Non-contact monitoring of agitation and use of a sheltering device in patients with dementia in emergency departments: a feasibility study

Background Agitation is common in geriatric patients with cognitive impairment, e.g. in persons with dementia (PWD), who are admitted to an emergency department (ED). It might be a first sign of upcoming delirium and is associated with a higher risk of an unfavorable clinical course. Hence, monitoring of vital signs and enhanced movement as indicators of upcoming agitation is essential in these patients during their stay in the ED. Since PWD rarely tolerate fixed monitoring devices, a novel developed non-contact monitoring system (NCMSys) might represent an appropriate alternative. Aim of this feasibility study was to test the validity of a NCMSys and of the tent-like “Charité Dome” (ChD), aimed to shelter PWD from the busy ED environment. Furthermore, effects of the ChD on wellbeing and agitation of PWD were investigated. Methods Both devices were attached to patient’s bed. Tests on technical validity and safety issues of NCMSys and ChD were performed at the iDoc institute with six healthy volunteers. A feasibility study evaluating the reliability of the NCMSys with and without the ChD was performed in the real-life setting of an ED and on a geriatric-gerontopsychiatric ward. 19 patients were included, ten males and nine females; mean age: 77.4 (55–93) years of which 14 were PWD. PWD inclusion criteria were age ≥ 55 years, a dementia diagnosis and a written consent (by patients or by a custodian). Exclusion criteria were acute life-threatening situations and a missing consent. Results Measurements of heart rate, changes in movement and sound emissions by the NCMSys were valid, whereas patient movements affected respiratory rate measurements. The ChD did not impact patients’ vital signs or movements in our study setting. However, 53% of the PWD (7/13) and most of the patients without dementia (4/5) benefited from its use regarding their agitation and overall wellbeing. Conclusions The results of this feasibility study encourage a future controlled clinical trial in geriatric ED patients, including PWD, to further evaluate if our concept of non-contact measurement of vital signs and movement combined with the “Charité Dome” helps to prevent upcoming agitation in this vulnerable patient group in the ED. Trial registration ICTRP: “Charité-Dome-Study - DRKS00014737” (retrospectively registered)

Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial

Background Negative symptoms of schizophrenia represent deficiencies in emotional responsiveness, motivation, socialisation, speech and movement. When persistent, they are held to account for much of the poor functional outcomes associated with schizophrenia. There are currently no approved pharmacological treatments. While the available evidence suggests that a combination of antipsychotic and antidepressant medication may be effective in treating negative symptoms, it is too limited to allow any firm conclusions. Objective To establish the clinical effectiveness and cost-effectiveness of augmentation of antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia. Design A multicentre, double-blind, individually randomised, placebo-controlled trial with 12-month follow-up Setting Adult psychiatric services, treating people with schizophrenia. Participants Inpatients or outpatients with schizophrenia, on continuing, stable antipsychotic medication, with persistent negative symptoms at a criterion level of severity. Interventions Eligible participants were randomised 1 : 1 to treatment with either placebo (one capsule) or 20 mg of citalopram per day for 48 weeks, with the clinical option at 4 weeks to increase the daily dosage to 40 mg of citalopram or two placebo capsules for the remainder of the study. Main Outcome Measures The primary outcomes were quality of life measured at 12 and 48 weeks assessed using the Heinrich’s Quality of Life Scale, and negative symptoms at 12 weeks measured on the negative symptom subscale of the Positive and Negative Syndrome Scale. Results No therapeutic benefit in terms of improvement in quality of life or negative symptoms was detected for citalopram over 12 weeks or at 48 weeks, but secondary analysis suggested modest improvement in the negative symptom domain, avolition/amotivation, at 12 weeks (mean difference –1.3, 95% confidence interval–2.5 to–0.09). There were no statistically significant differences between the two treatment arms over 48-week follow-up in either the health economics outcomes or costs, and no differences in the frequency or severity of adverse effects, including corrected QT interval prolongation. Limitations The trial under-recruited, partly because cardiac safety concerns about citalopram were raised, with the 62 participants recruited falling well short of the target recruitment of 358. Although this was the largest sample randomised to citalopram in a randomised controlled trial of antidepressant augmentation for negative symptoms of schizophrenia and had the longest follow-up, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. Conclusion Although adjunctive citalopram did not improve negative symptoms overall, there was evidence of some positive effect on avolition/amotivation, recognised as a critical barrier to psychosocial rehabilitation and achieving better social and community functional outcomes. Comprehensive assessment of side-effect burden did not identify any serious safety or tolerability issues. The addition of citalopram as a long-term prescribing strategy for the treatment of negative symptoms may merit further investigation in larger studies. Future Work Further studies of the viability of adjunctive antidepressant treatment for negative symptoms in schizophrenia should include appropriate safety monitoring and use rating scales that allow for evaluation of avolition/amotivation as a discrete negative symptom domain. Overcoming the barriers to recruiting an adequate sample size will remain a challenge.</p

Cigarette Smoking and Cognitive Function in Chinese Male Schizophrenia: A Case-Control study

Schizophrenic patients have higher smoking rates than the general population. Studies show that smoking may be a form of self-medication in an attempt to alleviate cognitive deficits in schizophrenic patients of European background. This study examined the relationships between smoking and cognitive deficits in Chinese schizophrenic patients, which have previously received little systemic study. We recruited 580 male chronic patients meeting DSM-IV criteria for schizophrenia and 175 male control subjects who were matched on age and education. The subjects completed a detailed cigarette smoking questionnaire, the Fagerstrom Test for Nicotine Dependence (FTND), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Patients also were rated on the Positive and Negative Symptom Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS). All five RBANS subscales except for the Visuospatial/Constructional index showed significantly lower cognitive performance for schizophrenics than normal controls. The schizophrenic smokers scored lower than the schizophrenic non-smokers on the RBANS total score and the Visuospatial/Constructional and Immediate Memory indices. Similarly, the control smokers scored lower than the control non-smokers on the RBANS total score and the Immediate Memory index . Also, the schizophrenic smokers consistently performed the poorest on the cognitive domains of the RBANS. Among the schizophrenic patients, smokers displayed significantly fewer negative symptoms than non-smokers. Using multivariate regression analysis the following variables were independently associated with the RBANS total score: years of education, PANSS negative symptom score, age at schizophrenia onset, and number of hospitalizations. Our results show that smoking is associated with significant cognitive impairment in both schizophrenic patients and normal controls, but the smokers with schizophrenia had a reduced level of negative symptoms, suggesting that the benefits of smoking for those with schizophrenia may be limited to certain aspects of a given clinical phenotype

Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion ofTrypanosoma cruzi

Proline is crucial for energizing critical events throughout the life cycle of Trypanosoma cruzi, the etiological agent of Chagas disease. The proline breakdown pathway consists of two oxidation steps, both of which producereducing equivalents as follows: the conversion of proline to Δ1-pyrroline-5-carboxylate (P5C), and the subsequent conversion of P5C to glutamate. We have identified and characterized the Δ1-pyrroline-5-carboxylate dehydrogenase from T. cruzi (TcP5CDH) and report here on how this enzyme contributes to a central metabolic pathway in this parasite. Size-exclusionchromatography, two-dimensional gel electrophoresis, and small angle x-ray scattering analysis of TcP5CDH revealed an oligomericstate composed of two subunits of six protomers. TcP5CDH was found to complement a yeast strain deficient in PUT2 activity,confirming the enzyme's functional role; and the biochemical parameters (Km, kcat, and kcat/Km) of the recombinant TcP5CDH were determined, exhibiting values comparable with those from T. cruzi lysates. In addition, TcP5CDH exhibited mitochondrial staining during the main stages of the T. cruzi life cycle. mRNA and enzymatic activity levels indicated the up-regulation (6-fold change) of TcP5CDH during the infectivestages of the parasite. The participation of P5C as an energy source was also demonstrated. Overall, we propose that thisenzymatic step is crucial for the viability of both replicative and infective forms of T. cruzi

Schizophrenia, cannabis and neurotrophins

Immer mehr junge Menschen konsumieren Cannabis in manchmal hohen Dosierungen, wenn ihr Gehirn noch nicht voll entwickelt ist und besonders empfindlich auf äußere Einflüsse reagiert. Cannabis kann psychotische Zustände auslösen und verstärken, schizophrene Erkrankungen begünstigen. In einer prospektiven Studie wurden insgesamt 157 ersterkrankte, bisher unbehandelte schizophrene Patienten klinisch untersucht und in Abhängigkeit von früherem Cannabis- oder zusätzlichem Substanzkonsum in Gruppen unterteilt. „Signifikanter Cannabiskonsum“ wurde definiert als täglicher Konsum von mindestens 0.5 Gramm Cannabis über mindestens zwei Jahre, kein Konsum“ als weniger als fünf Ereignisse insgesamt. Hierbei zeigten die Patienten mit vorherigem regelmäßigen Cannabiskonsum ein signifikant jüngeres Ersterkrankungsalter, waren meistens männlich und zeigten häufiger das Bild einer paranoiden Schizophrenie als diejenigen ohne Substanzkonsum. Neben den klinischen Parametern wurden die Neurotrophine Nerve growth factor (NGF) und Brain- derived neurotrophic factor (BDNF) im Serum bestimmt, zwei Proteine, die für Entwicklung, Reifung und Funktionsaufrechterhaltung des ZNS essentiell sind. Diese Neurotrophine können, zumindest unter experimentellen Bedingungen, die Bluthirnschranke passieren und somit die Serumkonzentration potentiell die zentrale Neurotrophinkonzentration repräsentieren, die, gemäß der Entwicklungshypothese der Schizophrenie, bei Schizophrenien verändert sein kann. Chronischer Cannabiskonsum kann neurotoxisch wirken, wir postulierten eine zusätzliche Veränderung bei schizophrenen Patienten mit früherem Cannabiskonsum. In dieser Untersuchung zeigte sich eine signifikante Erhöhung des NGF-Serumwertes bei Schizophrenen mit vorangegangenem Cannabismissbrauch (12.5fach) und noch weitere signifikante Erhöhung bei Konsum von mindestens zwei weiteren Drogen (>100fach), die bei Schizophrenie ohne Cannabis, gesunden Kontrollen und Cannabiskontrollen ohne Schizophrenie nicht zu finden war. Es mussten also vulnerable Gehirne im Hinblick auf die Schizophrenie und der Substanzkonsum zusammentreffen, um die NGF-Erhöhung zu bewirken. Für BDNF zeigte sich ein ähnliches Bild. Waren die Patienten behandelt und weitgehend remittiert, gab es keine Gruppenunterschiede mehr. Die Ergebnisse bestätigten sich in einer prospektiven Untersuchung im Behandlungsverlauf, sodass wir die Hochregulation von NGF bzw. BDNF bei den Doppeldiagnosepatienten als endogenen „Reparaturmechanismus“ interpretierten. Diese Interpretation wurde unterstützt durch Ergebnisse einer unabhängigen Untersuchung alkoholerkrankter (nicht schizophrener) Patienten, die, solange keine kognitiven Einbussen vorhanden waren, signifikant erhöhte NGF-Serumwerte zeigten, die bei irreparabel geschädigten Korsakoff-Patienten nicht mehr nachweisbar waren. In einer folgenden vergleichenden Untersuchung der kognitiven Funktionen der schizophrenen Patienten mit und ohne chronischen Cannabiskonsum vor Krankheitsausbruch, die jetzt behandelt und weitgehend remittiert waren, schnitt die Gruppe Schizophrenie plus Cannabiskonsum zumindest nie schlechter ab als die Gruppe schizophrener Patienten ohne Cannabiskonsum. In einigen Tests zeigten erstere sogar signifikant bessere Ergebnisse, bei jedoch insgesamt kleiner Stichprobe. In einer Untersuchung des P50 Sensory Gating als Korrelat der bei Schizophrenie potentiell auftretenden Filterstörung zeigten die ansonsten gesunden chronischen Cannabiskonsumenten Veränderungen wie sie für unbehandelte Schizophrene typisch sind. Zwischen den behandelten schizophrenen Patienten mit und ohne Cannabiskonsum sowie den gesunden Kontrollen zeigten sich keine Unterschiede. Insgesamt ist damit der Effekt von Cannabis auf das für Schizophrenie vulnerable Gehirn, zumindest vor dem klinisch erkennbaren Krankheitsbeginn, bisher nicht abschließend zu bewerten. Neben den zweifellos ungünstigen Wirkungen wie früherem Ersterkrankungsalter, Reexazerbation der bereits behandelten Schizophrenie bei erneutem Cannabiskonsum, gibt es möglicherweise auch protektive Faktoren, die z. B. zur besseren Erhaltung der langfristigen kognitiven Leistungsfähigkeit beitragen.Many young people consume cannabis in high doses at a time when the brain is not yet fully developed and reacts very sensitive to external influences. Cannabis can induce and exacerbate psychosis and provoke schizophrenia. In a prospective study we investigated 157 drug-naive first-episode schizophrenic patients and grouped them according to previous cannabis consumptionor additional drug consumption. Significant Cannabis consumption was defined as a daily intake of at least 0.5 gram of Cannabis for at least two years, no consumption as five times or less in a lifetime. As a result patients with previous regular cannabis consumption were significantly younger at disease onset, were mostly male and showed predominantly paranoid schozophrenia compared to those without substance abuse. Apart from clinical parameters we measured the neurotrophins NFG and BDNF in serum. Those two proteins are essentiel for the development, maturation and maintenance of function of the CNS. At least in experimental conditions they can pass the blood-brain barrier and thus their serum concentration might represent the central neurotrophin concentration that might be altered according to the developmental hypothesis of schizophrenia. Chronic Cannabis consumption can be neurotoxic and we postulated additional changes in schizophrenic patients with previous cannabis consumption. In our investigation schizophrenics with previous cannabis abuse showed a significant increase of serum-NGF concentrations (12.5 fold), even more so when at least two additional substances were consumed (>100fold). Schizophrenics without cannabis, healthy controls and cannabis controls showed no such changes. Thus, the two factors vulnerable brain and cannabis or additional substance abuse had to meet in order to result in increased serum- NGF. For BDNF the results were similar. When the patients were treated and remitted there were no more group differences. Those results were replicated in a further prospective study. We thus interpreted the up-regulation of NGF and BDNF in the dual diagnosis patients as endogenous repair mechanism. This interpretation was supported by a study with non-schizophrenic alcohol- dependent patients who showed increased NGF serum values as long as no cognitive changes had occurred. Korsakoff patients showed no more increase. A following investigation compared the cognitive function of treated schizophrenic patients with and without previous cannabis abuse. The previously cannabis abusing schizophrenic patients never showed inferior results to the non-abusers, in some tests they were even significantly better. In an investigation about P50 sensory gating the non-schizophrenic cannabis abusers showed changes typical for schizophrenia, this was in contrast to the (treated) schizophrenic patients and normal controls. All in all the effect of cannabis on the brain vulnerable to schizophrenia is not completely understood, at least when the chronic cannabis consumption precedes schizophrenia. Apart from unfavourable effects like younger age at disease onset and reexacerbation with further cannabis consumption there may be protective factors contributing to the preservation of cognitive function in schizophrenia

Neurotrophic factors - a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases?

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) belong to the protein family of neurotrophins. They both display profound neuromodulatory functions and are essentially involved in the survival and homeostatic maintenance of central and peripheral neurons during development and adulthood. Moreover, NGF and BDNF are known to modulate immune cell function and thus serve as mediators in the reciprocal cross talk between neurons and immune cells. Neurotrophic factors have been implicated in pathophysiological mechanisms of many diseases of the nervous and the immune system, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), neuropathy, pain, allergic bronchial asthma (BA) and neurotrophic keratitis. For all these diseases research has reached the point of creating strategies for therapeutic intervention with neurotrophins. In this review, we present an overview of the pathophysiology, therapeutic interventions and strategies concerning NGF and BDNF in the mentioned diseases