Developments in antipsychotic therapy with regard to hypotheses for schizophrenia

The typical antipsychotic drugs like chlorpromazine and haloperidol were discovered by serendipity in the 1950s. A number of so-called "me too" drugs with similar chemical structures and modes of action were marketed in the subsequent years. The first atypical antipsychotic, clozapine, was an exception because it lacked some of the pharmacological properties of the typical antipsychotics related to the extrapyrimidal motor system. This unique feature of clozapine significantly broadened understanding of the mode of action of antipsychotics, and created new hypotheses for schizophrenia. Hypothesis-orientated development of new drugs was only recently initiated. Abnormalities of the immune system in schizophrenia are being increasingly discussed: shifts in the levels of T helper cells subsets 1 and 2 (Th1 and Th2) have been observed, and studies with risperidone and the cyclooxengenase (COX2) inhibitor celecoxib as an add-on therapy have provided very promising results. The glutamate N-methyl-D-aspartate (NMDA) receptors have also been investigated in relation to neuropathological abnormalities in prefrontal areas of the brain of patients with schizophrenia. This may lead to new technologies like artificial networks related to the glutamate NMDA receptor system. New molecular biological techniques used in pharmacogenomics and proteomics offer new and exciting directions for future drug developments.     

X-ray digital subtraction angiography with 1 mol/L gadobutrol: results from a comparative porcine study With iodinated contrast agents

RATIONALE AND OBJECTIVES: To evaluate prospectively diagnostic accuracy of 1 mol/L gadobutrol as a contrast agent for intraarterial x-ray digital subtraction angiography (DSA) in comparison to iodinated, nonionic contrast media and 0.5 mol/L gadolinium-DTPA. METHODS: Flush arteriograms (ascending, descending, abdominal aorta, iliac, and femoral arteries) and selective angiograms (carotid, renal, and visceral arteries) were obtained from bilateral femoral arterial access (5 F sheaths) in 10 domestic pigs (70 kg body weight). Digital subtracted angiograms were obtained during injection of undiluted 1 mol/L gadobutrol, 300 mg I/mL iopromide, or 0.5 mol/L gadopentetate. Injection parameters (volume and velocity) were similar for all three contrast agents. In paired arteries, two different contrast media were used during the same angiographic run. Diagnostic quality and accuracy of the angiograms were evaluated on a three-step scale by three independent blinded investigators. RESULTS: Sufficient nonselective angiographic images were obtained in 90% of cases using iodinated contrast material. Gadobutrol achieved sufficient nonselective angiograms in 64%. Selective angiograms were sufficient in 98% using iodinated contrast material, 90% using 1 mol/L Gadobutrol and 48% using 0.5 mol/L Gd-DTPA. Adverse reactions to any of the used contrast agents were not noted. CONCLUSION: One mol/L Gadobutrol solution allows x-ray digital subtraction angiography with a diagnostic accuracy equivalent to 300 mg/mL iodinated contrast media, if selective injections are performed. Flush aortograms are of inferior image quality to iodinated contrast material.     

A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy

This multicentre randomised double blind crossover trial tested the short term efficacy of intravenous immunoglobulin (IVIg) 2.0 g/kg given over 24 or 48 hours in patients with paraproteinaemic demyelinating neuropathy (PDN). Twenty-two patients were randomised and completed the trial. After 2 weeks, the overall disability grade decreased during both IVIg treatment and placebo but neither change was significant nor was the mean difference between the treatment effects. After 4 weeks the overall disability decreased by a mean of 0.55 [0.67] grades during the IVIg period (p = 0.001) while it was substantially unmodified during the placebo period. The mean difference between the treatment effects was significant (p = 0.05). Overall during the IVIg period 10 patients improved and 11 were stable and one got worse. During the placebo period 4 patients improved, 4 deteriorated and 14 were stable. Many secondary outcome measures, including Rankin scale, time to walk 10 metres, grip strength, sensory symptoms score were significantly better during IVIg treatment. Two serious adverse events occurred during the trial, both during placebo treatment. In conclusion the trial showed some short-term benefit of IVIg in about half of the patients confirming previous observation. Received: 6 August 2001, Received in revised form: 6 March 2002, Accepted: 12 March 2002 RID="*" ID="*"The other members of the INCAT group are Jacques Aubry PhD, Institut de Biologie, INSERM Unit 463, 9 Quai Moncousu, 44 035 Nantes, France; Nicole Baumann MD, InSERM Unit 495, Salpetriere Hospital, 75 651 Paris, Cedex 13 France; Robert Hadden PhD, Michael Lunn, MD, Department of Neuroimmunology, Guy's, King's and St. Thomas' School of Medicine, Guy's Hospital, London SE1 9 UL, UK; Martin Knapp Phd, Personal Social Services Research Unit, London School of Economics and Political Science, Houghton Street, London WC2A 1AE, UK; Jean-Marc Léger MD, Pierre Bouche MD, Service d'Eplorations Functionelles de la Salpetriere, 47 Boulevard de l'Hospital, 75 651 Paris, Cedex 13, France; Radim Mazanec CSc, Charles University, 2^nd Medical School, University Hospital, V uvalu 84, Prague 5, Czech Republic; Nicoletta Meucci MD, Institute of Clinical Neurology, University of Milan, Ospedale Maggior-Policlinico, via Sforza, 20 122 Milan, Italy; Frans van der Meché PhD, Department of Neurology, Erasmus Medical Center Rotterdam, dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; and Klaus Toyka PhD, Universitat Würzburg, Josef-Schneider Strasse 2, 97 080 Würzburg, Germany Correspondence to Giancarlo Comi, MD     

De novo aphasic status epilepticus as presenting symptom of multiple sclerosis

Journal of Neurology -     

Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized,placebo-controlled,double-blind trial

In a randomized, placebo-controlled, double-blind study, we investigated whether statins alter cholesterol metabolites and reduce Abeta levels in the cerebrospinal fluid of 44 patients with Alzheimer's disease. Individuals were given up to 80mg simvastatin daily or placebo for 26 weeks. Overall, simvastatin did not significantly alter cerebrospinal fluid levels of Abeta40 and Abeta42. In post hoc analysis, simvastatin significantly decreased Abeta40 levels in the cerebrospinal fluid of patients with mild Alzheimer's disease. The reduction of Abeta40 correlated with the reduction of 24S-hydroxycholesterol. These changes were not observed in more severely affected patients.     

Cerebellum and speech perception: a functional magnetic resonance imaging study

A variety of data indicate that the cerebellum participates in perceptual tasks requiring the precise representation of temporal information. Access to the word form of a lexical item requires, among other functions, the processing of durational parameters of verbal utterances. Therefore, cerebellar dysfunctions must be expected to impair word recognition. In order to specify the topography of the assumed cerebellar speech perception mechanism, a functional magnetic resonance imaging study was performed using the German lexical items "Boden" ([bodn], Engl. "floor") and "Boten" ([botn], "messengers") as test materials. The contrast in sound structure of these two lexical items can be signaled either by the length of the wordmedial pause (closure time, CLT; an exclusively temporal measure) or by the aspiration noise of wordmedial "d" or "t" (voice onset time, VOT; an intrasegmental cue). A previous study found bilateral cerebellar disorders to compromise word recognition based on CLT whereas the encoding of VOT remained unimpaired. In the present study, two series of "Boden - Boten" utterances were resynthesized, systematically varying either in CLT or VOT. Subjects had to identify both words "Boden" and "Boten" by analysis of either the durational parameter CLT or the VOT aspiration segment. In a subtraction design, CLT categorization as compared to VOT identification (CLT - VOT) yielded a significant hemodynamic response of the right cerebellar hemisphere (neocerebellum Crus I) and the frontal lobe (anterior to Broca's area). The reversed contrast ( VOT - CLT) resulted in a single activation cluster located at the level of the supratemporal plane of the dominant hemisphere. These findings provide first evidence for a distinct contribution of the right cerebellar hemisphere to speech perception in terms of encoding of durational parameters of verbal utterances. Verbal working memory tasks, lexical response selection, and auditory imagery of word strings have been reported to elicit activation clusters of a similar location. Conceivably, representation of the temporal structure of speech sound sequences represents the common denominator of cerebellar participation in cognitive tasks acting on a phonetic code.     

Morphological alterations in the amygdala and hippocampus of mice during ageing

Declines in memory function and behavioural dysfunction accompany normal ageing in mammals. However, the cellular and morphological basis of this decline remains largely unknown. It was assumed for a long time that cell losses in the hippocampus accompany ageing. However, recent stereological studies have questioned this finding. In addition, the effect of ageing is largely unknown in another key structure of the memory system, the amygdala. In the present study, we have estimated neuronal density and total neuronal numbers as well as density of fragments of degenerated axons in different hippocampal subfields and amygdaloid nuclei. Comparisons were made among aged (21-26 months old) mice and normal adult littermates (8 months old). No significant volume loss occurs in the hippocampus of aged mice. Small but insignificant reductions in total neuronal numbers were found in the hippocampus and in the amygdaloid nuclei. In contrast to the mild effects of ageing upon neuronal numbers, fragments of degenerated axons were increased in both hippocampus and amygdala of aged mice. These data suggest that ageing does not induce prominent cell loss in the hippocampus or amygdala, but leads to degeneration of axons that innervate these forebrain structures. Thus, mechanisms underlying age-related dysfunction depend on parameters other than neuronal numbers, at least in the hippocampal formation and the amygdala.     

Rapid adaptation to internal states as a coding strategy in visual cortex?

Adaptation is a prominent feature of biological neuronal systems. A common interpretation of adaptation in terms of function is that it provides flexibility for a neuronal system to perform well under varying external conditions, for example by adjusting the input/output relation of a sensory system with reference to the ensemble of stimuli the organism currently perceives. This interpretation, however, only applies if the time-scale of adaptation is slower than the time-scale at which the environment changes. Experimentally it is observed, however, that adaptation can be very rapid. Spike-frequency adaptation of cortical neurons, for example, occurs on a time-scale of approximately 100 ms. Here we show that those rapid adaptation processes can also be understood within the framework of information theory. We start with the hypothesis that neuronal codes are designed to optimize the information a neuronal representation conveys about an input stimulus for any increasing time window beginning with stimulus onset, and we show that this implies a rapid adaptation of the neuronal code on the time-scale of stimulus presentation. Adaptation, however, does not occur because the state of the environment changes. Rather it is a reaction to changes of the organisms own internal state, e.g. the level of noise in the neuronal representation. We apply this approach to a model of an orientation hypercolumn in the primary visual cortex, and predict that inter-columnar interactions should adapt on the time-scale of a typical fixation period ( approximately 300 ms).     

Folate status in Germany 1997-2000

Data about folate intake and blood values of the German population, published between 1997 and 2000, have been reviewed. Median folate intake is about 250 micrograms/day in the adult population, which indicates a high likelihood of inadequate intake when compared to the Estimated Average Requirement (EAR) of 320 micrograms/day. Only a few studies have evaluated serum and erythrocyte folate or plasma homocysteine as a marker of folate status. The most representative data show that 25% of German women of childbearing age have an inadequate recent folate intake. Only 13.3% of the women have red blood cell folate values above the critical value of 400 micrograms/day established by Daly et al (1995). Folic acid fortification of food is shown to be responsible for about 25% of folate intake in the German child and adolescent population in one study. If we extrapolate these data to the general population, folic acid fortification could be the explanation for the differences observed between folate intake and blood values. The discrepancy might also be explained by slight inaccuracies in food composition tables. Folate intake from fortified food or from supplements is not taken into account in most of the studies, which is a variable that can lead to confusion. Nutrition surveys should adapt official composition tables for local food patterns, and include fortified commercial foods, in order to make folate intake data more accurate. However, representative serum and erythrocyte folate values are lacking for most age groups. Before taking public health measures concerning folate fortification of food, the real folate status of the German population should be established.     

Experiments on effects of an intermittent 16.7-Hz magnetic field on salivary melatonin concentrations, rectal temperature, and heart rate in humans

OBJECTIVES: The present experiments concerned the hypothesis that an intermittent, strong and extremely low frequency magnetic field reduces salivary melatonin levels and delays consecutively the nadirs of rectal temperature and heart rate. METHODS: Twelve healthy young men (18-25 years) participated in three randomly permuted sessions, which were performed as constant routines. The participants kept a strict bed rest over 26 h, air temperature was 20 degrees C, illumination < 30 lx, and sound level < 50 dBA. Salivary melatonin levels were determined hourly, rectal temperature and heart rate were registered continuously throughout. An intermittent magnetic field was administered in one session from 6 p.m. to 2 a.m. at 16.7 Hz, 0.2 mT and alternating on/off-periods of 15 s. This situation was compared with a control session without any additional stress. Another session was performed to determine the participants' ability to respond to a well-known melatonin-suppressing stress, namely bright light (1,500 lx, 10 p.m.-2 a.m.). RESULTS: Bright light inhibited melatonin synthesis in all 12 participants and delayed the nadirs of rectal temperature and heart rate. The only significant alteration that was associated with exposure to the magnetic field was a delay in the heart rate nadir, which was not mediated by an accordingly altered melatonin profile. CONCLUSION: The fact that the circadian rhythm of only the heart rate was altered indicates an internal dissociation which might constitute a health risk in the long run and needs to be investigated more extensively.