Chronische posttraumatische Schulterinstabilität

Chronic posttraumatic shoulder instability is characterized by trauma-associated, recurrent dislocations. Surgical treatment is indicated in most cases but it remains controversial how risk factors should be weighted to decide between arthroscopic Bankart repair (ABR), Latarjet or alternative procedures. Known risk factors for recurrence are patient age, hyperlaxity, sports profile and bone loss. Surgical techniques are discussed in detail. The ABR leads to high patient satisfaction and return to sports; however, in association with risk factors, recurrent dislocations are seen even several years later. Latarjet or bone block procedures lead to high patient satisfaction, sustainable stability as a revision procedure, but can also be primarily indicated for chronic instability depending on risk factors. Early complications are more frequent but of a minor nature in most cases. All techniques are known for a serious learning curve. If performed well, they do not seem to increase the risk of arthritis, which is most affected by the number of lifetime dislocations and higher energy trauma

Offene Latarjet-Patte-Operation nach Walch : Tipps, Tricks und Komplikationsvermeidung

Walch hat die Latarjet-Patte-Operation in offener Technik unter Anwendung eines Subskapularis-Splits in den 1980er-Jahren modifiziert, standardisiert und über Jahrzehnte mit großem Erfolg bei über 3500 Patienten angewandt. In Langzeitnachuntersuchungen wurden Rezidivraten von 1–5 % bei hoher Patientenzufriedenheit im Subjective Shoulder Value (SSV > 90 %) dokumentiert [1, 2]. Diese Ergebnisse konnten in Zürich durch Gerber reproduziert werden [3]. Die Methode hat in mehreren Langzeitstudien den Beweis des Erreichens dauerhafter Stabilität (Langzeitstabilität nach mehr als 6 bis 10 Jahren) bei Risikopatienten erbracht [2, 3], besonders für Wettkampfsportler [4,5,6], junge Patienten [7, 8] und Patienten mit glenoidalem Knochenverlust [1, 9]. Bei korrekter Operationstechnik entsteht kein klinisch relevanter Beweglichkeitsverlust, und es besteht kein Zusammenhang mit der Entstehung oder Progression einer Instabilitätsarthrose [10]. In einer randomisierten kontrollierten Studie (RCT) zeigte sich eine signifikant niedrigere Reluxationsrate für die Latarjet-Stabilisierung bei jungen Männern unter 25 Jahren im Vergleich zur arthroskopischen Bankart-Operation [8]

Distinct clinical symptom patterns in patients hospitalised with COVID-19 in an analysis of 59,011 patients in the ISARIC-4C study

COVID-19 is clinically characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied clustering techniques to a large prospective cohort of hospitalised patients with COVID-19 to identify clinically meaningful sub-phenotypes. We obtained structured clinical data on 59,011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25,477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33,534 cases recruited to ISARIC-4C, and in 4,445 cases recruited to a separate study of community cases. Unsupervised clustering identified distinct sub-phenotypes. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were also identified, alongside a sub-phenotype of patients reporting few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom sub-phenotypes were highly consistent in replication analysis within the ISARIC-4C study. Similar patterns were externally verified in patients from a study of self-reported symptoms of mild disease. The large scale of the ISARIC-4C study enabled robust, granular discovery and replication. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four sub-phenotypes are usefully distinct from the core symptom group: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms

Voltage-dependent inactivation gating at the selectivity filter of the MthK K+ channel

Voltage-dependent K+ channels can undergo a gating process known as C-type inactivation, which involves entry into a nonconducting state through conformational changes near the channel’s selectivity filter. C-type inactivation may involve movements of transmembrane voltage sensor domains, although the mechanisms underlying this form of inactivation may be heterogeneous and are often unclear. Here, we report on a form of voltage-dependent inactivation gating observed in MthK, a prokaryotic K+ channel that lacks a canonical voltage sensor and may thus provide a reduced system to inform on mechanism. In single-channel recordings, we observe that Po decreases with depolarization, with a half-maximal voltage of 96 ± 3 mV. This gating is kinetically distinct from blockade by internal Ca2+ or Ba2+, suggesting that it may arise from an intrinsic inactivation mechanism. Inactivation gating was shifted toward more positive voltages by increasing external [K+] (47 mV per 10-fold increase in [K+]), suggesting that K+ binding at the extracellular side of the channel stabilizes the open-conductive state. The open-conductive state was stabilized by other external cations, and selectivity of the stabilizing site followed the sequence: K+ ≈ Rb+ > Cs+ > Na+ > Li+ ≈ NMG+. Selectivity of the stabilizing site is weaker than that of sites that determine permeability of these ions, suggesting that the site may lie toward the external end of the MthK selectivity filter. We could describe MthK gating over a wide range of positive voltages and external [K+] using kinetic schemes in which the open-conductive state is stabilized by K+ binding to a site that is not deep within the electric field, with the voltage dependence of inactivation arising from both voltage-dependent K+ dissociation and transitions between nonconducting (inactivated) states. These results provide a quantitative working hypothesis for voltage-dependent, K+-sensitive inactivation gating, a property that may be common to other K+ channels

Robust, reproducible clinical patterns in hospitalised patients with COVID-19

Background: Severe COVID-19 is characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied simple machine learning techniques to a large prospective cohort of hospitalised patients with COVID-19 identify clinically meaningful sub-groups. Methods: We obtained structured clinical data on 59 011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25 477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33 534 cases recruited to ISARIC-4C, and in 4 445 cases recruited to a separate study of community cases. Findings: Unsupervised clustering identified distinct sub-groups. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were common, and a subgroup of patients reported few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom clusters were highly consistent in replication analysis using a further 35446 individuals subsequently recruited to ISARIC-4C. Similar patterns were externally verified in 4445 patients from a study of self-reported symptoms of mild disease. Interpretation: The large scale of the ISARIC-4C study enabled robust, granular discovery and replication of patient clusters. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four patterns are usefully distinct from the core symptom groups: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms. These observations deepen our understanding of COVID-19 and will influence clinical diagnosis, risk prediction, and future mechanistic and clinical studies. Funding: Medical Research Council; National Institute Health Research; Well-come Trust; Department for International Development; Bill and Melinda Gates Foundation; Liverpool Experimental Cancer Medicine Centre

Distinct clinical symptom patterns in patients hospitalised with COVID-19 in an analysis of 59,011 patients in the ISARIC-4C study

COVID-19 is clinically characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied clustering techniques to a large prospective cohort of hospitalised patients with COVID-19 to identify clinically meaningful sub-phenotypes. We obtained structured clinical data on 59,011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25,477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33,534 cases recruited to ISARIC-4C, and in 4,445 cases recruited to a separate study of community cases. Unsupervised clustering identified distinct sub-phenotypes. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were also identified, alongside a sub-phenotype of patients reporting few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom sub-phenotypes were highly consistent in replication analysis within the ISARIC-4C study. Similar patterns were externally verified in patients from a study of self-reported symptoms of mild disease. The large scale of the ISARIC-4C study enabled robust, granular discovery and replication. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four sub-phenotypes are usefully distinct from the core symptom group: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms

Long-Term Potentiation in the CA1 Hippocampus Induced by NR2A Subunit-Containing NMDA Glutamate Receptors Is Mediated by Ras-GRF2/Erk Map Kinase Signaling

BACKGROUND: NMDA-type glutamate receptors (NMDARs) are major contributors to long-term potentiation (LTP), a form of synaptic plasticity implicated in the process of learning and memory. These receptors consist of calcium-permeating NR1 and multiple regulatory NR2 subunits. A majority of studies show that both NR2A and NR2B-containing NMDARs can contribute to LTP, but their unique contributions to this form of synaptic plasticity remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that NR2A and NR2B-containing receptors promote LTP differently in the CA1 hippocampus of 1-month old mice, with the NR2A receptors functioning through Ras-GRF2 and its downstream effector, Erk Map kinase, and NR2B receptors functioning independently of these signaling molecules. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that NR2A-, but not NR2B, containing NMDA receptors induce LTP in pyramidal neurons of the CA1 hippocampus from 1 month old mice through Ras-GRF2 and Erk. This difference add new significance to the observation that the relative levels of these NMDAR subtypes is regulated in neurons, such that NR2A-containing receptors become more prominent late in postnatal development, after sensory experience and synaptic activity

Enhanced Secretion of Amylase from Exocrine Pancreas of Connexin32-deficient Mice

To determine whether junctional communication between pancreatic acinar cells contributes to their secretory function in vivo, we have compared wild-type mice, which express the gap junctional proteins connexin32 (Cx32) and connexin26, to mice deficient for the Cx32 gene. Pancreatic acinar cells from Cx32 (−/−) mice failed to express Cx32 as evidenced by reverse transcription–PCR and immunolabeling and showed a marked reduction (4.8- and 25-fold, respectively) in the number and size of gap junctions. Dye transfer studies showed that the extent of intercellular communication was inhibited in Cx32 (−/−) acini. However, electrical coupling was detected by dual patch clamp recording in Cx32 (−/−) acinar cell pairs. Although wild-type and Cx32 (−/−) acini were similarly stimulated to release amylase by carbamylcholine, Cx32 (−/−) acini showed a twofold increase of their basal secretion. This effect was caused by an increase in the proportion of secreting acini, as detected with a reverse hemolytic plaque assay. Blood measurements further revealed that Cx32 (−/−) mice had elevated basal levels of circulating amylase. The results, which demonstrate an inverse relationship between the extent of acinar cell coupling and basal amylase secretion in vivo, support the view that the physiological recruitment of secretory acinar cells is regulated by gap junction mediated intercellular communication

Direct knock-on of desolvated ions governs strict ion selectivity in K+ channels

The seeming contradiction that K+ channels conduct K+ ions at maximal throughput rates while not permeating slightly smaller Na+ ions has perplexed scientists for decades. Although numerous models have addressed selective permeation in K+ channels, the combination of conduction efficiency and ion selectivity has not yet been linked through a unified functional model. Here, we investigate the mechanism of ion selectivity through atomistic simulations totalling more than 400 μs in length, which include over 7,000 permeation events. Together with free-energy calculations, our simulations show that both rapid permeation of K+ and ion selectivity are ultimately based on a single principle: the direct knock-on of completely desolvated ions in the channels' selectivity filter. Herein, the strong interactions between multiple 'naked' ions in the four filter binding sites give rise to a natural exclusion of any competing ions. Our results are in excellent agreement with experimental selectivity data, measured ion interaction energies and recent two-dimensional infrared spectra of filter ion configurations

Alterations in glutamatergic signaling contribute to the decline of circadian photoentrainment in aged mice

Robust physiological circadian rhythms form an integral part of well-being. The aging process has been found to negatively impact systems that drive circadian physiology, typically manifesting as symptoms associated with abnormal/disrupted sleeping patterns. Here, we investigated the age-related decline in light-driven circadian entrainment in male C57BL/6J mice. We compared light-driven resetting of circadian behavioral activity in young (1e2 months) and old (14e18 months) mice and explored alterations in the glutamatergic pathway at the level of the circadian pacemaker, the suprachiasmatic nucleus (SCN). Aged animals showed a significant reduction in sensitivity to behavioral phase resetting by light. We show that this change was through alterations in N-Methyl-D-aspartate (NMDA) signaling at the SCN, where NMDA, a glutamatergic agonist, was less potent in inducing clock resetting. Finally, we show that this shift in NMDA sensitivity was through the reduced SCN expression of this receptor’s NR2B subunit. Only in young animals did an NR2B antagonist attenuate behavioral resetting. These results can help target treatments that aim to improve both physiological and behavioral circadian entrainment in aged populations