The patient-reported disease burden in adults with atopic dermatitis: a cross-sectional study in Europe and Canada.

BACKGROUND: Cross-sectional data on patient burden in adults with atopic dermatitis (AD) from real-world clinical practice are limited. OBJECTIVE: This study compared patient-reported burden associated with adult AD across severity levels from clinical practices in Canada and Europe. METHODS: This study included adults (18-65 years) diagnosed with AD by dermatologists, general practitioners or allergists. Participants categorized as mild (n = 547; 37.3%), moderate (n = 520; 35.4%) or severe (n = 400; 27.3%) based on Investigator's Global Assessment completed a questionnaire that included pruritus and pain numerical rating scales, Patient-Oriented-Scoring of Atopic Dermatitis (PO-SCORAD) itch and sleep visual analogue scales, Dermatology Life Quality Index (DLQI), and the Hospital Anxiety and Depression Scale (HADS). Participants were also stratified by inadequate efficacy/intolerance/contraindication to cyclosporine [Cyclo; n = 62 (4 mild, 18 moderate, 40 severe)] and any systemic immunomodulatory agent [IMM; n = 104 (13 mild, 31 moderate, 60 severe)] and compared with the severe group excluding participants identified as Cyclo/IMM. RESULTS: Age was similar across severity groups; the proportion of women was higher in the mild group relative to severe (61.2% vs. 50.5%; P < 0.001). Compared with moderate and mild, participants with severe AD had more comorbidities, higher itch and pain severity, worse sleep and higher levels of anxiety and depression (all P < 0.001). Mean ± SD DLQI score among participants with severe AD (16.2 ± 6.9) showed a large effect on quality of life that was higher than those with moderate (10.2 ± 6.3) and mild (5.5 ± 4.9) (both P < 0.001). The burden among Cyclo and IMM subgroups was generally similar to that of participants with severe AD. CONCLUSIONS: Adults with AD reported a substantial burden across multiple domains that was significantly higher in those with severe disease. The burden among participants in the Cyclo/IMM subgroups was similar to those with severe AD.

A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors.

We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids. The inhibitory effects of the compounds were examined for seven HDAC enzyme subtypes using a chemiluminescence-based assay.

Extending the maximum operation time of the MNSR reactor.

An effective modification to extend the maximum operation time of the Miniature Neutron Source Reactor (MNSR) to enhance the utilization of the reactor has been tested using the MCNP4C code. This modification consisted of inserting manually in each of the reactor inner irradiation tube a chain of three polyethylene-connected containers filled of water. The total height of the chain was 11.5cm. The replacement of the actual cadmium absorber with B(10) absorber was needed as well. The rest of the core structure materials and dimensions remained unchanged. A 3-D neutronic model with the new modifications was developed to compare the neutronic parameters of the old and modified cores. The results of the old and modified core excess reactivities (ρex) were: 3.954, 6.241 mk respectively. The maximum reactor operation times were: 428, 1025min and the safety reactivity factors were: 1.654 and 1.595 respectively. Therefore, a 139% increase in the maximum reactor operation time was noticed for the modified core. This increase enhanced the utilization of the MNSR reactor to conduct a long time irradiation of the unknown samples using the NAA technique and increase the amount of radioisotope production in the reactor.

Immunohistochemical expression of heparanase isoforms and syndecan-1 proteins in colorectal adenomas.

The proteoglycan syndecan-1 and the endoglucuronidases heparanase-1 and heparanase-2 are involved in molecular pathways that deregulate cell adhesion during carcinogenesis. Few studies have examined the expression of syndecan-1, heparanase-1 and mainly heparanase-2 proteins in non-neoplastic and neoplastic human colorectal adenoma tissues. The aim of this study was to analyze the correlation among the heparanase isoforms and the syndecan-1 proteins through immunohistochemical expression in the tissue of colorectal adenomas. Primary anti-human polyclonal anti-HPSE and anti-HPSE2 antibodies and primary anti-human monoclonal anti-SDC1 antibody were used in the immunohistochemical study. The expressions of heparanase-1 and heparanase-2 proteins were determined in tissue samples from 65 colorectal adenomas; the expression of syndecan-1 protein was obtained from 39 (60%) patients. The histological type of adenoma was tubular in 44 (67.7%) patients and tubular-villous in 21 (32.3%); there were no villous adenomas. The polyps were <1.0 cm in size in 54 (83.1%) patients and ≥1.0 cm in 11 (16.9%). The images were quantified by digital counter with a computer program for this purpose. The expression index represented the relationship between the intensity expression and the percentage of positively stained cells. The results showed that the average of heparanase-1, heparanase-2 and syndecan-1 expression index was 73.29 o.u./µm², 93.34 o.u./µm², and 55.29 o.u./µm², respectively. The correlation between the heparanase-1 and syndecan-1 expression index was positive (R=0.034) and significant (P=0.035). There was a negative (R= -0.384) and significant (P=0.016) correlation between the expression index of heparanase-1 and heparanase-2. A negative (R= -0.421) and significant (P=0.008) correlation between the expression index of heparanase-2 and syndecan-1 was found. We concluded that in colorectal adenomas, the heparanase-1 does not participate in syndecan-1 degradation; the heparanase-2 does not stimulate syndecan-1 degradation by the action of heparanase-1, and the heparanase-2 may be involved in the modulation of the heparanase-1 activity.

A comparative study of the neutron flux spectra in the MNSR irradiation sites for the HEU and LEU cores using the MCNP4C code.

A comparative study for fuel conversion from the HEU to LEU in the Miniature Neutron Source Reactor (MNSR) has been performed in this paper using the MCNP4C code. The neutron energy and lethargy flux spectra in the first inner and outer irradiation sites of the MNSR reactor for the existing HEU fuel (UAl4-Al, 90% enriched) and the potential LEU fuels (U3Si2-Al, U3Si-Al, U9Mo-Al, 19.75% enriched and UO2, 12.6% enriched) were investigated using the MCNP4C code. The neutron energy flux spectra for each group was calculated by dividing the neutron flux by the width of each energy group. The neutron flux spectra per unit lethargy was calculated by multiplying the neutron energy flux spectra for each energy group by the average energy of each group. The thermal neutron flux was calculated by summing the neutron fluxes from 0.0 to 0.625 eV, the fast neutron flux was calculated by summing the neutron fluxes from 0.5 MeV to 10 MeV for the existing HEU and potential LEU fuels. Good agreements have been noticed between the flux spectra for the potential LEU fuels and the existing HEU fuels with maximum relative differences less than 10% and 8% in the inner and outer irradiation sites.

Calculation and comparison of xenon and samarium reactivities of the HEU, LEU core in the low power research reactor.

Comparative studies for the conversion of the fuel from HEU to LEU in the Miniature Neutron Source Reactor (MNSR) have been performed using the MCNP4C and GETERA codes. The precise calculations of (135)Xe and (149)Sm concentrations and reactivities were carried out and compared during the MNSR operation time and after shutdown for the existing HEU fuel (UAl4-Al, 90% enriched) and the potential LEU fuels (U3Si2-Al, U3Si-Al, U9Mo-Al, 19.75% enriched and UO2, 12.6% enriched) in this paper using the MCNP4C and GETERA codes. It was found that the (135)Xe and (149)Sm reactivities did not reach their equilibrium reactivities during the daily operating time of the reactor. The (149)Sm reactivities could be neglected compared to (135)Xe reactivities during the reactor operating time and after shutdown. The calculations for the UAl4-Al produced the highest (135)Xe reactivity in all the studied fuel group during the reactor operation (0.39 mk) and after the reactor shutdown (0.735 mk), It followed by U3Si-Al (0.34 mk, 0.653 mk), U3Si2-Al (0.33 mk, 0.634 mk), U9Mo-Al (0.3 mk, 0.568 mk) and UO2 (0.24 mk, 0.448 mk) fuels, respectively. Finally, the results showed that the UO2 was the best candidate for fuel conversion to LEU in the MNSR since it gave the lowest (135)Xe reactivity during the reactor operation and after shutdown.

Risk factors for treatment resistance in unipolar depression: a systematic review.

BACKGROUND: Treatment resistant depression is a complex disorder and an important source of morbidity and mortality. Identification of risk factors of resistance may be useful to improve early recognition as well as treatment selection and prediction of outcome in patients with depression. METHODS: The aim of this paper was to review the current status of knowledge regarding risk factors of treatment resistance in unipolar depression, in patients who failed to respond to at least two successive and adequate antidepressant treatments. RESULTS: Systematic literature search yielded 8 publications exploring clinical and biological factors. Specific psychiatric comorbidities, psychosocial factors, clinical characteristics of the depressive episode and biological markers emerge as possible risk factor for treatment resistant depression. LIMITATIONS: Due to the lack of objective definition and diagnostic criteria for treatment resistant depression, and the paucity of reports on risk factors, our review only summarized a small number of studies. CONCLUSION: Future investigations of risk factors should help to improve the understanding of the mechanisms underlying resistance in mood disorders and contribute to improve their therapeutic management.

[French guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications]. / Recommandations françaises sur l'utilisation de la stimulation magnétique transcrânienne répétitive (rTMS) : règles de sécurité et indications thérapeutiques.

During the past decade, a large amount of work on transcranial magnetic stimulation (TMS) has been performed, including the development of new paradigms of stimulation, the integration of imaging data, and the coupling of TMS techniques with electroencephalography or neuroimaging. These accumulating data being difficult to synthesize, several French scientific societies commissioned a group of experts to conduct a comprehensive review of the literature on TMS. This text contains all the consensual findings of the expert group on the mechanisms of action, safety rules and indications of TMS, including repetitive TMS (rTMS). TMS sessions have been conducted in thousands of healthy subjects or patients with various neurological or psychiatric diseases, allowing a better assessment of risks associated with this technique. The number of reported side effects is extremely low, the most serious complication being the occurrence of seizures. In most reported seizures, the stimulation parameters did not follow the previously published recommendations (Wassermann, 1998) [430] and rTMS was associated to medication that could lower the seizure threshold. Recommendations on the safe use of TMS / rTMS were recently updated (Rossi et al., 2009) [348], establishing new limits for stimulation parameters and fixing the contraindications. The recommendations we propose regarding safety are largely based on this previous report with some modifications. By contrast, the issue of therapeutic indications of rTMS has never been addressed before, the present work being the first attempt of a synthesis and expert consensus on this topic. The use of TMS/rTMS is discussed in the context of chronic pain, movement disorders, stroke, epilepsy, tinnitus and psychiatric disorders. There is already a sufficient level of evidence of published data to retain a therapeutic indication of rTMS in clinical practice (grade A) in chronic neuropathic pain, major depressive episodes, and auditory hallucinations. The number of therapeutic indications of rTMS is expected to increase in coming years, in parallel with the optimisation of stimulation parameters.

Nasally inhaled pulsating aerosols: lung, sinus and nose deposition.

OBJECTIVES: Topical delivery of drugs to the sinuses is challenging and requires also particular administration manoeuvres from the patient. This study was conducted to investigate 1) the delivery efficiency of a pulsating aerosol (Vibrent prototype device) to the sinuses and the nose, 2) the aerosol fraction that will deposit in the lungs and 3) potential differences regarding sinus and nasal deposition ratio when comparing aerosol administration during two different administration routes. METHODS: An open label deposition study in healthy volunteers was conducted using 99mTc-DTPA radiolabeled pulsating aerosols in comparison to nasal pump sprays. Deposition and retention of pulsating aerosols was assessed by gamma camera imaging during spontaneous nasal breathing and during closed soft palate administration. RESULTS: Aerosol administration during nasal breathing vs. application with closed soft plate results in significant lung, nasal and sinus deposition. No significant differences were observed for nasal clearance. In comparison, drug delivery using nasal pump sprays resulted in non-significant sinus, 100 % nasal and non-significant lung deposition. The clearance kinetics after nasal pump spray delivery was significantly accelerated. DISCUSSION: The standard application mode of pulsation aerosols with closed soft palate results in negligible lung deposition and therefore limits drug delivery to the nasal cavity only, minimizing unwanted side effects. Administration during spontaneous nasal breathing shows only 10% lung deposition, which is tolerable during drug administration. Relevant paranasal sinus deposition is noted during both application modes and clearance kinetics remains essentially unchanged. In contrast, nasal pump sprays do not show sinus drug delivery and nasal drug residence time is shortened. CONCLUSION: Pulsating aerosols offer advantageous topical nasal and sinus drug delivery options.

Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.

Non-invasive unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex induces analgesic effects in focal chronic pain syndromes, probably by modifying central pain modulatory systems. Neuroimaging studies have shown bilateral activation of a large number of structures, including some of those involved in pain processing, suggesting that such stimulation may induce generalized analgesic effects. The goal of this study was to assess the effects of unilateral rTMS of the motor cortex on chronic widespread pain in patients with fibromyalgia. Thirty patients with fibromyalgia syndrome (age: 52.6 +/- 7.9) were randomly assigned, in a double-blind fashion, to two groups, one receiving active rTMS (n = 15) and the other sham stimulation (n = 15), applied to the left primary motor cortex in 10 daily sessions. The primary outcome measure was self-reported average pain intensity over the last 24 h, measured at baseline, daily during the stimulation period and then 15, 30 and 60 days after the first stimulation. Other outcome measures included: sensory and affective pain scores for the McGill pain Questionnaire, quality of life (assessed with the pain interference items of the Brief Pain Inventory and the Fibromyalgia Impact Questionnaire), mood and anxiety (assessed with the Hamilton Depression Rating Scale, the Beck Depression Inventory and the Hospital Anxiety and Depression Scale). We also assessed the effects of rTMS on the pressure pain threshold at tender points ipsi- and contralateral to stimulation. Follow-up data were obtained for all the patients on days 15 and 30 and for 26 patients (13 in each treatment group) on day 60. Active rTMS significantly reduced pain and improved several aspects of quality of life (including fatigue, morning tiredness, general activity, walking and sleep) for up to 2 weeks after treatment had ended. The analgesic effects were observed from the fifth stimulation onwards and were not related to changes in mood or anxiety. The effects of rTMS were more long-lasting for affective than for sensory pain, suggesting differential effects on brain structures involved in pain perception. Only few minor and transient side effects were reported during the stimulation period. Our data indicate that unilateral rTMS of the motor cortex induces a long-lasting decrease in chronic widespread pain and may therefore constitute an effective alternative analgesic treatment for fibromyalgia.

Therapeutic and neurophysiologic aspects of transcranial magnetic stimulation in schizophrenia.

The use of repetitive transcranial magnetic stimulation (rTMS) in psychiatry provides the therapeutic field with a new tool. Since its introduction in the mid 1980s, the vast majority of studies have focussed on depression. A growing body of evidence suggests that rTMS is effective in the treatment of depression if dorsolateral prefrontal cortex is stimulated. Less is known about its efficacy in schizophrenia. Neuroimaging investigations in schizophrenia suggest abnormalities in the prefrontal and temporoparietal cortex (TPC), which are correlated with psychopathological dimensions. Based on its modulatory effect, rTMS seems to be a promising tool in exploring cortical excitability and reducing auditory hallucinations (AH) and negative symptoms. Neurophysiologic studies of patients suffering from schizophrenia using rTMS indicate high cortical excitability and a lack of transcallosal inhibition. In the therapeutic field, researches provide encouraging results, even though some studies indicate limited benefits. The most promising therapeutic effect seems to be the capability of rTMS to reduce AH if TPC is targeted using slow-frequency. The current paper aims to provide a review of the literature of the use of rTMS in schizophrenia.

Transcranial magnetic stimulation in the treatment of schizophrenic symptoms: a double blind sham controlled study.

BACKGROUND: Schizophrenia is a disabling disease with a significant proportion of patients experiencing persistent symptoms. Repetitive transcranial magnetic stimulation (rTMS) is a promising new therapeutic tool that could benefit to schizophrenic patients. In this study we sought to assess the efficacy of active rTMS compared to sham stimulation in the treatment of patients with schizophrenia. METHOD: Eighteen schizophrenic patients according to DSM-IV criteria were randomly allocated to receive active or sham rTMS for 10 days over the left temporoparietal cortex (80% of the motor threshold, 1Hz, five trains of 1 min). Psychopathological dimensions were measured with the positive and negative syndrome scale and clinical global impression at baseline and after 10 session of rTMS. RESULTS: All patients were improved at the end of the trial but no significant group differences were found. Patients receiving sham stimulation showed the same pattern of improvement compared to active condition on all the subscales of the positive and negative syndrome scale and clinical global impression scores (p>0.05). CONCLUSION: In our study, active rTMS failed to show superiority over sham stimulation in the treatment of schizophrenic symptoms. Although previous results have shown that rTMS reduces auditory hallucination, its efficacy on other positive schizophrenic symptoms is not yet established. Nevertheless, the results of our study, even though negative, provide further insights in the pathophysiology of schizophrenia.

[Schizophrenia diagnostic announcement in a French psychiatric unit]. / Annonce du diagnostic de schizophrénie au sein d'un service de psychiatrie de secteur.

Announcement of schizophrenia diagnostic to the patients is a topical issue in France. The evolution in clinical practices, a better efficiency in therapeutic procedures and the fundamental right of the patient to obtain information have initialised the discussion of its interest. Spontaneous claim for information from the patient is rarely observed although awareness troubles might be reported at the instauration of the mental disorder or during its evolution. Methodological studies concerning the diagnostic announcement are limited. Except the Bayle studies recently published, only a few publications are available in France about the knowledge of their pathology and their need to be clearly informed. French scientific literature deals generally about medico-legal aspects of this information and consisted of survey about diagnostic announcement. International literature is more abundant and presents positive and negative aspects of the announcement. An information procedure of schizophrenia announcement to the patient has been developed in our hospitalisation unit of psychiatry. This procedure has taken place on the basis of the literature data, our specificity and our clinical experiences. For some Anglo-American psychiatrists who have proceeded to semi-structured interview in order to announce the diagnostic, information to the patients might improve the clinical relationship. Thus, compliance to the treatment is significantly increased. The ability of the patient to recognise the symptoms of the disease and to accept their consequences and the treatments is associated to a better social prognosis, daily activities and response to the treatment. The announcement impact justifies the prescription of neuroleptics, treatment that is notoriously perceived as prejudicial by the patients themselves or more commonly in the basic population. To obtain compliance to the treatment, a satisfactory acceptance of the mental disorder is required. Compliance is based on satisfactory information in order to gain the cooperation of the patient and its relative (10). Atkinson has classified four main types of arguments, the ethical principle to be informed, talk to explain and give sense to the symptoms, reduce the feeling of guilt perceived by the patient and his relative and enhance the collaboration between the patient and the nursing staff. According to Ferreri and Bayle studies French psychiatrists reluctance to announce schizophrenia diagnostic are the following: lack of request or of interrogations asked by the patient about their disease, diagnostic and prognosis uncertainty and irreversibility of the disease, complexity of the pathology and its origin which hinder an accessible explanation, cognitive disorders frequently observed with schizophrenic patients which may be associated with difficulties of understanding information, destabilization of the patient-nursing staff relationship and social stigmatisation risks. Other arguments like reluctance to give a "label" to the disease, too abstract diagnostic, a negative social vision and the possibility of discouragement for the relative are classically retrieved in French literature. In fact, divulgation of the term schizophrenia involves a panel of negative representations and is hindered by the confusion in the social imagination of such a term related with lost of control, quintessence of madness, dangerous behaviour possibilities, evil and incurability. Some psychiatrists do not transmit information arguing that significant obstruction of the future may be consecutive to the information. They prefer to use vague terms more socially acceptable like "nervous breakdown or depression, atypical or emotional disorder, dissociative troubles...". Information to the patient about his mental disorder is more frequent in psychiatry for affective, anxious and additive troubles than for schizophrenia. Our procedure of diagnostic announcement has been elaborated after preliminary discussion with the medical and nursing staff. Diagnostic of schizophrenia announcement has been presented by weighing the pros and cons according to the intemational literature. It clearly appeared that benefits for the patients prevail on the drawbacks. Nevertheless, inclusion and clinical supervision have to be carefully precised in particular to verify the ability to receive information. Short term objectives: deliver progressively information to the patient about his disease by means of an active and educational process with hope and optimism using a accessible language (explanation of each terms used with the intention of being well understood); quantify the impact of diagnostic announcement on the schizophrenic patient using clinical rating scales during a period of one month (clinical interview at day 1, day 7 and day 28). Mid term objectives: improve the global supervision and autonomy of schizophrenic by means of a therapeutic project helping the patient to become an active partner in the monitoring of his mental disorder; enhance a psycho-educational program after the procedure of announcement in order to optimise the observance of his treatment, increase his quality of life and answer to the requests of his relative; 45 patients (age 29.3 +/- 8.8 years old) have been included to be informed on their diagnostic since the elaboration of this procedure during a time period of 24 months. Time interval between the beginning of their pathology and the delivering of this information was 4.7 years. Most of them (56%) presented a paranoid type of schizophrenia. In most of the cases, the patients did not know their diagnostic or declared suffering from a diagnostic, which was erroneous; 80% of the 45 patients have complied with the procedure until its end. On more than 24 of following after the instauration of the diagnostic announcement procedure, these patients ha ve presented satisfactory observance to the medical supervision (medical consultation and drug intake); 60% of the patients were regularly present to their medical appointment. The number of patients included (45 patients) appears small compared to the time interval of the study (24 months) but was significant according to the great changes in our clinical approach. Thus, this procedure was not systematically applied, in particular the patients who did not want to be informed on their disease. Is it clinically relevant or not to announce diagnostic of schizophrenia to the patient? This issue remains questioned according to the few studies published at the present time, any consensus has been clearly presented on formal indications or contra-indications. If on an ethical side, this information appears logical, the medical and nursing staff should require special care. Special care must be taken before delivering information to the patients; each situation must be evaluated in order not to comply with an ideology of total and inadequate information, which could have serious consequences. Nevertheless, it appeared clearly that information must be given to stabilized patients with satisfactory insight. Moreover, psychotherapeutic projects become easier because patients awareness and understanding towards pathological symptoms are greatly improved. Partnership between patient and medical staff is the key of this dynamic and psycho-educative procedure, which opens new horizons in our therapeutic prospect.

[Transcranial magnetic stimulation in cognition and neuropsychology]. / Stimulation magnétique transcrânienne et fonctions cognitives.

Classical neuropsychology relies on patients with irreversible brain lesions and cognitive impairments give informations about normal brain function. Transcranial Magnetic Stimulation (TMS) is a non-invasive method which involves placing an electromagnetic coil on the scalp. A pulse generates a magnetic field and this one passes, unattenuated by the skin and scalp, into the cortex inducing a current which results in neural activity. The technique shows a good temporal resolution and, moreover, because it represents an interference technique, can be said to have excellent functional resolution. For this reason, TMS appears to be a new tool for research in neuropsychology, producing transitory 'virtual lesion'effects which could help to understand how, when and where cognitive tasks are performed. The purpose of this article is to review recent research using TMS in cognition and neuropsychology, in a non exhaustive way. In safety studies, single TMS over motor cortex can produce simple movements. Several groups have applied TMS to the study of visual processing and found an impaired detection of visual stimuli. In a same way, TMS can disrupt speech when it was delivered in the language dominant hemisphere. Studies on the memory effects of TMS have been conflicting and the results seem to depend on the choice of paradigm and parameters. Other study depicted improvements in executive functioning after TMS on the left middle frontal gyrus or a diminution in reaction time during an analogic reasoning task. Moreover, some facial emotions seem to be less recognizable after TMS. Although TMS seem to be a new tool for neuro-psychological investigations in healthy subjects, few studies reported cognitive effects of rTMS treatment in psychiatry. In a therapeutic view, many of these trials have supported a significant effect of TMS, but in some studies the effect is small and short lived. Several groups have reported on the use of rTMS as a treatment in resistant major depression and the impact on cognition functioning. Most of results tend to find no adverse cognitive effects after several weeks of daily rTMS in depressed patients, compared to Electroconvulsivo-therapy (ECT). The effects of transcranial magnetic stimulation (TMS) on hallucination severity and neurocognition were studied in a recent study. A statistically significant improvement was observed on a hallucination scale and on one cognitive measure. TMS is a promising tool for cognitive neuroscience and can provide complementary information to the one obtained using neuropsychological tests, and the one obtained using functional imaging techniques, which have superior spatial but inferior temporal resolution.

[Hepatic tolerance of atypical antipsychotic drugs]. / Tolérance hépatique des antipsychotiques atypiques.

The strategy in the choice of antipsychotic agent must take into account the hepatic tolerance according to non-negligible incidence of liver disorders among psychiatric population (presence of risk factors like alcoholism, drugs of abuse intake, polymedication including potentially hepatotoxic drugs.). More than 1 000 drugs have been listed as being responsible of hepatic side effects; 16% of these agents were neuropsychiatric drugs. Antidepressive drugs (tricyclic agents or SSRI), mood stabilizing agents and neuroleptic drugs have been implicated in biological or/and clinical hepatotoxicity. For these reasons, some psychotropic agents have been withdrawn of the pharmaceutical market like alpidem or medifoxamine. Atrium*, sometimes used to correct tremor induced by neuroleptic drugs, has been withdrawn recently, as well. Isolated elevations of hepatic enzymes occur frequently with phenothiazines drugs (frequency evaluated to 20%) but also with other classes of neuroleptic agents, as well. On the contrary, clinical hepatitis have been more rarely described with neuroleptic drugs like phenothiazine agents (0,1-1%) or with haloperidol (0,002%). The definition of hepatotoxicity is based on biological parameters (elevation of alkaline phosphatase enzyme, SGPT, SGOT and GGT) or on clinical abnormalities (hepatitis, jaundice.). Clinical hepatitis could be either cytolytic or cholestatic. Clinical diagnosis and the research of its origin may include many investigations like abdominal ultrasonogram and percutaneous liver biopsy. The present article describes the cases of hepatic disorders reported with AAD (Atypical Antipsychotic Drugs), which are available in France (amisulpride, clozapine, olanzapine, risperidone). This new pharmacological class of antipsychotic drugs has showed great interest to improve negative symptoms of schizophrenia and to reduce disabling side effects like dystonia. According to the bibliographic data available, the following points and information must be clinically taken into account. Frequency of hepatic troubles: according to the bibliographic data, AAD appeared generally well tolerated in most cases. The frequency of hepatic troubles remains in general very low or rare. The cases published were observed with clozapine, olanzapine and risperidone. Nevertheless, some authors have observed higher frequency of hepatic enzymes elevation with some AAD. In an investigation comparing hepatic tolerance of clozapine (n=167) versus haloperidol (n=71), 37,3% of clozapine treated patients showed a relevant SGPT increase versus 16,6% with haloperidol. Nature of the hepatic troubles: among the clinical observations, asymptomatic biological disorders of the hepatic function are generally described but cytolytic or cholestatic hepatitis were reported, as well. Symptomatic hepatic dysfunctions were, sometimes, associated with other disorders like convulsions, pneumonia or malignant syndrome. Thus, hepatic check-up may be relevant in case of significant side-effect outcome. Delay time before the hepatic episode: hepatic injuries generally occurred within the first weeks of treatment but this delay highly varied in the literature from 1 to 8 weeks, 12 days to 5 months, 1 day to 17 months for clozapine, olanzapine and risperidone, respectively. These delay times are very similar to those observed with other psychotropic drugs. Reversibility of the hepatic troubles and rechallenge of the responsible agent: all cases were reversible after the AAD withdrawal except with one patient (39 years old) treated by clozapine (350 mg/day) who developed a fulminant and irreversible hepatitis after 8 weeks of monotherapy. In most cases, the AAD was withdrawn after the hepatic episode according to the significant risk of irreversible alteration. Nevertheless, normalization of hepatic enzymes has been described despite AAD maintenance at the same dosage or after dosage reduction. Rechallenge of clozapine after a first episode was performed for three patients, only one redeveloped a new hepatic disorder. According to different authors, special care is required if maintenance or rechallenge of the agent is indispensable after a first episode of isolated hepatic enzyme elevation (i.e resistance or intolerance to other treatments). In this case, biological and clinical supervision has to be carefully scheduled, which demands a satisfactory compliance from the patient. On the contrary, in case of clinical hepatotoxicity, rechallenge or maintenance is absolutely inadvisable. Mechanism of the hepatic troubles: precise mechanisms of the hepatotoxicity remain unclear. Contrary to phenothiazine drugs, no information is available on the respective rule of the agents and their metabolites. Hypersensitivity syndrome or eosinophilia has been reported, suggesting a possible immuno-allergic mechanism. Presence of risk factors: risk factors have been retrieved, in some observations, like high daily dosage, high plasmatic concentration, age, alcoholism, obesity or antecedent of hepatic disorders like Gilbert syndrome. Special care is advisable with these patients. As hepatotoxicity has been observed after surdosage (or suicide attempt), a hepatic check-up has to be performed in these clinical situations. Co-medication with hepatotoxic drugs may increase the risk as it has been suggested. In many observations, co-medication made difficult the incrimination of the AAD in the hepatic disorders outcome. Monotherapy has the great advantage to make easier the withdrawal of the responsible agent and its substitution. As drugs of abuse like cocaine or ecstasy are notoriously responsible of hepatotoxicity, they represent a probable factor of risk. Moreover, their detection is fundamental during the clinical investigation. Conclusion - Diagnosis of toxic hepatitis is mainly based on the chronology between agent introduction and hepatic disorder onset but other causes must be excluded. Bibliographic data analysis greatly contributes to confirm toxic hepatitis diagnosis. Nevertheless, this article emphasized the limits of bibliographic review to compare drugs towards tolerance. Most of the bibliographic data were case-reports for which it was sometimes difficult to provide absolute evidence of the responsibility of the agent. Moreover, spontaneous notification to health national administration is rarely systematic, in particular with isolated elevation of hepatic enzymes, and even more rarely published in international reviews. Nevertheless, according to the present data available in the literature, systematic and regular hepatic survey does not seem necessary in absence of risk factors. As for other side effects, which may occur more or less rapidly, great advantages may be obtained from psycho-education programs associating the patients in order to detect the first symptoms. Because little long-term hepatic follow-up comparing AAD is available, controlled studies should be carried out to precise the frequency and the risk factors (covariables) to prevent hepatitis outcome.

[Transcranial magnetic stimulation in depression]. / La stimulation magnétique transcrânienne dans la dépression.

Among the new therapeutic techniques in psychiatry, transcranial magnetic stimulation (TMS) seems to bring a profit in the treatment of depressions. It uses the principle of inductance to generate a magnetic current, which in turn activates cortical neurons. Stimulation is highly focused and interests specific regions of the cerebral cortex. This therapeutic technique is generally well tolerated. Side effects are rare, the most hampering one is epileptic seizures. It is favored by high frequencies (above 5 Hz) and arises mainly with patients having a history of personal or family epileptic seizures. The first open trials, quickly confirmed by controlled studies showed the efficiency of TMS in depression. With depression, double blind randomized trials, using high frequencies, stimulation of the left dorsolateral prefrontal cortex give positive results with significant decrease of scores on depressive scales applied to resistant and non resistant depressions. Some studies have stimulated the right dorsolateral prefrontal cortex using low frequencies. The decrease of scores is also significant on depressive scales. The modulating effect of rTMS on cortical excitability of the brain justifies this distinction between high and low frequencies, high frequencies having a facilitating effect whereas low frequencies have an inhibitory effect.

A 23Na NMR study of the effect of D(+) and L(-) arabitol on NaDNA in aqueous solution.

The 23Na NMR quadrupolar relaxation in NaDNA aqueous solutions has been investigated in the presence of D(+) and L(-) arabitol. Quite different results were produced by the enantiomers, i.e. the addition of D(+) arabitol produced a small increase of the 23Na NMR relaxation rates, while in the presence of L(-) arabitol a significant decrease was observed. These findings were analysed and discussed in terms of an effective interaction of L(-) arabitol with DNA.