Selective inhibition of neurogenic, but not agonist‐induced contractions by phospholipase A2 inhibitors points to presynaptic phospholipase A2 functions in contractile neurotransmission to human prostate smooth muscle

Background Phospholipases A2 (PLA2) may be involved in α1-adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1-adrenergic contractions of the prostate, is still unknown. While α1-adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2. Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues. Methods Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1-adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls. Results Frequency-dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3 and 1 µM) neither affected EFS-induced contractions, nor contractions by α1-adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM). Conclusions Our findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1-adrenergic agonists occur PLA2-independent. Lacking sensitivity to montelukast excludes an involvement of PLA2-derived leukotrienes in promotion of contractile neurotransmission

Current status of habitat monitoring in the European Union according to Article 17 of the Habitats Directive, with an emphasis on habitat structure and functions and on Germany

Since the beginning of the 1990s, monitoring of habitats has been a widespread tool to record and assess changes in habitat quality, for example due to land use change. Thus, Article 11 of the Habitats Directive (92/43/EEC) requires, inter alia, monitoring of the conservation status of habitat types listed in Annex I of the Habitats Directive, carried out by the Member States of the European Union (EU). This monitoring provides the foundation for the National Reports on the measures implemented and their effectiveness (Art. 17 Habitats Directive), which Member States have to submit to the European Commission every six years. Based on these requirements, Member States have developed different monitoring programmes or have adapted previously existing monitoring schemes to include relevant aspects of the Habitats Directive. The parameter ‘structure and functions’ is a key parameter for the assessment of the conservation status of habitat types as it provides information on the quality of the habitats. A standardised questionnaire was developed and sent to the competent authorities of Member States to compare and analyse the assessment methods of the quality of habitat types. Responses were received from 13 of the 28 Member States, while it was possible to include another Member State in the analysis by evaluating appropriate literature. The analysis revealed very different approaches and progress amongst the Member States in the development and implementation of monitoring programmes tailored to the reporting obligations of Article 17 of the Habitats Directive. Some Member States established a special standardised monitoring programme for Article 11 of the Habitats Directive, while others used data from already existing programmes (e.g. habitat mapping, large-scale forest inventories, landscape monitoring). Most Member States responding to the questionnaire use monitoring based on samples but the data collection, sample sizes and level of statistical certainty differ considerably. The same applies to the aggregation of data and the methods for the assessment of the parameter ‘structure and functions’. In contrast to the assessment of conservation status as part of the reporting obligations according to Article 17 of the Habitats Directive, no standardised EU guidelines exist for monitoring. The present study discusses differences in the monitoring programmes and evaluates them with regard to the objectives of comparable assessments of conservation status of habitat types in the National Reports of Member States or at a biogeographical level

Superior Functional Outcome and Comparable Health-Related Quality of Life after Enhanced Recovery vs. Conventional THA: A Retrospective Matched Pair Analysis

Background: The concept of enhanced recovery after total hip arthroplasty is gaining worldwide interest, as it shortens the length of hospital stay without an increase of complications. The aim of the study was to investigate the functional outcome and health-related quality of life 12 months after cementless total hip arthroplasty with the use of an enhanced recovery concept in comparison to a conventional rehabilitation. Material and Methods: 320 patients were retrospectively analyzed who underwent primary cementless total hip arthroplasty (THA). A total of 123 of the patients received an enhanced recovery program (ERAS) and 197 patients a conventional rehabilitation (Non-ERAS). Twelve months postoperatively, a clinical examination was performed regarding satisfaction, function and pain. Results were evaluated using WOMAC, EQ-5D-5L and EQ-VAS. A 1:1 matching was performed to correct for confounding variables, regarding age, sex and ASA score. Finally, 122 patients (n = 61, in each group) were analyzed and compared. Results: Patients showed a significant improvement of WOMAC total score, subscale pain, subscale stiffness and subscale function from preoperative to the follow up after 12 months in both groups, with significantly superior results for the WOMAC total score for the ERAS group (p = 0.042). EQ-5D and EQ-5D VAS showed a significant improvement from preoperative to 12 months postoperative (p < 0.001) for both groups, while no difference regarding the group-comparison was shown. Conclusion: Health-related quality of life and functional outcome increased to excellent values after total hip arthroplasty with the use of an enhanced recovery concept and a conventional rehabilitation, with a superior WOMAC total score for ERAS and a tendency to better results for health-related quality of life for patients with ERAS within the follow up after 12 months

Nucleated red blood cells are a late biomarker in predicting intensive care unit mortality in patients with COVID-19 acute respiratory distress syndrome: an observational cohort study

BackgroundNucleated red blood cells (nRBC) are precursor cells of the erythropoiesis that are absent from the peripheral blood under physiological conditions. Their presence is associated with adverse outcomes in critically ill patients. This study aimed to evaluate the predictive value of nRBC on mortality in intensive care unit (ICU) patients with COVID-19 acute respiratory distress syndrome (ARDS).Material and methodsThis retrospective, observational cohort study analyzed data on 206 ICU patients diagnosed with COVID-19 ARDS between March 2020 and March 2022. The primary endpoint was ICU mortality, and secondary endpoints included ICU and hospital stay lengths, ventilation hours, and the time courses of disease severity scores and clinical and laboratory parameters.ResultsAmong the included patients, 68.9% tested positive for nRBC at least once during their ICU stay. A maximum nRBC of 105 µl-1 had the highest accuracy in predicting ICU mortality (area under the curve of the receiver operating characteristic [AUCROC] 0.780, p &lt; 0.001, sensitivity 69.0%, specificity 75.5%). Mortality was significantly higher among patients with nRBC &gt;105 µl-1 than ≤105 µl-1 (86.5% vs. 51.3%, p = 0.008). Compared to patients negative for nRBC in their peripheral blood, those positive for nRBC required longer mechanical ventilation (127 [44 - 289] h vs. 517 [255 - 950] h, p &lt; 0.001), ICU stays (12 [8 – 19] vs. 27 [13 – 51] d, p &lt; 0.001), and hospital stays (19 [12 - 29] d vs. 31 [16 - 58] d, p &lt; 0.001). Peak Sepsis-related Organ Failure Assessment (SOFA), Simplified Acute Physiology Score, PaO2/FiO2, interleukin-6, and procalcitonin values were reached before the peak nRBC level. However, the predictive performance of the SOFA (AUCROC 0.842, p &lt; 0.001) was considerably improved when a maximum SOFA score &gt;8 and nRBC &gt;105 µl-1 were combined.DiscussionnRBC predict ICU mortality and indicate disease severity among patients with COVID-19 ARDS, and they should be considered a clinical alarm signal for a worse outcome. nRBC are a late predictor of ICU mortality compared to other established clinical scoring systems and laboratory parameters but improve the prediction accuracy when combined with the SOFA score

Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex

Disorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor-MOB2-in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic and cellular analysis of both variants confirmed them to be loss-of-function with enhanced sensitivity to transcript degradation via nonsense mediated decay (NMD) or increased protein turnover via the proteasome. Knockdown of Mob2 within the developing mouse cortex demonstrated its role in neuronal positioning. Cilia positioning and number within migrating neurons was also impaired with comparable defects detected following a reduction in levels of an upstream modulator of Mob2 function, Dchs1, a previously identified locus associated with PH. Moreover, reduced Mob2 expression increased phosphorylation of Filamin A, an actin cross-linking protein frequently mutated in cases of this disorder. These results reveal a key role for Mob2 in correct neuronal positioning within the developing cortex and outline a new candidate locus for PH development

Expression of B-RAF V600E in Type II Pneumocytes Causes Abnormalities in Alveolar Formation, Airspace Enlargement and Tumor Formation in Mice

Growth factor induced signaling cascades are key regulatory elements in tissue development, maintenance and regeneration. Perturbations of these cascades have severe consequences, leading to developmental disorders and neoplastic diseases. As a major function in signal transduction, activating mutations in RAF family kinases are the cause of human tumorigenesis, where B-RAF V600E has been identified as the prevalent mutant. In order to address the oncogenic function of B-RAF V600E, we have generated transgenic mice expressing the activated oncogene specifically in lung alveolar epithelial type II cells. Constitutive expression of B-RAF V600E caused abnormalities in alveolar epithelium formation that led to airspace enlargements. These lung lesions showed signs of tissue remodeling and were often associated with chronic inflammation and low incidence of lung tumors. The inflammatory cell infiltration did not precede the formation of the lung lesions but was rather accompanied with late tumor development. These data support a model where the continuous regenerative process initiated by oncogenic B-RAF-driven alveolar disruption provides a tumor-promoting environment associated with chronic inflammation

Motor-Cortical Interaction in Gilles de la Tourette Syndrome

BACKGROUND: In Gilles de la Tourette syndrome (GTS) increased activation of the primary motor cortex (M1) before and during movement execution followed by increased inhibition after movement termination was reported. The present study aimed at investigating, whether this activation pattern is due to altered functional interaction between motor cortical areas. METHODOLOGY/PRINCIPAL FINDINGS: 10 GTS-patients and 10 control subjects performed a self-paced finger movement task while neuromagnetic brain activity was recorded using Magnetoencephalography (MEG). Cerebro-cerebral coherence as a measure of functional interaction was calculated. During movement preparation and execution coherence between contralateral M1 and supplementary motor area (SMA) was significantly increased at beta-frequency in GTS-patients. After movement termination no significant differences between groups were evident. CONCLUSIONS/SIGNIFICANCE: The present data suggest that increased M1 activation in GTS-patients might be due to increased functional interaction between SMA and M1 most likely reflecting a pathophysiological marker of GTS. The data extend previous findings of motor-cortical alterations in GTS by showing that local activation changes are associated with alterations of functional networks between premotor and primary motor areas. Interestingly enough, alterations were evident during preparation and execution of voluntary movements, which implies a general theme of increased motor-cortical interaction in GTS

The BAF complex interacts with Pax6 in adult neural progenitors to establish a neurogenic cross-regulatory transcriptional network

Numerous transcriptional regulators of neurogenesis have been identified in the developing and adult brain, but how neurogenic fate is programmed at the epigenetic level remains poorly defined. Here, we report that the transcription factor Pax6 directly interacts with the Brg1-containing BAF complex in adult neural progenitor

Feeling and showing : A new conceptualization of dispositional teacher enthusiasm and its relation to students' interest

Although teacher enthusiasm is a relevant variable in the teaching context, a clear definition is still lacking. Research on teacher enthusiasm is characterized by ambiguous conceptualizations of enthusiasm as either an affective characteristic of teachers or behaviors of expressiveness. Integrating these two notions, a new conceptualization of dispositional teacher enthusiasm, defined by teachers' positive affect and positive emotional expressivity, was developed. It was hypothesized that dispositional teacher enthusiasm would relate to students' interest, mediated by students' perceived teacher enthusiasm. Based on a correlational study design, secondary teachers (N = 75) from Switzerland reported on their enthusiasm, complemented by student ratings (N = 1523) on perceived enthusiasm and interest. Multilevel structural equation modeling revealed that dispositional teacher enthusiasm positively predicted students' interest, which was fully mediated by students' perceived enthusiasm, providing the basis of a valid definition of teacher enthusiasm. Based on this integrative definition, implications for future research are discussed