Delirium auf der Intensivstation [Delirium in the intensive care unit.]

The prevalence of delirium in the Intensive Care Unit (ICU) is reported to vary from 20 to 80 %. Delirium in the ICU is not only a frightening experience for the patient and his or her family, it is also a challenge for the nurses and physicians taking care of the patient. Furthermore, it is also associated with worse outcome, prolonged hospitalisation, increased costs, long-term cognitive impairment and higher mortality rates. Thus, strategies to prevent ICU-delirium in addition to the early diagnosis and treatment of delirium are important. The pathophysiology of delirium is still incompletely understood, but numerous risk factors for the development of delirium have been identified in ICU-patients, among which are potentially modifiable factors such as metabolic disturbances, hypotension, anaemia, fever and infection. Key factors are the prevention and management of common risk factors, including avoiding overzealous sedation and analgesia and creating an environment that enhances reintegration. Once delirium is diagnosed, treatment consists of the use of typical and atypical antipsychotics. Haloperidol is still the drug of choice for the treatment of delirium and can be given intravenously in incremental doses of 1 to 2 to 5 (to 10) mg every 15 - 20 minutes.

La implicació de les famílies immigrades en els processos educatius dels seus fills/es: estratègies davant l'èxit i el fracàs escolar

En el present projecte hem analitzat els determinants de les trajectòries educatives dels i les adolescents d'origen immigrant, centrant I'atenció en el paper de les seves famílies davant de I ‘èxit o fracàs escolar del seu fillla. Amb aquest objectiu, I'estudi combina tècniques quantitatives i qualitatives. Per una banda hem analitzat les dades longitudinals del Panel de Famílies i lnfancia, que ens permeten fer un seguiment de les trajectòries educatives i personals de 248 alumnes d'origen immigrant que al 2006 estudiaven I'ESO al llarg de la seva adolescència, i identificar els factors socials responsables de la seva diversificació. Els resultats indiquen que malgrat presentar actituds bastant favorables als estudis i I'assoliment educatiu, concentren diverses situacions de vulnerabilitat a la llar (dificultats socioeconòmiques, estructures familiars atípiques, i erosió de capital social), que incideixen negativament sobre els seus rendiments acadèmics. Per altra, hem realitzat 59 entrevistes semi-estructurades per a complementar i facilitar la interpretació dels resultats obtinguts a la recerca quantitativa i copsar les narratives dels propis protagonistes. Aquestes entrevistes s'han realitzat a: una submostra de les famílies d'aquests alumnes, seleccionades en funció de perfils d’èxit o fracàs educatiu de la trajectòria del menor (46), una submostra d'estudiants resilients (a), i una sèrie d'agents educatius i socials, que inclou membres d'equips directius de centres escolars, AMPA i entitats dedicades a I'atenció a la infància i les famílies (5). El projecte que presentem té una clara vocació de servei públic. L'objectiu és incrementar el coneixement de factors "extraescolars" que poden condicionar I ‘èxit escolar dels estudiants d'origen immigrant. Aquest coneixement constitueix la base per al disseny i orientació de programes d'acompanyament a les famílies dels infants en situació de risc. La nostra voluntat (que reflecteix el principal objectiu de I'lnstitut d’infància i Món Urbà, instituci6 que impulsa el projecte) és contribuir a la transferència de coneixement que pugui ser d'utilitat pels agents que treballen directament sobre les qüestions que estudiem.

Am I my brain or my genitals? A nature-culture controversy in the hermaphrodite debate from the mid-1960s to the late 1990s.

The groundbreaking and prophetic rhetoric of neuroscience has recently highlighted the fetal brain as the most promising organ for understanding why transsexuals feel "trapped in the wrong body", and for predicting whether children born with "ambiguous" genitalia will grow up to feel like a man or a woman.This article proposes a recent history of the cerebralization of intersexuality and of transsexuality as atypical neurodevelopmental conditions. It examines the ways in which the organizational theory of brain sex differentiation developed in the late 1950s in behavioral neuroendocrinology has gained increased prominence in and through controversies over best practice issues in the case management of intersex newborns, and the etiology of transsexuality.It focuses on the American context and on the leading warrior in this battle: Milton Diamond, now a most prominent figure in professional debates about the clinical management of intersexuality, and the intersex person's best friend. Persons with an intersexed or transsexual condition consider, not their gonads, but their brains, their core sense of self, as the primary determinant of sex. (Diamond and Beh 2005, 6-7, note 1)

The outer limiting membrane (OLM) revisited: clinical implications.

PURPOSE: The outer limiting membrane (OLM) is considered to play a role in maintaining the structure of the retina through mechanical strength. However, the observation of junction proteins located at the OLM and its barrier permeability properties may suggest that the OLM may be part of the retinal barrier. MATERIAL AND METHODS: Normal and diabetic rat, monkey, and human retinas were used to analyze junction proteins at the OLM. Proteome analyses were performed using immunohistochemistry on sections and flat-mounted retinas and western blotting on protein extracts obtained from laser microdissection of the photoreceptor layers. Semi-thin and ultrastructure analyses were also reported. RESULTS: In the rat retina, in the subapical region zonula occludens-1 (ZO-1), junction adhesion molecule (JAM), an atypical protein kinase C, is present and the OLM shows dense labeling of occludin, JAM, and ZO-1. The presence of occludin has been confirmed using western blot analysis of the microdissected OLM region. In diabetic rats, occludin expression is decreased and glial cells junctions are dissociated. In the monkey retina, occludin, JAM, and ZO-1 are also found in the OLM. Junction proteins have a specific distribution around cone photoreceptors and Müller glia. Ultrastructural analyses suggest that structures like tight junctions may exist between retinal glial Müller cells and photoreceptors. CONCLUSIONS: In the OLM, heterotypic junctions contain proteins from both adherent and tight junctions. Their structure suggests that tight junctions may exist in the OLM. Occludin is present in the OLM of the rat and monkey retina and it is decreased in diabetes. The OLM should be considered as part of the retinal barrier that can be disrupted in pathological conditions contributing to fluid accumulation in the macula.

Validation française de l'échelle d'expérience temporelle du plaisir [Validation of the Temporal Experience of Pleasure Scale (TEPS) in a French-speaking environment.]

INTRODUCTION: Anhedonia is defined as a diminished capacity to experience pleasant emotion and is commonly included among the negative symptoms of schizophrenia. However, if patients report experiencing a lower level of pleasure than controls, they report experiencing as much pleasure as controls with online measurements of emotion. OBJECTIVE: The Temporal Experience of Pleasure Scale (TEPS) measures pleasure experienced in the moment and in anticipation of future activities. The TEPS is an 18-item self-report measurement of anticipatory (10 items) and consummatory (eight items) pleasure. The goal of this paper is to assess the psychometric characteristics of the French translation of this scale. METHODS: A control sample was composed of 60 women and 22 men, with a mean age of 38.1 years (S.D.: 10.8). Thirty-six were without qualification and 46 with qualified professional diploma. A sample of 21 patients meeting DSM IV-TR criteria for schizophrenia was recruited among the community psychiatry service of the department of psychiatry in Lausanne. They were five women and 16 men; mean age was of 34.1 years (S.D.: 7.5). Ten obtained a professional qualification and 11 were without qualification. None worked in competitive employment. Their mean dose of chlorpromazine equivalent was 431mg (S.D.: 259). All patients were on atypical antipsychotics. The control sample fulfilled the TEPS and the Physical Anhedonia Scale (PAS). The patient sample fulfilled the TEPS and was independently rated on the Calgary Depression Scale and the Scale for Assessment of Negative Symptoms. For comparison with controls, patients were matched on age, sex and professional qualification. This required the supplementary recruitment of two control subjects. RESULTS: Results with the control sample indicate that the TEPS presents an acceptable internal validity with Crombach alphas of 0.84 for the total scale, 0.74 for the anticipatory pleasure scale and 0.79 for the consummatory pleasure scale. The confirmatory factor analysis indicated that the model is well adapted to our data (chi(2)/dl=1.333; df=134; p<0.0006; root mean square residual, RMSEA=0.064). External validity measured with the PAS showed R=-0.27 (p<0.05) for the consummatory scale and R=-0.26 for the total score. Comparisons between patients and matched controls indicated that patients were significantly lower than control on anticipatory pleasure (t=2.7, df(40), 2-tailed p=0.01; cohen's d=0.83) and on total score of the TEPS (t=2.8, df (40), 2-tailed p=0.01; cohen's d=0.87). The two samples did not differ on consummatory pleasure. The anticipatory pleasure factor and the total TEPS showed significant negative correlation with the SANS anhedonia, respectively R=-0.78 (p<0.01) for the anticipatory factor and R=-0.61 (p<0.01) for the total TEPS. There was also a negative correlation between the anticipatory factor and the SANS avolition of R=-0.50 (p<0.05). These correlations were maintained, with partial correlations controlling for depression and chlorpromazine equivalents. CONCLUSION: The results of this validation show that the French version of the TEPS has psychometric characteristics similar to the original version. These results highlight the discrepancy between results of direct or indirect report of experienced pleasure in patients with schizophrenia. Patients may have difficulties in anticipating the pleasure of future enjoyable activities, but not in experiencing pleasure once in an enjoyable activity. Medication and depression do not seems to modify our results, but this should be better controlled in a longitudinal study. The anticipatory versus consummatory pleasure distinction appears to be useful for the development of new psychosocial interventions, tailored to improve desire in patients suffering from schizophrenia. Major limitations of the study are the small size of patient sample and the under representation of men in the control sample.

Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivative as pontential antipsychotics

The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitargetstrategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in aneffort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Throughbiological and computational studies of 5-HT2A and D2 receptors, we identified the receptor serine residuesS3.36 and S5.46 as the molecular keys to explaining the differences in affinity and selectivity betweenthese new compounds for this group of receptors. Specifically, the ability of these compounds to establishone or two H-bonds with these key residues appears to explain their difference in affinity. In addition, wedescribe compound 2 (QF1004B) as a tool to elucidate the role of 5-HT2C receptors in mediating antipsychoticeffects and metabolic adverse events. The compound 16a (QF1018B) showed moderate to high affinitiesfor D2 and 5-HT2A receptors, and a 5-HT2A/D2 ratio was predictive of an atypical antipsychotic profile.

Investigating Gaze of Children with ASD in Naturalistic Settings.

BACKGROUND: Visual behavior is known to be atypical in Autism Spectrum Disorders (ASD). Monitor-based eye-tracking studies have measured several of these atypicalities in individuals with Autism. While atypical behaviors are known to be accentuated during natural interactions, few studies have been made on gaze behavior in natural interactions. In this study we focused on i) whether the findings done in laboratory settings are also visible in a naturalistic interaction; ii) whether new atypical elements appear when studying visual behavior across the whole field of view. METHODOLOGY/PRINCIPAL FINDINGS: Ten children with ASD and ten typically developing children participated in a dyadic interaction with an experimenter administering items from the Early Social Communication Scale (ESCS). The children wore a novel head-mounted eye-tracker, measuring gaze direction and presence of faces across the child's field of view. The analysis of gaze episodes to faces revealed that children with ASD looked significantly less and for shorter lapses of time at the experimenter. The analysis of gaze patterns across the child's field of view revealed that children with ASD looked downwards and made more extensive use of their lateral field of view when exploring the environment. CONCLUSIONS/SIGNIFICANCE: The data gathered in naturalistic settings confirm findings previously obtained only in monitor-based studies. Moreover, the study allowed to observe a generalized strategy of lateral gaze in children with ASD when they were looking at the objects in their environment.

β-Lactam Monotherapy vs β-Lactam-Macrolide Combination Treatment in Moderately Severe Community-Acquired Pneumonia: A Randomized Noninferiority Trial.

IMPORTANCE: The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial. OBJECTIVE: To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation. INTERVENTIONS: Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm. MAIN OUTCOMES AND MEASURES: Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7. RESULTS: After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms. CONCLUSIONS AND RELEVANCE: We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00818610.

Impaired activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 in cultured preadipocyte-derived adipocytes and myotubes of obese subjects.

Insulin resistance in obesity is partly due to diminished glucose transport in myocytes and adipocytes, but underlying mechanisms are uncertain. Insulin-stimulated glucose transport requires activation of phosphatidylinositol (PI) 3-kinase (3K), operating downstream of insulin receptor substrate-1. PI3K stimulates glucose transport through increases in PI-3,4,5-(PO(4))(3) (PIP(3)), which activates atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). However, previous studies suggest that activation of aPKC, but not PKB, is impaired in intact muscles and cultured myocytes of obese subjects. Presently, we examined insulin activation of glucose transport and signaling factors in cultured adipocytes derived from preadipocytes harvested during elective liposuction in lean and obese women. Relative to adipocytes of lean women, insulin-stimulated [(3)H]2-deoxyglucose uptake and activation of insulin receptor substrate-1/PI3K and aPKCs, but not PKB, were diminished in adipocytes of obese women. Additionally, the direct activation of aPKCs by PIP(3) in vitro was diminished in aPKCs isolated from adipocytes of obese women. Similar impairment in aPKC activation by PIP(3) was observed in cultured myocytes of obese glucose-intolerant subjects. These findings suggest the presence of defects in PI3K and aPKC activation that persist in cultured cells and limit insulin-stimulated glucose transport in adipocytes and myocytes of obese subjects.

Mixed testicular germ cell tumor presenting as metastatic pure choriocarcinoma involving the maxillary gingiva.

Gingival metastases are infrequent and invariably associated with a widespread disease and a poor prognosis. Because of their unremarkable clinical appearance, they can be difficult to distinguish from more common gingival hyperplastic or reactive lesions, such as pyogenic granuloma, peripheral giant cell granuloma, and peripheral ossifying granuloma. We are reporting here an unusual case of a 36-year-old man with a mixed testicular germ cell tumor presenting as a metastatic pure choriocarcinoma involving the maxillary gingiva, extending from the first left premolar to the left second maxillary molar, mimicking a 'benign looking' gingival mass. Gingival metastases may be the first manifestation of a widespread metastatic disease and therefore particular attention must be paid to gingival lesions associated with atypical clinical symptoms and/or signs.

Five-Year Denosumab Treatment of Postmenopausal Women with Osteoporosis: Results from the first two Years of the Freedom Trial Extension

Objectives : The FREEDOM trial1 open-label extension is designed to evaluate the long-term efficacy and safety of denosumab for up to 10 years. We report the results from the first 2 years of the extension, representing up to 5 years of denosumab exposure.Materials/Methods : Postmenopausal women enrolled in the extension previously completed FREEDOM. During the extension, all women receive denosumab (60 mg) every 6 months and calcium and vitamin D daily. For the FREEDOM denosumab group, the data reflect 5 years of denosumab treatment (long-term group). For the FREEDOM placebo group, the data reflect 2 years of denosumab treatment (de novo group). P-values are descriptive.Results : There were 4550 (70.2%) FREEDOM women enrolled in the extension (2343 long-term; 2207 de novo). During the 4th and 5th years of denosumab treatment, the long-term group had further 1.9% and 1.7% increases in lumbar spine BMD and further 0.7% and 0.6% increases in total hip BMD (all P<0.0001 compared with extension baseline). Total BMD increases with 5-year denosumab treatment were 13.7% (lumbar spine) and 7.0% (total hip). In the de novo group, BMD increased during the first 2 years of denosumab treatment by 7.9% (lumbar spine) and 4.1% (total hip) (all P<0.0001 compared with extension baseline). After denosumab administration, serum CTX was rapidly and maximally reduced in both groups with the characteristic attenuation observed at the end of the dosing interval, as previously reported.2 Incidences of new vertebral and nonvertebral fractures were low and below rates observed in the FREEDOM placebo group. Adverse event reports were similar for both groups: in the long-term group, 83.4% reported AEs and 18.9% were serious. In the de novo group, the percentages were 82.8% and 19.4%, respectively. In FREEDOM, the respective percentages were 92.8% and 25.8% in the denosumab group and 93.1% and 25.1% in the placebo group. Two subjects in the de novo group had AEs adjudicated to ONJ which healed without further complications ; one resolved within the 6-month dosing interval and denosumab was continued. There were no atypical femoral fractures.Conclusions : Denosumab treatment for 5 years was well-tolerated and continued to significantly reduce CTX and significantly increase BMD. Reference: 1)Cummings;NEJM;2009;361:756, 2)Eastell;JBMR;2010; doi-10.1002/jbmr.251 Disclosure of Interest: This study was funded by Amgen; S Papapoulos: Consulting fees from Amgen, Merck, Novartis, Procter & Gamble, GSK, and Wyeth; R Chapurlat: Research grants and/or consulting fees from Amgen, Merck, Novartis, sanofi-aventis, Roche, Servier, and Warner Chilcott;ML Brandi: Research grants and/or consulting fees from Amgen, Eli Lily, GSK, MSD, NPS, Nycomed, Roche, Servier, and Stroder; JP Brown: Research grants and/or consulting or speaking fees from Abott, Amgen, Bristol Myers Squibb, Eli Lilly, Pfizer, Roche, Novartis, Merck, and Warner Chilcott; E Czerwinski: Research grants from Amgen, Astrazeneca, Danone Research, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SantoSolve AS, and Servier; N Daizadeh, A Grauer, C Libanati: Employed by Amgen and own Amgen stocks or stock options; M-A Krieg, D Mellstrom, H Resch: None; S Radominski: Research grants from Amgen, Pfizer, Novartis, Bristol-Myers Squibb, Roche, and Aventis; Z Man: Lecture fees and/or consulting fees from Merck, Novartis, Roche, and sanofi-aventis. Novartis steering committee member; JA Roman: Research grants from Roche; J-Y Reginster: Research grants, consulting fees, and/or lecture fees from Amgen, Analis, Bristol Myers Squibb, Ebewee Pharma, Genevrier, GSK, IBSA, Lilly, Merck Sharp & Dhome, Negma, Novartis, Novo-Nordisk, Nycomed, NPS, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, UCB, Wyeth, and Zodiac; C Roux: Research grants and/or consulting fees from Amgen, MSD, Novartis, Servier, and Roche; SR Cummings: Research grants and/or consulting fees from Amgen, Eli Lilly, Novartis, and Merck; HG Bone: Research grants and/or consulting or speaking fees from Amgen, Eli Lilly, Merck, Nordic Bioscience, Novartis, Takeda, and Zelos

Early-onset acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and regressive autistic disorders with epileptic EEG abnormalities: the continuing debate.

Early-onset acquired epileptic aphasia (Landau-Kleffner syndrome) may present as a developmental language disturbance and the affected child may also exhibit autistic features. Landau-Kleffner is now seen as the rare and severe end of a spectrum of cognitive-behavioural symptoms that can be seen in idiopathic (genetic) focal epilepsies of childhood, the benign end being the more frequent typical rolandic epilepsy. Several recent studies show that many children with rolandic epilepsy have minor developmental cognitive and behavioural problems and that some undergo a deterioration (usually temporary) in these domains, the so-called "atypical" forms of the syndrome. The severity and type of deterioration correlate with the site and spread of the epileptic spikes recorded on the electroencephalogram within the perisylvian region, and continuous spike-waves during sleep (CSWS) frequently occur during this period of the epileptic disorder. Some of these children have more severe preexisting communicative and language developmental disorders. If early stagnation or regression occurs in these domains, it presumably reflects epileptic activity in networks outside the perisylvian area, i.e. those involved in social cognition and emotions. Longitudinal studies will be necessary to find out if and how much the bioelectrical abnormalities play a causal role in these subgroup of children with both various degrees of language and autistic regression and features of idiopathic focal epilepsy. One has to remember that it took nearly 40 years to fully acknowledge the epileptic origin of aphasia in Landau-Kleffner syndrome and the milder acquired cognitive problems in rolandic epilepsies.

Maladie coeliaque: état des lieux [An update on celiac disease].

Celiac disease is a well-known entity in pediatrics and pediatric gastroenterology that is now also frequently encountered in the adult population. Apart from typical symptoms, celiac disease can present with a wide range of manifestations that are sometimes atypical, scarce or purely extraintestinal. Serologic and genetic testing are useful tools in case of low clinical probability in the early diagnostic algorithm. Upper gastrointestinal endoscopy remains the mainstay to confirm the diagnosis especially in atypical clinical presentations. Complications are rare but can be severe. Although gluten-free diet often leads to complete recovery, compliance is not universal and alternative treatment strategies are under investigation.

Homeodomain-only protein HOP is a novel modulator of late differentiation in keratinocytes.

The homeodomain-only protein (HOP) contains an atypical homeodomain which is unable to bind to DNA due to mutations in residues important for DNA binding. Recently, HOP was reported to regulate proliferation/differentiation homeostasis in different cell types. In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Immunohistochemistry of human skin localized HOP to the granular layer in the epidermis. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation. Conversely, decreasing HOP expression using small interfering RNA markedly reduced the calcium-induced expression of late markers of differentiation in vitro, with the most prominent effect on profilaggrin (FLG) mRNA. Moreover, mRNA levels of profilaggrin and loricrin were downregulated in the epidermis of HOP knockout mice. Analysis of skin disorders revealed altered HOP expression in lichen planus, psoriasis and squamous cell carcinoma (SCC). Our data indicate that HOP is a novel modulator of late terminal differentiation in keratinocytes.