In humans, mutations in the genes encoding components of the dystrophin-glycoprotein complex cause muscular dystrophy. Specifically, primary mutations in the genes encoding ␣-, ␤-, ␥-, and ␦-sarcoglycan have been identified in humans with limb-girdle muscular dystrophy. Mice lacking ␥-sarcoglycan develop progressive muscular dystrophy similar to human muscular dystrophy. Without ␥-sarcoglycan, ␤-and ␦-sarcoglycan are unstable at the muscle membrane and ␣-sarcoglycan is severely reduced. The expression and localization of dystrophin, dystroglycan, and laminin-␣2, a mechanical link between the actin cytoskeleton and the extracellular matrix, appears unaffected by the loss of sarcoglycan. We assessed the functional integrity of this mechanical link and found that isolated muscles lacking ␥-sarcoglycan showed normal resistance to mechanical strain induced by eccentric muscle contraction. Sarcoglycandeficient muscles also showed normal peak isometric and tetanic force generation. Furthermore, there was no evidence for contraction-induced injury in mice lacking ␥-sarcoglycan that were subjected to an extended, rigorous exercise regimen. These data demonstrate that mechanical weakness and contraction-induced muscle injury are not required for muscle degeneration and the dystrophic process. Thus, a nonmechanical mechanism, perhaps involving some unknown signaling function, likely is responsible for muscular dystrophy where sarcoglycan is deficient.The dystrophin-glycoprotein complex (DGC) is a multimeric assembly of both transmembrane-and membrane-associated proteins found in both skeletal and cardiac muscle (1-4). Molecular and biochemical analyses have demonstrated that the DGC is composed of the following components: dystrophin, an elongated cytoskeletal protein that binds actin (5-7); sarcoglycan, a multisubunit transmembrane glycoprotein (8-10); dystroglycan, a laminin receptor that also binds dystrophin (11, 12); the syntrophins, mammalian homologues of the Torpedo 58-kDa postsynaptic protein (13-15); and dystrobrevin, a dystrophin-related, dystrophin-associated protein (16)(17)(18)(19)(20)(21). Mutations in the dystrophin gene result in Duchenne͞ Becker muscular dystrophy (DMD͞BMD), a common Xlinked disorder (5, 6). The mdx mouse is a spontaneously arising mutant that lacks full-length dystrophin and serves as a model for DMD (22).In muscle, there are at least four sarcoglycan subunits, ␣, ␤, ␥, and ␦, and mutations in any of these four can result in autosomal recessive muscular dystrophy (23-27). A more widely distributed fifth sarcoglycan, -sarcoglycan, recently has been identified (28,29), suggesting that sarcoglycan complexes may also function in tissues other than muscle. Sarcoglycan has a primary structure that includes an extracellular epidermal growth factor-like motif and is suggestive of a cell surface receptor (30); its exact role is unknown.Dystrophin binds actin at its amino terminus and along its rod domain (31-33). In the cytoplasm, the carboxyl terminus of dystrophin interacts with dystrog...

Summary Background Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. Funding British Heart Foundation.

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy. Methods RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.

Background: Acute ischaemic stroke (AIS) patients often show impaired cerebral autoregulation (CA). We tested the hypothesis that CA impairment and other alterations in cerebral haemodynamics are associated with stroke subtype and severity. Methods: AIS patients (n = 143) were amalgamated from similar studies. Data from baseline (< 48 h stroke onset) physiological recordings (beat-to-beat blood pressure [BP], cerebral blood flow velocity (CBFV) from bilateral insonation of the middle cerebral arteries) were calculated for mean values and autoregulation index (ARI). Differences were assessed between stroke subtype (Oxfordshire Community Stroke Project [OCSP] classification) and severity (National Institutes of Health Stroke Scale [NIHSS] score < 5 and 5–25). Correlation coefficients assessed associations between NIHSS and physiological measurements. Results: Thirty-two percent of AIS patients had impaired CA (ARI < 4) in affected hemisphere (AH) that was similar between stroke subtypes and severity. CBFV in AH was comparable between stroke subtype and severity. In unaffected hemisphere (UH), differences existed in mean CBFV between lacunar and total anterior circulation OCSP subtypes (42 vs. 56 cm•s^–1, p < 0.01), and mild and moderate-to-severe stroke severity (45 vs. 51 cm•s^–1, p = 0.04). NIHSS was associated with peripheral (diastolic and mean arterial BP) and cerebral haemodynamic parameters (CBFV and ARI) in the UH. Conclusions: AIS patients with different OCSP subtypes and severity have homogeneity in CA capability. Cerebral haemodynamic measurements in the UH were distinguishable between stroke subtype and severity, including the association between deteriorating ARI in UH with stroke severity. More studies are needed to determine their clinical significance and to understand the determinants of CA impairment in AIS patients.

The ideal technique for dynamic cerebral autoregulation (dCA) assessment in critically ill patients should provide considerable variability in blood pressure (BP) but without the need for patient cooperation. We proposed using rapid head positioning (RHP) over spontaneous BP fluctuations for dCA assessment in patients with acute ischemic stroke (AIS). Cerebral blood velocity (transcranial Doppler), beat-to-beat BP (Finometer), and end-tidal CO2 (capnography) were recorded during 5-min baseline and RHP in 16 controls (8 women and 8 men, mean age: 57 ± 16 yr) and 15 patients with AIS (7 women and 8 men, mean age: 69 ± 8 yr) at two (12 ± 8 days) and three visits (13.3 ± 6.9 h, 4.8 ± 3.2 days, and 93.9 ± 11.5 days from the symptom onset), respectively. All participants were able to complete the RHP protocol without difficulty. Compared with controls, patients with AIS were hypocapnic (all visits, P < 0.0024) and hypertensive ( visit 1, P = 0.011), although BP gradually reduced after the acute phase. RHP demonstrated greater beat-to-beat BP variability (BPV) in controls ( visits 1 and 2, P < 0.001) but not in patients with AIS at any visit. Compared with controls, a reduced autoregulation index (ARI) was demonstrated in patients with AIS, at visit 2 for the baseline recording but not at other visits or during RHP. The area under the receiver-operating curve was 0.53 and 0.54 for baseline and RHP, respectively. The RHP paradigm required minimal patient cooperation and could be considered a feasible alternative for assessing dCA, mainly in conditions leading to increased BPV. The lack of BPV increase in AIS with RHP deserves further investigation. NEW & NOTEWORTHY This study used rapid head positioning (RHP) to enhance blood pressure (BP) variability (BPV) to improve BP signal-to-noise ratio and reliability of dynamic cerebral autoregulation (dCA). RHP was well accepted by controls and acute ischemic stroke (AIS); the increased BPV induced in controls was not observed in AIS, suggesting BPV at rest was already elevated. RHP did not improve detection of impaired CA in AIS; further work is needed to understand the different responses observed.

We hypothesized that knowledge of cerebral autoregulation (CA) status during recanalization therapies could guide further studies aimed at neuroprotection targeting penumbral tissue, especially in patients that do not respond to therapy. Thus, we assessed CA status of patients with acute ischemic stroke (AIS) during intravenous r-tPA therapy and associated CA with response to therapy. AIS patients eligible for intravenous r-tPA therapy were recruited. Cerebral blood flow velocities (transcranial Doppler) from middle cerebral artery and blood pressure (Finometer) were recorded to calculate the autoregulation index (ARI, as surrogate for CA). National Institute of Health Stroke Score was assessed and used to define responders to therapy (improvement of ≥ 4 points on NIHSS measured 24-48 h after therapy). CA was considered impaired if ARI < 4. In 38 patients studied, compared to responders, non-responders had significantly lower ARI values (affected hemisphere: 5.0 vs. 3.6; unaffected hemisphere: 5.4 vs. 4.4, p = 0.03) and more likely to have impaired CA (32% vs. 62%, p = 0.02) during thrombolysis. In conclusion, CA during thrombolysis was impaired in patients who did not respond to therapy. this variable should be investigated as a predictor of the response to therapy and to subsequent neurological outcome. The key objective of current acute ischemic stroke (AIS) treatment is based on rapid blood flow restoration by thrombolysis, using intravenous recombinant tissue plasminogen activator (r-tPA), and/or mechanical arterial recanalization techniques 1-3. Several factors predict stroke outcome including age, initial stroke severity, arterial blood pressure (BP), site of occlusion, collaterals, and others 4,5. Nevertheless, complete or partial successful recanalization may not necessarily result in favorable outcome, with a number of predictors hypothesized 6,7. In particular, BP control may affect penumbral lesion size, with an optimal strategy still lacking evidence 8-10. Therapeutic BP manipulation may further impact on microvascular autoregulatory failure, as a consequence of an increase in lactate and free oxygen radicals in the occluded and/or reperfused tissues 11. Cerebral autoregulation (CA) refers to a set of physiological mechanisms that maintain the constancy of cerebral blood flow (CBF) despite wide variations in arterial BP. CA can be impaired within the first hours of ischemic stroke onset 11 ; as a consequence, BP control may be important for improving both the ischemic area in the brain and clinical outcome. Therefore, assessment of CA during recanalization therapy for AIS is relevant, and may influence future strategies for personalized BP control and associated neuroprotection. The aims of the present study were to assess CA status of responder and non-responder AIS patients to intravenous r-tPA during the therapy and after 24-48 h, and to test the hypothesis that CA during thrombolysis is associated with early response to therapy.

We studied cerebral blood velocity (CBV), and associated hemodynamic parameters during gradual changes in head positioning in a nonstroke group. CBV (transcranial Doppler ultrasound), beat‐to‐beat blood pressure (BP, Finometer), and end‐tidal carbon dioxide (ETCO 2, capnography) were recorded between lying flat (0°) and sitting up (30°) head positions, in 18 volunteers (10 female, mean age, 57 ± 16 years), at two visits (12 ± 8 days). A significant reduction was found between 5‐min FLAT (0°) and 5‐min SIT (30°) positions in CBV (visit 1: 4.5 ± 3.3%, P = 0.006; visit 2: 4.1 ± 3.5%, P = 0.003), critical closing pressure (CrCP; visit 1: 15.5 ± 14.0%, P = 0.0002; visit 2: 14.1 ± 7.8%, P = 0.009) and BP (visit 1: 8.3 ± 7.4%, P = 0.001; visit 2: 11.0 ± 11.3%, P < 0.001). For 5 min segments of data, the autoregulation index and other hemodynamic parameters did not show differences either due to head position or visit. For 30 sec time intervals, significant differences were observed in the following: (BP, P < 0.001; dominant hemisphere (DH) CBV, P < 0.005; nondominant hemisphere (NDH) CBV, P < 0.005; DH CrCP, P < 0.001; NDH CrCP, P < 0.001; DH resistance area product (RAP), P = 0.002; NDH RAP, P = 0.033). Significant static changes in BP, CBV and CrCP, and large transient changes in key hemodynamic parameters occur during 0° to 30°, and vice versa, with reproducible results. Further studies are needed following acute ischemic stroke to determine if a similar responses is present.

Dystrophin and its associated proteins, the sarcoglycans, are normally expressed in heart and skeletal muscle. Mutations that alter the expression of these membrane-associated proteins lead to muscular dystrophy (MD) and cardiomyopathy in humans. Because of the timing and nature of the accompanying cardiomyopathy, it has been suggested that cardiomyopathy develops as a secondary consequence of skeletal muscle dysfunction in the muscular dystrophies. To determine whether skeletal muscle dystrophy contributes to the development of sarcoglycan-mediated cardiomyopathy, we used mice lacking gamma-sarcoglycan and inserted a transgene that "rescued" gamma-sarcoglycan expression only in skeletal muscle. Gamma-sarcoglycan was expressed in skeletal muscle under the control of the skeletal muscle-specific myosin light chain 1/3 promoter. Gamma-sarcoglycan-null mice expressing this transgene fully restore gamma-sarcoglycan expression. Furthermore, the transgene-rescued mice lack the focal necrosis and membrane permeability defects that are a hallmark of MD. Despite correction of the skeletal muscle disease, focal degeneration and membrane permeability abnormalities persisted in cardiac muscle, and notably persisted in the right ventricle. Therefore, heart and skeletal muscle defects are independent processes in sarcoglycan-mediated muscular dystrophies and, as such, therapy should target both skeletal and cardiac muscle correction to prevent sudden death due to cardiomyopathy in the muscular dystrophies.