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Upper limb actions require intersegmental coordination of the scapula, shoulders, elbows, forearms, wrists, and hand muscles. Stroke hemiparesis, presenting as an impairment of an intersegmentally coordinated voluntary movement, is associated with altered integrity of corticospinal tract (CST) transmission from the motor cortex (M1) to muscles. Motor evoked potentials (MEPs) elicited by M1 transcranial magnetic stimulation (TMS) of “at rest” muscles, or as a backup, during muscle contraction have been used to identify CST integrity and predict the outcome after hemiparesis, under the implicit assumption that MEPs present in only one or two muscles are manifest surrogates of CST integrity for other muscles of the upper limbs. This study presents a method for applying TMS during motor tasks that involve proximal and distal muscles. It focuses on evaluating multi-muscle electromyography (EMG) and MEPs across all task-relevant limb segments. Protocols are presented for assessing voluntary motor behavior in individuals with hemiparetic stroke using isometric, unimanual, bimanual, and “REST” conditions that broaden the concept of the degree of CST integrity in order to inform clinical prescription for neurorehabilitation and distinguish its potential as a prognostic tool. Data describing the recordings of multi-muscle transcranial magnetic stimulation induced motor evoked potentials (TMS-MEP) will be presented in a case of subacute hemiparetic stroke to elucidate our perspective.

The molecular chaperone Hsp90 decreases with age but whether organisms can physiologically tune expression is unclear. Here, the authors show that mammalian cells can adjust Hsp90 levels to accumulating cellular stress by translational reprogramming.

The second-generation anticonvulsant lamotrigine is widely used in the psychiatric field as a mood stabilizer or antidepressant augmentation therapy. Although particularly older anticonvulsants are known for their potential to cause hypersensitivity syndromes, newer antiepileptic drugs do hold a certain risk as well. Presenting a case of a 32-year-old male inpatient of African ethnicity suffering from a primary severe depressive episode in the course of a recurrent major depressive disorder, we report the occurrence of a rapid-onset drug-induced pneumonitis. Herewith, the interstitial pneumonitis occurred after the initiation of 25 mg lamotrigine as an augmentation therapy. Except for the clear temporal correlation between the administration of lamotrigine and the onset of pneumonitis, we did not reveal any further potentially causal diagnostic hints. Importantly, no relevant genetic variations of metabolizing enzymes or drug interactions resulting in lamotrigine overdosage as a potential cause of toxicity were identified. Our experience with a potentially life-threatening adverse drug reaction shortly after the initiation of the largely well-tolerated lamotrigine suggests a potential side effect under the second-generation anticonvulsant although similar adverse events are deemed to be very rare.

Background and Hypothesis The dopamine theory of schizophrenia suggests that antipsychotics alleviate symptoms by blocking dopamine D2/3 receptors, yet a significant subset of patients does not respond adequately to treatment. To investigate potential predictors, we evaluated d -amphetamine-induced dopamine release and 1-year clinical outcomes in 21 antipsychotic-naive patients with first-episode schizophrenia. Study Design Twenty-one antipsychotic-naive patients (6 female) underwent dopamine D2/3 receptor radioligand [11C]-(+)-PHNO positron emission tomography. For estimating dopamine release, scans were performed with and without d -amphetamine pretreatment. The Positive and Negative Syndrome Scale was performed at regular intervals over 1 year while receiving treatment in a naturalistic setting (Clinical Trial Registry: EUDRACT 2010-019586-29). Study Results A group analysis revealed no significant differences in d -amphetamine-induced dopamine release between patients with or without clinically significant improvement. However, d -amphetamine-induced dopamine release in ventral striatum was significantly associated with reductions in positive symptoms (r  = 0.54, P  = .04; uncorrected P -values); release in globus pallidus correlated with a decrease in PANSS negative (r  = 0.58, P  = .02), general (r  = 0.53, P  = .04), and total symptom scores (r  = 0.063, P  = .01). Higher dopamine release in substantia nigra/ventral tegmental area predicted larger reductions in general symptoms (r  = 0.51, P  = .05). Post-amphetamine binding in putamen correlated positively with negative symptom scores at baseline (r  = 0.66, P  = .005) and throughout all follow-up visits. Conclusions These exploratory results support a relationship between d -amphetamine-induced dopamine release and the severity and persistence of symptoms during the first year of psychosis. [ABSTRACT FROM AUTHOR]

Introduction Silexan manufactured from Lavandula angustifolia showed favorable safety and efficacy in subthreshold and generalized anxiety disorder (GAD), mixed anxiety and depressive disorder (MADD), and further, especially subsyndromal psychiatric manifestations including depression, sleep disturbances, restlessness, fatigue and pain. Objectives Since the abovementioned clinical phenotypes were repeatedly observed in the course of the so-called post coronavirus-19 disease (COVID-19) syndrome, which were, importantly, of subsyndromal severity in the most cases, we were confident that Silexan will be efficacious also in this indication. Methods We report on three adult outpatients treated with Silexan due to psychiatric conditions that occurred in the context of a mild and short-lasting COVID-19 infection. Results A 38-years old female experienced fatigue, brain fog, inner tension, restlessness and sad mood with weepiness after recovery of her respiratory COVID-19 infection. Since she did not remit under ongoing psychotherapy (PT), Silexan 80 mg p.o.q.d. was additionally employed and very well tolerated. She achieved full remission of her subthreshold symptoms within one month. A 27-years old male developed GAD including anxiety, inner tension, restlessness, irritability, muscle aches, difficulties in concentrating and in controlling feelings of worry after he recovered from respiratory COVID-19. Following his preference, PT and Silexan 80 mg p.o.q.d. were initiated and very well tolerated. Because of partial response, Silexan was increased to 80 mg twice daily after three weeks. After additional two weeks, he was able to enjoy everyday activities and to comply with working demands without relevant difficulties. A 38-years old female developed a post COVID-19 syndrome with fatigue, anxiety, depression, inner tension, tachycardia, hopelessness and rumination. Due to the current MADD Bupropion 150 mg and subsequently 300 mg p.o.q.d. and Hydroxyzine 25 mg on demand were administered. Although clinical improvement was achieved, the patient discontinued the treatment due to subjective exacerbation of tachycardia and refused any further treatment optimization. Once she agreed to phyto-psychopharmacotherapy, Silexan 80 mg p.o.q.d. was employed and, while well tolerated, increased to 80 mg twice daily after two weeks. The patient was increasingly able to participate at her working and social activities again and stayed stable for four months. Conclusions To our knowledge, this is the first report on administering Silexan in subsyndromal and full-blown anxiety and depression with cognitive and psychosomatic symptoms that occurred in the context of COVID-19. While substantial clinical improvements were achieved, no relevant adverse effects occurred. Disclosure of Interest None Declared

Despite the widespread use of doxorubicin (DOX) as a chemotherapeutic agent, its severe cumulative cardiotoxicity represents a significant limitation. While the liposomal encapsulation of doxorubicin (Myocet, MYO) reduces cardiotoxicity, it is crucial to understand the molecular background of doxorubicin-induced cardiotoxicity. Here, we examined circular RNA expression in a translational model of pigs treated with either DOX or MYO and its potential impact on the global gene expression pattern in the myocardium. This study furthers our knowledge about the regulatory network of circRNA/miRNA/mRNA and its interaction with chemotherapeutics. Domestic pigs were treated with three cycles of anthracycline drugs (DOX, n = 5; MYO, n = 5) to induce cardiotoxicity. Untreated animals served as controls (control, n = 3). We applied a bulk mRNA-seq approach and the CIRIquant algorithm to identify circRNAs. The most differentially regulated circRNAs were validated under cell culture conditions, following forecasting of the circRNA–miRNA–mRNA network. We identified eight novel significantly regulated circRNAs from exonic and mitochondrial regions in the porcine myocardium. The forecasted circRNA–miRNA–mRNA network suggested candidate circRNAs that sponge miR-17, miR-15b, miR-130b, the let-7 family, and miR125, together with their mRNA targets. The identified circRNA–miRNA–mRNA network provides an updated, coherent view of the mechanisms involved in anthracycline-induced cardiotoxicity.

Upper limb actions require intersegmental coordination of the scapula, shoulders, elbows, forearms, wrists, and hand muscles. Stroke hemiparesis, presenting as an impairment of an intersegmentally coordinated voluntary movement, is associated with altered integrity of corticospinal tract (CST) transmission from the motor cortex (M1) to muscles. Motor evoked potentials (MEPs) elicited by M1 transcranial magnetic stimulation (TMS) of "at rest" muscles, or as a backup, during muscle contraction have been used to identify CST integrity and predict the outcome after hemiparesis, under the implicit assumption that MEPs present in only one or two muscles are manifest surrogates of CST integrity for other muscles of the upper limbs. This study presents a method for applying TMS during motor tasks that involve proximal and distal muscles. It focuses on evaluating multi-muscle electromyography (EMG) and MEPs across all task-relevant limb segments. Protocols are presented for assessing voluntary motor behavior in individuals with hemiparetic stroke using isometric, unimanual, bimanual, and "REST" conditions that broaden the concept of the degree of CST integrity in order to inform clinical prescription for neurorehabilitation and distinguish its potential as a prognostic tool. Data describing the recordings of multi-muscle transcranial magnetic stimulation induced motor evoked potentials (TMS-MEP) will be presented in a case of subacute hemiparetic stroke to elucidate our perspective. [ABSTRACT FROM AUTHOR]

Hop, also known as Stip1 or Sti1, facilitates substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Characterization of proteostasis-related pathways in STIP1 knock-out cell lines reveals that in eukaryotes Stip1 modulates the balance between protein folding and degradation.

BackgroundThe clinical high-risk for psychosis (CHR-P) paradigm was introduced to detect individuals at risk of developing psychosis and to establish preventive strategies. While current prediction of outcomes in the CHR-P state is based mostly on the clinical assessment of presenting features, several emerging biomarkers have been investigated in an attempt to stratify CHR-P individuals according to their individual trajectories and refine the diagnostic process. However, heterogeneity across subgroups is a key challenge that has limited the impact of the CHR-P prediction strategies, as the clinical validity of the current research is limited by a lack of external validation across sites and modalities. Despite these challenges, electroencephalography (EEG) biomarkers have been studied in this field and evidence suggests that EEG used in combination with clinical assessments may be a key measure for improving diagnostic and prognostic accuracy in the CHR-P state. The PSYSCAN EEG study is an international, multi-site, multimodal longitudinal project that aims to advance knowledge in this field.MethodsParticipants at 6 international sites take part in an EEG protocol including EEG recording, cognitive and clinical assessments. CHR-P participants will be followed up after 2 years and subcategorised depending on their illness progression regarding transition to psychosis. Differences will be sought between CHR-P individuals and healthy controls and between CHR-P individuals who transition and those who do not transition to psychosis using data driven computational analyses.DiscussionThis protocol addresses the challenges faced by previous studies of this kind to enable valid identification of predictive EEG biomarkers which will be combined with other biomarkers across sites to develop a prognostic tool in CHR-P. The PSYSCAN EEG study aims to pave the way for incorporating EEG biomarkers in the assessment of CHR-P individuals, to refine the diagnostic process and help to stratify CHR-P subjects according to risk of transition. This may improve our understanding of the CHR-P state and therefore aid the development of more personalized treatment strategies.

There are pronounced behavioural and neuroimaging parallels between cocaine abuse and narcissism. Although the observed commonalities are not specific to cocaine as opposed to other types of addiction, we argue that the relatively constrained molecular actions of cocaine and, more importantly, the covariance of narcissism-like behaviours with cocaine use build a strong case for taking the known effects of cocaine as a starting point for addressing the hitherto underinvestigated neurophysiology of narcissism. In this review, we discuss the potential relevance of cocaine abuse as a pharmacological model of narcissism. We outline previous research on the role of monoamines across several domains affected in narcissistic personality disorder and subclinical narcissism, namely, selected personality traits, social behaviour, emotional empathy and self-referential processing. We propose that dysregulation in dopamine signalling might underlie addiction-like features of narcissism and that altered serotonergic signalling may account for affective components of narcissism and, in particular, explain the differences between grandiose and vulnerable subtypes. In conclusion, we provide recommendations for future research.

Background: Valproic acid (VPA) has been increasingly shown to trigger hyperammonemic encephalopathies in patients suffering from urea cycle defects and in those receiving polypharmacy. Methods: We report on two cases of psychiatric inpatients with regular VPA intake who showed severe cognitive impairment due to non-cirrhotic hyperammonaemia without VPA overdosing. Results: In the first case, OTC deficiency appeared to be the underlying cause of a comatose state in a middle-aged bipolar female patient. Besides hyperammonemia, we identified increased plasma levels of glutamine and alanine, decreased plasma levels of arginine and urea, as well as increased urinary levels of orotate. In the second case, we observed severe cognitive impairment in a younger male patient with a current psychotic episode with predominant affective symptoms who we treated with polypharmacy including VPA and topiramate. Limitations: As this case series focused on individual patients, the results should be interpreted with caution and cannot be generalized. Conclusions: In patients receiving VPA, considering urea cycle deficiencies and potential drug interactions seems crucial for avoiding potential life-threatening symptoms.

BACKGROUND:Laypersons' efforts to initiate basic life support (BLS) in witnessed Out-of-Hospital Cardiac Arrest (OHCA) remain comparably low within western society. Therefore, in order to shorten no-flow times in cardiac arrest, several police-based first responder systems equipped with automated external defibrillators (Pol-AED) were established in urban areas, which subsequently allow early BLS and AED administration by police officers. However, data on the quality of BLS and AED use in such a system and its impact on patient outcome remain scarce and inconclusive. METHODS:A total of 85 Pol-AED cases were randomly assigned to a gender, age and first rhythm matched non-Pol-AED control group (n = 170) in a 1:2 ratio. Data on quality of BLS were extracted via trans-thoracic impedance tracings of used AED devices. RESULTS:Comparing Pol-AED cases and the control group, we observed a similar compression rate per minute (p = 0.677) and compression ratio (p = 0.651), mirroring an overall high quality of BLS administered by police officers. Time to the first shock was significantly shorter in Pol-AED cases (6 minutes [IQR: 2-10] vs. 12 minutes [IQR: 8-17]; p

Following previous studies, chronotype was related to sexual attitudes and behavior. Evening people tend to be more promiscuous and follow short-term mating strategies and extra-pair matings (EPM), which might lead to a higher reproductive success. In this study, one aim was to assess reproductive success directly by asking for children, and, second, to obtain a higher sample size for the analysis of sexual behavior and chronotype than in previous studies. N = 1,843 heterosexual persons (551 men, 1,288 women, 4 without data) responded to our online survey. Five hundred fifty-nine persons were single and 1,281 in a relationship; 203 reported having children (1.9 ± 0.81). Age was positively related and age at first intercourse was negatively related to the number of children. People being later chronotypes had fewer children, and shorter sleep duration was linked with more children. Extroversion was correlated with number of children, as was the long-term relationship orientation. Sociosexual orientation and EPM were unrelated to number of children. Age at first intercourse was earlier in evening people, and unrestricted sociosexuality was higher in late chronotypes. Morning orientation correlated with long-term relationship orientation and eveningness with short-term relationship orientation. Number of sexual partners was lower in morning people. Men were more evening oriented, later chronotypes, and slept shorter. There were no differences in sociosexual behavior, but men were less restricted in attitude and desire. Men scored higher on short-term relationship orientation and women higher on long-term relationship orientation. This study confirmed previous results about chronotype and sexual behavior but provided the first evidence that morningness was related to higher reproductive success.

Differences in daytime preferences can be described on the dimension of morningness-eveningness (continuous) or circadian typology (categorical) and are associated with our physiological functioning, which is reflected in body temperature and cortisol levels in the morning. The purpose of the present study was to explore the relationship between morningness-eveningness, stability and physiological markers (body temperature and cortisol) based on a three-dimensional conceptualization of morningness-eveningness using the Morningness-Eveningness-Stability Scale improved (MESSi). In contrast to previously used unidimensional measures, the MESSi determines circadian typology and its amplitude in three dimensions: Morning affect (MA), Eveningness (EV) and Stability/Distinctness (DI). Furthermore, the differences of the cortisol levels between weekday and weekend were examined. The sample ('N' = 42) consisted of extreme chronotypes (age 18–54 years; 'M' = 24.8 years, 'SD' = 5.83; 22 morning types [5 men and 17 women] and 20 evening types [8 men and 12 women]). The participants were asked to measure their skin temperature for one week and sample four saliva probes for cortisol determination. Morning types showed a better fit in the actual temperature data to the approximating data as compared to Evening types and showed a higher overall temperature. The Stability/Distinctness (DI) component of the MESSi was negatively correlated with the nadir. Morning types also showed higher cortisol levels than Evening types immediately after awakening. The cortisol levels were higher on a weekday compared to the weekend. To conclude, the present findings demonstrate that the skin temperature is weakly associated with morningness-eveningness and the stability of the circadian phase.

Hsp90β is a major chaperone involved in numerous cellular processes. Hundreds of client proteins depend on Hsp90β for proper folding and/or activity. Regulation of Hsp90β is critical to coordinate its tasks and is mediated by several post-translational modifications. Here, we focus on two phosphorylation sites located in the charged linker region of human Hsp90β, Ser226 and Ser255, which have been frequently reported but whose function remains unclear. Targeted measurements by mass spectrometry indicated that intracellular Hsp90β is highly phosphorylated on both sites (>90%). The level of phosphorylation was unaffected by various stresses (e.g., heat shock, inhibition with drugs) that impact Hsp90β activity. Mutating the two serines to alanines increased the amount of proteins interacting with Hsp90β globally and increased the sensitivity to tryptic cleavage in the C-terminal domain. Further investigation revealed that phosphorylation on Ser255 and to a lesser extent on Ser226 is decreased in the conditioned medium of cultured K562 cells, and that a non-phosphorylatable double alanine mutant was secreted more efficiently than the wild type. Overall, our results show that phosphorylation events in the charged linker regulate both the interactions of Hsp90β and its secretion, through changes in the conformation of the chaperone.

BACKGROUND:Cardio-pulmonary-resuscitation (CPR) training starting at the age of 12 years is recommended internationally. Training younger children is not recommended because young children lack the physical ability to perform adequate CPR and discouragement to perform CPR later is apprehended. The aim of this study was to answer the following questions: Are younger children discouraged after CPR training? Is discouragement caused by their lack in physical ability to perform adequate chest compressions on a standard manikin and would the use of manikins with a reduced resistance affect their motivation or performance? METHODS:We investigated the motivation and CPR performance of children aged 8-13 years after CPR training on manikins of different chest stiffness in a prospective, randomized, single-blind, controlled trial. 322 children underwent randomization and received 30 minutes CPR training in small groups at school. We used two optically identical resuscitation manikins with different compression resistances of 45kg and 30kg. Motivation was assessed with a self-administered questionnaire. Performance was measured with the Resusci®Anne SkillReporter™. FINDINGS:Motivation after the training was generally high and there was no difference between the two groups in any of the questionnaire items on motivation: Children had fun (98 vs. 99%; P = 0.32), were interested in the training (99 vs. 98%; P = 0.65), and were glad to train resuscitation again in the future (89 vs. 91%; P = 0.89). CPR performance was generally poor (median compression score (8, IQR 1-45 and 29, IQR 11-54; P

In our prospective non-randomized, single-center cohort study (n = 161), we have evaluated a multimarker approach including S100 calcium binding protein A12 (S100A1), interleukin 1 like-receptor-4 (IL1R4), adrenomedullin, copeptin, neutrophil gelatinase-associated lipocalin (NGAL), soluble urokinase plasminogen activator receptor (suPAR), and ischemia modified albumin (IMA) in prediction of subsequent cardiac adverse events (AE) during 1-year follow-up in patients with coronary artery disease. The primary endpoint was to assess the combined discriminatory predictive value of the selected 7 biomarkers in prediction of AE (myocardial infarction, coronary revascularization, death, stroke, and hospitalization) by canonical discriminant function analysis. The main secondary endpoints were the levels of the 7 biomarkers in the groups with/without AE; comparison of the calculated discriminant score of the biomarkers with traditional logistic regression and C-statistics. The canonical correlation coefficient was 0.642, with a Wilk’s lambda value of 0.78 and p < 0.001. By using the calculated discriminant equation with the weighted mean discriminant score (centroid), the sensitivity and specificity of our model were 79.4% and 74.3% in prediction of AE. These values were higher than that of the calculated C-statistics if traditional risk factors with/without biomarkers were used for AE prediction. In conclusion, canonical discriminant analysis of the multimarker approach is able to define the risk threshold at the individual patient level for personalized medicine.