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Background Early diagnosis is of substantial benefit for patients with Pompe disease. Yet underdiagnosing and substantial diagnostic delay are still frequent and the determinants of this are unknown. This study is the first to systematically investigate the diagnostic odyssey in Pompe disease from patients', parents', and physicians' perspectives. Methods Patients with infantile or late onset Pompe disease, their parents as well as their metabolic experts were invited to fill in respective surveys. The survey addressed perceived disease symptoms at onset and during the course of the disease, specialties of involved physicians, activities of patient-initiated search for diagnosis and the perceived impact of time to diagnosis on outcome. Results of experts' and patients'/parents' surveys were compared and expressed by descriptive statistics. Results and Discussion We collected data on 15 males and 17 females including 9 infantile and 23 late onset Pompe patients. All received the correct diagnosis at a metabolic or musculoskeletal expert center. Patients with direct referral to the expert center had the lowest diagnostic delay, while patients who were seen by several physicians, received the correct diagnosis after 44%-200% longer delay. The proportion of direct referral varied strongly between pediatricians (57%) and other disciplines (18%-36%). Conclusion Our study highlights a substantially larger diagnostic delay in Pompe patients that are not directly referred to expert centers for diagnostic work. Our findings may be used to develop more successful strategies for early diagnosis. Synopsis Diagnostic delay in Pompe disease is substantial particularly in patients that are not directly referred to expert centers for diagnostic workup, so facilitating direct referral may be a new strategy for early diagnosis.

Pharmacotherapy is a central component in the context of an overall therapeutic concept in the treatment of adults with attention deficit hyperactivity disorder (ADHD). In this concept psychosocial interventions with psychoeducation or specific psychotherapy measures also play an important role. In adults three compounds are currently approved for the pharmacological treatment of ADHD in Germany. The long-acting stimulants retarded methylphenidate preparations and lisdexamfetamine can be prescribed. Alternatively, the adrenergic uptake inhibitor atomoxetine can be used. In several meta-analyses good effectiveness and tolerance of these drugs on ADHD psychopathology has been shown. They also improve ADHD-related disorders of emotional regulation capability and disorganization in everyday life. Importantly, an improvement in everyday functionality and quality of life under medication could also be shown in several studies. In this review the evidence for pharmacotherapy of ADHD and its implementation into treatment of adult patients is presented.

Objective To estimate non-invasively the amount, recruitment pattern and discharge frequency of spinal motor neurons (MN) at contraction strength >20% of maximal voluntary contraction (MVC) of small hand muscles. Methods A peripheral collision technique was used and consisted of supramaximal electrical stimuli at Erb's point and at the wrist, synchronizing descending volleys of action potential during voluntary isometric contractions of the abductor digiti minimi muscle at 20–80% of MVC strength and 1–8 s of contraction duration. Responses of 13 healthy volunteers were quantified and analysed using a recently described model of MN behaviour. Results A linear relationship between MN discharge and force generation was noticed with R2 = 0.996, and was confirmed using the simulation results (R2 = 0.997) for contraction durations up to 8 s. For each investigated force level, discharge frequency and recruitment pattern were calculated for individual MN. Conclusions Using this method, MN discharge properties during voluntary activity can be estimated non-invasively. Significance This method provides new opportunities for the non-invasive study of MN behaviour, and could be expanded to patients with conduction failure and during fatigue.

Krebserkrankungen sind mit z. T. erheblichen psychischen und sozialen Belastungen verbunden. Die ambulanten psychosozialen Krebsberatungsstellen bieten Krebspatienten und ihren Bezugspersonen bei Bedarf ein niederschwelliges Unterstutzungsangebot und Hilfen in allen Krankheitsphasen an. Das Angebot aus Information, Beratung und konkreten Hilfestellungen orientiert sich an den Bedurfnissen des Ratsuchenden; es ist vertraulich, unabhangig und kostenfrei. Die Beratung erfolgt vorwiegend durch Fachkrafte der sozialen Arbeit, Psychologie und Medizin mit zusatzlicher psychoonkologischer Qualifikation. Steigende Krebsneuerkrankungen, die Entwicklungen in der Onkologie und die Chronifizierung der Erkrankung fuhren dazu, dass die ambulante psychosoziale Krebsberatung weiter an Bedeutung gewinnt.

Pompe disease is a rare autosomal-recessive disorder characterised by limb-girdle myopathy and respiratory weakness in the late-onset form (LOPD). Various mutations in the acid alpha-glucosidase gene lead to toxic lysosomal and extra-lysosomal glycogen accumulation in all organs due to ineffective glycogen clearance by the encoded enzyme. Only one randomized trial demonstrated beneficial effects of respiratory function and meters walked in the 6-min walking test with enzyme replacement therapy (ERT). These results were confirmed in several retrospective and prospective observations and in meta-analyses. Due to a potential lifelong therapy, moderate efficacy and high treatment costs time of ERT initiation and cessation is an ongoing matter of debate. So far, several national and international recommendations have been published with different criteria concerning diagnosis, initiation and cessation of ERT in LOPD. We therefore formally analysed recent published recommendations and consensus statements of LOPD using diagnostic nodes (DODES) as a special software tool. With DODES, an objective analysis becomes possible if the content of the recommendations is represented as algorithms using cross-compatible elements. This analysis formally disclosed both, areas of great heterogeneity and concordance for the diagnosis and management of LOPD and paved the way for a Pompe disease burden scale focussing on ERT initiation. According to this investigation further clinical research should concentrate on ERT in pre-symptomatic and severely affected LOPD patients and on cessation criteria for ERT as these issues are areas of international uncertainty and discordance.

Supplemental Digital Content is available in the text, Introduction: Intensive care unit-acquired weakness (ICU-AW) is often observed in critically ill patients with prolonged intensive care unit (ICU) stay. We hypothesized that evolving metabolic abnormalities during prolonged ICU stay are reflected by changing nutrient patterns in blood, urine and skeletal muscle, and that these patterns differ in patients with/without ICU-AW and between patients with/without sepsis. Methods: In a prospective single-center observational trial, we aim to recruit 100 critically ill patients (ICU length of stay ≥ 5 days) with severe sepsis/septic shock (“sepsis group”, n = 50) or severe head trauma/intracerebral hemorrhage (“CNS group”, n = 50). Patients will be sub-grouped for presence or absence of ICU-AW as determined by the Medical Research Council sum score. Blood and urine samples will be collected and subjected to comprehensive nutrient analysis at different time points by targeted quantitative mass spectrometric methods. In addition, changes in muscular tissue (biopsy, when available), muscular architecture (ultrasound), electrophysiology, body composition analyses (bioimpedance, cerebral magnetic resonance imaging), along with clinical status will be assessed. Patients will be followed-up for 180 and 360 days including assessment of quality of life. Discussion: Key objective of this trial is to assess changes in nutrient pattern in blood and urine over time in critically ill patients with/without ICU-AW by using quantitative nutrient analysis techniques. Peer-reviewed published NAChO data will allow for a better understanding of metabolic changes in critically ill patients on standard liquid enteral nutrition and will likely open up new avenues for future therapeutic and nutritional interventions.

Post-translational modification of histones is a crucial mode of transcriptional regulation in eukaryotes. A well-described acetylation modifier of certain lysine residues is the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex assembled around the histone acetyltransferase Gcn5 in Saccharomyces cerevisiae. We identified and characterized the SAGA complex in the rice pathogen Fusarium fujikuroi, well-known for producing a large variety of secondary metabolites (SMs). By using a co-immunoprecipitation approach, almost all of the S. cerevisiae SAGA complex components have been identified, except for the ubiquitinating DUBm module and the chromodomain containing Chd1. Deletion of GCN5 led to impaired growth, loss of conidiation and alteration of SM biosynthesis. Furthermore, we show that Gcn5 is essential for the acetylation of several histone 3 lysines in F. fujikuroi, that is, H3K4, H3K9, H3K18 and H3K27. A genome-wide microarray analysis revealed differential expression of about 30% of the genome with an enrichment of genes involved in primary and secondary metabolism, transport and histone modification. HPLC-based analysis of known SMs revealed significant alterations in the Δgcn5 mutant. While most SM genes were activated by Gcn5 activity, the biosynthesis of the pigment bikaverin was strongly increased upon GCN5 deletion underlining the diverse roles of the SAGA complex in F. fujikuroi.

Filamentous fungi produce a vast array of secondary metabolites (SMs) and some play a role in agriculture or pharmacology. Sequencing of the rice pathogen Fusarium fujikuroi revealed the presence of far more SM-encoding genes than known products. SM production is energy-consuming and thus tightly regulated, leaving the majority of SM gene clusters silent under laboratory conditions. One important regulatory layer in SM biosynthesis involves histone modifications that render the underlying genes either silent or poised for transcription. Here, we show that the majority of the putative SM gene clusters in F. fujikuroi are located within facultative heterochromatin marked by trimethylated lysine 27 on histone 3 (H3K27me3). Kmt6, the methyltransferase responsible for establishing this histone mark, appears to be essential in this fungus, and knock-down of Kmt6 in the KMT6kd strain shows a drastic phenotype affecting fungal growth and development. Transcription of four so far cryptic and otherwise silent putative SM gene clusters was induced in the KMT6kd strain, in which decreased expression of KMT6 is accompanied by reduced H3K27me3 levels at the respective gene loci and accumulation of novel metabolites. One of the four putative SM gene clusters, named STC5, was analysed in more detail thereby revealing a novel sesquiterpene.

INTRODUCTION The aim of this study was to compare orthodromic sural nerve conduction study (NCS) results using ultrasound-guided needle positioning (USNP) to surface electrode recordings. METHODS 51 healthy subjects aged 24 - 80 years, divided into 5 age groups, were examined. Electrical stimuli were applied behind the lateral malleolus. Sensory nerve action potentials (SNAPs) were recorded 8 and 15 cm proximally with surface and needle electrodes. RESULTS Mean SNAP amplitudes in µV (surface/needle electrodes) averaged 12.7 (SD 7.6)/40.6 (SD 20.8), P 60 years. SNAP amplitudes were smaller at the proximal recording location. DISCUSSION NCS using USNP yield higher amplitude responses than surface electrodes in all age groups at all recording sites. SNAP amplitudes are smaller at proximal recording locations due to sural nerve branching. This article is protected by copyright. All rights reserved.

Zwei Sesquiterpencyclasen aus Fusarium fujikuroi wurden in Escherichia coli exprimiert und gereinigt. Das erste Enzym war wegen einer kritischen Mutation inaktiv, die Aktivitat konnte aber durch Sequenzkorrektur per ortsgerichteter Mutagenese wiederhergestellt werden. Das mutierte Enzym und zwei naturlicherweise funktionale Homologe aus anderen Fusarien konvertierten Farnesyldiphosphat zu Guaia-6,10(14)-dien. Das zweite Enzym produzierte Eremophilen. Die absolute Konfiguration von Guaia-6,10(14)-dien wurde durch enantioselektive Synthese aufgeklart, wahrend die des Eremophilens aus dem Vorzeichen der optischen Drehung ableitbar war und derjenigen aus Pflanzen entgegengesetzt ist, aber mit der aus Sorangium cellulosum ubereinstimmt. Die Mechanismen beider Terpencyclasen wurden mithilfe diverser 13C- und 2H-markierter FPP-Isotopomere studiert.

Two sesquiterpene cyclases from Fusarium fujikuroi were expressed in Escherichia coli and purified. The first enzyme was inactive because of a critical mutation, but activity was restored by sequence correction through site-directed mutagenesis. The mutated enzyme and two naturally functional homologues from other fusaria converted farnesyl diphosphate into guaia-6,10(14)-diene. The second enzyme produced eremophilene. The absolute configuration of guaia-6,10(14)-diene was elucidated by enantioselective synthesis, while that of eremophilene was evident from the sign of its optical rotation and is opposite to that in plants but the same as in Sorangium cellulosum. The mechanisms of both terpene cyclases were studied with various (13) C- and (2) H-labelled FPP isotopomers.

The rice pathogenic fungus Fusarium fujikuroi is known to produce a large variety of secondary metabolites. Besides the gibberellins, causing the bakanae effect in infected rice seedlings, the fungus produces several mycotoxins and pigments. Among the 47 putative secondary metabolite gene clusters identified in the genome of F. fujikuroi, the fumonisin gene cluster (FUM) shows very high homology to the FUM cluster of the main fumonisin producer Fusarium verticillioides, a pathogen of maize. Despite the high level of cluster gene conservation, total fumonisin FB1 and FB2 levels (FBx) produced by F. fujikuroi were only 1-10 % compared to F. verticillioides under inducing conditions. Nitrogen repression was found to be relevant for wild-type strains of both species. However, addition of germinated maize kernels activated the FBx production only in F. verticillioides, reflecting the different host specificity of both wild-type strains. Over-expression of the pathway-specific transcription factor Fum21 in F. fujikuroi strongly activated the FUM cluster genes leading to 1000-fold elevated FBx levels. To gain further insights into the nitrogen metabolite repression of FBx biosynthesis, we studied the impact of the global nitrogen regulators AreA and AreB and demonstrated that both GATA-type transcription factors are essential for full activation of the FUM gene cluster. Loss of one of them obstructs the pathway-specific transcription factor Fum21 to fully activate expression of FUM cluster genes.

Although not curative, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase enzyme has shown to be effective in the treatment of late-onset Pompe disease (LOPD). For this potentially life-long treatment, little is known on the clinical effect of cessation and resuming ERT. Due to a Swiss supreme court decision on ERT reimbursement, a temporary stop of ERT occurred in our study population. The aim of this study was to report the 36-months follow-up assessments after resuming ERT. After resuming ERT, seven patients suffering from genetically and enzymatically confirmed LOPD had periodic, mandatory, prospective assessments of pulmonary function tests, muscle strength summary scores, distances walked in timed walking tests, and patient-reported questionnaires. Data were statistically analyzed for significant differences between time points at ERT cessation, at ERT resuming, and 36 months thereafter. After resuming ERT forced vital capacity (p = 0.007) and distance walked in the 6 min walk test (6-MWT, p = 0.011) significantly increased at 36 months. Compared to before ERT cessation, distance walked in 6-MWT at 36 months still remained significantly lower (p = 0.005). Self-reported scores in the fatigue severity scale significantly declined at 36 months after resuming ERT (p = 0.019). No other functional or reported parameter significantly changed at 36 months after resuming ERT. Our data suggests that long-term interruption of ERT in LOPD may lead to deterioration of clinical meaningful parameters and quality of life. In addition, a clinical restoration after ERT cessation is possible for most of the LOPD patients within a 36 months follow-up.

Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) in late-onset Pompe disease is moderately effective. Little is known about the clinical course after treatment termination and the resumption of ERT. In Switzerland, rhGAA therapy for Pompe disease was temporarily withdrawn after the federal court judged that the treatment costs were greatly out of proportion compared to the benefits. Re-treatment was initiated after the therapy was finally licensed. We retrospectively analysed seven Pompe patients, who underwent cessation and resumption of ERT (median age 43 years). The delay from first symptoms to final diagnosis ranged from 4 to 20 years. The demographics, clinical characteristics, assessments with the 6-min walking test (6-MWT), the predicted forced vital capacity (FVC) and muscle strength were analysed. Before initiation of ERT, all patients suffered from proximal muscle weakness of the lower limbs; one was wheelchair-bound and two patients received night-time non-invasive ventilation. Initial treatment stabilised respiratory function in most patients and improved their walking performance. After treatment cessation, upright FVC declined in most and the 6-MWT declined in all patients. Two patients needed additional non-invasive ventilatory support. Twelve months after resuming ERT, the respiratory and walking capacity improved again in most patients. However, aside for one patient, none of the patients reached the same level of respiratory function or distance walked in 6 min, as at the time of ERT withdrawal. We conclude that cessation of ERT in Pompe disease causes a decline in clinical function and should be avoided. Resuming treatment only partially recovers respiratory function and walking capacity.

HYPOTHESIS Facial nerve monitoring can be used synchronous with a high-precision robotic tool as a functional warning to prevent of a collision of the drill bit with the facial nerve during direct cochlear access (DCA). BACKGROUND Minimally invasive direct cochlear access (DCA) aims to eliminate the need for a mastoidectomy by drilling a small tunnel through the facial recess to the cochlea with the aid of stereotactic tool guidance. Because the procedure is performed in a blind manner, structures such as the facial nerve are at risk. Neuromonitoring is a commonly used tool to help surgeons identify the facial nerve (FN) during routine surgical procedures in the mastoid. Recently, neuromonitoring technology was integrated into a commercially available drill system enabling real-time monitoring of the FN. The objective of this study was to determine if this drilling system could be used to warn of an impending collision with the FN during robot-assisted DCA. MATERIALS AND METHODS The sheep was chosen as a suitable model for this study because of its similarity to the human ear anatomy. The same surgical workflow applicable to human patients was performed in the animal model. Bone screws, serving as reference fiducials, were placed in the skull near the ear canal. The sheep head was imaged using a computed tomographic scanner and segmentation of FN, mastoid, and other relevant structures as well as planning of drilling trajectories was carried out using a dedicated software tool. During the actual procedure, a surgical drill system was connected to a nerve monitor and guided by a custom built robot system. As the planned trajectories were drilled, stimulation and EMG response signals were recorded. A postoperative analysis was achieved after each surgery to determine the actual drilled positions. RESULTS Using the calibrated pose synchronized with the EMG signals, the precise relationship between distance to FN and EMG with 3 different stimulation intensities could be determined for 11 different tunnels drilled in 3 different subjects. CONCLUSION From the results, it was determined that the current implementation of the neuromonitoring system lacks sensitivity and repeatability necessary to be used as a warning device in robotic DCA. We hypothesize that this is primarily because of the stimulation pattern achieved using a noninsulated drill as a stimulating probe. Further work is necessary to determine whether specific changes to the design can improve the sensitivity and specificity.

Background Current state-of-the-art to diagnose peripheral neuropathy are neurological examination and electrodiagnostic studies. However, deeply situated nerves and plexus remain difficult to assess using these techniques, hence magnetic resonance neurography (MRN) emerged as a complementary method. MRN remains a qualitative approach and quantification, in terms of extraction of imaging biomarkers is needed to facilitate diagnosis and for follow-up examinations. Towards a multi-parametric quantitative imaging approach, accurate nerve segmentation needs to be performed first. Hampered by time-consuming manual annotation, we developed a semi-automatic, time-effective, hence clinically feasible segmentation approach based on machine-learning algorithms. In this study, we compared its performance on low- and high-resolution MRN. Materials and methods We acquired images of 9 healthy volunteers at the upper leg using 3 MRN sequences: lower resolution turbo inversion recovery magnitude (TIRM, voxel size of 78 × 78 × 4.0 mm3), lower resolution spin echo T2-weighted (T2, voxel size .52 × .52 × 4.0 mm3), and high resolution, fat-suppressed spin echo T2-weighted (hrT2, voxel size .25 × .25 × 3.3 mm3). An expert manually segmented the sciatic nerve on the T2 and hrT2 images (ground truth, GT). Our segmentation algorithm is based on a decision forest with context- and intensity-based descriptors. We split the images into two sets: a multi-modal low-resolution (TIRM and T2), and a mono-modal high-resolution (hrT2). We perform a leave-one-out cross-validation for both sets and calculate the Dice coefficient to the manually annotated GT. Cross-sectional areas (CSA) were calculated from the middle slice of the image stack. Results Dice coefficients of 0.723 ± 0.202 and 0.735 ± 0.080 are achieved for the low- and high-resolution MRN images (p = 0.858, CI 95 %). Segmentation results and 3-D renderings of the same nerve segmented in low- and high-resolution are shown in Fig. 1 . CSA for GT were 34.0 ± 5.5 mm2 (T2), and 35.4 ± 8.5 mm2 (hrT2), using semi-automatic segmentation 24.8 ± 7.6 mm2 (T2), and 25.7 ± 10.6 mm2 (hrT2). Discussion and conclusion Semi-automatic, hence fast peripheral nerve segmentation is feasible in both low- and high-resolution MRN images of the upper leg, providing image-based quantitative morphometric data. The equal performance of the low-resolution images might be due to the multi-modal setting, which possibly provides more discriminative descriptors for nerve. The lower CSA using semi-automatic segmentation is due to more rigorous segmentation constraints. Future work will include the application of our method to localize and quantify nerve lesions in images of patients diagnosed with peripheral neuropathy.

Objective To compare the individual latency distributions of motor evoked potentials (MEP) in patients with multiple sclerosis (MS) to the previously reported results in healthy subjects ( Firmin et al., 2011 ). Methods We applied the previously reported method to measure the distribution of MEP latencies to 16 patients with MS. The method is based on transcranial magnetic stimulation and consists of a combination of the triple stimulation technique with a method originally developed to measure conduction velocity distributions in peripheral nerves. Results MEP latency distributions in MS typically showed two peaks. The individual MEP latency distributions were significantly wider in patients with MS than in healthy subjects. The mean triple stimulation delay extension at the 75% quantile, a proxy for MEP latency distribution width, was 7.3 ms in healthy subjects and 10.7 ms in patients with MS. Conclusions In patients with MS, slow portions of the central motor pathway contribute more to the MEP than in healthy subjects. The bimodal distribution found in healthy subjects is preserved in MS. Significance Our method to measure the distribution of MEP latencies is suitable to detect alterations in the relative contribution of corticospinal tract portions with long MEP latencies to motor conduction.

The 2H-pyran-2-one gibepyrone A and its oxidized derivatives gibepyrones B–F have been isolated from the rice pathogenic fungus Fusarium fujikuroi already more than 20 years ago. However, these products have not been linked to the respective biosynthetic genes, and therefore, their biosynthesis has not yet been analyzed on a molecular level. Feeding experiments with isotopically labeled precursors clearly supported a polyketide origin for the formal monoterpenoid gibepyrone A, whereas the terpenoid pathway could be excluded. Targeted gene deletion verified that the F. fujikuroi polyketide synthase PKS13, designated Gpy1, is responsible for gibepyrone A biosynthesis. Next to Gpy1, the ATP-binding cassette transporter Gpy2 is encoded by the gibepyrone gene cluster. Gpy2 was shown to have only a minor impact on the actual efflux of gibepyrone A out of the cell. Instead, we obtained evidence that Gpy2 is involved in gene regulation as it represses GPY1 gene expression. Thus, GPY1 was up-regulated and gibepyrone A production was enhanced both extra- and intracellularly in Δgpy2 mutants. Furthermore, expression of GPY genes is strictly repressed by members of the fungus-specific velvet complex, Vel1, Vel2, and Lae1, whereas Sge1, a major regulator of secondary metabolism in F. fujikuroi, affects gibepyrone biosynthesis in a positive manner. The gibepyrone A derivatives gibepyrones B and D were shown to be produced by cluster-independent P450 monooxygenases, probably to protect the fungus from the toxic product. In contrast, the formation of gibepyrones E and F from gibepyrone A is a spontaneous process and independent of enzymatic activity.

The Wender-Reimherr adult attention deficit disorder scale (WRAADDS) is an internationally accepted attention-deficit hyperactivity disorder (ADHD) interview with an authorized German translation. The WRAADS not only assesses the symptoms of ADHD but also the severity of the symptoms using the Utah criteria. With the aim of economizing the diagnostic process the original English version of the Wender-Reimherr self-report questionnaire was translated into German (WR-SB) in order to evaluate the test psychometric properties.To explore the psychometric properties of the WR-SB within a classical test theory framework.The psychometric properties of the WR-SB were determined in a population of 122 adult ADHD patients and 79 healthy controls.For the individual WR-SB subscales the results showed an adequate discriminatory power and a high internal consistency. The correlation between the WRAADS and the WR-SB was significant and the retest reliability was high.The WR-SB is a brief, self-report instrument and an economical alternative to assess adult ADHD symptomatology using the Utah criteria. The results of this evaluation study showed the WR-SB to be a valid and reliable measurement for both clinical and research purposes.

Filamentous fungi produce a vast array of secondary metabolites (SMs) and some play a role in agriculture or pharmacology. Sequencing of the rice pathogen Fusarium fujikuroi revealed the presence of far more SM-encoding genes than known products. SM production is energy-consuming and thus tightly regulated, leaving the majority of SM gene clusters silent under laboratory conditions. One important regulatory layer in SM biosynthesis involves histone modifications that render the underlying genes either silent or poised for transcription. Here, we show that the majority of the putative SM gene clusters in F. fujikuroi are located within facultative heterochromatin marked by trimethylated lysine 27 on histone 3 (H3K27me3). Kmt6, the methyltransferase responsible for establishing this histone mark, appears to be essential in this fungus, and knock-down of Kmt6 in the KMT6kd strain shows a drastic phenotype affecting fungal growth and development. Transcription of four so far cryptic and otherwise silent putative SM gene clusters was induced in the KMT6kd strain, in which decreased expression of KMT6 is accompanied by reduced H3K27me3 levels at the respective gene loci and accumulation of novel metabolites. One of the four putative SM gene clusters, named STC5, was analysed in more detail thereby revealing a novel sesquiterpene.

HYPOTHESIS A multielectrode probe in combination with an optimized stimulation protocol could provide sufficient sensitivity and specificity to act as an effective safety mechanism for preservation of the facial nerve in case of an unsafe drill distance during image-guided cochlear implantation. BACKGROUND A minimally invasive cochlear implantation is enabled by image-guided and robotic-assisted drilling of an access tunnel to the middle ear cavity. The approach requires the drill to pass at distances below 1 mm from the facial nerve and thus safety mechanisms for protecting this critical structure are required. Neuromonitoring is currently used to determine facial nerve proximity in mastoidectomy but lacks sensitivity and specificity necessaries to effectively distinguish the close distance ranges experienced in the minimally invasive approach, possibly because of current shunting of uninsulated stimulating drilling tools in the drill tunnel and because of nonoptimized stimulation parameters. To this end, we propose an advanced neuromonitoring approach using varying levels of stimulation parameters together with an integrated bipolar and monopolar stimulating probe. MATERIALS AND METHODS An in vivo study (sheep model) was conducted in which measurements at specifically planned and navigated lateral distances from the facial nerve were performed to determine if specific sets of stimulation parameters in combination with the proposed neuromonitoring system could reliably detect an imminent collision with the facial nerve. For the accurate positioning of the neuromonitoring probe, a dedicated robotic system for image-guided cochlear implantation was used and drilling accuracy was corrected on postoperative microcomputed tomographic images. RESULTS From 29 trajectories analyzed in five different subjects, a correlation between stimulus threshold and drill-to-facial nerve distance was found in trajectories colliding with the facial nerve (distance 95%) at distances to the facial nerve below 0.5 mm. However, reduction in stimulus threshold to 0.3 mA or lower resulted in a decrease of facial nerve distance detection range below 0.1 mm (>95% sensitivity). Subsequent histopathology follow-up of three representative cases where the neuromonitoring system could reliably detect a collision with the facial nerve (distance

In this study we sought to evaluate the reproducibility of sensory nerve conduction studies (NCS) using ultrasound-guided needle positioning (USNP).

Der Patient prasentierte sich mit einer akut aufgetretenen, hochstgradigen, axonalen Radialisparese, die initial von starksten Schmerzen begleitet war. Differentialdiagnostisch wurde zunachst neben einer Kompressionsneuropathie zunachst auch an eine neuralgische Schulteramyotophie gedacht, doch bewies die am 1. Tag nach Auftreten der Paresen durchgefuhrte Neurographie eine Radialislasion am Oberarm. Nach langer Verlaufsbeobachtung, und nachdem anamnestisch, klinisch, elektrophysiologisch und bildgebend keine befriedigende Ursachenklarung gelungen war, wurde die Indikation zur chirurgischen Exploration gestellt. Intraoperativ zeigte sich eine Torquierung des N. radialis am Oberarm, welche reponiert werden konnte. Der weitere Verlauf war gunstig, heute, 2 Jahre nach Operation besteht eine zufriedenstellende Funktionalitat der betroffenen Hand.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders in children. ADHD is often chronic persisting into adulthood in about 60% of patients. The disorder is frequently associated with co-occurring disruptive, anxiety, mood and personality disorders as well as substance abuse. The diagnosis of ADHD has to be based on careful assessment of symptoms and impairments in the different phases of life. Recent neuroimaging and genetic data support the neurobiological basis of the disorder. Multimodal treatment options including stimulants, antidepressants and behavioral therapy play a fundamental role in the management of ADHD across the life span.

To evaluate the usefulness of ultrasound imaging to improve the positioning of the recording needle for nerve conduction studies (NCS) of the sural nerve.Orthodromic NCS of the sural nerve was performed in 44 consecutive patients evaluated for polyneuropathy. Ultrasound-guided needle positioning (USNP) was compared to conventional "blind" needle positioning (BNP), electrically guided needle positioning (EGNP), and to recordings with surface electrodes (SFN).The mean distance between the needle tip and the nerve was 1.1 mm with USNP compared to 5.1 mm with BNP (p0.0001). The mean amplitude of the sensory nerve action potential (SNAP) was 21 microV with USNP and 11 microV with BNP (p0.0001). Compared to BNP, nerve-needle distances and SNAP amplitudes did not improve with EGNP. SNAP amplitudes recorded with SFN were significantly smaller than with BNP, EGNP and USNP.Ultrasound increases the precision of needle positioning markedly, compared to conventional methods. The amplitude of the recorded SNAP is usually clearly greater using USNP. In addition, USNP is faster, less painful and less dependent on the patient.USNP is superior to BNP, EGNP, and SFN in accurate measurement of SNAP amplitude. It has a potential use in the routine near-nerve needle sensory NCS of pure sensory nerves.

OBJECTIVES: In patients with a clinically isolated syndrome (CIS), the time interval to convert to clinically definite multiple sclerosis (CDMS) is highly variable. Individual and geographical prognostic factors remain to be determined. Whether anti-myelin antibodies may predict the risk of conversion to CDMS in Swiss CIS patients of the canton Berne was the subject of the study. METHODS: Anti-myelin oligodendrocyte glycoprotein and anti-myelin basic protein antibodies were determined prospectively in patients admitted to our department. RESULTS: After a mean follow-up of 12 months, none of nine antibody-negative, but 22 of 30 antibody-positive patients had progressed to CDMS. Beta-Interferon treatment delayed the time to conversion from a mean of 7.4 to 10.9 months. CONCLUSIONS: In a Swiss cohort, antibody-negative CIS patients have a favorable short-term prognosis, and antibody-positive patients benefit from early treatment.

The interaction of He + ions with surfaces has been widely used as a tool to probe different properties of the surface. There are recent experiments that measure the spin polarization of electrons emitted during the neutralization of spin polarized He + ions impinging on the Al(0 0 1), Au(0 0 1) and Cu(0 0 1) surfaces. The experimental results show that (i) the spin polarization of the total emitted electron yield is about 30% for the three surfaces, being the preferable spin state that of the electron bound to the He + ion and (ii) the spin polarization of electrons emitted at higher energies is high (around 70% for Al(0 0 1) and 50% for Au(0 0 1) and Cu(0 0 1)) but decreases as electrons with lower energies are included. Here, we apply our local model to understand in a quantitative way these measurements. First, we calculate the energy distribution of electrons excited in the Auger neutralization of a He + ion. Next, we describe the transport and escape of these excited electrons to obtain the energy distribution of emitted electrons. The theoretical results allow us to explain the similarities and the differences found in these surfaces.

The backward and forward electron emission yields γB and γF have been calculated by Monte Carlo simulations for helium (He++, He+ or He0) ions incident on thin amorphous carbon foils with energies around the electronic stopping power maximum (0.2–2 MeV). Besides the direct excitation of target electrons by the incident projectile, we have taken into account the different charge changing processes (He++ ↔ He+ ↔ He0) undergone by the helium ion in the target. We discuss in particular the connection between the electron emission yield γ and the electronic stopping power (dE/dx)e. We compare our results with previously published experimental results.

Ion induced electron emission (IIEE) is usually described as a three-step process, i.e. electron excitation by the incident projectile, electron transport (and multiplication) and electron escape through the potential barrier at the surface. In many cases, the first step of the process has been carefully described. The second step of the process, i.e. electron transport and multiplication, has often been treated in a very rough way, a simple decreasing exponential law being sometimes used. It is precisely the aim of the present work to show the importance of a correct description of electron transport and multiplication in a theoretical calculation of IIEE. A short overview of the electron transport models developed for IIEE is given in this work. The so-called “Infinite medium slowing-down model” often used in recent works is evaluated by means of Monte Carlo simulations. In particular, the importance of considering correctly the semi-infinite character of the medium and the boundary condition at the vacuum-medium interface is discussed. Quantities like the electron escape depth are also briefly discussed. This evaluation has been performed in the particular case of protons ( 25 keV E H + 3 MeV , without charge exchange) incident on polycrystalline aluminium targets.

This article gives a review of the classification, diagnostic procedures and treatment of idiopathic inflammatory myopathies from a neurological point of view. The myositis syndromes can be subdivided into four groups, polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and necrotizing myopathy (NM), which substantially differ clinically and pathophysiologically. Myositis may also occur in association with cancer or autoimmune systemic diseases (overlap syndrome). Diagnosis of inflammatory myopathies is based on clinical symptoms, determination of creatine phosphokinase and acute phase parameters in blood (e.g. C-reactive protein and erythrocyte sedimentation rate), electromyography results and findings of magnetic resonance imaging (MRI) in muscle. A muscle biopsy is mandatory to confirm the diagnosis. High quality randomized controlled trials of treatment regimens for inflammatory myopathies are sparse; however, empirical experience indicates a clear effectiveness of immunosuppressive treatment of PM, DM and NM.

Alzheimer’s disease (AD) is a neurodegenerative disorder clinically characterized by a progressive loss of cognitive functions, including memory, language, praxis, judgment and orientation. Many patients also show significant noncognitive symptoms such as depression, psychosis, agitation, and personality changes (40). The etiology of AD remains unknown. Several hypotheses (e.g., amyloid deposition (1), tau hyperphosphorylation (42), metabolic dysfunctions (22), loss of synapses (27), increased oxidative stress (18), immunologic changes (9), and RNA mutations (43)) have been proposed to account for the neurodegenerative process, although the integration of all these different hypotheses into one etiopathogenetical cascade requires further work. One characteristic deficit in AD is the reduction of cholinergic transmission. Basal forebrain neurons, which provide the majority of cholinergic innervation in the cortex and hippocampus, start to degenerate early during the course of AD (45). The cortex and hippocampus show a marked decline in choline acetyltransferase (ChAT), the enzyme responsible for the synthesis of acetylcholine. The number of basal forebrain neurons and the level of ChAT have been shown to correlate with the severity of dementia and the loss of synapses in AD (15). Recent investigations have documented additional cholinergic insufficiencies in other brain regions such as the amygdaloid complex and putamen (11,37). The cholinergic deficit in AD has been a target for pharmacological treatment. Several possible strategies have been explored: – acetylcholine precursors – choline uptake enhancers – acetyl group donors – acetylcholine releasers – acetylcholinesterase inhibitors

7 páginas, 5 figuras.-- et al., Charge changing processes (electron capture and loss) of light ions moving inside metals contribute significantly to the electronemission at intermediate and low impact velocities. An improved method for the description of screening of the moving ion in the electron gas developed by Nagy et al. [Nucl. Instrum. Methods 1996;B115:58.] and Lifshitz et al. [Phys. Rev. A 1998;57:200] will be used to determine the velocity-dependent bound-state wave functions and binding energies related to the moving projectile. These wave functions and binding energies are the basic ingredients for the calculation of the electron capture and loss rates, which determine the equilibrium charge state fractions of the different projectile species, as well as for the calculation of the electron excitation during the charge transfer processes. Explicit calculations were performed for Mg. We compare the contribution of electronemission by decay of plasmons generated during the charge transfer processes with that of plasmon excitation by fast secondary electrons generated by binary ion–electron collisions. The total plasmon-mediated electron yield, obtained by summing the contributions of different mechanisms of each projectile species, weighted with the respective charge state fraction, will be compared with available experimental data.

ZusammenfassungDas Ziel dieser offenen, prospektiven Beobachtungsstudie war es, den klinischen Verlauf von Patienten mit Demenz unter der Therapie mit Rivastigmin, einem Azetylcholinund Butyrylcholinesterasehemmstoff, unter Praxisbedingungen zu untersuchen.867 Ärzte in Arztpraxen, Ambulanzen und Memory-Kliniken rekrutierten 1 214 Demenzpatienten, von denen 75% leicht bis mittelgradig (Mini-Mental-State-Test ≥ 10) und 25% schwergradig ausgeprägte Symptome aufwiesen. Die Patienten erhielten Rivastigminlösung peroral in einer durchschnittlichen Tagesdosierung von 6,7 mg über4 Monate.Unter Rivastigmin besserten sich die Patienten in allen untersuchten Symptombereichen (Gedächtnis-, Sprach-, Orientierungs-, Verhaltensund Alltagskompentenzstörungen) signifikant (p < 0,05). Bei Patienten mit schwergradiger Demenz war der therapeutische Effekt von Rivastigmin am stärksten ausgeprägt. Die Verträglichkeit von Rivastigmin wurde von 93,2% der behandelnden Ärzte als gut oder sehr gut beurteilt.Rivastigmin zeigte bei Patienten mit leicht bis schwergradiger Demenz unter Praxisbedingungen eine klinisch relevante Wirksamkeit und gute Verträglichkeit.

Objective To quantify repetitive discharges of spinal motor neurons (repMNDs) in response to single transcranial magnetic stimuli (TMS). To assess their contribution to the size of motor evoked potentials (MEPs). Methods We combined the triple stimulation technique (TST) with an additional nerve stimulus in the periphery (=quadruple stimulation; QuadS). The QuadS eliminates the first action potential descending on each axon after TMS, and eliminates effects on response size induced by desynchronization of these discharges, thereby allowing a quantification of motor neurons (MNs) discharging twice. In some instances, a quintuple stimulation (QuintS) was used, to quantify the number of MNs discharging three times. Recordings were from the abductor digiti minimi of 14 healthy subjects, using two different stimulation intensities and three different levels of facilitatory muscle precontractions. Results The threshold to obtain repMNDs was high. Their maximal size differed markedly between subjects, ranging from 8 to 52% of all MNs. Stimulation intensity and facilitatory muscle contraction, but not resting motor threshold, correlated with the amount of repMNDs. QuintS never yielded discernible responses, hence all observed repMNDs were double discharges. RepMNDs contributed to the MEP areas, but did not influence MEP amplitudes. Conclusions QuadS and QuintS allow precise quantification of repMNDs. The threshold of repMNDs is high and varies considerably between subjects. Significance repMNDs have to be considered when MEP areas are measured. Their analysis may be of interest in neurological disorders, but standardized stimulation parameters appear essential.

The forward and backward electron emission yields γ F and γ B have been calculated by Monte Carlo simulation for protons (H + ) and hydrogen atoms (H 0 ) (with energies between 25 keV and 5 MeV) incident on thin amorphous carbon foils. Direct electron excitations by the incident projectiles as well as electron excitations resulting from charge exchange processes undergone by H + or H 0 have been taken into account. For the latter, Auger and Shell processes have been considered. Subsequent electron transport has been considered in order to calculate the forward and backward electron emission yields γ F and γ B .

The forward ( γ F ) and backward ( γ B ) electron emission yields have been measured for protons incident on thin carbon foils for incident energies between 2 and 7 MeV as a function of the target thickness. Comparisons with theoretical results obtained by Monte Carlo simulations are presented. In particular, the Meckbach factor R γ = γ F / γ B is discussed.

Objective : To establish the triple stimulation technique (TST) for recordings from the first dorsal interosseus (FDI) and the abductor pollicis brevis muscles (APB), and to analyse the test–retest repeatability of the TST measurements in APB. Methods : The recently developed TST was slightly modified for recordings from small hand muscles to account for volume conducted activity from surrounding muscles. The TST combines transcranial magnetic stimulation (TMS) with a peripheral collision technique [Magistris et al. Brain 121 (1998) 437]. In contrast to conventional motor-evoked potentials (MEPs), it quantifies the number of conducting central motor neurons (expressed by the TST amplitude ratio, TST–AR). MEPs and TST were performed in 30 sides of 25 healthy subjects (target muscle FDI), and in 29 sides of 21 healthy subjects (target muscle APB). All APB recordings were repeated after 25±5.9 days. Results : The TST–AR averaged 97.4±2.5% in FDI and 95.9±4.7% in APB. There was a mean difference of the TST–AR ratio of 2.9±3.1% between the repeated APB recordings (95% limits of agreement±6.3%). Conclusions : TMS allows activation of virtually all motor neurons supplying FDI and APB, when effects of volume conduction are eliminated. Its test–retest repeatability is excellent. Significance : The TST is well suited for follow-up examinations of central motor conduction failures. The greater number of established target muscles widens its clinical applicability.

Objective : To quantify temperature induced changes (=Uhthoff phenomenon) in central motor conduction and their relation to clinical motor deficits in 20 multiple sclerosis (MS) patients. Methods : Self-assessment of vulnerability to temperature and clinical examination were performed. We used motor evoked potentials to measure central motor conduction time (CMCT) and applied the triple stimulation technique (TST) to assess conduction failure. The TST allows an accurate quantification of the proportion of conducting central motor neurons, expressed by the TST amplitude ratio (TST-AR). Results : Temperature induced changes of TST-AR were significantly more marked in patients with prolonged CMCT ( P =0.037). There was a significant linear correlation between changes of TST-AR and walking velocity ( P =0.0002). Relationships were found between pronounced subjective vulnerability to temperature and (i) abnormal CMCT ( P =0.02), (ii) temperature induced changes in TST-AR ( P =0.04) and (iii) temperature induced changes in walking velocity ( P =0.04). CMCT remained virtually unchanged by temperature modification. Conclusions : Uhthoff phenomena in the motor system are due to varying degrees of conduction block and associated with prolonged CMCT. In contrast to conduction block, CMCT is not importantly affected by temperature. Significance : This is the first study quantifying the Uhthoff phenomenon in the pyramidal tract of MS patients. The results suggest that patients with central conduction slowing are particularly vulnerable to develop temperature-dependent central motor conduction blocks.

It is well known that the charge state of incident ions has an influence on the stopping power as well as on the electron emission characteristics. We have studied here electron emission for protons and hydrogen atoms incident on polycrystalline Al targets for impact velocities up to 2v0 (v0 is the Bohr velocity). Besides the direct excitation of target electrons by the incident projectile, we have considered different charge changing processes that give rise to additional electron excitation, hence contributing to electron emission. These processes are also responsible for the charge state dynamics of the moving projectile. We compare our results with previous results and in particular with the predictions of the simple model proposed by Ghosh and Khare [Phys. Rev. 125 (1962) 1254].

Stopping power d E /d x and electron emission yield γ are known to be strongly influenced by electron capture and loss processes. In this work we consider proton impact on thin Al foils for impact velocities below two atomic units. We investigate the effect of the charge changing processes on the forward/backward electron emission yields, γ F and γ B as well as on the specific yields, Λ F and Λ B ( Λ = γ /(d E /d x )). The dependence of the emission yields and of the specific yields as a function of the target thickness is discussed in terms of the charge changing processes.

To characterize central motor conduction in relation to the clinical deficits and to the disease duration in 90 patients with acute relapsing-remitting MS (RR-MS) and in 51 patients with chronic primary or secondary progressive MS (P-MS).The triple stimulation technique (TST) was used to quantify the central motor conduction failure (expressed by the TST amplitude ratio) and conventional motor evoked potentials (MEPs) were used to measure the central motor conduction time (CMCT).The TST amplitude ratio was reduced in presence of a clinical motor deficit (p=0.02 for RR-MS, p0.01 for P-MS), but did not significantly differ in RR-MS and P-MS (p0.05) when patients with similar clinical motor deficit were compared. The CMCT was not related to the clinical motor deficit in both RR-MS and P-MS. However, the CMCT was markedly prolonged in P-MS, when patients with similar clinical motor deficit and with similar disease duration were compared (p0.01). The differences were not attributable to differential involvement of the spinal cord, which was similar in RR-MS and P-MS.Our results disclose differences between the central motor conduction in RR-MS and P-MS that are not related to disease severity, spinal cord involvement or disease duration.

High resolution electron spectra haven been taken for fast heavy ions at 1.78 and 5 MeV/u as well as for electrons of equal velocity incident on atomically clean Si targets. Various LVV-Auger electron structures are identified and for amorphous Si these peaks show a shift towards lower energy when the charge of the projectile is increased. This finding points to a nuclear-track potential inside the ion track. The comparison of the Auger electron spectra for amorphous Si and crystalline Si(1 1 1) 7×7 gives clear evidence for phase effects in the short-time dynamics of ion tracks.

For incident protons with velocities around 1 a.u., electron capture and loss processes are known to play an important role. In particular, electron emission as well as electronic stopping power are strongly influenced by the charge changing processes. Several different electron capture and loss processes have been identified [Solid State Phys. 43 (1990) 229], i.e. Auger valence band processes, shell processes and resonant coherent processes. In the latter, the incident projectile undergoes a periodic excitation due to the periodic crystalline potential so that an electron can be lost or captured. In the literature, several different choices have been made for the crystalline potential. It is precisely the aim of the present work to review and compare the various potentials used in the literature and to show the influence of this choice on the resonant coherent electron capture and loss cross sections.