A Sphingosine-1-Phosphate Receptor Modulator Attenuated Secondary Brain Injury and Improved Neurological Functions of Mice after ICH.

BACKGROUND: Stroke activates the immune system and induces brain infiltration by immune cells, aggravating brain injury. Poststroke immunomodulation via (S1P-)receptor modulation is beneficial; however, the S1P-modulator in clinical use (FTY-720) is unspecific, and undesirable side effects have been reported. Previously, we tested effects of a novel selective S1P-receptor modulator, Siponimod, on ICH-induced brain injury in acute stage of the disease. In the current study, we investigated whether protective effects of Siponimod, evaluated in a short-term study, will protect the brain of ICH animals at long term as well. METHODS: 134 C57BL/6N mice were divided into sham and ICH-operated groups. Collagenase model of ICH was employed. ICH animals were divided into Siponimod treated and nontreated. Dose- and time-dependent effects of Siponimod were investigated. Contraplay between development of brain injury and the number of lymphocytes infiltrating the brain was investigated by forelimb placing, T-Maze test, brain water content calculation, MRI scanning, and immunostaining. RESULTS: Depending on the therapeutic strategy, Siponimod attenuated the development of brain edema, decreased ICH-induced ventriculomegaly and improved neurological functions of animals after ICH. It was associated with less lymphocytes in the brain of ICH animals. CONCLUSION: Siponimod is able to decrease the brain injury and improves neurological functions of animals after ICH.

Ovarian reserve as a predictor of cumulative live birth.

OBJECTIVES: Develop an up to date prediction model using recent cycle data and key pre-treatment predictor variables to estimate a couple's individualised probability of a cumulative live birth after one cycle of ovarian stimulation and transfer of all frozen embryos, before the first embryo transfer. STUDY DESIGN: This was a retrospective cohort study. To estimate the cumulative live birth rate we only included couples who had used all embryos from their initial stimulation or achieved a live birth. We constructed a logistic regression model using live birth as a dependent variable and age group, duration of infertility, primary vs. secondary infertility, insemination method, cause of infertility, Anti-Mullerian Hormone (AMH), Follicle Stimulating Hormone (FSH) and antral follicle count (AFC) as our independent variables and used a backward elimination method to create the best fitting regression models to predict the probability of a cumulative live birth (p < 0.05 for elimination). RESULTS: There were 516 complete cycles of ovarian stimulation resulting in 357 livebirths giving a cumulative livebirth rate of 69.2 % (95 % CI 66.0-74.0). Women with a live birth had significantly lower median age (34 years [IQR 31-37] vs. 36 years [IQR 33-39], p = 0.01) and FSH (6.7 iu/L [IQR 5.8-7.9] vs. 7.4 iu/L [IQR 6.2-8.6] and a significantly higher median AMH (22.1 pmol/L [IQR 12.1-30.9] vs. 10.5 pmol/L [IQR 7.3-20.7], p = 0.01) and AFC (18 [IQR 12-26] vs. 12 [IQR 9-19], p = 0.01). The backward conditional logistic regression model retained age category, FSH category and AMH category as significant independent predictors. The area under the curve for this model was 0.68 (95 % CI 0.63 - 0.73). CONCLUSION: Our prediction model estimates a couple's individualised probability of achieving a live birth after their first complete cycle of IVF using all known pre-treatment predictors. LIMITATIONS, REASONS FOR CAUTION: The study population were only those eligible for NHS funded IVF treatment which have strict ovarian reserve criteria. Exclusion of those with very low egg reserve is likely to influence the predictive capacity of out model. Furthermore, our model was developed using cycle data from one unit and thus its predictive capacity has not been assessed on an independent cohort of women. We therefore welcome external geographical validation of our model prior to its use in clinical practice.

Serelaxin activates eNOS, suppresses inflammation, attenuates developmental delay and improves cognitive functions of neonatal rats after germinal matrix hemorrhage.

Germinal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury. Following GMH-mediated eNOS inhibition, inflammation arises, contributing to GMH-induced brain injury. We investigated the beneficial effects of Serelaxin, a clinical tested recombinant Relaxin-2 protein, on brain injury after GMH in rats. We investigated whether effects of Serelaxin are mediated by its ability to activate the GMH-suppressed eNOS pathway resulting in attenuation of inflammatory marker overproduction. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U). Seven day old Sprague-Dawley rat pups (P7) were used (n = 63). GMH animals were divided in vehicle or serelaxin treated (3 µg once, 30 µg once, 30 µg multiple, i.p., starting 30 after GMH and then daily). Sham operated animals were used. We monitored the developmental profile working memory and spatial function (T-maze and open field test respectively). At day 28, all rats underwent MRI-scans for assessment of changes in cortical thickness and white matter loss. Effects of Serelaxin on eNOS pathway activation and post-GMH inflammation were evaluated. We demonstrated that Serelaxin dose-dependently attenuated GMH-induced developmental delay, protected brain and improved cognitive functions of rats after GMH. That was associated with the decreased post-GMH inflammation, mediated at least partly by amelioration of GMH-induced eNOS inhibition.

Effects of an Articulated Ankle Foot Orthosis on Gait Biomechanics in Adolescents with Traumatic Brain Injury: A Case-Series Report.

PURPOSE: To quantify the effects of an articulated ankle foot orthosis on genu recurvatum gait in adolescents with traumatic brain injury (TBI). METHODS: Gait analysis was conducted in 2 individuals with TBI during over ground ambulation with (braced condition) and without (barefoot condition) the AAFO. For each participant, stride-by-stride gait data were compared to assess differences between barefoot and braced walking conditions. RESULTS: During the braced versus barefoot condition, both participants demonstrated reduced plantar flexion at initial contact, increased knee flexion at initial contact, reduced peak knee extension during stance, and reduced peak and integral of internal knee flexor moment during stance. CONCLUSIONS: The data suggest that the AAFO reduced plantar flexion during stance, therefore attenuating the anterior displacement of the ground reaction force vector (GRFV) relative to the ankle and knee joint axes, and leading to a reduction in knee hyperextension and the internal knee flexor moment during stance. We posit that the reduction in internal knee flexor moment may lead to a more sustainable gait pattern with less potential for mechanical stress on the posterior knee joint capsule.

Gluconacin from Gluconacetobacter diazotrophicus PAL5 is an active bacteriocin against phytopathogenic and beneficial sugarcane bacteria.

AIMS: This study aimed to explore the possibility of using the Gluconacin from Gluconacetobacter diazotrophicus strain PAL5 in the biological control of diverse sugarcane phytopathogenic bacteria. METHODS AND RESULTS: An in silico analysis was first employed to determine the phylogenetic relationship between Gram-negative/positive bacteriocin producers and Gluconacin. The analysis showed that this trait is widespread among tested bacterial species and a well-conserved gene within the Acetobacteraceae family. The bacteriocin gene (GDI_0415) present in the genome of strain PAL5 was than cloned in pDEST™17 and expressed in Escherichia coli BL21-AI™. A bioassay showed growth inhibition of Xanthomonas albilineans by the recombinant bacteriocin. Subsequent bioassays indicated different levels of antagonistic activity against the majority of the sugarcane phytopathogenic bacteria (Xanthomonas axonopodis pv. vasculorum, Acidovorax avenae subsp. avenae, Pseudomonas syringae pv. syringae, Xanthomonas vasicola pv. vasculorum). In addition, the bacteriocin was also antagonistic to some beneficial bacterial strains belonging to G. diazotrophicus and endophytic Bacillus species, which also colonize sugarcane plants. CONCLUSIONS: The GDI_0415 gene, responsible for the production of Gluconacin, is well conserved within the Acetobacteraceae family and presented antagonistic activity against phytopathogenic and a few beneficial sugarcane bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: The production of a recombinant protein, named Gluconacin, opens new avenues for the agro-biotechnology application in agriculture, mainly with regard to the sugarcane crop.

[Telemedicine in stroke care]. / Telemedizin in der Schlaganfallversorgung.

Telemedicine is already widely used in many telestroke networks and ensures stroke treatment close to the patient's home in rural and medically underserved areas. This is particularly effective when telemedicine is integrated into a stroke unit concept. While telemedically based thrombolysis therapy has become routine practice for many years, practical implementation of comprehensive mechanical thrombectomy and the related processes remains challenging. The main tasks for the future further include development of a structured stroke aftercare system in neurologically underserved areas and permanent assurance of high-quality stroke care in telemedically connected sites.

[Telemedicine: Comprehensive coverage and quality - Not a contradiction : Practical experience from the stroke network with telemedicine in northern Bavaria (STENO)]. / Telemedizin: Flächendeckung und Qualität ­ kein Widerspruch : Praktische Erfahrungen aus dem Schlaganfallnetzwerk mit Telemedizin in Nordbayern STENO.

Telemedicine is widely used in the field of stroke treatment. Following the pioneering and implementation phase, the quality of the whole stroke treatment process needs to be ensured in telemedically connected hospitals. This is particular important for telestroke hospitals without neurological expertise and can be achieved by integrating telemedicine into the stroke unit concept and stroke networks. The Stroke Network with Telemedicine in Northern Bavaria (STENO) provides an example of how quality management can be practically implemented. The implementation of STENO has established a network-wide quality management system which has been certified according to DIN EN ISO 9001:2008 since 2011.

[Invasive stroke treatment - Study results and clinical routine : Lost in translation?]. / Invasive Schlaganfallbehandlung - Studienergebnisse und klinische Routine : Lost in translation?

OBJECTIVE: How can the overwhelmingly positive results of the five randomized thrombectomy trials published in 2015 be transferred to the clinical routine? MATERIAL AND METHODS: Analysis of trial-specific characteristics with regard to implementation of mechanical thrombectomy into clinical routine. RESULTS: Stroke patients with symptomatic proximal artery occlusion are principally eligible for mechanical thrombectomy; however, the stroke patients included in the thrombectomy trials are not representative of all stroke patients. They were carefully selected according to clinical and imaging criteria as well as to the time window from symptom onset. Furthermore, they were treated in highly selected specialized stroke centers. Analysis of the five trials and the Catalan population-based SONIIA registry revealed that the observed number needed to treat (NNT) of 5 to reach a modified Rankin scale (mRS) score of 0-2 only applies to approximately 1 % of all stroke patients. The NNT for the remaining patients who are principally eligible for thrombectomy requires further study. Currently, centralization seems to be useful to facilitate mechanical thrombectomy in routine care leading to several problems that have to be dealt with in particular regions. Secondary transport to thrombectomy centers plays a major role in this context and has to be provided with highest priority. CONCLUSION: Only careful analysis of study results and the background circumstances will enable adequate organization and successful practical implementation of this highly effective therapy in the clinical routine. Regional conditions have to be considered and will be crucial in this context.

[Specialized neurological neurosurgical intensive care medicine]. / Spezialisierte neurologische neurochirurgische Intensivmedizin.

In Germany dedicated neurological-neurosurgical critical care (NCC) is the fastest growing specialty and one of the five big disciplines integrated within the German critical care society (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin; DIVI). High-quality investigations based on resilient evidence have underlined the need for technical advances, timely optimization of therapeutic procedures, and multidisciplinary team-work to treat those critically ill patients. This evolution has repeatedly raised questions, whether NCC-units should be run independently or better be incorporated within multidisciplinary critical care units, whether treatment variations exist that impact clinical outcome, and whether nowadays NCC-units can operate cost-efficiently? Stroke is the most frequent disease entity treated on NCC-units, one of the most common causes of death in Germany leading to a great socio-economic burden due to long-term disabled patients. The main aim of NCC employs surveillance of structural and functional integrity of the central nervous system as well as the avoidance of secondary brain damage. However, clinical evaluation of these severely injured commonly sedated and mechanically ventilated patients is challenging and highlights the importance of neuromonitoring to detect secondary damaging mechanisms. This multimodal strategy not only requires medical expertise but also enforces the need for specialized teams consisting of qualified nurses, technical assistants and medical therapists. The present article reviews most recent data and tries to answer the aforementioned questions.

Clot Burden and Collaterals in Anterior Circulation Stroke: Differences Between Single-Phase CTA and Multi-phase 4D-CTA.

PURPOSE: It has been reported that the extent of intravascular thrombi and the quality of collateral filling in computed tomography (CT) angiography are predictive for the clinical outcome in patients with acute stroke. We hypothesized that multi-phase four-dimensional CTA (4D-CTA) allows better assessment of clot burden and collateral flow compared with arterial single-phase CTA (CTA). METHODS: In 49 patients (33 female; age: 77 ± 12 years) with acute anterior circulation stroke, CTA and 4D-CTA reconstructed from dynamic perfusion CT data were analyzed for absolute thrombus length (TL), clot burden score (CBS), and collateral score (CS). The length of the filling defect was also defined on thin-slice nonenhanced CT as corresponding hyperdense middle cerebral artery sign (HMCAS) when present. RESULTS: There was good correlation (r = 0.62, p < 0.01) between the length of HMCAS (1.29 ± 0.62 cm) and TL in 4D-CTA (1.22 ± 0.51 cm). 4D-CTA and CTA significantly varied (p < 0.01) in TL (1.42 ± 0.73 cm (CTA) versus 1.11 ± 0.62 cm (4D-CTA)), CBS (median: 5, interquartile range: 4-7 (CTA) versus median: 6, interquartile range: 5-8 (4D-CTA); p < 0.001), and CS (median: 2, interquartile range: 1-2 (CTA) versus median: 3, interquartile range: 2-3 (4D-CTA); p < 0.001). Accordingly, CTA significantly overrated clot burden and underestimated collateral flow. CONCLUSIONS: 4D-CTA more closely defines clot burden and collateral supply in anterior circulation stroke than CTA, implicating an additional diagnostic benefit.

Evidence of CNIH3 involvement in opioid dependence.

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.

["Time is brain" in relapsing remitting multiple sclerosis. Current treatment concepts in immunotherapy]. / "Time is brain" bei der schubförmigen Multiplen Sklerose. Aktuelle Behandlungskonzepte in der Immuntherapie.

BACKGROUND: Despite highly divergent time scales of disease evolution in multiple sclerosis (MS) and ischemic stroke, clear analogies are apparent that may point the way to optimization of MS treatment. Inflammatory disease activity and neurodegeneration may induce potentially irreversible damage to central nervous system structures and thus lead to permanent disability. For the treatment of MS early detection of disease activity and early immunotherapy or treatment optimization are pivotal determinants of long-term outcomes. Such therapeutic concepts may be described with the catchy phrase "time is brain" as coined for the acute thrombolytic treatment of ischemic stroke. RESULTS AND DISCUSSION: For MS a "time is brain" concept would comprise an early initiation of first line therapy as well as sensitive and structured monitoring of disease activity under therapy in conjunction with a low threshold for timely treatment optimization to achieve sustained freedom from measurable disease activity. This approach may substantially improve the long-term outcome in patients who show insufficient response to platform therapies. The intersectorial collaboration in regional MS care networks involving office-based neurologists and specialized MS centers may facilitate the timely use of highly active therapies with their specific benefit-risk profiles thus supporting sustained stabilization of patient quality of life.

Radiation Induced DNA Double-Strand Breaks in Radiology.

UNLABELLED: Shortly after the discovery of X-rays, their damaging effect on biological tissues was observed. The determination of radiation exposure in diagnostic and interventional radiology is usually based on physical measurements or mathematical algorithms with standardized dose simulations. γ-H2AX immunofluorescence microscopy is a reliable and sensitive method for the quantification of radiation induced DNA double-strand breaks (DSB) in blood lymphocytes. The detectable amount of these DNA damages correlates well with the dose received. However, the biological radiation damage depends not only on dose but also on other individual factors like radiation sensitivity and DNA repair capacity. Iodinated contrast agents can enhance the x-ray induced DNA damage level. After their induction DSB are quickly repaired. A protective effect of antioxidants has been postulated in experimental studies. This review explains the prinicple of the γ-H2AX technique and provides an overview on studies evaluating DSB in radiologic examinations. KEY POINTS: Radiologic examinations including CT and angiography induce DNA double-strand breaks. Even after mammography a slight but significant increase is detectable in peripheral blood lymphocytes. The number of radiation induced double-strand breaks correlates well with the radiation dose. Individual factors including radiation sensitivity, DNA repair capacity and the application of iodinated contrast media has an influence on the DNA damage level.

Intensivtherapie des raumfordernden ischämischen Hemisphäreninfarkts: Zusammenfassung der NCS/DGNI-Leitlinie / Intensive care therapy of space-occupying large hemispheric infarction: summary of the NCS/DGNI guidelines

Der grobe ischämische Hemisphäreninfarkt ("large hemispheric infarction", LHI, Synonym maligner Mediainfarkt, MMI) ist eine schwerwiegende neurologische Erkrankung mit hoher Mortalität und Morbidität. Sowohl behandelnde Ärzte als auch Angehörige sehen sich insbesondere hinsichtlich konservativer Therapiemaßnahmen mit einer schwachen Datenlange konfrontiert. Aktuelle Leitlinien zur allgemeinen Schlaganfallbehandlung legen den Hauptfokus auf Risikofaktoren, Prävention und das akute Rekanalisierungsmanagement, beinhalten aber nur sehr limitierte Empfehlungen zur ggf. folgenden spezifischen intensivmedizinischen Behandlung. Um diese Lücke zu füllen, wurde kürzlich eine interdisziplinäre Konsensus-Konferenz der Neurocritical Care Society (NCS) und der Deutschen Gesellschaft für NeuroIntensiv- und Notfallmedizin (DGNI) zum intensivmedizinischen Management des MMI organisiert. Experten aus Neurologie, Neurointensivmedizin, Neurochirurgie, Neuroradiologie und Neuroanästhesie aus Europa und Nordamerika wurden auf Basis ihrer Expertise und ihrer Forschungsschwerpunkte ausgewählt. Arbeitsgruppen zu einzelnen Schwerpunktthemen erarbeiteten eine Reihe zentraler klinischer Fragestellungen zu diesem Thema und erstellten auf dem Boden der aktuellen Datenlage nach dem System Grading of Recommendation Assessment, Development and Evaluation (GRADE) Empfehlungen. Dies ist eine kommentierte Kurzfassung derselben.(AU)

Large hemispheric infarction (LHI), synonymously called malignant middle cerebral artery (MCA) infarction, is a severe neurological disease with a high mortality and morbidity. Treating physicians as well as relatives are often faced with few and low quality data when attempting to apply optimal treatment to these patients and make decisions. While current stroke treatment guidelines focus on risk factors, prevention and acute management, they include only limited recommendations concerning intensive care management of LHI. The Neurocritical Care Society (NCS) and the German Society for Neurocritical and Emergency Medicine (DGNI) organized an interdisciplinary consensus conference on intensive care management of LHI to meet this demand. European and American experts in neurology, neurocritical care, neurosurgery, neuroradiology and neuroanesthesiology were selected based on their expertise and research focus. Subgroups for several main topics elaborated a number of central clinical questions concerning this topic and evaluated the quality of the currently available data according to the grading of recommendation assessment, development and evaluation (GRADE) guideline system. Subsequently, evidence-based recommendations were compiled after weighing the advantages against the disadvantages of certain management options. This is a commented abridged version of the results of the consensus conference.(AU)

[Intensive care therapy of space-occupying large hemispheric infarction. Summary of the NCS/DGNI guidelines]. / Intensivtherapie des raumfordernden ischämischen Hemisphäreninfarkts. Zusammenfassung der NCS/DGNI-Leitlinie.

Large hemispheric infarction (LHI), synonymously called malignant middle cerebral artery (MCA) infarction, is a severe neurological disease with a high mortality and morbidity. Treating physicians as well as relatives are often faced with few and low quality data when attempting to apply optimal treatment to these patients and make decisions. While current stroke treatment guidelines focus on risk factors, prevention and acute management, they include only limited recommendations concerning intensive care management of LHI. The Neurocritical Care Society (NCS) and the German Society for Neurocritical and Emergency Medicine (DGNI) organized an interdisciplinary consensus conference on intensive care management of LHI to meet this demand. European and American experts in neurology, neurocritical care, neurosurgery, neuroradiology and neuroanesthesiology were selected based on their expertise and research focus. Subgroups for several main topics elaborated a number of central clinical questions concerning this topic and evaluated the quality of the currently available data according to the grading of recommendation assessment, development and evaluation (GRADE) guideline system. Subsequently, evidence-based recommendations were compiled after weighing the advantages against the disadvantages of certain management options. This is a commented abridged version of the results of the consensus conference.

Dynamic Angiography and Perfusion Imaging Using Flat Detector CT in the Angiography Suite: A Pilot Study in Patients with Acute Middle Cerebral Artery Occlusions.

BACKGROUND AND PURPOSE: Perfusion and angiographic imaging using intravenous contrast application to evaluate stroke patients is now technically feasible by flat detector CT performed by the angiographic system. The aim of this pilot study was to show the feasibility and qualitative comparability of a novel flat detector CT dynamic perfusion and angiographic imaging protocol in comparison with a multimodal stroke MR imaging protocol. MATERIALS AND METHODS: In 12 patients with acute stroke, MR imaging and the novel flat detector CT protocol were performed before endovascular treatment. Perfusion parameter maps (MTT, TTP, CBV, CBF) and MIP/volume-rendering technique images obtained by using both modalities (MR imaging and flat detector CT) were compared. RESULTS: Comparison of MIP/volume-rendering technique images demonstrated equivalent visibility of the occlusion site. Qualitative comparison of perfusion parameter maps by using ASPECTS revealed high Pearson correlation coefficients for parameters CBF, MTT, and TTP (0.95-0.98), while for CBV, the coefficient was lower (0.49). CONCLUSIONS: We have shown the feasibility of a novel dynamic flat detector CT perfusion and angiographic protocol for the diagnosis and triage of patients with acute ischemic stroke. In a qualitative comparison, the parameter maps and MIP/volume-rendering technique images compared well with MR imaging. In our opinion, this flat detector CT application may substitute for multisection CT imaging in selected patients with acute stroke so that in the future, patients with acute stroke may be directly referred to the angiography suite, thereby avoiding transportation and saving time.