A Combination of Caffeine Supplementation and Enriched Environment in an Alzheimer's Disease Mouse Model.

A variety of factors has been associated with healthy brain aging, and epidemiological studies suggest that physical activity and nutritional supplements such as caffeine may reduce the risk of developing dementia and, in particular, Alzheimer's disease (AD) in later life. Caffeine is known to act as a cognitive enhancer but has been also shown to positively affect exercise performance in endurance activities. We have previously observed that chronic oral caffeine supplementation and a treatment paradigm encompassing physical and cognitive stimulation by enriched environment (EE) housing can improve learning and memory performance and ameliorate hippocampal neuron loss in the Tg4-42 mouse model of AD. Here, we investigated whether these effects were synergistic. To that end, previous findings on individual treatments were complemented with unpublished, additional data and analyzed in depth by ANOVA followed by Bonferroni multiple comparison post tests. We further evaluated whether plasma neurofilament light chain levels reflect neuropathological and behavioral changes observed in the experimental groups. While a treatment combining physical activity and caffeine supplementation significantly improved learning and memory function compared to standard-housed vehicle-treated Tg4-42 in tasks such as the Morris water maze, no major additive effect outperforming the effects of the single interventions was observed.

Psychotherapists' openness to engage their patients in Psilocybin-Assisted Therapy for mental health treatment.

Despite psychedelic research initially ceasing in the 1970-80s, the findings documented encouraged researchers to re-examine the safety and efficacy of treating mental health with psychedelics. Of particular focus, psilocybin has shown to have therapeutic potential for a variety of mental health problems and was granted breakthrough therapy status by the FDA. Should psilocybin eventually become legally licensed, the success of Psilocybin-Assisted Therapy (PAT) may largely rely on clinicians' openness to engage their eligible patients with PAT. We therefore assessed 119 psychologists' openness to recommend PAT, perceived barriers/facilitators to informing patients about PAT, and factors affecting their openness to involve patients with PAT if FDA approved. While 77.4 % of psychologists agreed they would inform eligible patients about PAT, 91.6 % stated they would still recommend psychotherapies that do not involve psilocybin first. 76.5 % endorsed that knowledge on psilocybin would increase their likelihood to inform patients about PAT. More positive attitudes and beliefs about psilocybin, greater self-reported knowledge of psilocybin, personal history of psychedelic usage, and more positive attitudes towards medical cannabis (MC) was associated with greater openness to engage patients with PAT. Our regression analysis revealed that attitudes towards MC and beliefs about psilocybin were the only significant predictors of psychotherapists' openness towards PAT. These findings provide relevant information to institutions planning educational programs for mental health professionals about psilocybin and Psychedelic-Assisted Therapies.

Feasibility and preliminary efficacy of perioperative interventions in patients undergoing coronary artery bypass grafting: the randomized controlled I-COPE trial.

OBJECTIVES: Patients undergoing coronary artery bypass graft (CABG) surgery are exposed to multiple treatment-related stressors, which can impact coping and health-related quality of life (HRQoL). The objective of this trial was to analyse the feasibility and preliminary efficacy of a multi-component intervention that combines psychological support and reduction of hospital-specific stressors on HRQoL, length of hospital and intensive care unit stay, self-efficacy, and plasma interleukin (IL)-6 and -8 levels in CABG patients. METHODS: This three-arm, randomized controlled, single-centre pilot trial assessed the Intervention for CABG to Optimize Patient Experience in 88 patients undergoing elective CABG. Standard medical care (SMC, n = 29) was compared with 2 intervention groups: (i) psychological interventions to optimize treatment expectations (IA group, n = 30) and (ii) multi-component intervention (IB group, n = 29) with psychological interventions plus an additional treatment package (light therapy, noise reduction, music, and if desired, 360° images delivered via virtual reality). RESULTS: The implementation of psychological interventions in routine medical treatment was feasible (91.5% of participants completed all intervention sessions). Both interventions were associated with significantly shorter hospital stay compared to SMC (IA/IB 9.8/9.3 days vs SMC 12.5 days). Self-efficacy expectations at post-surgery were significantly higher compared to SMC both in the IA group (P = 0.011) and marginally in the IB group (P = 0.051). However, there were no treatment effects of the interventions on HRQoL and plasma levels of IL-6 or IL-8 after CABG. CONCLUSIONS: A perioperative multi-component intervention may lead to shorter hospital stay and higher self-efficacy after CABG. Further studies are needed to determine its impact on HRQoL and inflammation. CLINICAL TRIAL REGISTRATION NUMBER: Ethical approval (# 21/2/18) for the study was obtained from the Research Ethics Committee of the University of Göttingen Medical Center, and the trial was registered in the German Clinical Trials Register (DRKS00015309, https://www.drks.de/drks_web/setLocale_EN.do).

Impact of COVID-19 outbreak on regional STEMI care in Germany.

AIMS: To assess the impact of the lockdown due to coronavirus disease 2019 (COVID-19) on key quality indicators for the treatment of ST-segment elevation myocardial infarction (STEMI) patients. METHODS: Data were obtained from 41 hospitals participating in the prospective Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) study, including 15,800 patients treated for acute STEMI from January 2017 to the end of March 2020. RESULTS: There was a 12.6% decrease in the total number of STEMI patients treated at the peak of the pandemic in March 2020 as compared to the mean number treated in the March months of the preceding years. This was accompanied by a significant difference among the modes of admission to hospitals (p = 0.017) with a particular decline in intra-hospital infarctions and transfer patients from other hospitals, while the proportion of patients transported by emergency medical service (EMS) remained stable. In EMS-transported patients, predefined quality indicators, such as percentages of pre-hospital ECGs (both 97%, 95% CI = - 2.2-2.7, p = 0.846), direct transports from the scene to the catheterization laboratory bypassing the emergency department (68% vs. 66%, 95% CI = - 4.9-7.9, p = 0.641), and contact-to-balloon-times of less than or equal to 90 min (58.3% vs. 57.8%, 95%CI = - 6.2-7.2, p = 0.879) were not significantly altered during the COVID-19 crisis, as was in-hospital mortality (9.2% vs. 8.5%, 95% CI = - 3.2-4.5, p = 0.739). CONCLUSIONS: Clinically important indicators for STEMI management were unaffected at the peak of COVID-19, suggesting that the pre-existing logistic structure in the regional STEMI networks preserved high-quality standards even when challenged by a threatening pandemic. CLINICAL TRIAL REGISTRATION: NCT00794001.

Arresting visuospatial stimulation is insufficient to disrupt analogue traumatic intrusions.

Intrusive memories are a core symptom of Post-Traumatic Stress Disorder (PTSD). A growing body of analogue studies using trauma films suggest that carrying out specific demanding tasks (e.g., playing the video game Tetris, pattern tapping) after the analogue trauma can reduce intrusive memories. To examine the mechanism behind this effect, we tested whether mere engagement with attention-grabbing and interesting visual stimuli disrupts intrusive memories, and whether this depends on working memory resources and/or the concurrent activation of trauma film memories. In a total sample of 234 healthy participants, we compared no-task control conditions to a perceptual rating task with visually arresting video clips (i.e., non-emotional, complex, moving displays), to a less arresting task with non-moving, blurred pictures (Study 1), and to more demanding imagery tasks with and without repetitive reminders of the trauma film (Study 2). Generally, we found moderate to strong evidence that none of the conditions lead to differences in intrusion frequency. Moreover, our data suggest that intrusive memories were neither related to individual differences in working memory capacity (i.e., operation span performance; Study 1), nor to the degree of engagement with a visuospatial task (i.e., one-week recognition performance; Study 2). Taken together, our findings suggest that the boundary conditions for successful interference with traumatic intrusions may be more complex and subtle than assumed. Future studies may want to test the role of prediction errors during (re-)consolidation, deliberate efforts to suppress thoughts, or the compatibility of the task demands with the individual's skills.

[The risk of medical comorbidity in mental disorders with a particular focus on depressive syndromes]. / Somatisches Krankheitsrisiko bei psychischen Erkrankungen unter besonderer Berücksichtigung depressiver Syndrome.

The risk of medical comorbidity in mental disorders with a particular focus on depressive syndromes Objectives: It has long been recognized that certain mental disorders, and in particular depressive syndromes, are associated with increased medical comorbidity. However, reliable data on the prevalence of comorbid medical diagnoses as well as the impact of these comorbidities on mortality are often rare and sometimes conflicting. Methods: A systematic literature review was conducted using PubMed and Google Scholar to provide a critical account of the current state of research on the comorbidities of medical and mental disorders, with a particular focus on depressive syndromes. Results: Among patients with mental disorders, all-cause mortality is about doubled as compared to the general population causing a significantly shortened life expectancy in the range of one to two decades. This excess mortality is primarily due to increased physical morbidity and mortality, and it cannot be excluded that, for patients with severe mental disorders, excess mortality has been increased over time. Depressive syndromes are often linked to a broad range of somatic symptoms and can be found in diseases, such as heart disease, stroke, diabetes mellitus, overweight/obesity, and asthma. Conclusion: Current studies provide ample evidence of close interactions between physical and mental health. Further developments in the field of psychosomatic medicine should take into consideration the health-related consequences of these interactions.

Impact of an Artificial Digestion Procedure on Aluminum-Containing Nanomaterials.

Aluminum has gathered toxicological attention based on relevant human exposure and its suspected hazardous potential. Nanoparticles from food supplements or food contact materials may reach the human gastrointestinal tract. Here, we monitored the physicochemical fate of aluminum-containing nanoparticles and aluminum ions when passaging an in vitro model of the human gastrointestinal tract. Small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), ion beam microscopy (IBM), secondary ion beam mass spectrometry (TOF-SIMS), and inductively coupled plasma mass spectrometry (ICP-MS) in the single-particle mode were employed to characterize two aluminum-containing nanomaterials with different particle core materials (Al0, γAl2O3) and soluble AlCl3. Particle size and shape remained unchanged in saliva, whereas strong agglomeration of both aluminum nanoparticle species was observed at low pH in gastric fluid together with an increased ion release. The levels of free aluminum ions decreased in intestinal fluid and the particles deagglomerated, thus liberating primary particles again. Dissolution of nanoparticles was limited and substantial changes of their shape and size were not detected. The amounts of particle-associated phosphorus, chlorine, potassium, and calcium increased in intestinal fluid, as compared to nanoparticles in standard dispersion. Interestingly, nanoparticles were found in the intestinal fluid after addition of ionic aluminum. We provide a comprehensive characterization of the fate of aluminum nanoparticles in simulated gastrointestinal fluids, demonstrating that orally ingested nanoparticles probably reach the intestinal epithelium. The balance between dissolution and de novo complex formation should be considered when evaluating nanotoxicological experiments.

Cognitive-behavioral therapies for depression and substance use disorders: An overview of traditional, third-wave, and transdiagnostic approaches.

BACKGROUND: The co-occurrence of depression and substance use disorders (SUD) is highly prevalent and associated with poor treatment outcomes for both disorders. As compared to individuals suffering from either disorder alone, individuals with both conditions are likely to endure a more severe and chronic clinical course with worse treatment outcomes. Thus, current practice guidelines recommend treating these co-occurring disorders simultaneously. OBJECTIVES: The overarching aims of this narrative are two-fold: (1) to provide an updated review of the current empirical status of integrated psychotherapy approaches for SUD and depression comorbidity, based on models of traditional cognitive-behavioral therapy (CBT) and newer third-wave CBT approaches, including acceptance- and mindfulness-based interventions and behavioral activation (BA); and (2) to propose a novel theoretical framework for transdiagnostic CBT for SUD-depression, based upon empirically grounded psychological mechanisms underlying this highly prevalent comorbidity. RESULTS: Traditional CBT approaches for the treatment of SUD-depression are well-studied. Despite advances in the development and evaluation of various third-wave psychotherapies, more work needs to be done to evaluate the efficacy of such approaches for SUD-depression. CONCLUSION: Informed by this summary of the evidence, we propose a transdiagnostic therapy approach that aims to integrate treatment elements found in empirically supported CBT-based interventions for SUD and depression. By targeting shared cognitive-affective processes underlying SUD-depression, transdiagnostic treatment models have the potential to offer a novel clinical approach to treating this difficult-to-treat comorbidity and relevant, co-occurring psychiatric disturbances, such as posttraumatic stress.

Association of circulating 25-hydroxyvitamin D with mental well-being in a population-based, nationally representative sample of German adolescents.

OBJECTIVE: Numerous studies have linked vitamin D to health-related quality of life (hrQoL) in chronically ill adults or elderly subjects. The aim of this study was to evaluate the association between 25-hydroxyvitamin D (25(OH)D) and hrQoL in a population-based sample of German adolescents. METHODS: A total of n = 5066 study participants from the nationwide, representative German Health Interview and Examination Survey for Children and Adolescents (Kinder- und Jugendgesundheitssurvey) aged 11-17 years were included in this post hoc analysis. HrQoL was measured using the well-validated self- and parent-rated Children's Quality of Life questionnaires (KINDL-R), while the level of distress was assessed using the self- and proxy version of the Strengths and Difficulties Questionnaire (SDQ). Serum 25(OH)D concentrations were determined using a commercially available chemiluminescence immunoassay. RESULTS: Bivariate analyses demonstrated a significant positive association between 25(OH)D and hrQoL for both self- [estimate (E) = 0.82, 95 % confidence interval (95 % CI) 0.35-1.30, p = 0.001] and parent ratings (E = 1.33, 95 % CI 0.83-1.83, p < 0.001). In addition, we found negative correlations between 25(OH)D and self- (E = -0.34, 95 % CI -0.58 to -0.11, p = 0.005) and parent-reported total SDQ scores (E = -0.70, 95 % CI -1.03 to -0.37, p < 0.001). Generalized linear models adjusted for age, sex, body mass index, systolic blood pressure, migration background, socio-economic status, and sedentary screen time confirmed that 25(OH)D independently and significantly predicted better hrQoL (p ≤ 0.004). CONCLUSIONS: These findings linking 25(OH)D to better well-being in a nationally representative sample of German children and adolescents suggest beneficial effects of vitamin D on mental health. However, recommendations for vitamin supplementation in healthy children and adolescents are not warranted from our data.

Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic lateral sclerosis mouse models based on TDP-43 (Tardbp) and FUS mutations. Finally, we demonstrate that the melanocortin defect is primarily caused by serotonin loss in mutant SOD1(G86R) mice. Altogether, the current study combined clinical evidence and experimental studies in rodents to provide a mechanistic explanation for abnormalities in food intake and weight control observed in patients with amyotrophic lateral sclerosis. Importantly, these results also show that amyotrophic lateral sclerosis progression impairs responsiveness to classical drugs leading to weight gain. This has important implications for pharmacological management of weight loss in amyotrophic lateral sclerosis.

Early specific cognitive-behavioural psychotherapy in subjects at high risk for bipolar disorders: study protocol for a randomised controlled trial.

BACKGROUND: Bipolar disorders (BD) are among the most severe mental disorders with first clinical signs and symptoms frequently appearing in adolescence and early adulthood. The long latency in clinical diagnosis (and subsequent adequate treatment) adversely affects the course of disease, effectiveness of interventions and health-related quality of life, and increases the economic burden of BD. Despite uncertainties about risk constellations and symptomatology in the early stages of potentially developing BD, many adolescents and young adults seek help, and most of them suffer substantially from symptoms already leading to impairments in psychosocial functioning in school, training, at work and in their social relationships. We aimed to identify subjects at risk of developing BD and investigate the efficacy and safety of early specific cognitive-behavioural psychotherapy (CBT) in this subpopulation. METHODS/DESIGN: EarlyCBT is a randomised controlled multi-centre clinical trial to evaluate the efficacy and safety of early specific CBT, including stress management and problem solving strategies, with elements of mindfulness-based therapy (MBT) versus unstructured group meetings for 14 weeks each and follow-up until week 78. Participants are recruited at seven university hospitals throughout Germany, which provide in- and outpatient care (including early recognition centres) for psychiatric patients. Subjects at high risk must be 15 to 30 years old and meet the combination of specified affective symptomatology, reduction of psychosocial functioning, and family history for (schizo)affective disorders. Primary efficacy endpoints are differences in psychosocial functioning and defined affective symptomatology at 14 weeks between groups. Secondary endpoints include the above mentioned endpoints at 7, 24, 52 and 78 weeks and the change within groups compared to baseline; perception of, reaction to and coping with stress; and conversion to full BD. DISCUSSION: To our knowledge, this is the first study to evaluate early specific CBT in subjects at high risk for BD. Structured diagnostic interviews are used to map the risk status and development of disease. With our study, the level of evidence for the treatment of those young patients will be significantly raised. TRIAL REGISTRATION: WHO International Clinical Trials Platform (ICTRP), identifier: DRKS00000444, date of registration: 16 June 2010.

Sinecatechins (Polyphenon E) ointment for treatment of external genital warts and possible future indications.

INTRODUCTION: Sinecatechins was the first botanical drug licensed for treatment in humans in the US. It is approved for the topical treatment of external genital and perianal warts. Some properties of the polyphenolic components included in sinecatechins suggest additional therapeutic potential for other skin diseases. AREAS COVERED: Studies and articles describing therapeutic application of sinecatechins or green tea polyphenols in viral and proliferative skin diseases or investigating molecular activities relevant for the mode of action were identified by a PubMed search using 'sinecatechins', 'green tea polyphenols', 'polyphenon E' and 'EGCG', each combined with 'skin cancer' and 'genital warts' as search criteria. Although a number of molecular mechanisms of green tea polyphenols were described, the exact mode of action operative in regression of genital warts is not yet clear. It may involve both antiproliferative, pro-apoptotic and antiviral activities that probably also account for efficacy against other skin disorders. EXPERT OPINION: In addition to treatment of skin tumors, sinecatchins may also be used to protect against photocarcinogenesis. Considering antioxidative properties of polyphenols and the capability to enhance DNA repair, sinecatechins appears attractive for primary prevention of nonmelanoma skin cancer either as additive in sunscreens or as dietary supplement for oral administration.

Towards measurement of the Healthy Ageing Phenotype in lifestyle-based intervention studies.

INTRODUCTION: Given the biological complexity of the ageing process, there is no single, simple and reliable measure of how healthily someone is ageing. Intervention studies need a panel of measures which capture key features of healthy ageing. To help guide our research in this area, we have adopted the concept of the "Healthy Ageing Phenotype" (HAP) and this study aimed to (i) identify the most important features of the HAP and (ii) identify/develop tools for measurement of those features. METHODS: After a comprehensive assessment of the literature we selected the following domains: physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we hoped would provide a reasonably holistic characterisation of the HAP. We reviewed the literature and identified systematic reviews and/or meta-analysis of cohort studies, and clinical guidelines on outcome measures of these domains relevant to the HAP. Selection criteria for these measures included: frequent use in longitudinal studies of ageing; expected to change with age; evidence for strong association with/prediction of ageing-related phenotypes such as morbidity, mortality and lifespan; whenever possible, focus on studies measuring these outcomes in populations rather than on individuals selected on the basis of a particular disease; (bio)markers that respond to (lifestyle-based) intervention. Proposed markers were exposed to critique in a Workshop held in Newcastle, UK in October 2012. RESULTS: We have selected a tentative panel of (bio)markers of physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we propose may be useful in characterising the HAP and which may have utility as outcome measures in intervention studies. In addition, we have identified a number of tools which could be applied in community-based intervention studies designed to enhance healthy ageing. CONCLUSIONS: We have proposed, tentatively, a panel of outcome measures which could be deployed in community-based, lifestyle intervention studies. The evidence base for selection of measurement domains is less well developed in some areas e.g. social wellbeing (where the definition of the concept itself remains elusive) and this has implications for the identification of appropriate tools. Although we have developed this panel as potential outcomes for intervention studies, we recognise that broader agreement on the concept of the HAP and on tools for its measurement could have wider utility and e.g. could facilitate comparisons of healthy ageing across diverse study designs and populations.

The use of sinecatechins (polyphenon E) ointment for treatment of external genital warts.

INTRODUCTION: Sinecatechins is a standardized extract of green tea leaves, containing a mixture of catechin compounds. The 15% ointment has been approved for the topical treatment of condylomata acuminata (CA), caused by particular human papillomaviruses (HPV), mainly HPV types 6 and 11. OBJECTIVE: To update the use of sinecatechins for treatment of CA and to describe possible mechanisms involved in the mode of action. AREAS COVERED: The clearance rate of wart lesions after treatment with sinecatechins is similar to other topically applied drugs, like imiquimod and podophyllotoxin, but recurrences are seen less frequently after treatment with sinecatechins. The molecular mode of action underlying the clinical efficacy has yet not been characterized, but the following properties are likely to be involved in the regression of genital warts: activation of cellular immune reactions, induction of cell cycle arrest and apoptosis, inhibition of HPV gene expression. EXPERT OPINION: Sinecatechins is a safe and effective treatment option for CA. Due to the variety of molecular activities of catechins the product has great potential for application to other viral and tumor lesions in the future.

A successful treatment strategy in infants and adolescents with anorectal malformation and incontinence with combined hydrocolonic ultrasound and bowel management.

PURPOSE: Patients with anorectal malformation (ARM) frequently suffer postoperatively from fecal incontinence (25%) and constipation (75%). Depending on the type of malformation, some cases will not have a chance to control bowel movements. For these patients with fecal incontinence, we started to combine bowel management with hydrocolonic ultrasound to keep them clean. MATERIAL: From January 2003 until December 2010, overall 63 patients (aged 4-22 years) with ARM and fecal incontinence were treated by specific bowel management. Hydrocolonic ultrasound was used as a diagnostic parameter to determine stool texture and activity of the colon as well as to determine the appropriate volume which is needed to clean the colon. Each patient received an individually adjusted enema. Patients were classified into two groups: Group I: patients with incontinence and tendency to constipation and Group II: patients with incontinence and tendency to diarrhea. Subsequent controls were focused on problems such as bowel dilatation, bowel motility, constipation or too little enema due to the patient's growing. RESULTS: Up to now, 63 patients were investigated in our study (Group I n = 37 patients and Group II n = 26 patients). In addition, the patients were classified according to the type of malformation. With specific bowel management combined with hydrocolonic ultrasound, 97% of patients in Group I (36/37) stayed clean (demonstration of complete bowel control). All 57.7% of patients in Group II (15/26) stayed clean after daily bowel management, and 34.6% with smearing less than three times per week (n = 9/26). In addition, a specific diet and constipating medication were often necessary to get patients in Group II clean. CONCLUSIONS: Treating young patients with fecal incontinence is always a challenge. Hydrocolonic ultrasound diagnostically conclusive and less invasive. The combination with bowel management results in better bowel control and serves as a valuable tool in affected infants and adolescents. Thus, hydrocolonic ultrasound may be an essential instrument in postoperative diagnostic procedure and therapy of patients with fecal incontinence.

Is risk for mania associated with increased daydreaming as a form of mental imagery?

BACKGROUND: Bipolar disorder and risk for mania are associated with setting high goals and dysregulated goal pursuit. One mechanism mediating between setting high goals and manic symptoms could be daydreaming or more generally, mental imagery. 'Daydreams' (as one form of mental imagery) are characterized by the fact that the content is produced deliberately. Akiskal et al. (1995) reported that daydreaming prospectively predicted a switch from unipolar depression to bipolar disorder. We here hypothesized that risk for mania should also be associated with increased daydreaming after controlling for depression. METHOD: N=249 participants from a non-clinical, community sample completed several self-report measures including the Hypomanic Personality scale and Daydreaming scale. RESULTS: Hierarchical regression revealed that risk for mania predicted daydreaming after controlling for current and former depression. LIMITATIONS: Only self-report measures were used. The sample was a non-clinical, primarily White British sample, which has implications for generalizability. CONCLUSIONS: Despite limitations our results support the hypothesis that vulnerability for mania is associated with daydreaming. Daydreaming was related to mania and depression which highlights that it might be relevant for the etiology or maintenance of mood disorders.

Cardiotoxicity testing using pluripotent stem cell-derived human cardiomyocytes and state-of-the-art bioanalytics: a review.

In this article, recent progress in cardiotoxicity testing based on the use of immortalized cell lines or human embryonic stem cell (hESC) derived cardiomyocytes in combination with state-of-the-art bioanalytical methods and sensors is reviewed. The focus is on hESC-derived cells and their refinement into competent testing cells, but the access and utility of other relevant cell types are also discussed. Recent developments in sensor techniques and bioanalytical approaches for measuring critical cardiotoxicity parameters are highlighted, together with aspects of data evaluation and validation. Finally, recommendations for further research are given.

Cardiac slices as a predictive tool for arrhythmogenic potential of drugs and chemicals.

IMPORTANCE OF THE FIELD: cardiac arrhythmia represents one of the primary safety pharmacological concerns in drug development. The most prominent example is drug induced ventricular tachycardia of the Torsade des Pointes type. The mechanism how this type of arrhythmia develops is a complex multi-cellular phenomenon. It can only be insufficiently reflected by cellular or molecular assays. However, organ models - such as Langendorff hearts - or in vivo experiments are expensive and time consuming and not suitable for assays requiring an increased throughput. AREAS COVERED IN THIS REVIEW: here, we describe and review an assay bridging the gap between cardiomyocyte based assays and organ based systems - cardiac slices. This assay is reviewed in direct comparison with established safety pharmacological assays. WHAT THE READER WILL GAIN: while slices have played an important role in brain research for > 2 decades, cardiac slices are experiencing a renaissance due to the novel challenges in safety pharmacology just in the last few years. Cardiac slices can be cultured and recorded over several days. It is possible to access electrophysiological data with a high number of electrodes - up to 256 electrodes - embedded in the surface of a microelectrode array. TAKE HOME MESSAGE: cardiac slices close the gap between cellular and organ based assays in cardiac safety pharmacology. The tissue properties of a functional cardiac syncytium are more accurately reflected by a slice rather than a single cell.

Neoadjuvant treatment with weekly high-dose 5-fluorouracil as a 24h-infusion, folinic acid and biweekly oxaliplatin in patients with primary resectable liver metastases of colorectal cancer: long-term results of a phase II trial.

BACKGROUND: In 2003 Wein et al. published data after a short median follow up (23 months). Here we report on the long-term results. MATERIAL/METHODS: The patients (n=20) received a neoadjuvant treatment regimen comprising biweekly 85 mg/m2 oxaliplatin (L-OHP) (2h-infusion, d 1, 15, 29 qd 57) and 500 mg/m2 calcium folinic acid (FA) (1-2h-infusion, d 1, 8, 15, 22, 29, 36 qd 57) followed by 2600 mg/m2 5-Fluorouracil (5-FU) (24h-infusion, d 1, 8, 15, 22, 29, 36 qd 57). Two cycles of chemotherapy were administered, with a third being added when the treatment was well tolerated. Thereafter, curative resection of the liver metastases was attempted. RESULTS: After neoadjuvant therapy, imaging procedures revealed complete remission in 2 patients (10%) and partial remission in 18 patients (90%). Diarrhea (Common Toxicity Criteria toxicity grade 3) was observed in 6 patients (30%) as main symptom of toxicity, followed by vomiting in 3 patients (15%). Higher grade sensomotoric neuropathy did not present. The curative resectability rate (R0) was 80%. In 9 out of 18 patients (50%) undergoing surgical intervention minor postoperative complications occurred. No postoperative mortality was observed. Over a median follow up of 45,5 months the median survival of all patients is 3.0 years and the 5-year overall survival rate is 40%. The 5-year disease-free survival rate is 25%. CONCLUSIONS: Neoadjuvant treatment with 5-FU combined with FA and L-OHP proved to be highly effective and well tolerated. Disease-free survival rates and median overall survival rates are promising.

Long-term outcome of hyperthermic isolated limb perfusion (HILP) in the treatment of locoregionally metastasised malignant melanoma of the extremities.

OBJECTIVE: The aim is to analyse a modified standardised HILP procedure regarding the response rates, local recurrences and complication rates. PATIENTS AND METHODS: 152 patients (101 females, 51 males) with an average age of 62 years and locoregionally metastasised malignant melanoma underwent HILP using melphalan and dactinomycin between 1992 and 2007. Using M.D. Anderson's classification at the time of the perfusion 51 patients presented in stage IIIA, 43 patients in stage IIIAB and 58 patients in stage IV. If indicated, lymph node dissection was performed simultaneously just before perfusion of the extremity. RESULTS: Complete remission was observed in 91 (62.7%) of 145 patients, partial remission in 26 (17.9%) patients. 28 (19.3%) patients showed no response. The overall response rate was 80.7% (117 of 145 patients). Severe complications (Wieberdink IV/V) were seen in eight cases. The average recurrence-free survival was 17 months. The median survival was 39 months; the five-year overall survival rate was 38%. The overall survival rate was significantly influenced by the stage of the disease. CONCLUSION: HILP is an efficient therapy for multiple or recurrent in-transit metastases of malignant melanoma of the lower extremities. The efficiency increased by improving the technique of the perfusion. Long-term survival can be observed in patients without regional lymph node metastases or distant metastases.