[Juvenile stroke - what is important?] / Juveniler Schlaganfall ­ was gibt es zu beachten?

Stroke in young adults is a diagnostic and therapeutic challenge for all persons involved. Approximately 15% of ischemic strokes occur in young adults. Lack of awareness of the symptoms in emergency departments often results in delayed diagnosis and access to specific therapeutic options, such as revascularization. The causes are often heterogeneous and necessitate specific investigations. The etiology of juvenile stroke includes drug abuse, vasculitis and arteriopathies, such as reversible vasoconstriction syndrome and posterior reversible encephalopathy syndrome, although the prevalence of classical vascular risk factors is high. The most frequent causes of ischemic stroke in young adults are cardioembolism and microangiopathy; furthermore, dissection of vessels of the neck are more frequent compared to older patients. According to the results of currently available studies reperfusion strategies, such as intravenous fibrinolysis and mechanical thrombectomy are efficacious and safe in young patients.

[Cerebral amyloid angiopathy associated with inflammation]. / Zerebrale Amyloidangiopathie assoziiert mit Inflammation.

Cerebral amyloid angiopathy (CAA) associated with inflammation is a rare form of a potentially reversible encephalopathy in a subgroup of patients with CAA. The cerebral amyloid deposition can in isolated cases induce an inflammation predominantly of the cerebral blood vessels and a multifocal edema of the cerebral white matter. The courses can occur as monophasic, relapsing remitting and primarily progressive forms. We present seven cases with different courses of the disease and give an overview of the pathophysiology, clinical aspects and treatment of the disease with reference to the current literature. The cases presented show a very different and often difficult differential diagnostic clinical picture and all showed a significant improvement under steroid medication without signs of recurrence of the disease during the course. The recognition and early consistent treatment of inflammatory forms of CAA with and without direct inflammatory involvement of vessels can be decisive for successful treatment.

Oral fingolimod (FTY720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study.

BACKGROUND: Health-related quality of life (HRQoL) worsens with multiple sclerosis (MS) relapses and disease progression. Common symptoms including depression and fatigue may contribute to poor HRQoL. OBJECTIVES: To report exploratory analyses assessing the impact of fingolimod (FTY720) on HRQoL and depression in a phase II study of relapsing MS. METHODS: The Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and Beck Depression Inventory second edition (BDI-II) scores were assessed during a 6-month, placebo-controlled study and optional extension. RESULTS: HAQUAMS total score improved with fingolimod and worsened with placebo. Mean score change from baseline to month 6 was -0.02 with fingolimod 1.25 mg (p < 0.05 versus placebo), -0.01 with fingolimod 5.0 mg and + 0.12 with placebo. Categorical data supported a clinically important effect of fingolimod on HRQoL. Fingolimod 1.25 mg was also beneficial over placebo in the fatigue/thinking HAQUAMS sub-domain (p < 0.05 versus placebo). Change in mean BDI-II scores from baseline to month 6 and the proportion of patients with BDI-II scores indicative of clinical depression favored fingolimod 1.25 mg over placebo (p < 0.05 for both). At month 4, mean BDI-II and HAQUAMS total scores appeared to be maintained in fingolimod-treated patients. CONCLUSION: Fingolimod 1.25 mg may improve HRQoL and depression at 6 months compared with placebo in patients with relapsing MS.

Successful treatment of shrinking lung syndrome with rituximab in a patient with systemic lupus erythematosus.

Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE). We report the case of a 27-year-old woman with SLE presenting with a 2-year history of chest pain and progressive dyspnea. Respiratory function tests demonstrated severe restrictive ventilatory impairment. Chest x-ray demonstrated elevated hemi diaphragms and chest computed tomography showed no evidence of interstitial fibrosis, significant pleural disease or pulmonary emboli. Based on a diagnosis of SLS the patient received 4 months of high dose corticosteroids, mycophenolate and pain management with opiates. Her condition deteriorated and she was given a trial of rituximab. This resulted in marked improvement of the clinical condition and respiratory function tests that was maintained for 18 months. Subsequently, the patient represented with a similar clinical picture and another course of rituximab again produced remission. This is the first case report of reproducible remission of SLS in SLE treated with rituximab.

Localization of actin in Dictyostelium amebas by immunofluorescence.

Antibody prepared against avian smooth muscle actin has been used to localize actin in the slime mold, Dictyostelium discoideum. The distribution of actin in migrating cells is different from that in feeding cells. Migrating amebas display fluorescence primarily in advancing regions whereas feeding amebas show uniform fluorescence throughout. The reaction is specific for actin since the fluorescence observed is blocked when the antibody is absorbed by actin purified from avian skeletal muscle, human platelets, and Dictyostelium. These results, in addition to describing the distribution of actin in D. discoideum, demonstrate that actins from these diverse sources share at least one common antigenic determinant.

Assembly of keratin onto PtK1 cytoskeletons: evidence for an intermediate filament organizing center.

Purified keratin, solubilized in 8 M of urea, was added to Triton X-100-extracted PtK1 cells in 5 mM PIPES buffer. The buffer conditions induced assembly of keratin filaments which appear to associate with nuclei of extracted cells. These keratin fibers extend beyond the original margin of the cells and frequently form bridges between adjacent cells. Electron microscopy shows that keratin filaments associate closely with the surface of the nucleus. We suggest that the site of association between keratin and the nucleus may represent an intermediate filament organizing center.

Structural and biochemical aspects of cell motility in amebas of Dictyostelium discoideum.

Amebas of Dictyostelium discoideum contain both microfilaments and microtubules. Microfilaments, found primarily in a cortical filament network, aggregate into bundles when glycerinated cells contract in response to Mg-ATP. These cortical filaments bind heavy meromyosin. Microtubules are sparse in amebas before aggregation. Colchicine, griseofulvin, or cold treatments do not affect cell motility or cell shape. Saltatory movement of cytoplasmic particles is inhibited by these treatments and the particles subsequently accumulate in the posterior of the cell. Cell motility rate changes as Dicytostelium amebas go through different stages of the life cycle. Quantitation of cellular actin by sodium dodecyl sulfate-polyacrylamide gel electrophoresis shows that the quantity of cellular actin changes during the life cycle. These changes in actin are directly correlated with changes in motility rate. Addition of cyclic AMP to Dictyostelium cultures at the end of the feeding stage prevents a decline in motility rate during the preaggregation stage. Cyclic AMP also modifies the change in actin content of the cells during preaggregation.

Association of creatine phosphokinase with the cytoskeleton of cultured mammalian cells.

Using an antibody specific for creatine phosphokinase (CPK), we have discovered an association between that enzyme and the cytoskeleton. Immunofluorescence observations show that CPK is associated with intermediate filaments in PTK cells and BALB/3T3 cells. The CPK distribution also follows intermediate filaments when cells are treated with colchicine.

The development and validation of the Unidimensional Fatigue Impact Scale (U-FIS).

BACKGROUND: The multidimensional assessment of fatigue is complicated by the interrelation of its multiple causes and effects. OBJECTIVE: The purpose of the research was to develop a unidimensional assessment of fatigue (U-FIS). METHODS: Data collected with the Fatigue Impact Scale (FIS) were subjected to Rasch analysis to identify potential problems with the scale. Additional items for the U-FIS were generated from interviews with UK MS patients. The U-FIS was tested for face and content validity in patient interviews and included in a validation survey to determine dimensionality (Rasch model), reliability and validity. RESULTS: The original FIS was not unidimensional when subscale items were combined. The modification of the FIS and addition of a number of items allowed the development of a 22-item unidimensional scale (U-FIS) that was reliable (Cronbach Alpha = 0.96; test-retest = 0.86,) and valid given correlations with the Nottingham Health Profile and ability to distinguish between MS severity groups. There was no significant difference in U-FIS scores according to MS type. CONCLUSION: It is valid to conceptualize the functional impact of fatigue as unidimensional. The U-FIS is a reliable and valid questionnaire that will allow the measurement of this construct in clinical studies.

The amount of solid cerebral microemboli during carotid stenting does not relate to the frequency of silent ischemic lesions.

BACKGROUND AND PURPOSE: Carotid artery stent placement (CAS) may be associated with clinically silent cerebral lesions. We prospectively evaluated the association of the number of solid cerebral microemboli during unprotected CAS with the frequency of silent cerebral lesions as detected by diffusion-weighted MR imaging (DWI). METHODS: We performed multifrequency transcranial Doppler detection of solid microemboli in the ipsilateral middle cerebral artery (MCA) during CAS in 27 consecutive patients with symptomatic high-grade carotid stenoses. No embolus protection was used in any of the cases. DWI before and 24 +/- 2 hours after CAS was used to detect new ischemic lesions. RESULTS: We detected 484 solid microemboli in 17 patients (63%). On MR imaging 24 +/- 2 hours after CAS, 6 patients (22%) had developed 13 new clinically silent DWI lesions within the ipsilateral MCA territory. In patients with Doppler evidence of solid emboli during CAS, the incidence of new DWI lesions was higher (29%) than in patients without Doppler evidence of solid emboli during the procedure (10%); this difference was not statistically significant (P = .25). The number of solid microemboli during CAS in patients with new ipsilateral DWI lesions was not significantly different from that in patients without new ipsilateral DWI lesions. CONCLUSIONS: Solid microembolism is a common event during unprotected CAS; however, the frequency of procedure-related silent cerebral lesions appears to be independent of the number of solid cerebral microemboli during the procedure.

Glycoprotein IIb/IIIa Inhibitor Bridging and Subsequent Endovascular Therapy in Vertebrobasilar Occlusion in 120 Patients.

PURPOSE: The treatment mode in acute vertebrobasilar occlusion (VBO) remains uncertain. We analyzed efficacy and safety of intravenous glycoprotein IIb/IIIa inhibitor (IV GPI) plus subsequent intra-arterial thrombolysis with or without additional endovascular mechanical therapy (percutaneous transluminal angioplasty/stenting or thrombus aspiration) and sought treatment factors that predict good clinical outcome. METHODS: We retrospectively analyzed 120 cases of patients with angiographically proven acute VBO. Multivariate logistic regression was used to identify independent predictors for clinical outcome and included level of consciousness, age, sex, time to angiography, GPI agent, admission mode, occlusion type, recanalization success, and endovascular treatment mode. Clinical follow-up was dichotomized in no to moderate disability (modified Rankin scale (mRS) 0-3) vs. severe disability or death (mRS 4-6). RESULTS: Median National Institutes of Health stroke scale (NIHSS) score on admission was 32, and mean NIHSS score was 24. A total of 49 patients (41 %) developed no to moderate disability (mRS 0-3), and 39 patients (33 %) died. Thrombolysis in myocardial infarction 2/3 recanalization success was achieved in 97 patients (80.8 %). Symptomatic intracerebral hemorrhages occurred in 11 patients (9 %). Mild impairment of consciousness (p < 0.001) and embolic occlusion type (p = 0.01) were significant predictors of favorable outcome. Clinical outcome in recanalized patients was better, but not statistically significant (p = 0.055). CONCLUSIONS: Our results indicate that combined therapy with IV GPI and subsequent endovascular therapy may be a valid treatment strategy in acute VBO. With this treatment approach, a preserved vigilance before treatment and an embolic occlusion type are associated with no to moderate disability.

Altering the state of phosphorylation of rat liver keratin intermediate filaments by ethanol treatment in vivo changes their structure.

Dephosphorylation of keratin intermediate filaments (IF) in livers from ethanol-fed rats relative to controls occurs concurrently with a reorganization of the distribution of IF in the cells. One possible molecular mechanism for this reorganization is a phosphorylation-induced conformational change in the keratin that propagates as a change in the polymerization of the keratin subunits. To test this hypothesis, the structure of liver keratin IF, from both control and alcohol-fed rats, was explored by circular dichroism (CD), tryptophan fluorescence quenching, and 13C nuclear magnetic resonance (NMR). Keratin IF were isolated from livers of control rats and from livers of rats that had ethanol included in their feed for 6-40 weeks. A significant decrease in the intensity of the CD spectrum of keratin IF from livers of ethanol-treated animals, relative to controls, was observed. These data suggested either that a change in conformation or an increase in conformational motility in the keratin IF from ethanol-treated animals occurred as a result of the ethanol-induced dephosphorylation. 13C NMR data were obtained to distinguish between these two possibilities. An increase in resonance intensity of some 13C NMR resonances was observed in the keratin IF from livers of ethanol-treated animals, relative to controls. The CD and NMR data were therefore consistent with an increase in conformational motility of the rod domain in these keratin IF. No significant change was observed in the quenching of tryptophan fluorescence by KI. The change in protein dynamics detected in these experiments could be the molecular basis for the alteration of keratin IF organization in alcoholic hepatitis.

Clopidogrel Resistance in Neurovascular Stenting: Correlations between Light Transmission Aggregometry, VerifyNow, and the Multiplate.

BACKGROUND AND PURPOSE: Clopidogrel resistance is blamed for thromboembolic complications in neurovascular stent placement. Platelet-function assays are weakly standardized. The aim of this study was to correlate the results of 3 different platelet-inhibition measurements (from light transmission aggregometry, the VerifyNow P2Y12 test, and the Multiplate analyzer) and their relation to periprocedural thromboembolic complications in elective neurovascular stent placement. MATERIALS AND METHODS: Clopidogrel resistance was determined on the day of the intervention according to predefined platelet reactivity cutoff values. All 3 tests were performed in 103 consecutive neurovascular stent-placement procedures in 97 patients (extracranial, n = 77; intracranial, n = 26). RESULTS: The clopidogrel resistance rates were 47.6% (light transmission aggregometry), 50.5% (VerifyNow), and 35.9% (Multiplate). In 67% of the patients, clopidogrel resistance was present according to at least one method. The correlations of qualitative results that classified a patient as responsive or resistant to clopidogrel were 67.9% for light transmission aggregometry with VerifyNow, 77.7% for light transmission aggregometry with the Multiplate, and 66% for VerifyNow with the Multiplate. Periprocedural thromboembolic complications (n = 9) occurred more frequently in patients who were determined by all 3 methods to be clopidogrel resistant. The difference was most pronounced with light transmission aggregometry (complication rates, 14.4% [clopidogrel-resistant patients] vs 3.7% [clopidogrel-responsive patients]). Sensitivity and specificity rates of clopidogrel resistance in relation to embolic complications were, respectively, 78% and 55% for light transmission aggregometry, 67% and 51% for VerifyNow, and 44% and 67% for the Multiplate. CONCLUSIONS: Clopidogrel resistance is a frequent finding in patients who undergo neurovascular stent placement. The correlations among the different testing methods are only modest and differ considerably. Light transmission aggregometry results seem to correlate with thromboembolic complications more accurately than with VerifyNow and Multiplate point-of-care methods.

[Not Available]. / IQWiG Arbeitspapier GA15-02: "Stents zur Behandlung intrakranieller Stenosen: VISSIT Studie und Akutbehandlung in Deutschland". Kommentar des Berufsverbandes der Neuroradiologen (BDNR), der Deutschen Gesellschaft für Neuroradiologie (DGNR), der Deutschen Gesellschaft für Neurologie (DGN) und der Deutschen Schlaganfall-Gesellschaft (DSG).

There is an ongoing discussion about reimbursement of stent-angioplasty for the treatment of intracranial stenoses in Germany. The discussion was initiated by the statutory health insurance companies after publication of the SAMMPRIS study results, which were in favor for medical management compared to stent-angioplasty with the Wingspan® stent system. A report (Rapid report N14-01) mainly based on SAMMPRIS was written by the German Institute for Quality and Efficiency in Health Care (IQWiG) and serves as a basis for the decision-making process. This report was previously commented by the medical societies involved. Limitations of the SAMMPRIS trial and vital indications for intracranial stenting were outlined in this comment (acute vessel occlusion, hemodynamic impairment, recurrent symptoms under medical treatment). Currently also emergency stent procedures are a matter of debate. In this context a second IQWiG report was commissioned (GA 15 - 02) addressing the results of the VISSIT trial, the transferability of the results of the first report to emergency treatments and the practice of emergency intracranial stent treatment in Germany. Regarding transferability of results the main conclusion was that there was no evidence that the results of the studies analyzed for the first report (mainly SAMMPRIS) could not be transferred to emergency treatments. From a medical professional and scientific standpoint it is inacceptable to compare outcomes of a secondary prophylactic treatment with emergency procedures. The analysis of emergency treatments in Germany based on retrospective case series with a cumulative number of 31 patients. Since most emergency procedures are performed in a clinical context and are not necessarily subject to scientific evaluation, this does not reflect current practice in Germany. The first part of this statement briefly outlines the design of SAMMPRIS and VISSIT and the interpretation of the trial results from a professional perspective. The current state of discussion regarding reimbursement of intracranial stenting is summarized. The second section contains a detailed comment on the current IQWiG report GA15-02 "Stents for the treatment of intracranial artery stenosis: VISSIT study and acute treatment in Germany".

IQWiG Arbeitspapier GA15-02: "Stents zur Behandlung intrakranieller Stenosen: VISSIT Studie und Akutbehandlung in Deutschland" : Kommentar des Berufsverbandes der Neuroradiologen (BDNR), der Deutschen Gesellschaft für Neuroradiologie (DGNR), der Deutschen Gesellschaft für Neurologie (DGN) und der Deutschen Schlaganfall-Gesellschaft (DSG).

There is an ongoing discussion about reimbursement of stent-angioplasty for the treatment of intracranial stenoses in Germany. The discussion was initiated by the statutory health insurance companies after publication of the SAMMPRIS study results, which were in favor for medical management compared to stent-angioplasty with the Wingspan® stent system. A report (Rapid report N14-01) mainly based on SAMMPRIS was written by the German Institute for Quality and Efficiency in Health Care (IQWiG) and serves as a basis for the decision-making process. This report was previously commented by the medical societies involved. Limitations of the SAMMPRIS trial and vital indications for intracranial stenting were outlined in this comment (acute vessel occlusion, hemodynamic impairment, recurrent symptoms under medical treatment).Currently also emergency stent procedures are a matter of debate. In this context a second IQWiG report was commissioned (GA 15 - 02) addressing the results of the VISSIT trial, the transferability of the results of the first report to emergency treatments and the practice of emergency intracranial stent treatment in Germany6. Regarding transferability of results the main conclusion was that there was no evidence that the results of the studies analyzed for the first report (mainly SAMMPRIS) could not be transferred to emergency treatments. From a medical professional and scientific standpoint it is inacceptable to compare outcomes of a secondary prophylactic treatment with emergency procedures. The analysis of emergency treatments in Germany based on retrospective case series with a cumulative number of 31 patients. Since most emergency procedures are performed in a clinical context and are not necessarily subject to scientific evaluation, this does not reflect current practice in Germany.The first part of this statement briefly outlines the design of SAMMPRIS and VISSIT and the interpretation of the trial results from a professional perspective. The current state of discussion regarding reimbursement of intracranial stenting is summarized. The second section contains a detailed comment on the current IQWiG report GA15-02 "Stents for the treatment of intracranial artery stenosis: VISSIT study and acute treatment in Germany".

Alteration of intermediate filament distribution in PtK1 cells by acrylamide.

PtK1 cells were treated with low concentrations of acrylamide resulting in disruption of intermediate filament networks. An optimum treatment, 5 mM acrylamide in culture medium for 4 h, resulted in formation of a juxtanuclear aggregate containing both keratin and vimentin intermediate filaments. Actin-containing stress fibers and microtubules appeared normal after this treatment. Cells recovered when acrylamide was washed out of the cultures, and normal keratin and vimentin networks reappeared. These cells were capable of proliferation and grew to confluence. Acrylamide-treated cells appeared to locomote normally, showing membrane ruffling and changes in shape, but cytoplasmic organelles did not appear to move normally throughout the cell but remained at the cell center. These observations indicate that acrylamide is a useful intermediate filament inhibitor that does not affect other cytoskeletal elements.