Effects of intensive arm training with the rehabilitation robot ARMin II in chronic stroke patients: four single-cases

BACKGROUND: Robot-assisted therapy offers a promising approach to neurorehabilitation, particularly for severely to moderately impaired stroke patients. The objective of this study was to investigate the effects of intensive arm training on motor performance in four chronic stroke patients using the robot ARMin II. METHODS: ARMin II is an exoskeleton robot with six degrees of freedom (DOF) moving shoulder, elbow and wrist joints. Four volunteers with chronic (>or= 12 months post-stroke) left side hemi-paresis and different levels of motor severity were enrolled in the study. They received robot-assisted therapy over a period of eight weeks, three to four therapy sessions per week, each session of one hour.Patients 1 and 4 had four one-hour training sessions per week and patients 2 and 3 had three one-hour training sessions per week. Primary outcome variable was the Fugl-Meyer Score of the upper extremity Assessment (FMA), secondary outcomes were the Wolf Motor Function Test (WMFT), the Catherine Bergego Scale (CBS), the Maximal Voluntary Torques (MVTs) and a questionnaire about ADL-tasks, progress, changes, motivation etc. RESULTS: Three out of four patients showed significant improvements (p < 0.05) in the main outcome. The improvements in the FMA scores were aligned with the objective results of MVTs. Most improvements were maintained or even increased from discharge to the six-month follow-up. CONCLUSION: Data clearly indicate that intensive arm therapy with the robot ARMin II can significantly improve motor function of the paretic arm in some stroke patients, even those in a chronic state. The findings of the study provide a basis for a subsequent controlled randomized clinical trial.

ARMin: a robot for patient-cooperative arm therapy

Task-oriented, repetitive and intensive arm training can enhance arm rehabilitation in patients with paralyzed upper extremities due to lesions of the central nervous system. There is evidence that the training duration is a key factor for the therapy progress. Robot-supported therapy can improve the rehabilitation allowing more intensive training. This paper presents the kinematics, the control and the therapy modes of the arm therapy robot ARMin. It is a haptic display with semi-exoskeleton kinematics with four active and two passive degrees of freedom. Equipped with position, force and torque sensors the device can deliver patient-cooperative arm therapy taking into account the activity of the patient and supporting him/her only as much as needed. The haptic display is combined with an audiovisual display that is used to present the movement and the movement task to the patient. It is assumed that the patient-cooperative therapy approach combined with a multimodal display can increase the patient's motivation and activity and, therefore, the therapeutic progress.

Prospective, multicenter, single-arm study of mechanical thrombectomy using Solitaire Flow Restoration in acute ischemic stroke

BACKGROUND AND PURPOSE Mechanical thrombectomy using stent retriever devices have been advocated to increase revascularization in intracranial vessel occlusion. We present the results of a large prospective study on the use of the Solitaire Flow Restoration in patients with acute ischemic stroke. METHODS Solitaire Flow Restoration Thrombectomy for Acute Revascularization was an international, multicenter, prospective, single-arm study of Solitaire Flow Restoration thrombectomy in patients with large vessel anterior circulation strokes treated within 8 hours of symptom onset. Strict criteria for site selection were applied. The primary end point was the revascularization rate (thrombolysis in cerebral infarction ≥2b) of the occluded vessel as determined by an independent core laboratory. The secondary end point was the rate of good functional outcome (defined as 90-day modified Rankin scale, 0-2). RESULTS A total of 202 patients were enrolled across 14 comprehensive stroke centers in Europe, Canada, and Australia. The median age was 72 years, 60% were female patients. The median National Institute of Health Stroke Scale was 17. Most proximal intracranial occlusion was the internal carotid artery in 18%, and the middle cerebral artery in 82%. Successful revascularization was achieved in 79.2% of patients. Device and procedure-related severe adverse events were found in 7.4%. Favorable neurological outcome was found in 57.9%. The mortality rate was 6.9%. Any intracranial hemorrhagic transformation was found in 18.8% of patients, 1.5% were symptomatic. CONCLUSIONS In this single-arm study, treatment with the Solitaire Flow Restoration device in intracranial anterior circulation occlusions results in high rates of revascularization, low risk of clinically relevant procedural complications, and good clinical outcomes in combination with low mortality at 90 days. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCT01327989.

Role of the B1 short arm in laminin self-assembly

Laminin self-assembles into a basement membrane polymer through specific low-affinity interactions. Recently, it was shown that the terminal short-arm domain (domains VI and V) of the B1 chain (fragment E4) possesses one of the laminin self-interaction sites [Schittny, J.C. & Yurchenco, P.D. (1990) J. Cell Biol. 110, 825-832], but that the binding partner(s) of this domain is unknown. Using affinity retardation chromatography we now investigate the domain(s) fragment E4 binds to. The elution of E4 was clearly retarded on immobilized laminin and fragment E1' (three-chain short-arm complex excluding the distal part of the B1 chain), but not on immobilized E4 in calcium containing buffer and at 37 degrees C. Under the same conditions, E1' strongly interacts with immobilized E4. In addition, E1' is able to non-covalently cross-link soluble E4 to immobilized E4. No further interaction of laminin and E4 with additional fragments (P1', A, B2 and B1 chain short-arm complex without B1-domains VI-IV and without globules; E8, distal long arm and G1-3; E3, long-arm G subdomains 4 and 5) could be demonstrated. These data are interpreted as evidence that (a) the primary laminin-laminin bonds are formed between the short arms of laminin, that (b) the terminal B1 short-arm domain (E4) can interact with the short arm(s) of the A and/or B2 chain(s) (domain E1'), but does not self-interact, and that (c) due to at least three self-binding sites, laminin polymerization behaves co-operatively.

Terminal short arm domains of basement membrane laminin are critical for its self-assembly

Laminin self-assembles into large polymers by a cooperative two-step calcium-dependent mechanism (Yurchenco, P. D., E. C. Tsilibary, A. S. Charonis, and H. Furthmayr. 1985. J. Biol. Chem. 260:7636-7644). The domain specificity of this process was investigated using defined proteolytically generated fragments corresponding to the NH2-terminal globule and adjacent stem of the short arm of the B1 chain (E4), a complex of the two short arms of the A and B2 chains attached to the proximal stem of a third short arm (E1'), a similar complex lacking the globular domains (P1'), and the distal half of the long arm attached to the adjacent portion of the large globule (E8). Polymerization, followed by an increase of turbidity at 360 nm in neutral isotonic TBS containing CaCl2 at 35 degrees C, was quantitatively inhibited in a concentration-dependent manner with laminin fragments E4 and E1' but not with fragments E8 and P1'. Affinity retardation chromatography was used for further characterization of the binding of laminin domains. The migration of fragment E4, but not of fragments E8 and P1', was retarded in a temperature- and calcium-dependent fashion on a laminin affinity column but not on a similar BSA column. These data are evidence that laminin fragments E4 and E1' possess essential terminal binding domains for the self-aggregation of laminin, while fragments E8 and P1' do not. Furthermore, the individual domain-specific interactions that contribute to assembly are calcium dependent and of low affinity.

The ceramide kinase inhibitor NVP-231 inhibits breast and lung cancer cell proliferation by inducing M phase arrest and subsequent cell death

Background and Purpose Ceramide kinase (CerK) catalyzes the generation of ceramide-1-phosphate which may regulate various cellular functions, including inflammatory reactions and cell growth. Here, we studied the effect of a recently developed CerK inhibitor, NVP-231, on cancer cell proliferation and viability and investigated the role of cell cycle regulators implicated in these responses. Experimental Approach The breast and lung cancer cell lines MCF-7 and NCI-H358 were treated with increasing concentrations of NVP-231 and DNA synthesis, colony formation and cell death were determined. Flow cytometry was performed to analyse cell cycle distribution of cells and Western blot analysis was used to detect changes in cell cycle regulator expression and activation. Key Results In both cell lines, NVP-231 concentration-dependently reduced cell viability, DNA synthesis and colony formation. Moreover it induced apoptosis, as measured by increased DNA fragmentation and caspase-3 and caspase-9 cleavage. Cell cycle analysis revealed that NVP-231 decreased the number of cells in S phase and induced M phase arrest with an increased mitotic index, as determined by increased histone H3 phosphorylation. The effect on the cell cycle was even more pronounced when NVP-231 treatment was combined with staurosporine. Finally, overexpression of CerK protected, whereas down-regulation of CerK with siRNA sensitized, cells for staurosporine-induced apoptosis. Conclusions and Implications Our data demonstrate for the first time a crucial role for CerK in the M phase control in cancer cells and suggest its targeted inhibition, using drugs such as NVP-231, in combination with conventional pro-apoptotic chemotherapy.

Invasive coronary treatment strategies for out-of-hospital cardiac arrest: a consensus statement from the European association for percutaneous cardiovascular interventions (EAPCI)/stent for life (SFL) groups

Due to significant improvement in the pre-hospital treatment of patients with out-of-hospital cardiac arrest (OHCA), an increasing number of initially resuscitated patients are being admitted to hospitals. Because of the limited data available and lack of clear guideline recommendations, experts from the EAPCI and "Stent for Life" (SFL) groups reviewed existing literature and provided practical guidelines on selection of patients for immediate coronary angiography (CAG), PCI strategy, concomitant antiplatelet/anticoagulation treatment, haemodynamic support and use of therapeutic hypothermia. Conscious survivors of OHCA with suspected acute coronary syndrome (ACS) should be treated according to recommendations for ST-segment elevation myocardial infarction (STEMI) and high-risk non-ST-segment elevation -ACS (NSTE-ACS) without OHCA and should undergo immediate (if STEMI) or rapid (less than two hours if NSTE-ACS) coronary invasive strategy. Comatose survivors of OHCA with ECG criteria for STEMI on the post-resuscitation ECG should be admitted directly to the catheterisation laboratory. For patients without STEMI ECG criteria, a short "emergency department or intensive care unit stop" is advised to exclude non-coronary causes. In the absence of an obvious non-coronary cause, CAG should be performed as soon as possible (less than two hours), in particular in haemodynamically unstable patients. Immediate PCI should be mainly directed towards the culprit lesion if identified. Interventional cardiologists should become an essential part of the "survival chain" for patients with OHCA. There is a need to centralise the care of patients with OHCA to experienced centres.

Patterns of Religious Education Policy in Switzerland. The Long Arm of Distanced Christians?

In spite of its different cantonal jurisdictions and traditions, the development of religious education in Switzerland over the past decade has taken a common direction: the state has assumed a more active role in the field of religious education in public (state-run) schools. In this article, we ask the question: How do key social actors interpret these reforms and how do these interpretations relate to the social structure of religion in Switzerland, in particular with respect to the majority category of the so-called distanced Christians? Drawing on qualitative interviews with members of the schools’ teaching staff, school administrators, and church representatives, the article highlights a dominant interpretative pattern that frames the socially accepted representation of religion in public schools. Thus, rather than addressing the pedagogical dimension of religious education, we discuss the significance of this pattern for the debate on the public presence of religion in Switzerland and Europe.

Do different anesthesia regimes affect hippocampal apoptosis and neurologic deficits in a rodent cardiac arrest model?

Background Different anesthesia regimes are commonly used in experimental models of cardiac arrest, but the effects of various anesthetics on clinical outcome parameters are unknown. We conducted a study in which we subjected rats to cardiac arrest under medetomidine/ketamine or sevoflurane/fentanyl anesthesia. Methods Asystolic cardiac arrest for 8 minutes was induced in 73 rats with a mixture of potassium chloride and esmolol. Daily behavioral and neurological examination included the open field test (OFT), the tape removal test (TRT) and a neurodeficit score (NDS). Animals were randomized for sacrifice on day 2 or day 5 and brains were harvested for histology in the hippocampus cornus ammonis segment CA1. The inflammatory markers IL-6, TNF-α, MCP-1 and MIP-1α were assessed in cerebrospinal fluid (CSF). Proportions of survival were tested with the Fisher’s exact test, repeated measurements were assessed with the Friedman’s test; the baseline values were tested using Mann–Whitney U test and the difference of results of repeated measures were compared. Results In 31 animals that survived beyond 24 hours neither OFT, TRT nor NDS differed between the groups; histology was similar on day 2. On day 5, significantly more apoptosis in the CA1 segment of the hippocampus was found in the sevoflurane/fentanyl group. MCP-1 was higher on day 5 in the sevoflurane/fentanyl group (p = 0.04). All other cyto- and chemokines were below detection threshold. Conclusion In our cardiac arrest model neurological function was not influenced by different anesthetic regimes; in contrast, anesthesia with sevoflurane/fentanyl results in increased CSF inflammation and histologic damage at day 5 post cardiac arrest.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019)

BACKGROUND Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa-the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)-includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.