Does risperidone improve verbal working memory in treatment-resistant schizophrenia?

OBJECTIVE: Treatment efficacy in schizophrenia is typically defined in terms of symptom reduction. However, new antipsychotic medications could potentially have an impact on aspects of disability, such as neurocognitive deficits. The authors evaluated the effects of risperidone on verbal working memory, a memory component of theoretical interest because of its link to prefrontal activity and of practical interest because of its link to psychosocial rehabilitation. METHOD: Verbal working memory of 59 treatment-resistant schizophrenic patients was assessed as part of a randomized, double-blind comparison of treatment with risperidone and haloperidol. Verbal working memory was measured under both distracting and nondistracting conditions at baseline and after 4 weeks of both fixed- and flexible-dose pharmacotherapy. RESULTS: Risperidone treatment had a greater beneficial effect on verbal working memory than haloperidol treatment across testing conditions (with and without distraction) and study phases (fixed and flexible dose). The treatment effect remained significant after the effects of benztropine cotreatment, change in psychotic symptoms, and change in negative symptoms were controlled. Neither benztropine status nor symptom changes were significantly related to memory performance. CONCLUSIONS: Treatment with risperidone appears to exert a more favorable effect on verbal working memory than treatment with a conventional neuroleptic. The beneficial effect appears to be due, at least partially, to a direct effect of the drug, possibly through antagonism of the 5-HT2A receptor. Results from this study suggest that pharmacotherapeutic efficacy in schizophrenia treatment could be broadened to include impact on neurocognitive abilities.     

The offensive subtype of Taijin-kyofu-sho in New York City: the phenomenology and treatment of a social anxiety disorder

The action of two isomers of thioctic acid was tested in-vitro by using the hippocampal slice technique. Various models to induce hyperexcitability of the pyramidal cells were used in order to characterize the drug action. Increases of the applied glucose above the usual concentration of 10 mM lead to a concentration dependent enhancement of the population spike amplitude peaking in a 200% increase at a concentration of 30 mM, whereas lower glucose concentrations result in diminished amplitudes. Both isomers of thioctic acid antagonize the hyperexcitability to a different degree with IC50's of 43 microM and 281 microM for the l- and the d-isomer, respectively. As thioctic acid passes the blood brain barrier very well, these results might suggest a protective action of thioctic acid on the brain during hyperglycemic episodes in diabetic patients. Regarding the mechanism of action, thioctic acid firstly reverses the effect of 6 mM calcium in the superfusion fluid and secondly reverses the effect of apamin, an highly selective neurotoxin of bee venom, acting as the most specific blocker of the small conductance calcium dependent potassium channel. As this channel has been described to occur also in liver, an interaction with it may underly the central and peripheral action of thioctic acid. Together with the already available evidence, these experiments support the hypothesis that thioctic acid can be regarded as a stereoselective neuroprotective agent preventing cells from being damaged by excess of calcium or hyperexcitability induced by blockade of a specific class of potassium channels.     

Evanescent wave fibre optic sensor for detection of L. donovani specific antibodies in sera of kala azar patients

An easy-to-use technique for detection of antibodies specific for the parasite L. donovani in human serum sample has been developed. The method is based on an evanescent wave generated from a tapered configuration of decladded optical fibre and does not require any volumetric measurement. Tapered fibres are immobilized with the purified cell surface protein of L. donovani by covalent bonding. Treated fibres are incubated with the patient serum for 10 min followed by incubation with goat anti human IgG tagged FITC. Fluorescent intensity from the fibre has been shown to be proportional to L. donovani specific antibodies present in the test sera. Direct readings can be obtained after signal enhancement through a photomultiplier tube within 5 min. The system, when tested on 12 positive sera, did not show any false negative result. Also, no false positive result was obtained with serum samples of patients infected with leprosy, tuberculosis, typhoid and malaria, showing the specificity of the sensor and efficacy of the technique.     

The role of beta-sheet interactions in domain stability, folding, and target recognition reactions of calmodulin

Single-residue mutations have been made of the hydrophobic Ile or Val residue in position 8 of each of the four calcium-binding loop sequences (sites I-IV) of Drosophila calmodulin. These highly conserved residues are part of the hydrophobic core of either calmodulin domain and are involved in the structural link of two calcium-binding sites via a short antiparallel beta-sheet. In the apo-form, the replacement of Ile (or Val) by Gly causes a significant destabilization, shown by the unfolding of the secondary structure of the domain carrying the mutation. In the presence of calcium, the deficiency in alpha-helical structure at 20 degrees C is restored for the mutants at site I, II, or III but not at site IV, which requires the further binding of a high-affinity target peptide to re-establish the native conformation. The extent of the destabilization is seen in the depression of the melting temperature of individual domains, which can be as large as 80 degrees C in the case of Ca4-CaM(V136G). However, because of low values of the unfolding enthalpy for calmodulin domains, only relatively low values of <2 kcal/mol are implied for DeltaDeltaG, the free energy of destabilization due to mutation. Consistent with this, the secondary structure of any unfolded mutant domain is highly sensitive to solvent composition and is largely refolded in the presence of 12.5% (v/v) aqueous trifluoroethanol. Compared to wild-type calmodulin, the affinities of the mutants for calcium and target peptides from sk-MLCK at 20 degrees C are significantly reduced but the effects are relatively small. These results indicate that the conformation of calmodulin can be dramatically altered by mutation of a single highly conserved residue but that changes in solvent or the binding of a target sequence can readily compensate for this, restoring the wild-type properties. The results also suggest that the integrity of both the apo- and holo-forms of calmodulin is important for the maintenance of its biological function and confirm the importance of conserving the structural function of the residues involved in the beta-sheet interactions.     

Functional and morphometric evaluation of offspring kidney after intrauterine undernutrition

Pregnant rats were subjected to 50% food restriction during the first or the second half of pregnancy, or throughout pregnancy. The effects of intrauterine food restriction, on kidney function and morphometry were studied in newborn and adult (3 months) offspring. No differences in glomerular diameter were observed in newborn restricted rats compared with controls. The number of glomeruli was significantly lower both in newborn and 3-month-old restricted rats. However, glomerular diameter was increased in 3-month-old rats, which suggests that hypertrophic stimuli were present. The medulla/cortex ratio increased in adult rats submitted to food restriction during pregnancy, a finding that agrees with the preserved sodium and acid excretion, and the normal osmolar and free water clearance observed in these groups. These results show that the reduction in glomerular number is still present 3 months after birth in the progeny of mothers submitted to severe food restriction during pregnancy, suggesting impairment of glomerulogenesis even after birth. Intra utero undernutrition can be regarded as an experimental model of glomerular hypertrophy.     

Nerve stimulation and denervation induce differential patterns of immediate early gene mRNA expression in skeletal muscle

Many properties of skeletal muscle cells are closely regulated by motor nerves. Neuromuscular synaptic transmission (including the 'activity' it triggers) mediates many of these effects, while denervation results in a different spectrum of muscle cell changes. However, little is known about the early regulatory events that occur in mature muscle cells in response to muscle activity or denervation. We have examined the effects of motor nerve stimulation and denervation on the expression of 4 immediate early genes (IEGs)--c-jun, junB, zif268, and nur77--in mature mouse gastrocnemius muscle. Electrical stimulation of the sciatic nerve in a pattern of brisk intermittent exercise induced a marked rise in zif268 and c-jun mRNA levels within 45 min, a minimal rise in junB, and no change in nur77 mRNA levels. By contrast, surgical denervation resulted in a marked increase of c-jun, a slight rise in junB, and no change in nur77 or zif268 mRNA levels. These findings show that neural stimulation and denervation lead to differential patterns of IEG expression. The selectivity of these patterns suggests that differential IEG expression may play an important role in regulating the specific phenotypic changes in skeletal muscles that result from denervation, innervation, and various patterns of stimulation.