The development of a clinical syndrome of asymptomatic pancreatitis and eosinophilia after treatment with clozapine in schizophrenia: implications for clinical care, recognition and management.

Clozapine, the first atypical antipsychotic, is indicated for the treatment of therapy-resistant schizophrenia. It needs to be monitored closely because of its well-known potential side-effects, especially agranulocytosis. We present a case of a middle-aged woman with chronic schizophrenia, who was treated with clozapine and developed a clinical syndrome of asymptomatic pancreatitis and eosinophilia within the fifth week of treatment. Asymptomatic pancreatitis has rarely been reported up to now and is not recognized as a typical side-effect of clozapine. In our opinion, pancreatic enzymes should be monitored especially in the first 6 weeks of clozapine treatment.

Vertebral osteomyelitis and endocarditis of a pacemaker lead due to Granulicatella (Abiotrophia) adiacens.

Systemic infection due to Granulicatella (formerly Abiotrophia), a species of nutrition-deficient gram-positive cocci, is rare. We present the case of a 68-year-old diabetic male who presented with back pain and a history of fever and chills. Imaging studies revealed vertebral osteomyelitis of the Th 10/11 region. Transesophageal echocardiography disclosed a vegetation adjacent to the pacemaker lead and blood cultures grew Granulicatella adiacens. A diagnosis of vertebral osteomyelitis and endocarditis due to G. adiacens was made and the patient improved with bed rest and medical treatment alone. Granulicatella ssp. should always be part of the differential diagnosis of fastidious bacteria in vertebral osteomyelitis and endocarditis.

Forming classes by stimulus frequency: behavior and theory.

Visual classification is the way we relate to different images in our environment as if they were the same, while relating differently to other collections of stimuli (e.g., human vs. animal faces). It is still not clear, however, how the brain forms such classes, especially when introduced with new or changing environments. To isolate a perception-based mechanism underlying class representation, we studied unsupervised classification of an incoming stream of simple images. Classification patterns were clearly affected by stimulus frequency distribution, although subjects were unaware of this distribution. There was a common bias to locate class centers near the most frequent stimuli and their boundaries near the least frequent stimuli. Responses were also faster for more frequent stimuli. Using a minimal, biologically based neural-network model, we demonstrate that a simple, self-organizing representation mechanism based on overlapping tuning curves and slow Hebbian learning suffices to ensure classification. Combined behavioral and theoretical results predict large tuning overlap, implicating posterior infero-temporal cortex as a possible site of classification.

Human event-related potentials and distraction during selective listening.

Event-related brain potentials were recorded from healthy human subjects while they attended to one of two auditory stimulus channels (defined by location, left and right of a fixation point, and pitch) in order to detect rare target events. The distracting properties of periodic noise (vs. continuous noise, experiment 1) and backward speech (vs. forward speech, experiment 2) presented from a third speaker located behind the subjects were investigated. A typical attention effect with a larger negativity for attended tones was observed in both experiments. Backward speech led to a significantly reduced target detection rate for the first four stimuli after onset of the distractor accompanied by a reduced event-related brain potential (ERP)-attention effect and a reduced fronto-central N2b component for the target stimuli. This indicates that irrelevant information leads to an attention decrement of about 1 s duration.

A kinetic study comparing the light-reversal properties of carbon monoxide inhibition of ethylmorphine, benzphetamine, and 7-ethoxycoumarin dealkylation with those of hydroxylation of 17-hydroxyprogesterone and testosterone.

The light-reversal properties of carbon monoxide (CO) inhibition of the dealkylation of benzphetamine, ethylmorphine, and 7-ethoxycoumarin by microsomes from phenobarbital (PB)-induced rat livers were compared with those of the 6 beta-, 7 alpha-, and 16 alpha-hydroxylations of testosterone by the same rat hepatic microsomes and C-21 hydroxylation of 17-OH progesterone by steer adrenal microsomes. CO inhibited all reactions studied to essentially the same degree. The significant finding was that the dealkylations were reversed most effectively by light of wavelengths between 440 and 445 nm, rather than around 450 nm, the optimal wavelength for steroid hydroxylations. Moreover, the dealkylations required several-fold higher light intensities for equivalent light reversal. These studies suggest that the heme protein-CO complex responsible for dealkylations has a spectrum corresponding to the shape of the pass band of the 445-nm filter, whereas that of the steroid hydroxylations has its light-reversal maximum at 450 nm and appears to be broader. The measurable differences in the light-reversal properties between the monooxygenations of two groups of substrates, (i) dealkylations and (ii) hydroxylations of lipid substrates, furnish biophysical properties that allow a better characterization of microsomal monooxygenases which should be of value in forwarding progress in the study of these systems.

Comparative kinetic studies of the dealkylation reaction and steroid hydroxylations in various oxygen and carbon monoxide:oxygen atmospheres.

The time-course kinetics of the cytochrome P-450-catalyzed dealkylations of the exogenous compounds benzphetamine, ethylmorphine, codeine, and 7-ethoxycoumarin were compared to the hydroxylation of the endogenous compound testosterone. Using liver microsomes from phenobarbital-induced rats, the time course of the demethylations of ethylmorphine, codeine, and especially benzphetamine was characterized by a fast initial phase of enzymatic activity and then a steady decline in the rate throughout the remainder of the reaction. In contrast, under the same experimental conditions, both the dealkylation of 7-ethoxycoumarin and the hydroxylation of testosterone showed no initial fast phase of activity and a constant rate of product formation for most of the remainder of the time course. The difference also held for the carbon monoxide inhibition studies in which the degree inhibition of the demethylation reactions by a variety of CO:O2 mixtures was time dependent, in contrast to the constant, time-independent degree of CO inhibition of the other two reactions. The kinetics of the demethylation reactions could not be explained by enzyme destruction, back reaction, or product adduct formation and were further confirmed by measurements of the rate of O2 utilization and NADPH oxidation. The complexity of the demethylation reaction should be taken into consideration in any detailed studies of the monooxygenation reaction system.

Reductive titration of cytochrome P-450 in rat liver microsomes.

Microsomal cytochromes b5 and P-450 of rat liver have been titrated with standardized sodium dithionite solution with a newly developed titrating apparatus that allows spectrophotometric monitoring of the reduction process while strictly O2-free conditions are maintained throughout the procedure. Cytochrome b5 and other electron acceptors in the microsomal preparation were saturated with reducing equivalents prior to addition of carbon monoxide to the system. Continued titration in the presence of CO revealed that 1 electron equivalent was required for the formation of P-450(Fe2+)-CO. These results are in agreement with previous findings of 1 electron equivalence for cytochrome P-450 of adrenocortical mitochondria and P-450CAM.

Inhibition by CO of hepatic benzo[a]pyrene hydroxylation and its reversal by monochromatic light.

Inhibition by CO of benzo[a]pyrene hydroxylation was studied in hepatic microsomes from rats pretreated with phenobarbital, 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin, from animals treated with vehicle (saline or corn oil, respectively), and in a reconstituted microsomal cytochrome P-448 system prepared from rats treated with 3-methylcholanthrene. In all preparations the hydroxylation was inhibited by CO, and this inhibition was most effectively reversed by irradiation with monochromatic light of 450 nm wavelength. These observations provide direct evidence that the oxygen-activating component of all the examined benzo[a]pyrene hydroxylase systems is a P-450-type heme protein. The only striking difference observed in these systems was the low CO sensitivity of the benzo[a]pyrene hydroxylase reaction in microsomes from animals treated with 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Half-maximal inhibition occurred at CO/O2 ratios of 9--12, rather than at 1--2, which is the usual range for P-450-linked mixed-function oxidase reactions. In contrast, the reconstituted benzo[a]pyrene hydroxylase system, with purified cytochrome P-448 from 3-methylcholanthrene-induced rats, exhibited a considerably higher sensitivity towards CO (CO/O2 ratio approximately 1), well within the range for mixed-function oxidase reactions. It is concluded that the observed diminished CO sensitivity of microsomal benzo[a]pyrene hydroxylase in 3-methylcholanthrene- or 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats results from alterations in the composition and/or structural organization of the microenvironment of cytochrome P-448 in the endoplasmic reticulum in response to the inducing action of polycyclic aromatic hydrocarbons and related agents, and is not related to changes in the heme protein P-448 per se. The detailed nature of these changes is the subject of ongoing studies.

Comparison of the induction course, biophysical chemical interactions and photochemical action spectra of phenobarbital and 3-methylcholanthrene induce hepatic microsomal P-450.

A comparison has been made of the physical and chemical properties of hepatic microsomal P-450 and associated enzyme systems from rats treated with phenobarbital or with 3-methylcholanthrene and other polycyclic aryl hydrocarbons. The results of these studies, though preliminary in nature, indicate clearly that the aryl-induced mixed-function oxidase systems differ significantly from the PB-induced ones in time course of induction, spectral properties, hyroxylase and demethylase activities, CO-inhibition of these reactions and light-reversal of the inhibition. The results support and extend the findings of other investigators regarding the differential biophysical and biochemical properties of aryl-induced systems and provide an experimental design for studying these properties in greater depth at the maximum of aryl induction.