Diagnostic delay in Hidradenitis suppurativa investigated using data from social media and from statutory health insurances.

BACKGROUND: The chronic inflammatory skin disease hidradenitis suppurativa (HS) leads to severe pain and reduced quality of life. Nonetheless, it often takes years until a correct diagnosis is made. In this analysis, disease-related experiences and pathways of patients with HS were investigated and compared with the physicians' perspective. METHODS: Public posts on forums and social media as well as results of a survey conducted among dermatologists and their patients on the actual medical care reality of HS in Germany were analysed. Furthermore, claims data from German health insurance companies were evaluated. RESULTS: Patients with HS suffer from a 43.3% reduction in working ability. Dermatology (26.5%) was the most frequently consulted specialty, with HS diagnosed predominantly in the inpatient setting (43.8%). Abscesses were described as the most frequent alternative diagnosis in HS patients (53.2%). Patient-reported changes of physicians in dermatology (34.1%) and surgery (42.4%) occurred predominantly within the specialty. Dermatology received most referrals from general practitioners (67.1%), but only 12.1% from surgeons. CONCLUSION: There is an urgent need to reduce the delay in diagnosis and the prolonged burden of disease in patients with HS. Therefore, awareness of the disease, its detection and treatment which goes beyond dermatology should be promoted, if possible as part of medical studies.

Drug switching in axial spondyloarthritis patients in Germany - a social listening analysis.

Background: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease which primarily affects the axial skeleton resulting in chronic back pain and stiffness. According to the guideline, the first-line treatment includes non-steroidal anti-inflammatory drugs (NSAIDs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and non-pharmacological treatment. Second line treatment involves biological disease-modifying antirheumatic drugs (bDMARDs) such as tumour necrosis factor and interleukin-17 inhibitors. Objectives: The aim of this social media listening research project was to analyse switches of medication and the reasons thereof to gain valuable insights into real-life journeys of patients suffering from axSpA. Methods: Publicly available posts in German-speaking disease-specific forums were scanned for disease-specific keywords and commonly used drugs by axSpA patients on the Permea platform. Posts containing at least two key words were selected and switches between medications were manually labelled. A total of 287 scraped posts between 01 July 2010 and 04 Feb 2022 were analysed. Results: The largest group of described medication switches was initially using bDMARDs. Switches to a different bDMARD, termination of medication and switches to glucocorticoids were most frequently named. Patients on NSAIDs switched to glucocorticoids, a different NSAID or bDMARD, whereas patients on csDMARDs most frequently changed to bDMARDs. In all medication groups the main reason for switching was insufficient efficacy and side effects. Additionally, for the medication groups bDMARDs, csDMARDs and corticosteroids, pregnancy and lactation were given as a reason for switching, whereas patients in the NSAID group never mentioned pregnancy and breastfeeding as a reason for switching treatment. Conclusion: Our analysis shows medication switches based on real-life patient experiences shared with peers in a social listening setting. We also show medication switches differing from advised guidelines. Gathering real-life insights into patients' journey dealing with chronic diseases allows us to understand, and thereby improve patient care and treatment.

Intrathecal nusinersen administration in adult spinal muscular atrophy patients with complex spinal anatomy.

BACKGROUND: Intrathecal administration of nusinersen in adult spinal muscular atrophy (SMA) patients presents challenges owing to severe scoliosis and previous spinal surgery with metal implantation. In patients with a complex spinal situation, the potential risks of the intrathecal administration may lead to delayed treatment initiation. METHODS: In this study, we analyzed 53 CT-guided lumbar punctures of 11 adult nonambulatory SMA type 2 and 3 patients. All patients had scoliosis and six patients had previously undergone metal implantation. RESULTS: Drug administration was successful in 100% of the patients and none of the patients opted for treatment discontinuation. Complete osseous fusion precluded conventional posterior interlaminar access in eight lumbar punctures in four patients, which required alternative routes including transforaminal punctures and translaminar drilling. Median duration of all lumbar punctures was 9 min and median radiation exposure was 100 mGy* cm. The most common adverse event was post-lumbar puncture syndrome that occurred in five lumbar punctures (9.4%). CONCLUSIONS: Our data demonstrate that nusinersen can be successfully, safely, and rapidly administered in adult SMA patients with complex spinal conditions and suggest the translaminar drilling technique as an alternative delivery route. Therefore, intrathecal nusinersen treatment should not be withheld from patients because of severe spine deformities, however, drug efficacy in adult SMA patients needs to be investigated in further studies.

Mechanical thrombectomy for basilar artery occlusion: efficacy, outcomes, and futile recanalization in comparison with the anterior circulation.

BACKGROUND: Performing mechanical thrombectomy (MT) in patients with basilar artery occlusion (BAO) is currently not evidence-based. OBJECTIVE: To compare patients' outcome, relative merits of achieving recanalization, and predictors of futile recanalization (FR) between BAO and anterior circulation large vessel occlusion (ACLVO) MT. METHODS: In the multicenter BEYOND-SWIFT registry (NCT03496064), univariate and multivariate (displayed as adjusted Odds Ratios, aOR and 95% confidence intervals, 95%-CI) outcome comparisons between BAO (N=165) and ACLVO (N=1574) were performed. The primary outcome was favorable outcome at 90 days (modified Rankin Scale, mRS 0-2). Secondary outcome included mortality, symptomatic intracranial hemorrhage (sICH) and FR. The relative merits of achieving successful recanalization between ACLVO and BAO were evaluated with interaction terms. RESULTS: MT in BAO was more often technically effective and equally safe in regards to mortality and sICH when compared to ACLVO. When adjusting for baseline differences, there was no significant difference between BAO vs ACLVO regarding rates of favorable outcome (aOR 0.986, 95%-CI 0.553 - 1.758). However, BAO were associated with increased rates of FR (aOR 2.146, 95%-CI 1.267 - 3.633). Predictors for FR were age, stroke severity, maneuver count and intracranial stenting. No significant heterogeneity on the relative merits of achieving successful recanalization on several outcome parameters were observed when comparing BAO and ACLVO. CONCLUSIONS: In selected patients, similar outcomes can be achieved in BAO and ACLVO patients treated with MT. Randomized controlled trials comparing patient selection and interventional strategies seem warranted to avoid FR. TRIAL REGISTRATION NUMBER: NCT03496064.

Endovascular Stroke Treatment on Single-Plane vs. Bi-Plane Angiography Suites : Technical Considerations and Evaluation of Treatment Success.

INTRODUCTION: Endovascular stroke therapy is mostly available in comprehensive stroke centers with state of the art bi-plane angiography suites. The aim of the present study was to analyze if it is justifiable to treat patients with alternative x­ray machines in the case of capacity constraints, or if it is mandatory to refer patients in such cases. Secondly, we wanted to draw conclusions for the feasibility of different logistic approaches in stroke treatment, such as a "helistroke" concept. METHODS: This was a retrospective dual center analysis of all patients treated on a single-plane angiography suite between 2009 and 2017. A propensity scored matching analysis at a 1:3 ratio was performed with patients treated on a bi-plane angiography suite to receive homogeneous groups. RESULTS: A total of 42 patients were treated on a single-plane angiography suite and were compared to 126 patients treated on a bi-plane angiography suite. No significant differences in technical parameters, procedure times, recanalization success and complications could be detected. Also, there was no difference in the clinical outcome between the two groups. The only significant difference was the higher amount of radiation dose used on the bi-plane angiography machines to achieve the final results (205,660 mGy × cm2 vs. 114,565 mGy × cm2; p < 0.001). DISCUSSION: In an era of an ever-changing stroke infrastructure and an increasing demand in thrombectomy procedures, it is feasible and safe for experienced neurointerventionalists to perform endovascular stroke procedures on single-plane angiography units.

Spinal ependymoma in adults: a multicenter investigation of surgical outcome and progression-free survival.

OBJECTIVE Spinal ependymomas are rare glial neoplasms. Because their incidence is low, only a few larger studies have investigated this condition. There are no clear data concerning prognosis and therapy. The aim of the study was to describe the natural history, perioperative clinical course, and local tumor control of adult patients with spinal ependymomas who were surgically treated under modern treatment standards. METHODS The authors performed a multicenter retrospective study. They identified 158 adult patients with spinal ependymomas who had received surgical treatment between January 2006 and June 2013. The authors analyzed the clinical and histological aspects of these cases to identify the predictive factors for postoperative morbidity, tumor resectability, and recurrence. RESULTS Gross-total resection (GTR) was achieved in 80% of cases. At discharge, 37% of the patients showed a neurological decline. During follow-up the majority recovered, whereas 76% showed at least preoperative status. Permanent functional deterioration remained in 2% of the patients. Transient deficits were more frequent in patients with cervically located ependymomas (p = 0.004) and in older patients (p = 0.002). Permanent deficits were independently predicted only by older age (p = 0.026). Tumor progression was observed in 15 cases. The 5-year progression-free survival (PFS) rate was 80%, and GTR (p = 0.037), WHO grade II (p = 0.009), and low Ki-67 index (p = 0.005) were independent prognostic factors for PFS. Adjuvant radiation therapy was performed in 15 cases. No statistically relevant effects of radiation therapy were observed among patients with incompletely resected ependymomas (p = 0.079). CONCLUSIONS Due to its beneficial value for PFS, GTR is important in the treatment of spinal ependymoma. Gross-total resection is feasible in the majority of cases, with acceptable rates of permanent deficits. Also, Ki-67 appears to be an important prognostic factor and should be included in a grading scheme for spinal ependymomas.

Impact of time to endovascular reperfusion on outcome differs according to the involvement of the proximal MCA territory.

BACKGROUND: The time interval between symptom onset and reperfusion is a major determinant of the benefit of endovascular therapy (ET) and patients' outcome. The impact of time may be attenuated in patients with robust collaterals. However, not all regions in the middle cerebral artery (MCA) territory have access to collaterals. PURPOSE: To evaluate if the involvement of the poorly collateralized proximal MCA territory has an impact on the degree of time dependency of patients' outcome. METHODS: Patients with MCA occlusions treated with ET and involvement/sparing of the proximal striatocapsular MCA territory (SC+/SC-, each n=97) were matched according to their symptom onset to reperfusion times (SORTs). Correlation and impact of time on outcome was evaluated with strata of SC+/SC- using multivariate logistic regression models (LRMs), including interaction terms. Discharge National Institute of Health Stroke Scale (NIHSS-DIS) score <5 and discharge modified Rankin Scale (mRS-DIS) score ≤2 were prespecified outcome measures. RESULTS: A stronger correlation between all outcome measures (NIHSS-DIS/ΔNIHSS/mRS-DIS) and SORTs was found for SC+ patients than for SC-patients. SORTs were significant variables in LRMs for mRS-DIS score ≤2 and NIHSS-DIS score <5 in SC+ but not in SC- patients. Interaction of SC+ and SORTs was significant in LRMs for both endpoints. CONCLUSION: Time dependency of outcome after ET is more pronounced if parts of the proximal MCA territory are affected. This may reflect the lack of collateralization in the striatocapsular region and a more stringent cell death with time. If confirmed, this finding may affect the selection of patients based on different time windows according to the territory at risk.

PROTECT: PRoximal balloon Occlusion TogEther with direCt Thrombus aspiration during stent retriever thrombectomy - evaluation of a double embolic protection approach in endovascular stroke treatment.

PURPOSE: Stent retriever-based mechanical thrombectomy (MT) for emergent large vessel occlusions (ELVO) is often complicated by thrombus fragmentation causing distal embolization and embolization to new vascular territories. Well-established embolic protection approaches include proximal flow arrest and distal aspiration techniques during stent retriever maneuvers. Aiming at the reduction of thrombus fragmentation during MT we evaluated a technical approach combining proximal balloon occlusion together with direct thrombus aspiration during MT: the PROTECT technique. METHODS: We performed a case-control study comparing the PROTECT technique with sole distal aspiration during MT regarding technical and procedural parameters, n=200 patients with ELVO of either the terminus of the internal carotid artery or the proximal middle artery were included. RESULTS: PROTECT resulted in a shorter procedure time (29 vs 40 min; P=0.002), in a higher rate of successful recanalizations (100% vs 78%; P=0.001) and a higher rate of complete reperfusions (70% vs 39%; P<0.001) compared with sole distal aspiration during MT. CONCLUSION: The PROTECT technique is a promising new approach to significantly reduce thrombus fragmentation and, hence distal embolization during MT. This safe and efficient technique needs to be validated in larger trials to confirm our results.

The Cerebral Surfactant System and Its Alteration in Hydrocephalic Conditions.

INTRODUCTION: Pulmonary Surfactant reduces surface tension in the terminal airways thus facilitating breathing and contributes to host's innate immunity. Surfactant Proteins (SP) A, B, C and D were recently identified as inherent proteins of the CNS. Aim of the study was to investigate cerebrospinal fluid (CSF) SP levels in hydrocephalus patients compared to normal subjects. PATIENTS AND METHODS: CSF SP A-D levels were quantified using commercially available ELISA kits in 126 patients (0-84 years, mean 39 years). 60 patients without CNS pathologies served as a control group. Hydrocephalus patients were separated in aqueductal stenosis (AQS, n = 24), acute hydrocephalus without aqueductal stenosis (acute HC w/o AQS, n = 16) and idiopathic normal pressure hydrocephalus (NPH, n = 20). Furthermore, six patients with pseudotumor cerebri were investigated. RESULTS: SP A-D are present under physiological conditions in human CSF. SP-A is elevated in diseases accompanied by ventricular enlargement (AQS, acute HC w/o AQS) in a significant manner (0.67, 1.21 vs 0.38 ng/ml in control, p<0.001). SP-C is also elevated in hydrocephalic conditions (AQS, acute HC w/o AQS; 0.87, 1.71 vs. 0.48 ng/ml in controls, p<0.001) and in Pseudotumor cerebri (1.26 vs. 0.48 ng/ml in controls, p<0.01). SP-B and SP-D did not show significant alterations. CONCLUSION: The present study confirms the presence of SPs in human CSF. There are significant changes of SP-A and SP-C levels in diseases affecting brain water circulation and elevation of intracranial pressure. Cause of the alterations, underlying regulatory mechanisms, as well as diagnostic and therapeutic consequences of cerebral SP's requires further thorough investigations.

Independent Control of the Static and Dynamic Components of the Chlamydomonas Flagellar Beat.

When the green alga Chlamydomonas reinhardtii swims, it uses the breaststroke beat of its two flagella to pull itself forward [1]. The flagellar waveform can be decomposed into a static component, corresponding to an asymmetric time-averaged shape, and a dynamic component, corresponding to the time-varying wave [2]. Extreme lightening conditions photoshock the cell, converting the breaststroke beat into a symmetric sperm-like beat, which causes a reversal of the direction of swimming [3]. Waveform conversion is achieved by a reduction in magnitude of the static component, whereas the dynamic component remains unchanged [2]. The coupling between static and dynamic components, however, is poorly understood, and it is not known whether the static component requires the dynamic component or whether it can exist independently. We used isolated and reactivated axonemes [4] to investigate the relation between the two beat components. We discovered that, when reactivated in the presence of low ATP concentrations, axonemes displayed the static beat component in absence of the dynamic component. Furthermore, we found that the amplitudes of the two components depend on ATP in qualitatively different ways. These results show that the decomposition into static and dynamic components is not just a mathematical concept but that the two components can independently control different aspects of cell motility: the static component controls swimming direction, whereas the dynamic component provides propulsion.

Volume versus standard coils in the treatment of intracranial aneurysms.

BACKGROUND: Volume coils were developed to improve occlusion rates of intracranial aneurysms. Previous studies have shown increased packing density and comparable occlusion rates, but subgroup analyses of aneurysm size have not been carried out. OBJECTIVE: To evaluate the safety and efficacy of the Penumbra Coil 400 (PC400) system in treating intracranial aneurysms compared with standard diameter coils. METHODS: A monocentric retrospective case review of 260 aneurysms in 233 patients was carried out. In 37 aneurysms the PC400 system was used, while 223 aneurysms were treated with conventional coils. Previously treated aneurysms and aneurysms treated with flow diverters were excluded. Aneurysm and procedure characteristics, packing density, postprocedural and follow-up occlusion grades as well as coil compaction were evaluated. RESULTS: Aneurysms treated with PC400 coils had higher volume (218.9 vs 47.1 mm(3), p<0.001), wider necks (3.0 vs 2.5 mm, p=0.005), and greater dome/neck ratio (2.0 vs 1.6, p=0.001) in comparison with aneurysms treated with conventional coils. Compared with controls, in the PC400 group we achieved higher packing densities (43.2% vs 34.4%, p<0.001; in aneurysms ≥7 mm 42.2% vs 27.8%, p<0.001). On follow-up angiography we observed less coil compaction (23.8% vs 64.3%, p=0.003) and less aneurysm recurrence (14.3% vs 40.5%, p=0.046) in aneurysms ≥7 mm when using the PC400 system. CONCLUSIONS: Use of the PC400 system as opposed to conventional coils suggests that the PC400 system is safe and effective in treating intracranial aneurysms. Despite having been applied in a potentially more difficult-to-treat group, the use of PC400 was associated with less coil compaction and aneurysm recurrence in aneurysms ≥7 mm.

Mechanical thrombectomy versus systemic thrombolysis in MCA stroke: a distance to thrombus-based outcome analysis.

BACKGROUND: Acute ischemic stroke due to occlusion of the middle cerebral artery (MCA) has a poor outcome. The distance to thrombus (DT) from the carotid T can predict the outcome after intravenous thrombolysis (IVT). With a DT <16 mm, fewer than 50% of patients treated with IVT have a favorable outcome. OBJECTIVE: To compare stent retriever-based endovascular mechanical thrombectomy (MT) plus additional IVT (IVT-MT) with IVT alone. MATERIALS AND METHODS: Patients with MCA occlusion proved by CT angiography with a DT <16 mm, treated with either IVT alone or with stent retriever-based endovascular IVT-MT, were included in this study. Changes in National Institutes of Health Stroke Scale (NIHSS), the 7-day NIHSS, and the 90-day modified Rankin Scale (mRS) scores were analyzed by treatment modality. RESULTS: Of 621 patients, 87 fulfilled all inclusion criteria. Fifty-nine patients were treated with IVT and 28 with IVT-MT. Although patients treated with IVT-MT had had significantly more severe strokes than those treated with IVT alone (initial NIHSS 16 (7-18) vs 14 (5-22); p=0.032), both the short- and long-term outcomes were significantly better in this patient group (NIHSS improvement on day 7: 10.9±6.3 vs 6.7±6.7; p=0.008/90-day mRS: 2 (0.75-2.5) vs 4 (2-6); p=0.003). CONCLUSIONS: In patients with an acute MCA occlusion and a DT <16 mm, IVT-MT leads to a significantly better outcome than in patients treated with IVT alone.

Vertebral artery injury during foraminal decompression in "low-risk" cervical spine surgery: incidence and management.

OBJECTIVES: Vertebral artery injury (VAI) during foraminal decompression in cervical spine surgery in the absence of repositioning or screw stabilization is rare. Without immediate recognition and treatment, it may have disastrous consequences. We aimed to describe the incidence and management of iatrogenic VAI in low-risk cervical spine surgery. MATERIALS AND METHODS: The records of all patients who underwent surgical procedures of the cervical spine between January 2007 and May 2012 were retrospectively consecutively evaluated. Anterior cervical discectomy and fusion or arthroplasty as well as dorsal foraminal decompression through the Frykholm approach in degenerative diseases were defined as low-risk surgeries (n = 992). RESULTS: VAI occurred in 0.3 % (n = 3) of 992 procedures: in one case during a dorsal foraminal decompression, and in two cases during the anterior cervical discectomy and fusion (ACDF) of two or four levels, respectively. In the first case, the VAI was intraoperatively misdiagnosed. Despite an initially uneventful course, the patient suffered hemorrhage from a pseudoaneurysm of the injured VA 1 month after surgery. The aneurysm was successfully occluded by endovascular coiling. In both ACDF cases, angiography and endovascular stenting of the lacerated segment proceeded immediately after the surgery. All three patients suffered no permanent deterioration. CONCLUSIONS: In a high-volume surgical center, the incidence of VAI during low-risk cervical spine surgery is extremely low, comprising 0.3 % of all cases. The major risks are delayed sequels of the vessel wall laceration. In cases of VAI, immediate angiographic diagnostics and generous indications for endovascular treatment are obligatory.

Learning curve of 3D fluoroscopy image-guided pedicle screw placement in the thoracolumbar spine.

BACKGROUND CONTEXT: During the past decade, a disproportionate increase of spinal fusion procedures has been observed. Along with this trend, image-guided spine surgery has been experiencing a renaissance in the recent years. A wide range of different navigation systems are available on the market today. However, only few published studies assess the learning curves concerning these new spinal navigation techniques. So far, a study on the learning curve for intraoperative three-dimensional fluoroscopy (3DFL)-navigated pedicle screw (PS) placement is still lacking. PURPOSE: The purpose of the study was to analyze the learning curve for 3DFL-navigated thoracolumbar PS placement. STUDY DESIGN/SETTING: The study design included a prospective case series. PATIENT SAMPLE: A cohort of 145 patients were recruited from January 2011 to June 2012. OUTCOME MEASURES: The outcome measures were duration of intraoperative 3D scans, PS placement, PS accuracy on postoperative computed tomography (CT) scans, and PS-related revisions and complications. METHODS: From the introduction of spinal navigation to our department in January 2011 until June 2012, the learning curve for the duration of intraoperative 3D scan acquisition (navigation or control scan) and placement time per screw, intraoperative screw revisions, screw-related complications, revision surgeries, and PS accuracy on postoperative CT scans were assessed in 145 patients undergoing dorsal navigated instrumentation for 928 PS (736 lumbosacral and 192 thoracic). The observed time span was divided into four intervals. Results of the second, third, and last periods were compared with the first (reference) period, respectively. RESULTS: The mean navigation 3D scan time decreased (first and fourth periods) from 15.4±7.8 (range, 4-40) to 8.4±3.3 (3-15) minutes (p<.001). The mean control 3D scan time (after PS placement) decreased from 11.2±4.8 (5-25) to 6.6±3.0 (3-15) minutes (p<.001). The mean PS insertion time decreased from 5.3±2.5 (1-15) to 3.2±2.3 (1-17) minutes (p<.001). The mean proportion of correctly positioned PS (all 928) according to the Gertzbein and Robbins classification grades A and B increased initially from 83.1% (first period) to 95.1% (second period, p=.001), 96.4% (third period, p=.002), and 92.4% (fourth period, p=.049). No learning effect was found with respect to intraoperative screw revisions. There was one revision surgery. CONCLUSIONS: We could demonstrate significant learning effects for 3DFL-navigated PS placement with regard to intraoperative 3D scan acquisition, PS placement time, and PS accuracy.

Hippocampal damage and affective disorders after treatment of cerebral aneurysms.

Despite good neurological outcome after the treatment of ruptured or incidental cerebral aneurysms, many patients complain about mood disturbances such as anxiety and depression. The present study investigated the nature of these affective disorders, their trigger factors, and corresponding structural brain changes. We assessed 63 patients matched by history of previous subarachnoid hemorrhage (SAH) and treatment modality (clipping vs. coiling) by a test battery including the Hospital Anxiety and Depression Scale (HADS) and beck depression inventory-II (BDI-II). MR imaging for the evaluation of structural changes included H(1)-MR spectroscopy, hippocampal volumetry, and diffusion tensor imaging (DTI). The applied multimodal imaging revealed no significant differences between patients with previous SAH and patients with incidental aneurysms; there were also no substantial differences between patients with and without previous SAH with respect to depression and anxiety. However, we observed significantly higher mean HADS scores in patients treated surgically versus patients treated by coiling (p < 0.01). BDI-II tended to be higher in surgically treated patients, but this difference appeared statistically insignificant. Surgically treated patients displayed substantial hippocampal damage in all imaging techniques: reduction in mean concentrations of N-acetylaspartate (p = 0.04), hippocampal volume reduction (p = 0.012), and diffusion disorder (p = 0.02). The structural alterations correlated significantly with the increased HADS scores. In contrast to endovascular treatment, aneurysm surgery seems to be associated with an increased incidence of mood disorders corresponding to hippocampal neuronal loss, independent of preceding SAH.

CO2 has no therapeutic effect on early microvasospasm after experimental subarachnoid hemorrhage.

In addition to delayed vasospasm also early brain injury, which occurs during the first few days after subarachnoid hemorrhage (SAH) when large cerebral arteries are still fully functional, plays an important role for the outcome after SAH. In the current study, we investigated the hypothesis that carbon dioxide (CO2), a strong cerebral vasodilator, has a therapeutic potential against early posthemorrhagic microvasospasm. C57BL/6 mice (n=36) and Sprague-Dawley rats (n=23) were subjected to sham surgery or SAH by filament perforation. The pial microcirculation in the mice was visualized 3 and 24 hours after SAH using intravital fluorescence microscopy. Partial pressure of CO2 (PaCO2) was modulated by hyper- or hypoventilation or by inhalation of 10% CO2. In rats, CO2-mediated changes in cerebral blood flow (CBF) were measured at the same time points using laser Doppler fluxmetry. Increased PaCO2 caused vasodilatation in sham-operated animals. Following SAH, however, cerebral arterioles were nonreactive to CO2. This lack of microvascular CO2 reactivity was accompanied by a complete loss of CO2-induced hyperemia. Our data show that CO2 is not able to dilate spastic microvessels and to increase CBF early after SAH. Future therapeutic approaches will therefore need to address mechanisms beyond CO2.

Sarcomeric pattern formation by actin cluster coalescence.

Contractile function of striated muscle cells depends crucially on the almost crystalline order of actin and myosin filaments in myofibrils, but the physical mechanisms that lead to myofibril assembly remains ill-defined. Passive diffusive sorting of actin filaments into sarcomeric order is kinetically impossible, suggesting a pivotal role of active processes in sarcomeric pattern formation. Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments. We propose that the coalescence of crosslinked actin clusters could be key for sarcomeric pattern formation. In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation. The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.

Striated acto-myosin fibers can reorganize and register in response to elastic interactions with the matrix.

The remarkable striation of muscle has fascinated many for centuries. In developing muscle cells, as well as in many adherent, nonmuscle cell types, striated, stress fiberlike structures with sarcomere-periodicity tend to register: Based on several studies, neighboring, parallel fibers at the basal membrane of cultured cells establish registry of their respective periodic sarcomeric architecture, but, to our knowledge, the mechanism has not yet been identified. Here, we propose for cells plated on an elastic substrate or adhered to a neighboring cell, that acto-myosin contractility in striated fibers close to the basal membrane induces substrate strain that gives rise to an elastic interaction between neighboring striated fibers, which in turn favors interfiber registry. Our physical theory predicts a dependence of interfiber registry on externally controllable elastic properties of the substrate. In developing muscle cells, registry of striated fibers (premyofibrils and nascent myofibrils) has been suggested as one major pathway of myofibrillogenesis, where it precedes the fusion of neighboring fibers. This suggests a mechanical basis for the optimal myofibrillogenesis on muscle-mimetic elastic substrates that was recently observed by several groups in cultures of mouse-, human-, and chick-derived muscle cells.