personality disorder (MPD) should be considered in cases where there have been multiple diagnoses, failure of conventional treatments, a mixture of psychiatric and somatic symptoms, and/or extremely rapid shifts in symptoms and level of function. Proper diagnosis and treatment often leads to a significant amelioration in symptoms and increase in level of function for a patient previously refractory to treatment.

The clinical phenomenology of multiple personality disorder: review of 100 recent cases.

The clinical syndrome of multiple personality disorder (MPD) is an unusual dissociative condition that has been poorly characterized. In an attempt to better delineate the clinical phenomenology of MPD, 100 recent cases were collected on a 386-item questionnaire completed by clinicians involved in the treatment of MPD patients. This study documents the existence of a clinical syndrome characterized by a core of depressive and dissociative symptoms and a childhood history of significant trauma, primarily child abuse.

Carbachol triggering of desynchronized sleep phenomena: enhancement via small volume infusions.

Two physical factors affecting the behavioral effects of drugs microinjected into the pontine tegmentum have been studied. Reducing the volume of vehicle produced a dramatic enhancement of the capacity of the long-acting cholinergic agent carbachol to induce desynchronized (D) sleep-like behavior (Dcarb). Enhancement of Dcarb was also achieved by substitute passive diffusion for active pumping of a given volume of carbachol solution. Controlling these two physical factors makes Dcarb a compelling experimental model for the study of D sleep mechanisms. The results also give support to the concept of a localized population of cholinoceptive neurons in the pontine reticular formation whose activation is a key step in the generation of physiological D.

The Israeli high-risk study: statistical overview and discussion.

We have attempted to provide an overview of the initial evaluation of high-risk and control children. Summary measures of pathology were calculated for each clinical evaluation and objective test of the subjects. Correlational analysis revealed a pattern of intercorrelations among clinical subjective measures of pathology, and among objective measures, with no significant cross-correlations between the two types of measures. The one exception was the presence of neurological soft signs, which tended to correlate with both clinically and objectively measured pathology. Cluster analysis revealed three groups of subjects: a small group of index subjects who performed poorly on both clinical and objective measures; a larger cluster, predominantly index subjects, who showed clinical but not objective pathology; and a third group, including most of the controls, who functioned relatively well on both types of measures. Index subjects tended to show more consistent pathology across both clinical-subjective and objective examinations than controls. We hypothesize that our results stem from underlying deficits in attention, motor function, and perceptual-motor integration in offspring of schizophrenic patients. The finding of an inverse relationship between degree of pathology and age among the index children raises the possibility that developmental lags also play a part in the pathology of our high-risk subjects.

The NIMH-Israeli schizophrenia project: the history of a high-risk study.

We have reviewed some of the difficulties encountered in bringing this study to completion. Among our special problems were the necessity of collecting large numbers of measures on a relatively small study population, the need to recruit and maintain a staff over long periods of time, the wide geographical separation between staff members responsible for design and those responsible for execution of the study, and the difficulties of conducting longitudinal research in a politically unstable part of the world. Centralization of data and data analysis proved a crucial step in bringing the study to its present level of completion.

Adult outcomes of high-risk children: differential effects of town and kibbutz rearing.

We conducted a followup study 15 years after the initial examination of 46 of the Israeli children at risk for schizophrenia (index cases) and 44 of the control children. Thus, we were able to contact and examine 90 of the surviving 99 subjects of the investigation. Half of the subjects had grown up in the communal child-rearing setting of a kibbutz, and half had been raised by their own parents in cities in Israel. The kibbutz-index cases, at average age 25, show the highest incidence of psychiatric disorder. Environmental factors that may have led to this outcome are discussed.

Clinical observation of high-risk children.

Systematic observations of the behavior of high-risk and control children were made during the clinical interview, the neurological examination, psychometric testing, and the experimental psychological test battery. Children were unaware that observations of them were being made and recorded. In all four examination settings, index children were seen as impaired relative to control children in their communication skills, ability to relate to the examiners, and motor behavior. There were no consistent differences between town and kibbutz subjects, and no interactions with genetic background. However, index boys showed a general trend toward greater pathology than index girls.

Clinical-subjective evaluation of high-risk children: integration and discussion.

Clinical evaluations of index and control children from the point of view of the clinical interview, observations of the subjects during testing, the subjects' parents, and their teachers were compared. There was general agreement that index children showed more psychopathological symptoms, poorer ego development, poorer interpersonal relations, and poorer use of leisure time than their controls. By contrast, behaviors related to aggression, phobias, shame, sleep pathology, eating disorders, frustration tolerance, sexual behavior, and verbal communication skills failed to show consistent group differences. Index boys showed greater anxiety than their controls, while there were no such differences among the girls. Rearing environment exerted no apparent effect on the psychosocial functioning of the children. Factor analysis disclosed that a general factor, accounting for 32.6 percent of the variance, discriminated between index and control children, while several special factors, which represented rarely seen traits, did not discriminate. Group differences, therefore, appeared to stem from global impairment of psychosocial functioning rather than from several distinct patterns of deficit. The present results are in general agreement with previously reported evaluations of children at risk for schizophrenia.

Atypical depression.

Atypical depressions are those characterized by high levels of phobic anxiety or by reversed vegetative symptoms such as hypersomnia and hyperphagia. Patients with such depressions may present overtly for treatment. However, they may also present within other diagnostic categories such as personality disorder or somatic complaints. The comparative roles of monoamine oxidase inhibitors, heterocyclic antidepressants, and other biologic treatments for atypical depressions are discussed.