Publications by authors named "Johannes Vester"

19 Publications

  • Page 1 of 1

European Academy of Neurology and European Federation of Neurorehabilitation Societies guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke.

Eur J Neurol 2021 Sep 21;28(9):2831-2845. Epub 2021 Jun 21.

RoNeuro Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania.

Background And Purpose: Early pharmacological support for post-stroke neurorehabilitation has seen an abundance of mixed results from clinical trials, leaving practitioners at a loss regarding the best options to improve patient outcomes. The objective of this evidence-based guideline is to support clinical decision-making of healthcare professionals involved in the recovery of stroke survivors.

Methods: This guideline was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. PubMed, Cochrane Library and Embase were searched (from database inception to June 2018, inclusive) to identify studies on pharmacological interventions for stroke rehabilitation initiated in the first 7 days (inclusive) after stroke, which were delivered together with neurorehabilitation. A sensitivity analysis was conducted on identified interventions to address results from breaking studies (from end of search to February 2020).

Results: Upon manually screening 17,969 unique database entries (of 57,001 original query results), interventions underwent meta-analysis. Cerebrolysin (30 ml/day, intravenous, minimum 10 days) and citalopram (20 mg/day, oral) are recommended for clinical use for early neurorehabilitation after acute ischaemic stroke. The remaining interventions identified by our systematic search are not recommended for clinical use: amphetamine (5, 10 mg/day, oral), citalopram (10 mg/day, oral), dextroamphetamine (10 mg/day, oral), Di-Huang-Yi-Zhi (2 × 18 g/day, oral), fluoxetine (20 mg/day, oral), lithium (2 × 300 mg/day, oral), MLC601(3 × 400 mg/day, oral), phosphodiesterase-5 inhibitor PF-03049423 (6 mg/day, oral). No recommendation 'for' or 'against' is provided for selegiline (5 mg/day, oral). Issues with safety and tolerability were identified for amphetamine, dextroamphetamine, fluoxetine and lithium.

Conclusions: This guideline provides information for clinicians regarding existing pharmacological support in interventions for neurorecovery after acute ischaemic stroke. Updates to this material will potentially elucidate existing conundrums, improve current recommendations, and hopefully expand therapeutic options for stroke survivors.
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http://dx.doi.org/10.1111/ene.14936DOI Listing
September 2021

Cerebrolysin after moderate to severe traumatic brain injury: prospective meta-analysis of the CAPTAIN trial series.

Neurol Sci 2021 Feb 23. Epub 2021 Feb 23.

Department of Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Introduction: This prospective meta-analysis summarizes results from the CAPTAIN trial series, evaluating the effects of Cerebrolysin for moderate-severe traumatic brain injury, as an add-on to usual care.

Materials And Methods: The study included two phase IIIb/IV prospective, randomized, double-blind, placebo-controlled clinical trials. Eligible patients with a Glasgow Coma Score (GCS) between 6 and 12 received study medication (50 mL of Cerebrolysin or physiological saline solution per day for ten days, followed by two additional treatment cycles with 10 mL per day for 10 days) in addition to usual care. The meta-analysis comprises the primary ensembles of efficacy criteria for 90, 30, and 10 days after TBI with a priori ordered hypotheses based on multivariate, directional tests.

Results: A total 185 patients underwent meta-analysis (mean admission GCS = 10.3, mean age = 45.3, and mean Baseline Prognostic Risk Score = 2.8). The primary endpoint, a multidimensional ensemble of functional and neuropsychological outcome scales indicated a "small-to-medium" sized effect in favor of Cerebrolysin, statistically significant at Day 30 and at Day 90 (Day 30: MW = 0.60, 95%CI 0.52 to 0.66, p = 0.0156; SMD = 0.31; OR = 1.69; Day 90: MW = 0.60, 95%CI 0.52 to 0.68, p = 0.0146; SMD = 0.34, OR = 1.77). Treatment groups showed comparable safety and tolerability profiles.

Discussion: The meta-analysis of the CAPTAIN trials confirms the safety and efficacy of Cerebrolysin after moderate-severe TBI, opening a new horizon for neurorecovery in this field. Integration of Cerebrolysin into existing guidelines should be considered after careful review of internationally applicable criteria.
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http://dx.doi.org/10.1007/s10072-020-04974-6DOI Listing
February 2021

fMRI Revealed Reduced Amygdala Activation after Nx4 in Mildly to Moderately Stressed Healthy Volunteers in a Randomized, Placebo-Controlled, Cross-Over Trial.

Sci Rep 2020 03 2;10(1):3802. Epub 2020 Mar 2.

Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, 72076, Germany.

Social stress contributes to major societal health burdens, such as anxiety disorders and nervousness. Nx4 has been found to modulate stress responses. We investigated whether dampening of such responses is associated with neuronal correlates in brain regions involved in stress and anxiety. In a randomized, placebo-controlled, double-blind, cross-over trial, 39 healthy males took a single dose (three tablets) of either placebo or Nx4, 40 to 60 minutes before an fMRI scan session. We here report on drug effects on amygdala responses during a face-matching task, which was performed during a complex test battery further including resting-state brain connectivity and a social stress experiment. The first of the Primary Outcomes, defined in a hierarchical order, concerned reduced amygdala effects after intake of verum compared to placebo. We found a statistically significant reduction in differential activations in the left amygdala for the contrast negative faces versus forms during verum versus placebo condition. Our results indicate that effects of Nx4 can be monitored in the brain. Previously noted effects on stress responses may thus be modulated by affective brain regions including the amygdala.
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http://dx.doi.org/10.1038/s41598-020-60392-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052227PMC
March 2020

Regeneration of Denervated Skeletal Muscles - Brunelli's CNS-PNS Paradigm.

J Med Life 2019 Oct-Dec;12(4):342-353

Department of Neurology, University Medical Center Schleswig-Holstein, Lübeck, Germany.

The restoration of voluntary muscle activity in posttraumatic paraplegia in both animal experiments and other clinical applications requires reproducibility of a technically-demanding microsurgical procedure, limited by physicians' understanding of Brunelli's spinal cord grafting paradigm. The insufficient clinical investigation of the long-term benefits of the CNS-PNS graft application warrants additional inquiry. The objective of this study is to explore the potential benefits of the first replicated, graft-induced neuroregeneration of denervated skeletal muscle regarding long-term clinical outcomes and to investigate the effect of Cerebrolysin on neuromodulation. A randomized study evaluating 30 rats, approved by the National Animal Ethics Advisory Committee was performed. The medication was administered postoperatively. For 14 days, 12 rats received Cerebrolysin (serum), 11 received NaCl 0.9% (shams), and 7 were controls. For microsurgery, the lateral corticospinal tract T10 was grafted to the denervated internal obliquus abdominal muscle. On day 90, intraoperative proof of reinnervation was observed. On day 100, 15 rats were euthanized for fixation, organ removal, and extensive histology-morphology examination, and the Wei-Lachin statistical procedure was employed. After an open revision of 16 rats, 8 were CMAP positive. After intravenous Vecuronium application, two (Cerebrolysin, NaCl) out of two rats showed an incomplete compound muscle action potential (CMAP) loss due to glutamatergic and cholinergic co-transmission, while two others showed a complete loss of amplitude. Cerebrolysin medication initiated larger restored muscle fiber diameters and less scarring. FB+ neurons were not observed in the brain but were observed in the Rexed laminae. Brunelli's concept was successfully replicated, demonstrating the first graft induced existence of cholinergic and glutamatergic neurotransmission in denervated grafted muscles. Statistics of the histometric count of muscle fibers revealed larger fiber diameters after Cerebrolysin. Brunelli's CNS-PNS experimental concept is suitable to analyze graft-neuroplasticity focused on the voluntary restoration of denervated skeletal muscles in spinal cord injury. Neuroprotection by Cerebrolysin is demonstrated.
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http://dx.doi.org/10.25122/jml-2019-0063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993288PMC
April 2020

Efficacy and safety of cerebrolysin in neurorecovery after moderate-severe traumatic brain injury: results from the CAPTAIN II trial.

Neurol Sci 2020 May 2;41(5):1171-1181. Epub 2020 Jan 2.

Department of Biometry and Clinical Research, idv Data Analysis and Study Planning, Gauting, Germany.

Introduction: The objective of this trial was to evaluate the efficacy and safety of Cerebrolysin in treating patients after moderate to severe traumatic brain injury (TBI) as an adjunct to standard care protocols. The trial was designed to investigate the clinical effects of Cerebrolysin in the acute (neuroprotective) stage and during early and long-term recovery as part of a neurorestorative strategy.

Materials And Methods: The study was a phase IIIb/IV single-center, prospective, randomized, double-blind, placebo-controlled clinical trial. Eligible patients with a Glasgow Coma Score (GCS) between 7 and 12 received study medication (50 ml of Cerebrolysin or physiological saline solution per day for 10 days, followed by two additional treatment cycles with 10 ml per day for 10 days) in addition to standard care. We tested ensembles of efficacy criteria for 90, 30, and 10 days after TBI with a priori ordered hypotheses using a multivariate, directional test, to reflect the global status of patients after TBI.

Results: The study enrolled 142 patients, of which 139 underwent formal analysis (mean age = 47.4, mean admission GCS = 10.4, and mean Baseline Prognostic Risk Score = 2.6). The primary endpoint, a multidimensional ensemble of 13 outcome scales, indicated a "small-to-medium"-sized effect in favor of Cerebrolysin, statistically significant at day 90 (MW = 0.59, 95% CI 0.52 to 0.66, P = 0.0119). Safety and tolerability observations were comparable between treatment groups.

Conclusion: Our trial confirms previous beneficial effects of the multimodal, biological agent Cerebrolysin for overall outcome after moderate to severe TBI, as measured by a multidimensional approach. Study findings must be appraised and aggregated in conjunction with existing literature, as to improve the overall level of insight regarding therapeutic options for TBI patients. The widely used pharmacologic intervention may benefit from a large-scale observational study to map its use and to establish comparative effectiveness in real-world clinical settings.
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http://dx.doi.org/10.1007/s10072-019-04181-yDOI Listing
May 2020

Differences in Health-Related Quality of Life after Traumatic Brain Injury between Varying Patient Groups: Sensitivity of a Disease-Specific (QOLIBRI) and a Generic (SF-36) Instrument.

J Neurotrauma 2020 05 31;37(10):1242-1254. Epub 2020 Jan 31.

Institute of Medical Psychology and Medical Sociology, University Medical Center Göttingen, Göttingen, Germany.

Factors associated with health-related quality of life (HRQOL) in patients after traumatic brain injury (TBI) include severity of initial injury, different grades of trauma recovery, sociodemographic status, and psychological characteristics. Yet, sensitivity of HRQOL instruments to such effects is often underexplored. Thus, we aimed to compare the capacity of the disease-specific QOLIBRI (Quality of Life after Brain Injury) and the generic Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey(SF-36) to detect significant differences in HRQOL between patients. Patients ( = 795) completed HRQOL, sociodemographic, clinical, psychological, and health status questionnaires. Univariate (Wilcoxon-Mann-Whitney) and multi-variate (Wei-Lachin) non-parametric analyses were conducted using the Wilcoxon-Mann-Whitney approach to compare the sensitivity of the QOLIBRI and the SF-36. For both instruments, HRQOL was particularly influenced by patients' reliance on others, depression, anxiety, and recovery status, whereas smaller effects were found for living arrangements and participation in leisure activities. Both HRQOL instruments were sensitive to group differences, but the QOLIBRI was able to detect a greater number of and finer differences between specific patient groups, which is particularly important in clinical and therapeutic contexts. This finding is likely explained by the QOLIBRI's greater specificity to disease-specific aspects of consequences of TBI. This head-to-head HRQOL instrument comparison resulted in a recommendation for the use of the QOLIBRI when detailed insight in the subjective consequences and impact of TBI on patients is required.
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http://dx.doi.org/10.1089/neu.2019.6627DOI Listing
May 2020

VaD - An Integrated Framework for Cognitive Rehabilitation.

CNS Neurol Disord Drug Targets 2018 04;17(1):22-33

Department of Clinical Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Background & Objective: Vascular dementia is the second most common cause of dementia, with clinical features that depend on neural substrates affected by the vascular lesions. Like most neurological disorders, it involves alterations that range from the molecular level to neuronal networks. Such alterations begin as compensatory mechanisms that reshape every subsystem involved in the brain's homeostasis. Although there have been recent huge advances in understanding the pathophysiology of cognitive dysfunction, a suitable therapeutic approach to vascular dementia remains elusive. Pharmacological interventions have failed to sustainably improve cognitive function, and it is a well-known fact that there is a need to change the current view for providing neuroprotection and enhancing neurorecovery after stroke. Studies regarding cognitive training are also faced with the difficulty of drawing up protocols that can embrace a holistic approach in cognitively impaired patients.

Conclusion: This review will present a brief synthesis of current results from basic research data and clinical studies regarding pharmacological and non-pharmacological interventions in vascular dementia and will offer an integrated view from the perspective of systems biology.
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http://dx.doi.org/10.2174/1871527317666180219164545DOI Listing
April 2018

Safety and efficacy of Cerebrolysin in early post-stroke recovery: a meta-analysis of nine randomized clinical trials.

Neurol Sci 2018 Apr 16;39(4):629-640. Epub 2017 Dec 16.

Department of Clinical Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Victor Babes Street No. 8, 400012, Cluj-Napoca, Romania.

This meta-analysis combines the results of nine ischemic stroke trials, assessing efficacy of Cerebrolysin on global neurological improvement during early post-stroke period. Cerebrolysin is a parenterally administered neuropeptide preparation approved for treatment of stroke. All included studies had a prospective, randomized, double-blind, placebo-controlled design. The patients were treated with 30-50 ml Cerebrolysin once daily for 10-21 days, with treatment initiation within 72 h after onset of ischemic stroke. For five studies, original analysis data were available for meta-analysis (individual patient data analysis); for four studies, aggregate data were used. The combination by meta-analytic procedures was pre-planned and the methods of synthesis were pre-defined under blinded conditions. Search deadline for the present meta-analysis was December 31, 2016. The nonparametric Mann-Whitney (MW) effect size for National Institutes of Health Stroke Scale (NIHSS) on day 30 (or 21), combining the results of nine randomized, controlled trials by means of the robust Wei-Lachin pooling procedure (maximin-efficient robust test), indicated superiority of Cerebrolysin as compared with placebo (MW 0.60, P < 0.0001, N = 1879). The combined number needed to treat for clinically relevant changes in early NIHSS was 7.7 (95% CI 5.2 to 15.0). The additional full-scale ordinal analysis of modified Rankin Scale at day 90 in moderate to severe patients resulted in MW 0.61 with statistical significance in favor of Cerebrolysin (95% CI 0.52 to 0.69, P = 0.0118, N = 314). Safety aspects were comparable to placebo. Our meta-analysis confirms previous evidence that Cerebrolysin has a beneficial effect on early global neurological deficits in patients with acute ischemic stroke.
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http://dx.doi.org/10.1007/s10072-017-3214-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884916PMC
April 2018

Effects of a systemic enzyme therapy in healthy active adults after exhaustive eccentric exercise: a randomised, two-stage, double-blinded, placebo-controlled trial.

BMJ Open Sport Exerc Med 2016 12;2(1):e000191. Epub 2017 Mar 12.

Sportmedizin, Gilching, Germany.

Background: Systemic enzyme therapy may improve symptoms of exhaustive eccentric exercise due to anti-inflammatory properties.

Methods: In a randomised, placebo-controlled, two-stage clinical trial, systemic enzyme therapy (Wobenzym) was administered for 72 hours before and 72 hours following a day on which subjects performed an exhaustive eccentric exercise (isokinetic loading of the quadriceps). Efficacy criteria (maximal strength and pain) and time points were selected to account for the multidimensional nature of exercise-induced muscle damage symptoms. Subjects were randomised in a crossover (stage I, n=28) and parallel group design (stage II, n=44).

Results: Analysis of stage I data demonstrated a significant superiority (Mann-Whitney=0.6153; p=0.0332; one sided) for systemic enzyme therapy compared with placebo. Stage II was designed as a randomised controlled parallel group comparison. Heterogeneity (I>0.5) between stages led to separate analyses of stage I (endurance-trained subjects) and stage II (strength-trained subjects). Combined analysis resulted in no evidence for corresponding treatment effects. Analysis of pooled biomarker data, however, demonstrated significant favourable effects for systemic enzyme therapy in both stages.

Conclusion: Systemic enzyme therapy before and after exhaustive eccentric exercise resulted in higher maximal concentric strength in the less strength-trained subjects (stage I) and in significant favourable effects on biomarkers (inflammatory, metabolic and immune) in all subjects. The application of these findings needs further evaluation.
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http://dx.doi.org/10.1136/bmjsem-2016-000191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569274PMC
March 2017

Safety and efficacy of Cerebrolysin in motor function recovery after stroke: a meta-analysis of the CARS trials.

Neurol Sci 2017 Oct 13;38(10):1761-1769. Epub 2017 Jul 13.

Department of Clinical Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Victor Babes Street No. 8, 400012, Cluj-Napoca, Romania.

This meta-analysis combines the results of two identical stroke studies (CARS-1 and CARS-2) assessing efficacy of Cerebrolysin on motor recovery during early rehabilitation. Cerebrolysin is a parenterally administered neuropeptide preparation approved for the treatment of stroke. Both studies had a prospective, randomized, double-blind, placebo-controlled design. Treatment with 30 ml Cerebrolysin once daily for 3 weeks was started 24-72 h after stroke onset. In addition, patients participated in a standardized rehabilitation program for 21 days that was initiated within 72 h after stroke onset. For both studies, the original analysis data were used for meta-analysis (individual patient data analysis). The combination of these two studies by meta-analytic procedures was pre-planned, and the methods were pre-defined under blinded conditions. The nonparametric Mann-Whitney (MW) effect size of the two studies on the ARAT score on day 90 indicated superiority of Cerebrolysin compared with placebo (MW 0.62, P < 0.0001, Wei-Lachin pooling procedure, day 90, last observation carried forward; N = 442). Also, analysis of early benefit at day 14 and day 21 by means of the National Institutes of Health Stroke Scale, which is regarded as most sensitive to early improvements, showed statistical significance (MW 0.59, P < 0.002). The corresponding number-needed-to-treat (NNT) for clinically relevant changes in early NIHSS was 7.1 (95% CI: 4 to 22). Cerebrolysin had a beneficial effect on motor function and neurological status in early rehabilitation patients after acute ischemic stroke. Safety aspects were comparable to placebo, showing a favourable benefit/risk ratio.
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http://dx.doi.org/10.1007/s10072-017-3037-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605586PMC
October 2017

Cerebrolysin and Recovery After Stroke (CARS): A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial.

Stroke 2016 Jan 12;47(1):151-9. Epub 2015 Nov 12.

From the Department of Clinical Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania (D.F.M.); Max Planck Institute for Metabolism Research, Cologne, Germany (W.-D.H.); Department of Neurology, SHR Gesundheitszentrum Bad Wimpfen GmbH, Bad Wimpfen, Germany (V.H.); Department of Neurology, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania (O.B.); Department of Neurology, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania (C.D.P.); Department of Biometry and Clinical Research, IDV Data Analysis and Study Planning, Krailling, Germany (J.C.V., V.W.R.); Department of Clinical Research, EVER Neuro Pharma GmbH, Unterach, Austria (E.D., D.M., H.M.); Department of Neurology, Neurosurgery and Genetics, Russian National Research Medical University, Moscow City Hospital No. 8 for Neuropsychiatry, Moscow, Russia (A.G.); and "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania (D.F.M.).

Background And Purpose: The aim of this trial was to investigate whether stroke patients who receive Cerebrolysin show improved motor function in the upper extremities at day 90 compared with patients who receive a placebo.

Methods: This study was a prospective, randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Patients were treated with Cerebrolysin (30 mL/d) or a placebo (saline) once daily for 21 days, beginning at 24 to 72 hours after stroke onset. The patients also participated in a standardized rehabilitation program for 21 days that was initiated within 72 hours after stroke onset. The primary end point was the Action Research Arm Test score on day 90.

Results: The nonparametric effect size on the Action Research Arm Test score on day 90 indicated a large superiority of Cerebrolysin compared with the placebo (Mann-Whitney estimator, 0.71; 95% confidence interval, 0.63-0.79; P<0.0001). The multivariate effect size on global status, as assessed using 12 different outcome scales, indicated a small-to-medium superiority of Cerebrolysin (Mann-Whitney estimator, 0.62; 95% confidence interval, 0.58-0.65; P<0.0001). The rate of premature discontinuation was <5% (3.8%). Cerebrolysin was safe and well tolerated.

Conclusions: Cerebrolysin had a beneficial effect on function and global outcome in early rehabilitation patients after stroke. Its safety was comparable with that of the placebo, suggesting a favorable benefit/risk ratio. Because this study was exploratory and had a relatively small sample size, the results should be confirmed in a large-scale, randomized clinical trial.

Clinical Trial Registration: URL: http://www.clinicaltrialsregister.eu. Unique identifier: 2007-000870-21.
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http://dx.doi.org/10.1161/STROKEAHA.115.009416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689177PMC
January 2016

GFAP and antibodies against NMDA receptor subunit NR2 as biomarkers for acute cerebrovascular diseases.

J Cell Mol Med 2015 Sep 17;19(9):2253-61. Epub 2015 Jun 17.

Department of Microbiology and Epidemiology, University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania.

We studied whether the serum levels of glial fibrillary acidic protein (GFAP) and of antibodies against the N-methyl-d-aspartate receptor subunit NR2 (NR2 RNMDA ) can discriminate between intracerebral haemorrhage (ICH) and ischaemic stroke (IS) in stroke patients. We prospectively recruited patients with suspected stroke (72 confirmed) and 52 healthy controls. The type of brain lesion (ICH or IS) was established using brain imaging. The levels of GFAP and of antibodies against NR2 RNMDA were measured in blood samples obtained within 12 hrs after stroke onset and 24, 48 and 72 hrs and 1 and 2 weeks later using ELISA immunoassay. Improvement in diagnostic performance was assessed in logistic regression models designed to predict the diagnosis and the type of stroke. GFAP peaks early during haemorrhagic brain lesions (at significantly higher levels), and late in ischaemic events, whereas antibodies against NR2 RNMDA have significantly higher levels during IS at all time-points. Neither of the two biomarkers used on its own could sufficiently discriminate patients, but when they are used in combination they can differentiate at 12 hrs after stroke, between ischaemic and haemorrhagic stroke with a sensitivity and specificity of 94% and 91%, respectively.
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http://dx.doi.org/10.1111/jcmm.12614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568929PMC
September 2015

Clinically relevant effectiveness of focused extracorporeal shock wave therapy in the treatment of chronic plantar fasciitis: a randomized, controlled multicenter study.

J Bone Joint Surg Am 2015 May;97(9):701-8

Klinik für Orthopädie und Unfallchirurgie, Universitätsklinikum Schleswig Holstein, Arnold Heller Strasse, 24105 Kiel, Germany.

Background: The effectiveness of extracorporeal shock wave therapy in the treatment of plantar fasciitis is controversial. The objective of the present study was to test whether focused extracorporeal shock wave therapy is effective in relieving chronic heel pain diagnosed as plantar fasciitis.

Methods: Two hundred and fifty subjects were enrolled in a prospective, multicenter, double-blind, randomized, and placebo-controlled U.S. Food and Drug Administration trial. Subjects were randomized to focused extracorporeal shock wave therapy (0.25 mJ/mm(2)) or placebo intervention, with three sessions of 2000 impulses in weekly intervals. Primary outcomes were both the percentage change of heel pain on the visual analog scale composite score (pain during first steps in the morning, pain with daily activities, and pain with a force meter) and the Roles and Maudsley score at twelve weeks after the last intervention compared with the scores at baseline.

Results: Two hundred and forty-six patients (98.4%) were available for intention-to-treat analysis at the twelve-week follow-up. With regard to the first primary end point, the visual analog scale composite score, there was a significant difference (p = 0.0027, one-sided) in the reduction of heel pain in the extracorporeal shock wave therapy group (69.2%) compared with the placebo therapy group (34.5%). Extracorporeal shock wave therapy was also significantly superior to the placebo therapy for the Roles and Maudsley score (p = 0.0006, one-sided). Temporary pain and swelling during and after treatment were the only device-related adverse events observed.

Conclusions: The results of the present study provide proof of the clinically relevant effect size of focused extracorporeal shock wave therapy without local anesthesia in the treatment of recalcitrant plantar fasciitis, with success rates between 50% and 65%.

Level Of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.M.01331DOI Listing
May 2015

Cerebrolysin in mild-to-moderate Alzheimer's disease: a meta-analysis of randomized controlled clinical trials.

Dement Geriatr Cogn Disord 2015 26;39(5-6):332-47. Epub 2015 Mar 26.

McGill Center for Studies in Aging, Montreal, Que., Canada.

Objective: The aim of this study was to provide a systematic and quantitative summary of benefit and risk of Cerebrolysin in patients with mild-to-moderate Alzheimer's disease (AD) and to avoid major deficiencies of an earlier meta-analysis.

Design: This is a meta-analysis of randomized double-blind placebo-controlled clinical trials.

Data Sources: Trials were identified with the help of PubMed, the Cochrane Dementia Group database, the Center for Collaborative Neurosciences, and references from reviews; no language restrictions were applied.

Study Selection: All randomized double-blind placebo-controlled studies on 30 ml/day of Cerebrolysin in mild-to-moderate AD were included.

Results: There were 6 eligible randomized controlled trials comparing Cerebrolysin with placebo. For all studies, either individual patient data and/or published data (aggregate data) were available. Analyses were based on the odds ratio (OR) for dichotomized global clinical change and for safety criteria, on the standardized mean difference (SMD) for pooling of cognitive function, and on the Mann-Whitney statistic (MW) for multivariate analysis of 'global benefit' (combined effect of global clinical change and cognitive function). Cerebrolysin was significantly more effective than placebo at 4 weeks regarding cognitive function (4 weeks: SMD -0.40 points; 95% CI -0.66 to -0.13; p = 0.0031; 6 months: SMD -0.37 points; 95% CI -0.90 to 0.16; p = 0.1710), at 4 weeks and 6 months regarding global clinical change (4 weeks: OR 3.32; 95% CI 1.20-9.21; p = 0.0212; 6 months: OR 4.98; 95% CI 1.37-18.13; p = 0.0150), and at 4 weeks and 6 months regarding 'global benefit' (combined efficacy criteria; 4 weeks: MW 0.57, 95% CI 0.53-0.61; p = 0.0006; 6 months: MW 0.57; 95% CI 0.53-0.61; p = 0.0010). The safety aspects of Cerebrolysin were comparable to placebo.

Conclusion: This meta-analysis provides evidence that Cerebrolysin has an overall beneficial effect and a favorable benefit-risk ratio in patients with mild-to-moderate AD. Cerebrolysin as a therapeutic agent should be considered by clinicians seeking treatment options for mild-to-moderate AD.
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http://dx.doi.org/10.1159/000377672DOI Listing
October 2015

Cerebrolysin Asian Pacific trial in acute brain injury and neurorecovery: design and methods.

J Neurotrauma 2015 Apr 28;32(8):571-80. Epub 2015 Jan 28.

1 Division of Neurosurgery, Prince of Wales Hospital, the Chinese University of Hong Kong , Hong Kong, China .

Traumatic brain injury (TBI) is one of the leading causes of injury-related death. In the United States alone, an estimated 1.7 million people sustain a TBI each year, and approximately 5.3 million people live with a TBI-related disability. The direct medical costs and indirect costs such as lost productivity of TBIs totaled an estimated $76.5 billion in the U.S. in the year 2000. Improving the limited treatment options for this condition remains challenging. However, recent reports from interdisciplinary working groups (consisting primarily of neurologists, neurosurgeons, neuropsychologists, and biostatisticians) have stated that to improve TBI treatment, important methodological lessons from the past must be taken into account in future clinical research. An evaluation of the neuroprotection intervention studies conducted over the last 30 years has indicated that a limited understanding of the underlying biological concepts and methodological design flaws are the major reasons for the failure of pharmacological agents to demonstrate efficacy. Cerebrolysin is a parenterally-administered neuro-peptide preparation that acts in a manner similar to endogenous neurotrophic factors. Cerebrolysin has a favorable adverse effect profile, and several meta-analyses have suggested that Cerebrolysin is beneficial as a dementia treatment. CAPTAIN is a randomized, double-blind, placebo-controlled, multi-center, multinational trial of the effects of Cerebrolysin on neuroprotection and neurorecovery after TBI using a multidimensional ensemble of outcome scales. The CAPTAIN trial will be the first TBI trial with a 'true' multidimensional approach based on full outcome scales, while avoiding prior weaknesses, such as loss of information through "dichotomization," or unrealistic assumptions such as "normal distribution."
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http://dx.doi.org/10.1089/neu.2014.3558DOI Listing
April 2015

Placebo controlled, prospectively randomized, double-blinded study for the investigation of the effectiveness and safety of the acoustic wave therapy (AWT(®)) for cellulite treatment.

J Cosmet Laser Ther 2013 Jun 21;15(3):155-62. Epub 2013 May 21.

Praxis und Laserzentrum, Haydnplatz 4, A-6020 Insbruck, Austria.

Placebo controlled double-blinded, prospectively randomized clinical trial with 17 patients (11 verum, 5 placebo) for evaluation of cellulite treatment with Acoustic Wave Therapy, (AWT(®)) was performed. The patients were treated once a week for 7 weeks, a total of 8 treatments with the D-ACTOR(®) 200 by Storz Medical AG. Data were collected at baseline, before 8th treatment, at 1 month (follow-up 1) and at 3 months (follow-up 2) after the last treatment with a patients' questionnaire, weight control, measurement of circumference and standardized photography. Treatment progress was further documented using a specially designed 3D imaging system (SkinSCAN(3D), 3D-Shape GmbH) providing an objective measure of cellulite (primary efficacy criteria). Patient's questionnaire in the verum group revealed an improvement in number and depth of dimples, skin firmness and texture, in shape and in reduction of circumference. The overall result (of skin waviness, Sq and Sz, surface and volume of depressions and elevations, Vvv and Vmp) at two follow-up visits indicates a more than medium sized superiority (MW = 0.6706) and is statistically significant (pWei-Lachin = 0.0106). The placebo group revealed no statistical significance. No side effects were seen. This indicates the efficacy and safety of AWT(®) for patients with cellulite.
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http://dx.doi.org/10.3109/14764172.2012.759235DOI Listing
June 2013

Comparison of radial versus focused extracorporeal shock waves in plantar fasciitis using functional measures.

Foot Ankle Int 2010 Jan;31(1):1-9

Institute of Sports Medicine Frankfurt, Otto-Fleck-Schneise 10, 60528 Frankfurt/Main, Germany.

Background: Recent literature shows evidence for effective treatment for plantar fasciitis using either focused or radial shock waves. Up to now no research has been available which compares these different procedures. We hypothesized (H(0) Hypothesis) that for plantar fasciitis, outcomes following focused or radial shock wave treatment were equal.

Materials And Methods: For this pilot study, 39 patients suffering from recalcitrant plantar fasciitis were randomized in two groups. Treatment was performed in three sessions. Once a week 2000 impulses of radial (0.17 mJ/mm(2)) or focused (0.20 mJ/mm(2)) shock waves were applied. Efficacy was determined by multivariate analysis of eight single variables including changes in Foot Functional Index, neuromuscular performance (Single leg drop and long jump, postural stability, isokinetic testing), and by a composite score from baseline to 12 weeks followup. Multivariate Wilcoxon tests (Wei-Lachin procedure) and formal meta-analytic procedure with adjustment for subgroups was performed to determine the adjusted effect sizes with their corresponding confidence intervals.

Results: The overall result (;;Crude Pooling'') shows ;;small'' superiority of the focused extracorporeal shock wave therapy (MW = 0.55, LB-CI = 0.4644). Adjusted for age the focused treatment exhibited ;;more than small'' superiority (MW = 0.59, LB-CI > 0.5) and this result is statistically significant (LB-CI = 0.5067, benchmark for equality = 0.5).

Conclusion: This study provides some evidence for focused extracorporeal shock wave treatment being superior to radial extracorporeal shock wave therapy for recalcitrant plantar fasciitis.
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http://dx.doi.org/10.3113/FAI.2010.0001DOI Listing
January 2010

Radial extracorporeal shock wave therapy is safe and effective in the treatment of chronic recalcitrant plantar fasciitis: results of a confirmatory randomized placebo-controlled multicenter study.

Am J Sports Med 2008 Nov 1;36(11):2100-9. Epub 2008 Oct 1.

Department of Orthopedic and Traumatology, Technical University Munich, Klinikum Rechts der Isar, Germany.

Background: Radial extracorporeal shock wave therapy is an effective treatment for chronic plantar fasciitis that can be administered to outpatients without anesthesia but has not yet been evaluated in controlled trials.

Hypothesis: There is no difference in effectiveness between radial extracorporeal shock wave therapy and placebo in the treatment of chronic plantar fasciitis.

Study Design: Randomized, controlled trial; Level of evidence, 1.

Methods: Three interventions of radial extracorporeal shock wave therapy (0.16 mJ/mm(2); 2000 impulses) compared with placebo were studied in 245 patients with chronic plantar fasciitis. Primary endpoints were changes in visual analog scale composite score from baseline to 12 weeks' follow-up, overall success rates, and success rates of the single visual analog scale scores (heel pain at first steps in the morning, during daily activities, during standardized pressure force). Secondary endpoints were single changes in visual analog scale scores, success rates, Roles and Maudsley score, SF-36, and patients' and investigators' global judgment of effectiveness 12 weeks and 12 months after extracorporeal shock wave therapy.

Results: Radial extracorporeal shock wave therapy proved significantly superior to placebo with a reduction of the visual analog scale composite score of 72.1% compared with 44.7% (P = .0220), and an overall success rate of 61.0% compared with 42.2% in the placebo group (P = .0020) at 12 weeks. Superiority was even more pronounced at 12 months, and all secondary outcome measures supported radial extracorporeal shock wave therapy to be significantly superior to placebo (P < .025, 1-sided). No relevant side effects were observed.

Conclusion: Radial extracorporeal shock wave therapy significantly improves pain, function, and quality of life compared with placebo in patients with recalcitrant plantar fasciitis.
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http://dx.doi.org/10.1177/0363546508324176DOI Listing
November 2008
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