Procedural learning in schizophrenia can reflect the pharmacologic properties of the antipsychotic treatments.

BACKGROUND: Conventional and atypical antipsychotics have different affinities for D2 receptors, and these receptors are principally located in the striatum. Given that this cerebral structure was previously found to play a major role in procedural learning, the antipsychotic treatment in schizophrenia may be determinant for the procedural learning profile of these patients. OBJECTIVE: The current study was aimed at verifying whether procedural learning differs in patients with schizophrenia treated with conventional antipsychotics and patients treated with atypical antipsychotics. METHOD: Forty-five patients with schizophrenia were divided into 3 different groups according to their pharmacologic treatment: (1) haloperidol, a classical neuroleptic with high D2 receptor affinity; (2) clozapine, an atypical neuroleptic with practically no D2 receptor affinity; and (3) risperidone, an atypical neuroleptic that nevertheless shows high D2 receptor affinity. Patients were compared to 35 control subjects on a visuomotor procedural learning task (mirror drawing). RESULTS: All patients were able to learn the task. However, those treated with haloperidol showed some degree of learning impairment, while those treated with clozapine or risperidone did not show this impairment. In addition, performance per se, regardless of the learning, was found to be affected in the haloperidol and risperidone, but not in the clozapine groups. CONCLUSION: Procedural learning in schizophrenia may be differentially affected, depending on the pharmacologic profiles of the antipsychotics used for the treatment of this illness.     

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.     

Does Preoperative Coronary Angioplasty Improve Perioperative Cardiac Outcome?

Background: Percutaneous coronary intervention (PCI) is performed in patients with coronary artery disease who are undergoing major noncardiac procedures to reduce perioperative cardiac morbidity and mortality. However, the impact of this approach on postoperative outcome remains controversial.

Methods: The authors analyzed a cohort of 1,152 patients after abdominal aortic surgery in which 78 patients underwent PCI. A propensity score analysis was performed. Also, using a logistic regression model, the authors determined variables associated with a severe postoperative coronary event or a death in patients without PCI. Then, in patients with PCI, they compared the expected and observed outcome.

Results: Five variables (age > 75 yr, blood transfusion > 3 units, repeated surgery, preoperative hemodialysis, and previous cardiac failure) independently predicted (with 94% correctly classified) a severe postoperative coronary event, and five variables (age > 75 yr, repeated surgery, previously abnormal ST segment/T waves, previous hypertension, and previous cardiac failure) independently predicted (with 97% correctly classified) postoperative death. In the PCI group, the observed percentages of patients with a severe postoperative coronary event (9.0% [95% confidence interval, 4.4-17.4]) or death (5.1% [95% confidence interval, 2.0-12.5]) were not significantly different from the expected percentages (8.2 and 6.9%, respectively). When all patients were pooled together, the odds ratios of PCI were not significant. The propensity score analysis provided a similar conclusion.     

A new five factor model of schizophrenia

Schizophrenic psychopathology is heterogeneous and multidimensional. Various strategies have been developed over the past several years to assess and measure more accurately discrete domains of psychopathology. One of the more fruitful strategies to investigate more homogenous domains of psychopathology has been the positive-negative syndrome approach. However, this approach is unable to address a number of important issues. Most schizophrenics present a mixed syndrome; the criteria for what constitutes a positive and negative syndrome are variable; distinguishing primary from secondary negative symptoms can be difficult. In order to address some of these problems, we propose the introduction of a five syndrome model based on a reanalysis of factor analytic procedures used on 240 schizophrenics assessed with the Positive and Negative Syndrome Scale (PANSS). We present data on a 5-factor solution which appears to best fit the psychopathological data and which is supported by three independent and comparable factor analyses; negative, positive, excitement, cognitive and depression/anxiety domains of psychopathology give patients their individual mark. Data on internal consistency of the five factors and on initial validation using demographic and clinical variables are presented.     

Synaptogenesis in the Prefrontal Cortex of Rhesus Monkeys

Since the turn of the century, the prefrontal association areasof the cerebral cortex have been thought to be among the lastregions of the cortical mantle to develop. We have examinedthe course of synaptogenesis in the macaque prefrontal cortexby quantitative electron microscopic analysis in 25 rhesus monkeysranging in age from embryonic day 47 (E47) to 20 years of age.A series of overlapping electron micrographs spanning the wholecortical thickness in each animal provided data on the number,the proportion, and the density of synapses per unit area (N_A)and per unit volume (N_V) of neuropil. The tempo and kinetics of synapse formation in prefrontal cortexclosely resemble those described for sensory and motor areas,particularly during the stages of synapse acquisition and overproduction(Rakic et al., 1986). In young embryos, we describe a precorticalphase (E47-E78), when synapses are found only above and below,but not within, the cortical plate. Following that, there isan early cortical phase, from E78 to E104, during which synapsesaccumulate within the cortical plate, initially exclusivelyon dendritic shafts. The next rapid phase of synaptogenesisbegins at 2 months before birth and ends approximately at 2months after birth, culminating with a mean density of 750 millionsynapses per cubic micrometer. This accumulation is largelyaccounted for by a selective increase in axospine synapses inthe supragranular layers. The period of explosive synaptic densityis followed by a protracted plateau stage that lasts from 2months to 3 years of age when synaptic density remains relativelyconstant. The final period of decline, from 3 years throughover 20 years of age, is marked by a slight but statisticallysignificant decline in synaptic density. Concurrent recruitment of synapses with that of sensory andmotor areas supports the concept that the initial establishmentof cortical circuitry is governed by general mechanisms commonto all areas, independent of their specific functional domain.The finding that synaptic density is relatively stable fromearly adolescence through puberty (the plateau period) is indicativeof the importance, in primates, of a consistent and high synapticdensity during the formative years when learning experiencesare most intense.     

Regional Distribution of Neurofibrillary Tangles and Senile Plaques in the Cerebral Cortex of Elderly Patients: A Quantitative Evaluation of a One-Year Autopsy Population from a Geriatric Hospital

Detailed analyses of the neuropathologic changes in the cerebralcortex of elderly individuals and Alzheimer's disease patientshave demonstrated that certain components of the neocorticaland hippocampal circuits are likely to be selectively vulnerable.Based on the distribution of neurofibrillary tangles (NFTs)and senile plaques, it has been proposed that a global cortico-corticaldisconnection leads to the loss of integrated functions observedin Alzheimer's disease. In order to investigate the distributionof lesions associated with aging as well as with the earliestsymptoms of senile dementia, we performed a quantitative neuropathologicavaluation of a large series of elderly patients representingthe entire autopsy population for the year 1989 from a geriatrichospital. Among the 145 cases quantitatively assessed, therewere 102 nondemented patients, 33 patients presenting clinicallywith globally intact intellectual function but early signs ofimpairment of specific cognitive functions, and 10 cases withsenile dementia of the Alzheimer type. All of the cases hadNFTs in layer II of the entorhinal cortex, regardless of theirclinical diagnosis, and most cases had some NFTs in the CA1field of the hippocampus. Severe pathologic changes within theinferior temporal neocortex were observed only in the dementedcases. The extent of amyloid deposition was not correlated withthe clinical diagnosis and seemed to be present in the neocorticalareas earlier than in the hippocampal formation. Also, severalcases contained NFTs without amyloid deposition, but amyloidnever occurred without NFTs. These results suggests that involvementof certain structures within the hippocampal formation is aconsistent feature of aging. Thus, involvement of the hippocampalformation may be a necessary, but not sufficient, conditionfor the clinical expression of dementia, which is likely tobe more closely related to the progressive degeneration of selectneuronal populations in the neocortex.