Muscle preflex response to perturbations in locomotion: In vitro experiments and simulations with realistic boundary conditions.

Neuromuscular control loops feature substantial communication delays, but mammals run robustly even in the most adverse conditions. In vivo experiments and computer simulation results suggest that muscles' preflex-an immediate mechanical response to a perturbation-could be the critical contributor. Muscle preflexes act within a few milliseconds, an order of magnitude faster than neural reflexes. Their short-lasting action makes mechanical preflexes hard to quantify in vivo. Muscle models, on the other hand, require further improvement of their prediction accuracy during the non-standard conditions of perturbed locomotion. Our study aims to quantify the mechanical work done by muscles during the preflex phase (preflex work) and test their mechanical force modulation. We performed in vitro experiments with biological muscle fibers under physiological boundary conditions, which we determined in computer simulations of perturbed hopping. Our findings show that muscles initially resist impacts with a stereotypical stiffness response-identified as short-range stiffness-regardless of the exact perturbation condition. We then observe a velocity adaptation to the force related to the amount of perturbation similar to a damping response. The main contributor to the preflex work modulation is not the change in force due to a change in fiber stretch velocity (fiber damping characteristics) but the change in magnitude of the stretch due to the leg dynamics in the perturbed conditions. Our results confirm previous findings that muscle stiffness is activity-dependent and show that also damping characteristics are activity-dependent. These results indicate that neural control could tune the preflex properties of muscles in expectation of ground conditions leading to previously inexplicable neuromuscular adaptation speeds.

[Digitally supported rheumatological screening consultation : How useful is a questionnaire scoring system (RhePort)?] / Digital unterstützte rheumatologische Screeningsprechstunde : Wie hilfreich ist ein Fragebogen-Scoringsystem (RhePort)?

Regarding scarce capacities an early detection consultation (EDC) was established to discriminate patients in an outpatient setting with inflammatory from non-inflammatory rheumatic diseases. A total of 500 patients suspected of having a rheumatic disease received an appointment within 2 weeks. They were interviewed with the help of a digital questionnaire (RhePort), briefly physically examined followed by a determination of CRP. The questionnaire answers were scored using an algorithm within RhePort (from 0 = non-inflammatory to 4 = highly probably inflammatory). Likewise, after completion of the EDC, the rheumatologists scored the overall assessment. The RhePort score and EDC score were compared with the "true" diagnosis made in a detailed second examination after an average of 10 weeks. In 490 evaluable patients 133 inflammatory (27%) and 357 noninflammatory rheumatic diseases (73%) were diagnosed. A classification based solely on the RhePort questionnaire (score > 1) identified 103 out of 129 as inflammatory (sens. 80%) and 125 out of 355 as non-inflammatory (spec. 35%) resulting in an AUC of 0.62 after ROC analysis. With a score > 1, the rheumatological assessment after EDC classified 130 out of 133 patients as inflammatory (sensitivity 98%) and 261 out of 357 as non-inflammatory (specificity 73%). The combined EDC can decisively increase the sensitivity and specificity compared to an "automated" survey by means of a digital questionnaire alone. In addition to the early identification and treatment of inflammatory patients, rapid identification of patients who are not in need of rheumatological treatment can create capacities for care.

How velocity impacts eccentric force generation of fully activated skinned skeletal muscle fibers in long stretches.

Ecccentric muscle contractions are fundamental to everyday life. They occur markedly in jumping, running, and accidents. Following an initial force rise, stretching of a fully activated muscle can result in a phase of decreasing force ("Give") followed by force redevelopment. However, how the stretch velocity affects "Give" and force redevelopment remains largely unknown. We investigated the force produced by fully activated single-skinned fibers of rat extensor digitorum longus muscles during long stretches. Fibers were pulled from length 0.85 to 1.3 optimal fiber length at a rate of 1%, 10%, and 100% of the estimated maximum shortening velocity. "Give" was absent in slow stretches. Medium and fast stretches yielded a clear "Give." After the initial force peak, forces decreased by 11.2% and 27.8% relative to the initial peak force before rising again. During the last half of the stretch (from 1.07 to 1.3 optimal fiber length, which is within the range of the expected descending limb of the force-length relationship), the linear force slope tripled from slow to medium stretch and increased further by 60% from medium to fast stretch. These results are compatible with forcible cross-bridge detachment and redevelopment of a cross-bridge distribution, and a viscoelastic titin contribution to fiber force. Accounting for these results can improve muscle models and predictions of multibody simulations.NEW & NOTEWORTHY Eccentric muscle contractions are part of our daily lives. We found that force increased monotonically during slow stretches of fully activated muscle fibers, whereas higher stretch velocities resulted in an increasing drop in force after an initial increase and a final steeper rise in force. Cross-bridges cannot explain the observed force traces. This requires a viscoelastic non-cross-bridge contribution. Considering these results can improve muscle models and predictions of multibody simulations.

Power Amplification Increases With Contraction Velocity During Stretch-Shortening Cycles of Skinned Muscle Fibers.

Muscle force, work, and power output during concentric contractions (active muscle shortening) are increased immediately following an eccentric contraction (active muscle lengthening). This increase in performance is known as the stretch-shortening cycle (SSC)-effect. Recent findings demonstrate that the SSC-effect is present in the sarcomere itself. More recently, it has been suggested that cross-bridge (XB) kinetics and non-cross-bridge (non-XB) structures (e.g., titin and nebulin) contribute to the SSC-effect. As XBs and non-XB structures are characterized by a velocity dependence, we investigated the impact of stretch-shortening velocity on the SSC-effect. Accordingly, we performed in vitro isovelocity ramp experiments with varying ramp velocities (30, 60, and 85% of maximum contraction velocity for both stretch and shortening) and constant stretch-shortening magnitudes (17% of the optimum sarcomere length) using single skinned fibers of rat soleus muscles. The different contributions of XB and non-XB structures to force production were identified using the XB-inhibitor Blebbistatin. We show that (i) the SSC-effect is velocity-dependent-since the power output increases with increasing SSC-velocity. (ii) The energy recovery (ratio of elastic energy storage and release in the SSC) is higher in the Blebbistatin condition compared with the control condition. The stored and released energy in the Blebbistatin condition can be explained by the viscoelastic properties of the non-XB structure titin. Consequently, our experimental findings suggest that the energy stored in titin during the eccentric phase contributes to the SSC-effect in a velocity-dependent manner.

Cross-Bridges and Sarcomeric Non-cross-bridge Structures Contribute to Increased Work in Stretch-Shortening Cycles.

Stretch-shortening cycles (SSCs) refer to the muscle action when an active muscle stretch is immediately followed by active muscle shortening. This combination of eccentric and concentric contractions is the most important type of daily muscle action and plays a significant role in natural locomotion such as walking, running or jumping. SSCs are used in human and animal movements especially when a high movement speed or economy is required. A key feature of SSCs is the increase in muscular force and work during the concentric phase of a SSC by more than 50% compared with concentric muscle actions without prior stretch (SSC-effect). This improved muscle capability is related to various mechanisms, including pre-activation, stretch-reflex responses and elastic recoil from serial elastic tissues. Moreover, it is assumed that a significant contribution to enhanced muscle capability lies in the sarcomeres itself. Thus, we investigated the force output and work produced by single skinned fibers of rat soleus muscles during and after ramp contractions at a constant velocity. Shortening, lengthening, and SSCs were performed under physiological boundary conditions with 85% of the maximum shortening velocity and stretch-shortening magnitudes of 18% of the optimum muscle length. The different contributions of cross-bridge (XB) and non-cross-bridge (non-XB) structures to the total muscle force were identified by using Blebbistatin. The experiments revealed three main results: (i) partial detachment of XBs during the eccentric phase of a SSC, (ii) significantly enhanced forces and mechanical work during the concentric phase of SSCs compared with shortening contractions with and without XB-inhibition, and (iii) no residual force depression after SSCs. The results obtained by administering Blebbistatin propose a titin-actin interaction that depends on XB-binding or active XB-based force production. The findings of this study further suggest that enhanced forces generated during the active lengthening phase of SSCs persist during the subsequent shortening phase, thereby contributing to enhanced work. Accordingly, our data support the hypothesis that sarcomeric mechanisms related to residual force enhancement also contribute to the SSC-effect. The preload of the titin molecule, acting as molecular spring, might be part of that mechanism by increasing the mechanical efficiency of work during physiological SSCs.

Developing an mHealth app for post-stroke upper limb rehabilitation: Feedback from US and Ethiopian rehabilitation clinicians.

Stroke is the leading cause of adult disability worldwide, with 70 percent of survivors exhibiting residual impairments of the upper limb that require frequent in-person visits to rehabilitation clinic over several months. This study explored rehabilitation clinician's preferences for design features to be included in an mHealth-enabled app for post-stroke upper limb rehabilitation. Data were collected via online survey, sampling participants from Ethiopia (n = 69) and the United States (n = 75). Survey results indicated that Ethiopian and US rehabilitation clinicians have different opinions about the importance of design features that should be included in a stroke tele-rehabilitation system which are likely due to differences in culture, the availability of human and physical resources, and how the field of rehabilitation is organized and managed. Our results, thus, indicate that mHealth technologies must be tailored to the geographical and cultural context of the end users.

Pulmonary manifestation of a Langerhans cell sarcoma: case report and review of the literature.

In the following, we describe the very rare case of Langerhans cell sarcoma (LCS) in the lung. Throughout the medical literature, only a few cases have been published, and, to the best of our knowledge, this is the first case to be reported in Germany. The patient was an 81-year-old man who showed symptoms such as chronic cough and weight loss. Clinical examination including needle biopsy indicated a high possibility of carcinoma in the right lung and in the mediastinum; however, the final histopathological diagnosis after immunohistochemistry gave evidence of LCS. LCS is a neoplastic proliferation of Langerhans cells with malignant cytological features exhibiting a very aggressive behaviour. LCS can be distinguished from other carcinomas, lymphomas and sarcomas by the typical morphological features of Langerhans cells and the immunophenotype with a consistent expression of S-100 protein and CD1a. In contrast to Langerhans cell histiocytosis, the LCS consists of Langerhans cells with high atypia and a very high mitotic rate.

Histologic analysis of renal leukocyte infiltration in antineutrophil cytoplasmic antibody-associated vasculitis: importance of monocyte and neutrophil infiltration in tissue damage.

OBJECTIVE: The histopathologic lesions in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been studied extensively, but the exact composition of the cellular infiltrate is unclear. We undertook this study to analyze renal leukocyte infiltration and the cellular distribution within glomeruli and interstitium in 65 renal biopsy samples obtained from patients newly diagnosed as having AAV. METHODS: Renal cellular tissue infiltration was assessed with an immunoperoxidase method. Furthermore, the infiltrating cell types were correlated with clinical and histopathologic data. RESULTS: The predominant interstitial infiltrating cells were T lymphocytes, while monocytes and, to a lesser extent, granulocytes constituted the dominant infiltrating cell types in glomeruli. Interestingly, lymphocyte infiltration was predominantly periglomerular, especially around glomeruli with sclerosis or heavy crescent formation, while interstitial monocyte and neutrophil infiltration was diffusely distributed over the interstitial tissue. A significant correlation was found for the glomerular infiltration of CD68-positive macrophages with the presence of glomerular necrosis as well as with the number of glomeruli with crescents (P < 0.0001 and P = 0.005, respectively). No correlation was found for interstitial fibrosis with the infiltration of any leukocyte subset. Furthermore, a significant correlation was found for the interstitial as well as for the glomerular infiltration of CD68-positive macrophages with serum creatinine concentration at the time of biopsy (P = 0.001 and P = 0.006, respectively). CONCLUSION: These data underscore a major role of monocytes in addition to neutrophils in the tissue damage of AAV.

Interventional radiology and the musculoskeletal system.

Imaging-guided interventional procedures are becoming increasingly important in clinical rheumatology, since arthrocentesis of peripheral joints and the spine, as well as soft tissue injections, have a high rate of para-articular localisation when performed as blind techniques. Ultrasound-guided needle placement is the method of choice for interventional procedures on peripheral joints and for soft tissue injections. Fluoroscopy and computed tomography (CT) are not recommended for these indications due to the application of ionising radiation and the high procedural effort. By contrast, CT and magnetic resonance imaging are preferred for a variety of percutaneous procedures on the spine and sacroiliac joints. The increasing use of these methods for interventional purposes should improve both technical and procedural quality, thus ensuring cost-effectiveness and patient safety.

ANCA-associated vasculitis with renal involvement: an outcome analysis.

BACKGROUND: The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a group of heterogeneous diseases. This study was undertaken to investigate the outcome of Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and renal-limited vasculitis (RLV). Furthermore, we analysed the differences in patients with proteinase 3-ANCA (PR3-ANCA) and those with myeloperoxidase-ANCA (MPO-ANCA), which have not been assessed in a homogeneously treated group of patients with renal involvement. METHODS: In this retrospective analysis, 80 patients with a new diagnosis of WG, MPA or RLV with biopsy-proven renal involvement were followed over a median of 46.7 months (range: 0.8-181.9 months). All patients had induction treatment with cyclophosphamide and oral corticosteroids. RESULTS: At the end of follow-up, 23% were dependent on dialysis. Renal survival was significantly worse in patients with WG compared with patients with MPA or RLV (P = 0.04). A higher rate of end-stage renal disease (ESRD) was noticed in PR3-ANCA- vs MPO-ANCA-positive patients. A total of 21 patients (26%) died. Predictors of patient mortality were development of ESRD, older age and the maximum creatinine in the first month. Mortality was found to be higher in patients with WG and was significantly higher in PR3-ANCA-positive cases (P = 0.02). The relative risk of death was 9.32 times higher in PR3-ANCA- vs MPO-ANCA-positive patients. CONCLUSIONS: Our data underscore the pathogenetic potential of ANCA by demonstrating a more aggressive disease state and a poorer outcome in patients with PR3-ANCA.

Specific inhibition of Egr-1 prevents mesangial cell hypercellularity in experimental nephritis.

BACKGROUND: Mesangial cell proliferation is a frequent finding in glomerulonephritis. In cultured mesangial cells, we demonstrated that inhibition of the zinc finger transcription factor, early growth response gene-1 (Egr-1), by specific antisense oligonucleotides (AS ODN) blocks mesangial cell proliferation. Therefore, we here investigated the effect of Egr-1 inhibition on the course of an experimental mesangioproliferative glomerulonephritis in vivo. METHODS: On day 3 after induction of anti-Thy-1.1 nephritis, specific glomerular oligonucleotide transfer was achieved by injection of an oligonucleotide/hemagglutinating virus of Japan/liposome mixture into the left renal artery. The right kidney was left untreated. RESULTS: Induction of nephritis led to a sixfold induction of Egr-1 protein on day 6 of disease. This increase in Egr-1 expression was reduced by 48% in the left kidney by transfer of specific AS ODN. In parallel, the increases in glomerular cellularity, number of mitoses, and glomerular tuft area observed in day 6 nephritic animals were inhibited in the left kidney by 60%, 53%, and 50%, respectively. Changes in the right kidney were not significantly influenced. Likewise, control oligonucleotides showed no effect. Finally, the expression of platelet-derived growth factor-B (PDGF-B), a known target gene of Egr-1, was repressed by transfer of specific AS ODN against Egr-1. CONCLUSION: We conclude that the transcription factor Egr-1 plays a critical role for mesangial cell proliferation in vivo. Interfering with the induction of Egr-1 or with its target genes could give rise to novel therapeutic principles in mesangioproliferative glomerulonephritis.