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.

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.

[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.

["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.

[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.

[Serotonin transporter gene and stress reactivity in unipolar depression. Role of the HPA system as endophenotype of the SLC6A4 gene]. / Serotonintransportergen und Stressreagibilität bei unipolarer Depression. Rolle des HPA-Systems als Endophänotyp des Gens SLC6A4.

BACKGROUND: A length polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with both depression and hypothalamic-pituitary-adrenal (HPA) system activity. A dysregulation of the HPA system is considered to be a candidate endophenotype of depression. The objective of the present study was an investigation of a possible gene-endophenotype-interaction between 5-HTTLPR and HPA system activity in a sample of inpatients with major depression. MATERIALS AND METHODS: A total of 237 inpatients with major depression were genotyped for 5-HTTLPR and participated in a combined dexamethasone-corticotropin-releasing hormone test (Dex-CRH test) as well as using the Hamilton score (Hamilton rating scale for depression) to determine the severity of the psychopathology. RESULTS: Patients with the ss-genotype showed a significantly higher HPA -system activity in comparison to patients with the lI-genotype, but no association between 5-HTTLPR and the severity of psychopathology could be detected. CONCLUSIONS: The results of the current study demonstrate an influence of 5-HTTLPR on dysregulation of the HPA system in patients with major depression and support the hypothesis that 5-HTTLPR- and HPA-system-interaction constitutes an important component in the pathogenesis of depression.

[Cerebrovascular complications of immunologically mediated heparin-induced thrombocytopenia]. / Zerebrovaskuläre Komplikationen der Heparininduzierten Thrombozytopenie Typ II (HIT-II).

Immunologically mediated heparin-induced thrombocytopenia (HIT) is a thrombotic disease caused by antibodies occurring after heparin exposure. Thrombocytopenia occurs within a few days after heparin exposure, about half of HIT-patients develop venous or arterial thrombotic complications. Neurological complications of HIT are mainly ischaemic stroke and sinus vein thrombosis. To ensure the primary clinical diagnosis functional and immunological assays for antibody detection are available. The probability for the occurrence of HIT depends on the nature of heparin employed (LMWH vs. UFH) and individual patient characteristics such as gender and primary disease (medical vs. surgical patients). In the case of suspected HIT heparin administration should be discontinued immediately and replaced by an alternative anticoagulation to prevent the expansion or development of further thrombotic complications. Herein we report a case of a patient suffering from HIT-associated embolic cerebral ischaemic stroke.

Advances in the management of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is one of the most detrimental sub-types of stroke and accounts for 10-15% of all strokes Qureshi et al. (Lancet 373(9675):1632-1644, 2009). ICH has an incidence of 10-30 cases per 100,000 people/year which is increasing and expected to double by the year 2050 Qureshi et al. (N Engl J Med 344 (19):1450-1460, 2001). Mortality rates still remain poor (30-50%) and functional dependency after ICH is high (~75%) van Asch et al. (Lancet Neurol 9 (2):167-176, 2010). Up to now, all randomized controlled trials investigating treatment approaches in ICH have failed to document improvements on clinical endpoints Mayer et al. (N Engl J Med 358 (20):2127-2137, 2008); Brouwers and Goldstein (Neurotherapeutics 9 (1):87-98, 2012). Only a specialized treatment of severely injured patients at dedicated neuro intensive care units [NICU] has been shown to be beneficial Qureshi et al. (Lancet 373(9675):1632-1644, 2009); Suarez et al. (Crit Care Med 32 (11):2311-2317, 2004). Currently, ongoing trials are investigating aggressive blood pressure lowering, hemostatic therapies, different operative strategies, intraventricular thrombolysis as well as neuroprotective approaches, and brain edema therapies. This review will summarize advanced treatment strategies and novel approaches which are currently under investigation.

Waiting for platelet counts causes unsubstantiated delay of thrombolysis therapy.

BACKGROUND: Platelet counts (PCs) <100,000/µl are considered as a contraindication for intravenous thrombolysis (IVT). While US guidelines recommend IVT initiation before the availability of clotting tests, the guidelines of the European Stroke Organization give no such practical advice. We aimed to assess the incidence of thrombocytopenia in IVT patients, outcome after thrombolysis in affected patients and the time gained by initiating treatment prior to availability of PC results. METHODS: All patients with thrombocytopenia were identified in our prospectively acquired thrombolysis database. Baseline demographic data, intracerebral hemorrhage rates as well as functional outcome were assessed. The median time between initiation of thrombolysis and availability of PCs was calculated. RESULTS: Of 625 IVT patients, 3 (0.5%) had thrombocytopenia at stroke onset. None of them developed intracerebral hemorrhage (ICH) or died during the follow-up. Waiting for PCs would have delayed treatment in 72.4% of the patients, with a median hypothetical delay of 22 min (interquartile range: 11-41 min). CONCLUSIONS: To date, there are no sufficient data to evaluate the ICH risk in thrombocytopenic patients. However, thrombocytopenia is rare in IVT patients. Thus, generally waiting for PC results prior to initiation of IVT is not warranted. Avoiding this significant delay yields shorter door-to-needle times and potentially more effective treatment.

Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis.

The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult.

Association analysis of NOTCH4 loci in schizophrenia using family and population-based controls.

A genetic association between NOTCH4 and schizophrenia has previously been proposed. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observation. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.

GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia.

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.

Multiple sclerosis relapses are not associated with exercise.

Since multiple sclerosis (MS) often affects physically active young individuals, it is important to know if exercise can result in increased disease activity. Therefore we used a self-report questionnaire to examine the relationship of different levels of sports activity and relapses in 632 patients with MS. In order to analyse whether subjective recall might have biased the results, we performed, in a subgroup of our sample, an objective assessment of clinical data and physical fitness parameters. We were unable to find any association between sports activity and clinical relapses in either of the two analyses. The group with highest activity even shows the lowermost mean values, standard deviations and range concerning the number of relapses. Our data suggest that physical activity has no significant influence on clinical disease activity.

Radiopacity of intracerebral hemorrhage correlates with perihemorrhagic edema.

BACKGROUND: Experimental evidence indicates that iron plays a key role in edema formation after intracerebral hemorrhage (ICH). We investigated the relationship between ICH radiopacity on CT as a marker of hematoma iron content and perihemorrhagic edema (PHE) after ICH. METHODS: We retrospectively investigated patients with spontaneous lobar and ganglionic supratentorial ICH who received follow-up CT scans during the first 7days after symptom onset (d1, d2-4, d5-7). Measurements of ICH and edema volumes were taken using a semiautomatic threshold-based volumetric algorithm. Radiopacity of the blood clot was determined using the mean Hounsfield unit (HU) count of the ICH. RESULTS: A total of 117 patients aged 71.92±11.55years with spontaneous ICH (34.63±32.44ml) were included in the analysis. Mean ICH radiopacity was 59.7±3.4HU. We found significantly larger relative PHE at d2-4 (1.7±0.9 vs. 1.3±0.8; P=0.032) and d5-7 (2.0±1.3 vs. 1.3±0.9; P=0.007) and larger peak relative PHE (2.3±1.6 vs. 1.6±1.1; P=0.006) in patients with ICH radiopacity >60HU (n=59), as compared to patients with ICH radiopacity <60HU (n=58). CONCLUSIONS: Higher ICH radiopacity, reflecting higher in vivo hematoma iron content, is associated with more PHE after ICH.

Sex differences in perihemorrhagic edema evolution after spontaneous intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Clinical data on sex differences in perihemorrhagic edema (PHE) after intracerebral hemorrhage (ICH) are lacking. METHODS: Patients with spontaneous supratentorial ICH who had received standard conservative treatment were identified retrospectively. PHE development was assessed over a 14-day period on follow-up CT scans (days 1, 2-4, 5-7, 8-11, and 12-14). ICH and PHE volumes were assessed semiautomatically and compared between men and women. RESULTS: A total of 387 patients (233 men) were included. Starting at days 2-4, women showed lower PHE values (P < 0.05; days 2-4, 8-11) or a trend toward significance (P ≤ 0.1; days 5-7, 12-14). CONCLUSIONS: Female sex may predict lower PHE volumes.

Physical activity in multiple sclerosis: a comparative study of vitamin D, brain-derived neurotrophic factor and regulatory T cell populations.

BACKGROUND: Previous studies suggest beneficial effects of exercise in multiple sclerosis (MS). However, knowledge on the effects of physical activity on the immune system is limited. OBJECTIVE: To assess potential relationships between cardiorespiratory fitness, cognitive function, and immune parameters in physically active and inactive MS patients. METHODS: We identified 83 patients with relapsing-remitting disease, an unrestricted walking range, and stable interferon-ß treatment from our data base. Based on the subjective report of physical activity, the lower/inactive (n = 21) and upper/active quartiles (n = 21) of patients were selected. We assessed the frequency of T cells, B cells, NK cells, monocytes and regulatory T cell populations by flow cytometry, measured brain-derived neurotrophic factor and vitamin D serum levels by ELISA, and conducted spiroergometry and transcranial sonography. RESULTS: Physical activity and cardiorespiratory fitness were not associated with brain-derived neurotrophic factor, frequency of T regulatory cells or any other immune cell subpopulation. However, we found a positive correlation of vitamin D serum levels with cardiorespiratory fitness. CONCLUSION: Overall, we found no negative effect of physical activity on the immune system. The association between vitamin D and cardiorespiratory fitness most likely reflects longer hours of sunlight exposure in active patients, suggesting a desirable 'side- effect' of physical activity.

[Posterior reversible encephalopathy syndrome]. / Posteriores reversibles Enzephalopathiesyndrom.

Posterior reversible encephalopathy syndrome (PRES) is a clinically and radiologically defined syndrome characterized by seizures, headaches, visual disturbances, and altered mental status or focal neurological deficits. Imaging frequently shows abnormalities in the posterior brain regions, especially the occipital and the parietal lobes. PRES has been described in association with a wide spectrum of underlying causes. The most common conditions include hypertension, renal disease, preeclampsia/eclampsia, or status post transplantation. The pathophysiology of PRES has not been sufficiently elucidated as yet; however, endothelial damage caused by different mechanisms possibly plays a central role. The prognosis of PRES is usually benign when intensive care and withdrawal of the causative agent is instituted early. Delay in diagnosis and treatment may lead to complications and permanent neurological deficits. The clinical and radiological landmarks of this syndrome as well as causes, pathophysiological hypotheses, and the basic therapeutic principles of PRES are the subject of the present review.