Decision support system for the diagnosis of schizophrenia disorders.

Clinical decision support systems are useful tools for assisting physicians to diagnose complex illnesses. Schizophrenia is a complex, heterogeneous and incapacitating mental disorder that should be detected as early as possible to avoid a most serious outcome. These artificial intelligence systems might be useful in the early detection of schizophrenia disorder. The objective of the present study was to describe the development of such a clinical decision support system for the diagnosis of schizophrenia spectrum disorders (SADDESQ). The development of this system is described in four stages: knowledge acquisition, knowledge organization, the development of a computer-assisted model, and the evaluation of the system's performance. The knowledge was extracted from an expert through open interviews. These interviews aimed to explore the expert's diagnostic decision-making process for the diagnosis of schizophrenia. A graph methodology was employed to identify the elements involved in the reasoning process. Knowledge was first organized and modeled by means of algorithms and then transferred to a computational model created by the covering approach. The performance assessment involved the comparison of the diagnoses of 38 clinical vignettes between an expert and the SADDESQ. The results showed a relatively low rate of misclassification (18-34%) and a good performance by SADDESQ in the diagnosis of schizophrenia, with an accuracy of 66-82%. The accuracy was higher when schizophreniform disorder was considered as the presence of schizophrenia disorder. Although these results are preliminary, the SADDESQ has exhibited a satisfactory performance, which needs to be further evaluated within a clinical setting.

Effect of deuterium oxide on actomyosin motility in vitro.

Actin filament velocities in an in vitro motility assay system were measured both in heavy water (deuterium oxide, D(2)O) and water (H(2)O) to examine the effect of D(2)O on the actomyosin interaction. The dependence of the sliding velocity on pD of the D(2)O assay solution showed a broad pD optimum of around pD 8.5 which resembled the broad pH optimum (pH 8.5) of the H(2)O assay solution, but the maximum velocity (4.1+/-0.5 microm/s, n=11) at pD 8.5 in D(2)O was about 60% of that (7.1+/-1.1 microm/s, n=11) at pH 8.5 in H(2)O. The K(m) values of 95 and 80 microM and V(max) values of 3.2 and 5.1 microm/s for the D(2)O and H(2)O assay were obtained by fitting the ATP concentration dependence of the velocity (at pD and pH 7.5) to the Michaelis-Menten equation. The K(m) value of actin-activated Mg-ATPase activity of myosin subfragment 1 (S1) was decreased from 50 microM [actin] in H(2)O to 33 microM [actin] in D(2)O without any significant changes in V(max) (9.4 s(-1) in D(2)O and 9.3 s(-1) in H(2)O). The rate constants of ADP release from the acto-S1-ADP complex measured by the stopped flow method were 361+/-26 s(-1) (n=27) in D(2)O and 512+/-39 s(-1) (n=27) in H(2)O at 6 degrees C. These results suggest that the decrease in the in vitro actin-myosin sliding velocity in D(2)O results from a slowing of the release of ADP from the actomyosin-ADP complex and the increase in the affinity of actin for myosin in the presence of ATP in D(2)O.

Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects.

The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by delta 9-THC in normal volunteers, and whether this effect occurs by a general block of the action of delta 9-THC or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg delta 9-THC, 1 mg/kg CBD, a mixture containing 0.5 mg/kg delta 9-THC and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by delta 9-THC, however this effect also extended to marihuana-like effects and to other subjective alterations induced by delta 9-THC. This antagonism does not appear to be caused by a general block of delta 9-THC effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of delta 9-THC. These results suggest that the effects of CBD, as opposed to those of delta 9-THC, might be involved in the antagonism of effects between the two cannabinoids.

Enzyme-linked sandwich immunoassay of ornithine delta-aminotransferase from rat liver using antibody-coupled glass rods as solid phase.

A macromolecular antigen, ornithine delta-aminotransferase [EC 2.6.1.13] from rat liver (OAT) was assayed by the sandwich procedure using rabbit (anti-OAT) Fab'-beta-D-galactosidase complex and rabbit (anti-OAT) IgG-coupled glass rods as a solid phase. The Fab' fragments of the rabbit (anti-OAT) IgG were conjugated with beta-D-galactosidase [EC 3.2.1.23] from Escherichia coli using N, N'-o-phenylenedimaleimide. The rabbit (anti-OAT) IgG was coupled to the aminoalkylsilyl glass rods using glutaraldehyde. The rabbit (anti-OAT) IgG-coupled glass rods were incubated with OAT and then with the rabbit (anti-OAT) Fab'-beta-D-galactosidase complex. The amount of OAT was determined from the activity of beta-D-galactosidase bound to the glass rods. A minimum of 0.03 fmoles of OAT could be determined by this method and use of the glass rods gave greater reproducibility, and was more sensitive and simpler than use of Sepharose 4B.

Validity study of the Brazilian version of the Calgary Depression Scale for Schizophrenia.

INTRODUCTION: Although depression is a well-established feature of schizophrenia, it is difficult to measure, because it overlaps with negative symptoms and extrapyramidal symptoms (EPS). Routinely adopted depression scales were not designed to be used in--cases of schizophrenia, and are known to perform poorly when trying to distinguish depression from other symptoms. OBJECTIVE: The aim of this study was to evaluate the validity of the Brazilian version of the Calgary Depression Rating Scale for Schizophrenia (CDSS). METHOD: Outpatients from four mental health units in the city of São Paulo, diagnosed as having schizophrenia by DSM-IV criteria, were evaluated by two independent raters who applied the DSM-IV depression criteria. All patients were assessed by means of the CDSS, the Positive and Negative Syndrome Scale (PANSS), and the Extrapyramidal Symptom Rating Scale (ESRS). RESULTS: Eighty patients were recruited for the study. The analysis was carried out by comparing the DSM-IV criteria of depression with the CDSS scores, by means of the receiver operating characteristic (ROC) curves. The area under the ROC curve for major depression was 0.95 (SD = 0.02), and at a cut-off point of 6/7 the validity coefficients were as follows: sensibility 77%, specificity 92%, positive predictive value 67% and negative predictive value 95%. The area under the ROC curve for minor depression was 0.95 (SD = 0.02), and at a cut-off point of 4/5 the validity coefficients were as follows: sensibility 95%, specificity 88%, positive predictive value 75% and negative predictive value 98%. The correlation coefficients between the CDSS scores, the PANSS negative and positive subscale scores, and the ESRS scores were all below 0.50. CONCLUSION: It can be concluded that the Brazilian version of the CDSS is a valid research tool to assess depressive episodes for stabilized patients with schizophrenia.

Evidence for the essential role of myosin subfragment-2 in the ATP-dependent actin-myosin sliding in muscle contraction.

The role of myosin subfragment-2 (myosin S-2) in muscle contraction was studied by using an in vitro motility assay system in which the ATP-dependent sliding between myosin-coated polystyrene beads and actin filament arrays (actin cables) of giant algal cells were recorded under constant external loads provided with a centrifuge microscope. With antibody to myosin S-2 below 0.3 mg/ml, the maximum "isometric" force generated by myosin molecules on the bead decreased markedly, but the unloaded bead-sliding velocity along actin cables did not change appreciably, indicating a decrease in the number of myosin molecules interacting with actin cables. The antibody at 0.3-1.5 mg/ml decreased not only the maximum isometric force, but also the unloaded bead-sliding velocity in a dose-dependent manner. With the antibody at 1.5-3 mg/ml, the beads eventually stopped moving to remain attached to actin cables. These beads could be readily detached from actin cables with very small centrifugal forces, indicating very weak actin-myosin linkages. The antibody had no effect on rigor actin-myosin linkages formed before the antibody application. These results are consistent with the view that myosin S-2 plays an essential role in muscle contraction.

Force-velocity relation of sliding of skeletal muscle myosin, arranged on a paramyosin filament, on actin cables.

To investigate in vitro ATP-dependent sliding of regularly arranged myosin molecules on actin filaments, we prepared thick hybrid filaments in which myosin molecules isolated from rabbit skeletal muscle were arranged around the paramyosin core (length, 10-20 micron; diameter,

Measurement of ATP turnover during shortening and lengthening of rabbit psoas myofibrils using a fluorescent ATP analog.

In order to study ATP turnover during shortening and lengthening of rabbit psoas myofibrils, we have used fluorescence microscopy in which the displacement of a fluorescent nucleotide analog, 2'(3')-O-[N-[2-[[Cy3] amido] ethyl] carbamoyl]-adenosine 5' triphosphate (Cy3-EDA-ATP) bound to cross-bridge on flash photolysis of caged ATP was measured [Chaen et al. (1997) Biophys. J. 73, 2033-2042]. In the previous paper, we reported that when a myofibril was imposed to shorten with a constant velocity by a piezo-electric actuator, the nucleotide displacement rate constant initially increased to 0.7 s-1 with increasing shortening velocity and then declined with a further increase in shortening velocity. The rate constant during lengthening measured in the present experiment was found to be not significantly affected. These results suggest that the cross-bridge kinetics show a asymmetrical dependence on the mechanical strain in the cross-bridges, namely, the rate constants are not significantly affected at higher strain during lengthening but depend on the lower strain during shortening.

Family expectation, social adjustment and gender differences in a sample of schizophrenic patients.

A case series to study factors related to family expectation regarding schizophrenic patients was conducted in an out-patient setting in the city of S. Paulo, Brazil. Patients diagnosed as presenting schizophrenia by the ICD 9th Edition and having had the disease for more than four years were included in the study. Family Expectation was measured by the difference between the Katz Adjustment Scale (R2 and R3) scores based on the relative's expectation and the socially expected activities of the patient (Discrepancy Score), and social adjustment was given by the DSM-III-R Global Assessment Scale (GAS). Outcome assessments were made independently, and 44 patients comprised the sample (25 males and 19 females). The Discrepancy mean score was twice as high for males as for females (p < 0.02), and there was an inverse relationship between the discrepancy score and social adjustment (r = -0.46, p < 0.001). Moreover, sex and social adjustment exerted independent effects on the discrepancy score when age, age at onset and number of psychiatric admissions were controlled by means of a multiple regression technique. There was an interaction between sex and social adjustment, the inverse relationship between social adjustment and discrepancy score being more pronounced for males. These findings are discussed in the light of the potential association between the family environment, gender and social adjustment of schizophrenic patients, and the need for further research, i.e. ethnographic accounts of interactions between patient and relatives sharing households particularly in less developed countries.

Attention in schizophrenia and in epileptic psychosis.

The adaptive behavior of human beings is usually supported by rapid monitoring of outstanding events in the environment. Some investigators have suggested that a primary attention deficit might trigger symptoms of schizophrenia. In addition, researchers have long discussed the relationship between schizophrenia and the schizophrenia-like psychosis of epilepsy (SLPE). On the basis of these considerations, the objective of the present study was to investigate attention performance of patients with both disorders. Patient age was 18 to 60 years, and all patients had received formal schooling for at least four years. Patients were excluded if they had any systemic disease with neurologic or psychiatric comorbidity, or a history of brain surgery. The computer-assisted TAVIS-2R test was applied to all patients and to a control group to evaluate and discriminate between selective, alternating and sustained attention. The TAVIS-2R test is divided into three parts: one for selective attention (5 min), the second for alternating attention (5 min), and the third for the evaluation of vigilance or sustained attention (10 min). The same computer software was used for statistical analysis of reaction time, omission errors, and commission errors. The sample consisted of 36 patients with schizophrenia, 28 with interictal SLPE, and 47 healthy controls. The results of the selective attention tests for both patient groups were significantly lower than that for controls. The patients with schizophrenia and SLPE performed differently in the alternating and sustained attention tests: patients with SLPE had alternating attention deficits, whereas patients with schizophrenia showed deficits in sustained attention. These quantitative results confirmed the qualitative clinical observations for both patient groups, that is, that patients with schizophrenia had difficulties in focusing attention, whereas those with epilepsy showed perseveration in attention focus.

[Transvaginal ultrasonographic assessment of endometrium during hMG-hCG cycles].

Daily changes in the thickness and texture of the endometrium were assessed by transvaginal sonography in 15 natural (cycles 'cycle-A) and 24 stimulated cycles (cycle-B: hMG-hCG cycles; hCG 10,000 IU was injected on the day after the dominant follicle reached 18mm in three-directional radius, n = 7) (cycle-C: hCG 3,000 IU injections on the 5th, 9th and 13th day after hCG 10,000 injection were added to cycle-B, n = 10) (cycle-D: hCG 1,000 IU instead of 3,000 IU of cycle-C, n = 7). The duration of the luteal phase was 15, 9, 17 and 18 days in cycle-A, cycle-B, cycle-C and cycle-D, respectively. The thickness of the endometrium increased lineally until ovulation day (D +/- 0) (thickness: 10.7mm) in cycle-A, but in stimulated cycles it revealed a significantly rapid increase until D-4 (10.9mm) and then reached a plateau. The ratio of the thickness of the hyperechoic area to the total thickness of the endometrium reached 100% (D + 9) in cycle-A. The ratio reached only 72% (Max, D + 4) in cycle-B, but the effect of luteal support was shown to reach 89% and 85% (Max, D + 7) in cycle-C and cycle-D. The serum progesterone level in stimulated cycles revealed a rapid increase until D + 5, but it had an unstable pattern in cycle-C and cycle-D. It was shown that luteal support was necessary to offset the luteal phase defect caused by stimulation with hMG.

Measurement of nucleotide exchange rate constants in single rabbit soleus myofibrils during shortening and lengthening using a fluorescent ATP analog.

The kinetics of displacement of a fluorescent nucleotide, 2'(3')-O-[N[2-[[Cy3]amido]ethyl]carbamoyl]-adenosine 5'-triphosphate (Cy3-EDA-ATP), bound to rabbit soleus muscle myofibrils were studied using flash photolysis of caged ATP. Use of myofibrils from this slow twitch muscle allowed better resolution of the kinetics of nucleotide exchange than previous studies with psoas muscle myofibrils (, Biophys. J. 73:2033-2042). Soleus myofibrils in the presence of Cy3-EDA-nucleotides (Cy3-EDA-ATP or Cy3-EDA-ADP) showed selective fluorescence staining of the A-band. The K(m) for Cy3-EDA-ATP and the K(d) for Cy3-EDA-ADP binding to the myofibril A-band were 1.9 microM and 3.8 microM, respectively, indicating stronger binding of nucleotide to soleus cross-bridges compared to psoas cross-bridges (2.6 microM and 50 microM, respectively). After flash photolysis of caged ATP, the A-band fluorescence of the myofibril in the Cy3-EDA-ATP solution under isometric conditions decayed exponentially with a rate constant of 0.045 +/- 0.007 s(-1) (n = 32) at 10 degrees C, which was about seven times slower than that for psoas myofibrils. When a myofibril was allowed to shorten with a constant velocity, the nucleotide displacement rate constant increased from 0.066 s(-1) (isometric) to 0.14 s(-1) at 20 degrees C with increasing shortening velocity up to 0.1 myofibril length/s (V(max), the shortening velocity under no load was approximately 0. 2 myofibril lengths/s). The rate constant was not significantly affected by an isovelocity stretch of up to 0.1 myofibril lengths/s. These results suggest that the cross-bridge kinetics are not significantly affected at higher strain during lengthening but depend on the lower strain during shortening. These data also indicate that the interaction distance between a cross-bridge and the actin filament is at least 16 nm for a single cycle of the ATPase.

Measurement of nucleotide release kinetics in single skeletal muscle myofibrils during isometric and isovelocity contractions using fluorescence microscopy.

Rabbit psoas muscle myofibrils, in the presence of the fluorescent nucleotide analog 2'(3')-O-[N-[2-[[Cy3]amido]ethyl]carbamoyl]-adenosine 5' triphosphate (Cy3-EDA-ATP), showed selective fluorescence staining of the A-band with a reduced fluorescence at the M-line. Addition of Cy3-EDA-ATP to a myofibril in the presence of Ca2+ caused auxotonic shortening against a compliant glass microneedle. These results indicate that Cy3-EDA-ATP is a substrate for myosin in the myofibril system. The kinetics of nucleotide release from a single myofibril, held isometrically between two needles, were measured by the displacement of prebound Cy3-EDA-ATP on flash photolysis of caged ATP. The A-band fluorescence of the myofibril decayed exponentially with a rate constant of 0.3 s(-1) at 8 degrees C, an order of magnitude faster than that for isolated thick filaments in the absence of actin. When a myofibril was imposed to shorten with a constant velocity by a piezoelectric actuator, the nucleotide displacement rate constant initially increased to 0.7 s(-1) with increasing shortening velocity and then declined with a further increase in shortening velocity. These results demonstrate that the displacement rates of Cy3-EDA-nucleotides bound to the cross-bridges in the contracting myofibril reflect a process that shows strain dependence.

Enzyme-linked sandwich immunoassay of macromolecular antigens using the rabbit antibody-coupled glass rod as a solid phase.

A highly sensitive sandwich immunoassay of macromolecular antigens using the rabbit antibody Fab' - beta-D-galactosidase complex and the rabbit antibody immunoglobulin-G-coupled glass rod as a solid phase is described. The Fab' fragments of rabbit antibody IgG are conjugated with beta-D-galactosidase from Escherichia coli using N,N'-o-phenylenedimaleimide. Rabbit antibody IgG is coupled to the aminoalkylsilyl glass rods (3 mm in diameter and 5 mm in length) using glutaraldehyde. A wide range of the concentrations of rabbit IgG fraction (20-2000 mug/ml) is effective for coupling, and the amount of rabbit immunoglobulin G coupled can be controlled. The smallest amounts of ornithine delta-aminotransferase from rat liver, human immunoglobulin G and 2,4-dinitrophenyl human immunoglobulin G that can be determined are 0.03, 0.3 and 0.04 fmol, respectively. The sensitivity of the assay for these antigens is affected mainly by the non-specific binding of the complexes to the solid phase and the ability of antigen molecules, adsorbed on the solid phase, to bind specifically the complexes. The assay with the rabbit antibody immunoglobulin-G-coupled glass rods is simpler and more sensitive than that with the rabbit antibody immunoglobulin-G-coupled Sepharose 4B.

Effects of delta9-tetrahydrocannabinol and cannabinol in man.

The interaction of delta9-tetrahydrocannabinol (delta9-THC) and cannabinol (CBN) was studied in man. Five male volunteers were given placebo, 50 mg CBN, 25 mg delta9-THC, 12.5 mg delta9-THC + 25 mg CBN, and 25 mg delta9-THC + 50 mg CBN (orally). Administrations were spaced 1 week apart. With physiological measures, delta9-THC produced an increase in heart rate while CBN did not. When combined, no change of the delta9-THC effect occurred. No changes occurred on the electrocardiogram, blood pressure, or body temperature. With psychophysical measures no changes occurred in pain thresholds or skin sensitivity as a function of drug treatment. In time estimates of the passage of 1 minute, delta9-THC alone produced underestimates of the passage of 1 minute and CBN alone had no effect. In combination the two drugs had a tendency to produce significant overestimates and underestimates of the passage of 1 minute. On a 66-item adjective-pair drug reaction scale, the volunteers reported feeling drugged, drunk, dizzy, and drowsy under the delta9-THC condition, but not under the CBN condition. With combined drug treatment, volunteers reported feeling more drugged, drunk, dizzy, and drowsy than under the delta9-THC condition alone. None of the drug treatments produced significant changes on other items which included items on perception, emotion, cognition and sociability. It appears that CBN increases the effect of delta9-THC on some aspects of physiological and psychological processes, but that these effects are small and cannot account for the greater potency which has been reported when plant material is used.

The mode of ATP-dependent microtubule-kinesin sliding in the auxotonic condition.

Kinesin is a motor protein that converts chemical energy derived from ATP hydrolysis into mechanical work to transport cellular components along microtubules. We studied the properties of ATP-dependent microtubule-kinesin sliding with two different in vitro assay systems. In one assay system, a kinesin-coated glass microneedle (elastic coefficient, 1-2.5 pN microns -1) was made to slide along an axoneme. Using this system, we obtained the relationship between the force (= load) on the microneedle and the velocity of microneedle-kinesin sliding in the auxotonic condition, in which the load on the microtubule-kinesin contacts increased as sliding progressed. The force-velocity curve was upwardly convex (maximum velocity Vmax, 0.58 +/- 0.15 microns s-1; maximum isometric force P0, 5.0 +/- 1.6 pN) and was similar to that of in vitro actin-myosin sliding in the auxotonic condition, suggesting that the two motor protein systems have fundamental kinetic properties in common. In the other assay system, an axoneme attached to a glass microneedle (elastic coefficient, 4-5 pN microns -1) was made to slide on a kinesin-coated glass surface (Vmax, 0.68 +/- 0.17 microns s-1; P0, 46.1 +/- 18.6 pN). The change in shape of the axoneme indicated an enormous flexibility of randomly oriented kinesin molecules.

Metabolic fate of 1-hexylcarbamoyl-5-fluorouracil in rats.

1. The metabolic fate of a new antitumour agent, 1-hexylcarbamoyl-5-fluoro [6-14C]uracil (14C-HCFU) in rats after oral administration was compared with that of 5-fluoro[6-14C]uracil (14C-FU). 2. Tissue radioactivity reached a max. 1 to 3 h after administration of 14C-HCFU and 0.5 h after 14C-FU. 3. Both drugs were excreted rapidly, mostly in urine. Expired 14CO2 from 14C-HCFU was significantly less than that from 14C-FU. 4. Unchanged FU was not detected in plasma 3 h after administration of 14C-FU, whereas FU was detected in plasma 5 h after 14C-HCFU. The pyrimidine ring of 14C-HCFU might be degradated more slowly than that of 14C-FU. 5. 1-(5-Carboxypentylcarbamoyl)-5-fluorouracil and 1-(3-carboxypropylcarbamoyl)-5-fluorouracil were identified as the major urinary metabolites of 14C-HCFU.

Attention in schizophrenia and in epileptic psychosis

The adaptive behavior of human beings is usually supported by rapid monitoring of outstanding events in the environment. Some investigators have suggested that a primary attention deficit might trigger symptoms of schizophrenia. In addition, researchers have long discussed the relationship between schizophrenia and the schizophrenia-like psychosis of epilepsy (SLPE). On the basis of these considerations, the objective of the present study was to investigate attention performance of patients with both disorders. Patient age was 18 to 60 years, and all patients had received formal schooling for at least four years. Patients were excluded if they had any systemic disease with neurologic or psychiatric comorbidity, or a history of brain surgery. The computer-assisted TAVIS-2R test was applied to all patients and to a control group to evaluate and discriminate between selective, alternating and sustained attention. The TAVIS-2R test is divided into three parts: one for selective attention (5 min), the second for alternating attention (5 min), and the third for the evaluation of vigilance or sustained attention (10 min). The same computer software was used for statistical analysis of reaction time, omission errors, and commission errors. The sample consisted of 36 patients with schizophrenia, 28 with interictal SLPE, and 47 healthy controls. The results of the selective attention tests for both patient groups were significantly lower than that for controls. The patients with schizophrenia and SLPE performed differently in the alternating and sustained attention tests: patients with SLPE had alternating attention deficits, whereas patients with schizophrenia showed deficits in sustained attention. These quantitative results confirmed the qualitative clinical observations for both patient groups, that is, that patients with schizophrenia had difficulties in focusing attention, whereas those with epilepsy showed perseveration in attention focus.