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Purpose: To evaluate the classification performance of a new method to individualize reference ranges for biomarkers of muscle recovery in elite handball. Methods: In a longitudinal observational study, creatine kinase (CK) and urea levels were assessed in 16 male elite handball players during the 2019–20 preseason. Blood samples were collected at prespecified time points when players were considered either recovered or nonrecovered. Initially, linear mixed-effects models were calculated, as outlined in the study design, to examine the effect of recovery status on CK and urea levels. Finally, a fixed-effect model was calculated for urea based on the law of parsimony. Individualized reference ranges were calculated using a recently published algorithm. To investigate whether the individualized approach resulted in a more accurate classification of recovery status (recovered or nonrecovered), it was compared with a group-based approach derived from the same data set, utilizing predefined error rates. Results: Linear mixed-effects models showed a large effect of recovery status on CK (P d = 3.49) and a small effect on urea (P = .018, d = 0.382). In contrast to CK (P = .017), urea had no significant interindividual variation. Hence, individualization was examined only for CK. The numerical decrease in both CK error rates by the individualized approach was significant for the test-pass error rate (P = .0196, ϕ = .19). Conclusions: Our findings underscore the critical role of CK for monitoring in team sports such as handball. The observed improvement in CK error rates suggests a promising opportunity to individualize biochemical monitoring, although further studies encompassing larger sample sizes are warranted.

Introduction Diabetic ketoacidosis (DKA) is a life-threatening illness which classically presents with polyuria, polydipsia, and polyphagia that can rapidly progress to severe dehydration and altered mental status from cerebral edema. Younger patients may present with subtle or atypical symptoms that are critical to recognize and emergently act upon. Such patients are often cared for by teams in the emergency department (ED) requiring multidisciplinary collaboration. Methods This simulation case was designed for pediatric emergency medicine fellows and residents. The case was a 14-month-old male who presented to the ED with respiratory distress and dehydration. The team was required to perform an assessment, manage airway, breathing and circulation, and recognize and initiate treatment for DKA including judicious fluid administration and an insulin infusion. The patient developed altered mental status with signs of cerebral edema requiring the initiation of cerebral protection strategies. We created a debriefing guide and a participant evaluation form. Results Forty-two participants completed this simulation across seven institutions including attendings, residents, fellows, and nurses. The scenario was rated by participants on a 5-point Likert scale and was generally well received (M = 5.0). Participants rated the simulation case as effective in teaching how to recognize (M = 4.8) and manage (M = 4.5) DKA with cerebral edema in a pediatric patient. Discussion This simulation represents a resource for learners in the pediatric ED in the recognition and management of a toddler with DKA and can be adapted to learners at all levels and tailored to various learning environments.

Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule SMN2 splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.

The aim of this study was twofold. First, we aimed to assess the impact of forced diuresis with early furosemide injection on the detection rate of local recurrence in prostate cancer patients with biochemical recurrence referred for (68)Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC ((68)Ga-PSMA-11) PET/CT. Second, we determined whether intravenous administration of furosemide shortly after tracer injection increases renal washout of (68)Ga-PSMA-11 before it binds to the PSMA receptor with possible influence on biodistribution and intensity of tracer uptake in organs with physiologic tracer accumulation. Methods: In a retrospective analysis, 2 different groups with 220 prostate cancer patients each, referred for (68)Ga-PSMA-11 PET/CT because of biochemical recurrence after primary therapy, were compared: patients in group 1 (median prostate-specific antigen, 1.30 ng/mL) received no preparation before imaging, whereas patients in group 2 (median prostate-specific antigen, 0.82 ng/mL) were injected with 20 mg of furosemide and 500 mL of sodium chloride (NaCl 0.9%) immediately after tracer injection. The presence of local recurrence was assessed visually. In addition, the intensity of tracer accumulation in organs with physiologic tracer uptake was evaluated. Results: The detection rate of lesions judged positive for local recurrence was significantly higher in patients receiving furosemide than in patients without preparation: 56 cases (25.5%) versus 38 cases (17.3%), respectively (P = 0.048). Median maximum SUVs (SUV(max)) of organs with physiologic uptake of (68)Ga-PSMA-11 in groups 1 and 2 were urinary bladder (63.0 vs. 8.9), kidney (55.6 vs. 54.5), liver (9.9 vs. 9.4), spleen (11.2 vs. 11.9), small bowel (16.2 vs. 17.1), parotid gland (19.2 vs. 19.6), lacrimal gland (8.9 vs. 10.9), blood-pool activity (2.2 vs. 2.3), muscle (1.0 vs. 1.1), and bone (1.6 vs. 1.6). Apart from bladder activity, no significant reduction of tracer accumulation was found in the patient group receiving furosemide. Conclusion: Injection of 20 mg of furosemide at the time point of radiotracer administration significantly increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence referred for (68)Ga-PSMA-11 PET/CT. As intensity of (68)Ga-PSMA-11 uptake in organs with physiologic uptake is not significantly reduced, a negative impact of early furosemide injection on targeting properties and biodistribution of (68)Ga-PSMA-11 seems unlikely.

The monitoring of athletes has become a focus in elite-level team sports and research in recent years. The goal is to optimise load management for maximising performance. Due to the considerable amount of data gathered during monitoring in team sports, the trend is towards integrating different monitoring methods in a software-based tool. In addition, decision-support systems are used in order to enable coaches to make quick decisions to control further burdens. This article is intended to give an overview of the large number of monitoring methods used in contact team sports, to consider their test quality criteria and to check a useful application of monitoring methods for team handball, taking into account the sports-specific requirements. PubMed-based review of the literature. Narrative review focusing on current data from the years 2010 to 2019. Demands on athletes in elite team handball vary depending on the playing position. Therefore, individualised load control is necessary. Monitoring methods with proven validity and reliability should ideally be used in a multivariate approach to represent the various aspects of external and internal load, recovery and fatigue, well-being and readiness. It is important to know the meaningful change for each athlete while using a monitoring method. This circumstance necessitates an individualised approach for each parameter. There are not many studies on the use of monitoring methods in team handball, neither in the amateur field nor in an elite sports environment. Nevertheless, based on evidence from other contact team sports, a recommendation for a combined use of monitoring methods can be given. Burden, time and cost/benefit should always be considered. There is a considerable need for research regarding the use of athlete monitoring in team handball. The combination of monitoring methods proposed in this article can be used as a framework for studies with handball players in an elite sports environment in order to implement an increasingly handball-specific monitoring concept in the future. Das Monitoring von Athleten ist in den letzten Jahren in den Fokus des Spitzensports und der Forschung gerückt. Das Ziel ist die Optimierung der Trainings und Belastungssteuerung. Aufgrund der erheblichen Datenmenge im zeitlichen Verlauf eines Monitorings geht der Trend in Mannschaftssportarten zur Integration einer sinnvollen Auswahl von verschiedenen Monitoringverfahren in eine Softwarelösung. Zusätzlich kommen hier Systeme zur Entscheidungsunterstützung zum Einsatz, um den Trainern eine schnelle Entscheidung im Rahmen der Trainings- und Belastungssteuerung zu ermöglichen. Dieser Artikel soll einen Überblick über die Vielzahl an eingesetzten Monitoringverfahren in Kontakt-Mannschaftssportarten geben, deren Testgütekriterien berücksichtigen und eine sinnvolle Anwendung für den Hallenhandball unter Beachtung der sportartspezifischen Anforderungen prüfen. PubMed-basierte Literaturrecherche. Narrativer Review mit Fokus auf aktuellen Daten aus den Jahren 2010–2019. Im Hallenhandball existieren für die Athleten je nach Spielposition verschiedene Anforderungsprofile. Daher ist eine individualisierte Belastungssteuerung notwendig. Monitoringverfahren mit nachgewiesener Validität und Reliabilität sollten idealerweise in einem multivariaten Ansatz angewendet werden, um die verschiedenen Aspekte der Belastung und Beanspruchung, Erholung und Ermüdung, Wohlbefinden und Bereitschaft zu trainieren/zu spielen darzustellen. Dabei ist es wichtig, für jeden Athleten die bedeutsame Änderung in einem Monitoringverfahren zu kennen. Dieser Umstand macht eine individualisierte Herangehensweise für jeden Zielparameter unerlässlich. Es existieren sehr wenige Studien hinsichtlich der Anwendung von Monitoringverfahren bei Handballern, weder im Amateurbereich noch in einer Spitzensportumgebung. Dennoch kann anhand der Evidenz aus anderen Kontakt-Mannschaftssportarten eine Empfehlung für einen kombinierten Einsatz von Monitoringverfahren gegeben werden. Dabei sollte stets ein Kosten-Nutzen-Ansatz berücksichtigt werden. Es besteht Forschungsbedarf bezüglich des Einsatzes eines Athletenmonitorings im Hallenhandball. Der in diesem Artikel vorgeschlagene Monitoringansatz kann als Grundlage für Studien in einer Spitzensportumgebung genutzt werden, um in Zukunft ein zunehmend handballspezifischeres Konzept zu implementieren.

to assess the influence of intravenous hydration and forced diuresis with furosemide in two different dosages (20 vs 40 mg) on the intensity of tracer accumulation in the urinary collection system and on the occurrence of halo artefact surrounding the urinary bladder and kidneys in [Comparison of four groups with 50 patients each, receiving different preparation prior to [Halo artefact of the urinary bladder was present in twelve patients without preparation, in eight patients receiving only sodium chloride, in one patient injected with 20 mg furosemide/sodium chloride and in two patients receiving 40 mg furosemide/sodium chloride, showing a median SUVPerforming [

Diagnostic imaging plays an important role in the detection of paraganglioma (PGL), pheochromocytoma (PCC), and neuroblastoma (NB). Anatomic imaging, for example CT or MRI, offers high sensitivity in these neuroendocrine tumors (NET) but only moderate specificity, often associated with difficulties in clearly distinguishing between NET and non-NET. Functional imaging, as in the use of different radioisotopes, is indispensable in oncological imaging. The introduction of PET and PET/CT, respectively, led to a dramatic improvement in both malignant and non-malignant PGL, PCC, and NB, assessing the exact tumor extent. This review gives an overview of functional and anatomical imaging in PGL, PCC, and NB.

The purpose of this study was to investigate the diagnostic performance ofSixteen metastatic PC patients with known skeletal metastases, who underwent bothIn contrast to 468 PET-positive lesions suggestive of bone metastases onIn comparison to

The aim of this study was to compare the accuracy ofThree men and seven women (age range 26-73 years) with anatomical and/or histologically proven disease were included in this study. Three patients had either metastatic head-and-neck paragangliomas (HNPGLs) or multifocal PGL, and seven patients had nonmetastatic disease. Comparative evaluation included morphological imaging with CT, functional imaging withOn a per-patient basis

PET/CT withEighty consecutive PC patients referred toA total of 55 lesions consistent with malignancy on 60 min whole body imaging exhibited also pathologicEarly dynamic imaging in

As part of the innate host response neutrophils release neutrophil extracellular traps (NETs), protein:DNA complexes that contain a number of antimicrobial peptides (AMPs), such as cathelicidin. Human cathelicidin in its active form, LL37, has potent antimicrobial activity against bacteria. However, whether LL37 derived from NETs contributes to antimicrobial activity against intracellular pathogens remains unclear. Here, we report that NETs induced by mycobacteria contain cathelicidin. Human macrophages internalized NET-bound cathelicidin, which is transported to lysosomal compartments. Furthermore, using a model of in vitro-generated LL37:DNA complexes we found that LL37 derived from such complexes attacks mycobacteria in macrophage phagolysosomes resulting in antimicrobial activity. Taken together, our results suggest a mechanism by which LL37 in complex with DNA contributes to host defence against intracellular bacteria in human macrophages.

Glucocorticoids are extensively used to treat inflammatory diseases; however, their chronic intake increases the risk for mycobacterial infections. Meanwhile, the effects of glucocorticoids on innate host responses are incompletely understood. In this study, we investigated the direct effects of glucocorticoids on antimycobacterial host defense in primary human macrophages. We found that glucocorticoids triggered the expression of cathelicidin, an antimicrobial critical for antimycobacterial responses, independent of the intracellular vitamin D metabolism. Despite upregulating cathelicidin, glucocorticoids failed to promote macrophage antimycobacterial activity. Gene expression profiles of human macrophages treated with glucocorticoids and/or IFN-γ, which promotes induction of cathelicidin, as well as antimycobacterial activity, were investigated. Using weighted gene coexpression network analysis, we identified a module of highly connected genes that was strongly inversely correlated with glucocorticoid treatment and associated with IFN-γ stimulation. This module was linked to the biological functions autophagy, phagosome maturation, and lytic vacuole/lysosome, and contained the vacuolar H+-ATPase subunit a3, alias TCIRG1, a known antimycobacterial host defense gene, as a top hub gene. We next found that glucocorticoids, in contrast with IFN-γ, failed to trigger expression and phagolysosome recruitment of TCIRG1, as well as to promote lysosome acidification. Finally, we demonstrated that the tyrosine kinase inhibitor imatinib induces lysosome acidification and antimicrobial activity in glucocorticoid-treated macrophages without reversing the anti-inflammatory effects of glucocorticoids. Taken together, we provide evidence that the induction of cathelicidin by glucocorticoids is not sufficient for macrophage antimicrobial activity, and identify the vacuolar H+-ATPase as a potential target for host-directed therapy in the context of glucocorticoid therapy.

An unexpected role for the classical complement cascade in the elimination of central nervous system (CNS) synapses has recently been discovered. Complement proteins are localized to developing CNS synapses during periods of active synapse elimination and are required for normal brain wiring. The function of complement proteins in the brain appears analogous to their function in the immune system: clearance of cellular material that has been tagged for elimination. Similarly, synapses tagged with complement proteins may be eliminated by microglial cells expressing complement receptors. In addition, developing astrocytes release signals that induce the expression of complement components in the CNS. In the mature brain, early synapse loss is a hallmark of several neurodegenerative diseases. Complement proteins are profoundly upregulated in many CNS diseases prior to signs of neuron loss, suggesting a reactivation of similar developmental mechanisms of complement-mediated synapse elimination potentially driving disease progression.

et al., Calmodulin (CaM) is the major component of calcium signaling pathways mediating the action of various effectors. Transient increases in the intracellular calcium level triggered by a variety of stimuli lead to the formation of Ca2+/CaM complexes, which interact with and activate target proteins. In the present study the role of Ca2+/CaM in the regulation of the ligand-dependent activation of the epidermal growth factor receptor (EGFR) has been examined in living cells. We show that addition of different cell permeable CaM antagonists to cultured cells or loading cells with a Ca2+ chelator inhibited ligand-dependent EGFR auto(trans)phosphorylation. This occurred also in the presence of inhibitors of protein kinase C, CaM-dependent protein kinase II and calcineurin, which are known Ca2+- and/or Ca2+/CaM-dependent EGFR regulators, pointing to a direct effect of Ca2+/CaM on the receptor. Furthermore, we demonstrate that down-regulation of CaM in conditional CaM knock out cells stably transfected with the human EGFR decreased its ligand-dependent phosphorylation. Substitution of six basic amino acid residues within the CaM-binding domain (CaM-BD) of the EGFR by alanine resulted in a decreased phosphorylation of the receptor and of its downstream substrate phospholipase Cγ1. These results support the hypothesis that Ca2+/CaM regulates the EGFR activity by directly interacting with the CaM-BD of the receptor located at its cytosolic juxtamembrane region., This work was financed by grants (to A. V.) from the Ministerio de Ciencia e Innovación (SAF2008-00986 and SAF2011-23494) and the European Commission (contract ITN 289033); Grant from the Danish Research Council (to M. W. B.), the Lundbeck Foundation, AP Møller Fonden, Dagmar Marshall Fonden, Willumsen Fonden, Danielsen Fonden, and Wedell Wedellsborg Fonden.

Neutrophil extracellular traps (NETs), large chromatin structures casted with various proteins, are externalized by neutrophils upon induction by both self- and non-self-stimuli. It has become clear that NETs are potent triggers of inflammation in autoimmune skin diseases. Moreover, the ability of NETs to trap pathogens suggests a crucial role in innate host defense. However, the outcome of the encounter between pathogens and NETs remains highly controversial. Here, we discuss recent insights into the morphology and formation of NETs, their role in skin inflammation and how NETs might contribute to host protection in skin infection.

The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.

During the initial stage of neuromuscular junction (NMJ) formation, nerve-derived agrin cooperates with muscle-autonomous mechanisms in the organization and stabilization of a plaque-like postsynaptic specialization at the site of nerve–muscle contact. Subsequent NMJ maturation to the characteristic pretzel-like appearance requires extensive structural reorganization. We found that the progress of plaque-to-pretzel maturation is regulated by agrin. Excessive cleavage of agrin via transgenic overexpression of an agrin-cleaving protease, neurotrypsin, in motoneurons resulted in excessive reorganizational activity of the NMJs, leading to rapid dispersal of the synaptic specialization. By contrast, expression of cleavage-resistant agrin in motoneurons slowed down NMJ remodeling and delayed NMJ maturation. Neurotrypsin, which is the sole agrin-cleaving protease in the CNS, was excluded as the physiological agrin-cleaving protease at the NMJ, because NMJ maturation was normal in neurotrypsin-deficient mice. Together, our analyses characterize agrin cleavage at its proteolytic α- and β-sites by an as-yet-unspecified protease as a regulatory access for relieving the agrin-dependent constraint on endplate reorganization during NMJ maturation.

The synaptic serine protease neurotrypsin is thought to be important for adaptive synaptic processes required for cognitive functions, because humans deficient in neurotrypsin suffer from severe mental retardation. In the present study, we describe the biochemical characterization of neurotrypsin and its so far unique substrate agrin. In cell culture experiment as well as in neurotrypsin-deficient mice, we showed that agrin cleavage depends on neurotrypsin and occurs at two conserved sites. Neurotrypsin and agrin were expressed recombinantly, purified, and assayed in vitro. A catalytic efficiency of 1.3 x 10(4) M(-1) x s(-1) was determined. Neurotrypsin activity was shown to depend on calcium with an optimal activity in the pH range of 7-8.5. Mutagenesis analysis of the amino acids flanking the scissile bonds showed that cleavage is highly specific due to the unique substrate recognition pocket of neurotrypsin at the active site. The C-terminal agrin fragment released after cleavage has recently been identified as an inactivating ligand of the Na+/K+-ATPase at CNS synapses, and its binding has been demonstrated to regulate presynaptic excitability. Therefore, dysregulation of agrin processing is a good candidate for a pathogenetic mechanism underlying mental retardation. In turn, these results may also shed light on mechanisms involved in cognitive functions.