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This research project examines the effects of X-rays on cellulose and some moulds frequently found on paper. The aim was to identify applications for X-ray irradiation that can be used as a disinfection method for archival material. The question was if X-rays are suitable as an alternative to gamma radiation and if they are less harmful. For this purpose, the minimum X-ray dose required to reduce the microbial count to a harmless level was determined. The material-altering effect was examined on samples treated with X-rays and gamma radiation. Spectrophotometric measurements showed that there is no noticeable colour change with either type of radiation. The determination of the molecular weight distribution, in turn, showed that the molar mass of the cellulose is considerably reduced with both treatment methods. Using mechanical tests, however, it could be demonstrated that this has no significant influence on the tensile strength. The examination of the oxidation behaviour also showed no significant difference between the differently treated samples. The studies demonstrated that both methods have an almost identical effect on cellulose. Thus, X-ray treatment is primarily a supplement to the known disinfection methods and is particularly suitable for objects that would not withstand treatment with alcohol.

OBJECTIVE: Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to market authorization (MA). For treatment of - especially young - children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to "off-label" use of ASMs. Even though "off-label" ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if "on-label" ASM, in mono- or polytherapy, fails to achieve adequate seizure control. METHODS: The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first- and second-line treatment preferences but also to illustrate the use of "off-label" drugs in childhood epilepsies. RESULTS: Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed "off-label" in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap. SIGNIFICANCE: We report the relatively common use of "off-label" prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence-based guidelines. ispartof: EPILEPSIA OPEN vol:8 issue:1 pages:77-89 ispartof: location:United States status: published

Introduction Patients with variants in the GNAO1 gene may present with life-threatening dystonic storm. There is little experience using pallidal deep brain stimulation (DBS) as an emergency treatment in such cases. Case description We report on a 16-year-old girl with a variant in the GNAO1 gene (c.626G > T; p.(Arg209Leu)) who was admitted to the intensive care unit with medically refractory dystonic storm with secondary complications inducing rhabdomyolysis and acute colitis. Emergency pallidal DBS resulted in rapid improvement of dystonic storm and the subsidence of rhabdomyolysis and colitis. There were no further episodes of dystonic storm during follow-up of 2 years. Conclusion Pallidal DBS is a useful treatment option for GNAO1-related dystonic storm with secondary complications which can be performed as an emergency surgery.

Introduction: Acute occlusion of the anterior spinal artery and subsequent spinal ischemic infarction lead to anterior spinal artery syndrome characterized by back pain and bilateral flaccid paresis with loss of protopathic sensibility. As a rare cause fibrocartilaginous embolism has been described and is associated with sports or unusual strain. Case report: Following gymnastic exercise the day before symptom-onset, the 11 y.o. girl presented with neck pain, paresis of arms and legs and impaired deep tendon reflexes. She was unable to lift her arms, grasp, stand, walk and had urinary incontinence. MRI revealed a longitudinal T2 hyperintense signal in the anterior spinal cord from C3-C6 with accompanying bilateral diffusion restriction involving gray matter bilaterally at the level of C4 and C5 and unilaterally at the level of C3/4. The adjacent annulus fibrosus of the intervertebral disc showed a fissure without disc protrusion. Treatment with prednisolone and enoxaparin was started within 12 hours of symptom-onset and continued over 6 days and 8 weeks, respectively. After 2 months, her motor function gradually improved, spinal imaging showed persistent T2 signal hyperintense defects at the level of C4/5. After 5 months, there was only slight impairment affecting elevation and abduction of the right arm. Discussion: Following physical exercise, the patient suffered from acute anterior spinal cord ischemia with imaging findings in line with a presumed fibrocartilaginous embolism. Unlike most cases, our patient showed almost complete recovery following treatment with prednisolone and enoxaparin. We speculate that the positive outcome is related to rapid treatment initiation.

Wood pellets on the German pellet market mainly consist of spruce wood, but other wood species are increasingly used during pellet production. Moreover, additives such as starch or kaolin can be added to improve fuel quality and combustion behavior. Consequently, wood pellets vary in their physical and chemical properties and this variation might affect combustion behavior in stoves and boilers. In this study, eight different wood species were used for pellet production at the Technology and Support Centre (TFZ). Three types of starch and one type of kaolin were added to spruce wood without bark, using two additivation levels (starch: 0.5 w-% and 1.8 w-%, kaolin: 0.17 and 0.34 w-%). All pellet assortments were analyzed according to international standards for solid biofuels and additional methods. Fuels were combusted in a 6-kW pellet stove and a 15-kW pellet boiler. Selection of wood species had a significant impact on CO emissions for the pellet stove ranging between 85 and 4189 mg/m3 and on TPM emissions ranging between 23 and 263 mg/m3. Similar combustion behavior was observed for the pellet boiler but on a lower emission level. Kaolin reduced CO and TPM emissions as well as slag formation when the additivation level was set according to stoichiometric calculations. When kaolin was overdosed, it had a negative impact on TPM emissions mainly in the pellet boiler, probably due to entrainment. Regarding particles from incomplete combustion, a negative impact of overdosed kaolin was observed. Overall, at the current state of the art, the pellet stove showed larger sensitivity towards variable pellet qualities compared to the automatic pellet boiler. This calls for further improvements in fuel design and stove technology.

Contains fulltext : 248229.pdf (Publisher’s version ) (Closed access) BACKGROUND: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function. METHODS: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities. RESULTS: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains. CONCLUSION: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature. TAKE- HOME MESSAGE: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome.

The blenniids of the genus Scartichthys are one of the most common fishes of Central and South American Pacific coastal reefs. This being said, Scartichthys spp. remain difficult to identify in the field, and identification is particularly challenging across the c. 6000 km where three of the four currently accepted species are known to occur in sympatry. A reason for this is that the main taxonomic characters from traditional taxonomy are indeed elusive. In addition, at the same time, species can display multiple colour patterns in the field, depending on their ontogenetic stage, habitat association and reproductive behaviour. Overall, molecular characterization is warranted to help address these issues. In this study, the authors have used a novel approach to revise the genus by combining colouration, morphological and molecular data of representative specimens of the four currently valid species and seven described colour patterns. From this, the authors show that only three of the four species should be considered as valid; Scartichthys gigas (Steindachner, 1876), Scartichthys variolatus (Valenciennes, 1836) and Scartichthys viridis (Valenciennes, 1836), whereas Scartichthys crapulatus (Williams, 1990) should be synonymized with S. viridis. In the same way, the analyses in this study show that one of the colour patterns attributed so far only to S. gigas is characteristic of the juvenile stages of S. viridis. The time-calibrated phylogeny of this study shows that this genus is relatively young and that the estimated time of divergence between S. gigas and S. viridis is c. 1.71 Ma. In comparison, the Desventuradas and Juan Fernandez Islands endemic S. variolatus diverged c. 1.95 Ma. The results of this study help to clarify the taxonomy of Scartichthys.

Summary Background Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups. Methods We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity. Findings 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8–59·0, IQR 9–23) and a mean weight of 9·1 kg (range 4·0–15·0, IQR 7·4–10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p Interpretation This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored. Funding None. Translation For the German translation of the abstract see Supplementary Materials section.

Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018–2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing.

Little is known about clinical symptomatology and genetics of juvenile onset Pompe disease (JOPD). The aims of this study were to analyze how these children are diagnosed, what clinical problems they have, and how phenotype is related to genotype. To accomplish this, we analyzed retrospectively data of 34 patients diagnosed after their first and before completion of their 18th birthday. Median age at diagnosis was 3.9 (range 1.1–17) years. Eight patients (23.5%) developed initial symptoms in the first year, 12 (35%) between 1 and 7 years, and 6 (18%) thereafter. Eight (23.5%) had no clinical symptoms at the time of diagnosis. Indications for diagnostics were a positive family history in three (9%), hyperCKemia in eight (23.5%), motor developmental delay in three (9%), and muscle weakness and/or pain in 17 (50%). Rare clinical signs were failure to thrive, recurrent diarrhea, and suspected hepatopathy with glycogen storage. Thirty-two different mutations were identified. Twenty-seven patients (79.5%) carried the milder c.32–13T > G mutation, known to be associated with a broad range of phenotypes. Three out of eight patients manifesting within the first year of life showed generalized muscle weakness, hypertrophic cardiomyopathy, and had to be ventilated during the course of disease, thereby demonstrating clinical overlap with infantile onset Pompe disease.These findings demonstrate that the phenotype of JOPD is broad and that the differential is not only restricted to neuromuscular disorders. Genotypic analysis was useful to delineate subjects with early onset JOPD from those with IOPD, but overall genotype–phenotype correlation was poor.

Objective This study aimed to measure health-related quality of life (HRQOL) in children and adolescents with tuberous sclerosis complex (TSC) and quality of life (QOL) and depressive symptoms among caregivers. Methods Adequate metrics were used to assess HRQOL in children and adolescents with TSC (4-18 years, KINDLR) as well as QOL (EQ-5D) and symptoms of depression (BDI-II) among caregivers. Predictors for reduced HRQOL and depressive symptoms were identified by variance analysis, ordinal regression, and bivariate correlation. Results The mean HRQOL score was 67.9 ± 12.7, and significantly lower values were associated with increasing age, attending special needs education, TSC-associated psychiatric symptoms, and drug-related adverse events. The mean QOL of caregivers was 85.4 ± 15.7, and caregiver's sex, TSC mutation locus, familial TSC clustering, special needs education, degree of disability, care dependency, presence of TSC-associated psychiatric symptoms, and TSC severity were significant predictors of lower QOL. Depressive symptoms were identified in 45.7% of caregivers, associated with female sex of the caregiver, familial TSC clustering, special needs education, and presence of TSC-associated psychiatric symptoms of the child. Multivariate regression analysis revealed adolescence and drug-related adverse events as significant predictors for lower HRQOL in TSC children, and TSC2 variants predicted lower QOL and depressive symptoms in caregivers. Conclusion Compared with other chronic diseases, such as headache, diabetes or obesity, children with TSC have significantly lower HRQOL, which further decreases during adolescence. A decreased HRQOL of patients correlates with a lower QOL and increased symptoms of depression of their caregivers. These results may improve the comprehensive therapy and care of children and adolescents with TSC and their families and caregivers. Trial registration DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.

In Germany, wood pellets must fulfill high quality standards to be utilized in small-scale furnaces. According to current legislation, i.e., the 1st BImSchV, only ENplus A1–certified pellets may be used. Despite these strict requirements, physical fuel parameters can vary within the permissible range and variation usually increases due to fuel transport and storage. Fluctuations in physical fuel parameters may have a strong influence on combustion, especially in pellet stoves with a low degree of automation regarding fuel control and air supply. During this study, pellet length, moisture content, and the content of fines of spruce wood pellets were varied artificially at three levels for each parameter. All pellets were analyzed according to international standards for solid biofuels. Fuels were combusted in a 6 kW pellet stove and selected assortments in a 15 kW pellet boiler. For the pellet stove, pellet length had a significant influence on gaseous but not on total particulate matter (TPM) emissions. Both, rather short (10.3 mm) and long (17 mm) pellets caused an increase in emissions. In contrast, for the boiler, no significant effect of pellet length on gaseous and TPM emissions was observed. A low moisture content (3 w-%) led to increased CO, organic gaseous carbon (OGC), and TPM emissions in the pellet stove. This could be especially relevant for furnaces with very simple or no heat output control as it is common in most pellet stoves. High content of fines (3 to 10 w-%) led to a significant increase in gaseous emissions (CO up to fivefold, OGC up to tenfold) and TPM emissions (up to 1.4-fold) in the pellet stove most likely due to elevated particle entrainment. Overall, the state-of-the-art pellet stove showed larger sensitivity towards variable pellet qualities compared to the automatically stoked pellet boiler; thus, improvements in fuel design and stove technology are recommended. Overall, this study has provided important insights into the influence of pellet length, fines content, and moisture content on emissions from pellet stoves and pellet boilers, which can help drive future technical development in the areas of fuel flexibility and emission reduction.

ZUSAMMENFASSUNG Einleitung Die 5q-assoziierte spinale Muskelatrophie ist eine der schwersten und häufigsten genetischen Erkrankungen. In den letzten Jahren wurden innovative Therapiemethoden entwickelt, die auf der Modifikation des SMN2-Gens, z.B. mittels Spleißmodifikatoren oder dem Ersatz des geschädigten SMN1-Gens basieren (Genersatztherapie, GRT). Es ist bekannt, dass die GRT von Off-Target-Effekten wie einer vorübergehenden Erhöhung der Leber- und Herzenzyme begleitet wird, die in der Regel keine ernsthafte klinische Relevanz haben. Wir berichten über ein 4 Jahre altes Mädchen, das nach GRT bei 5q- SMA eine TMA entwickelte. Fallzusammenfassung Ein 4 Jahre altes Mädchen bildete 7 Tage nach einer GRT mit Onasemnogene-Abeparvovec eine TMA mit hämolytischer Anämie, Thrombozytopenie und Nierenversagen. Letzteres war gekennzeichnet durch eine Kreatinin-Erhöhung, Oligurie, Hypertonie, Protein- und Hämaturie und Ödeme. Nach Therapie mit Eculizumab und Gabe von Antihypertensiva normalisierten sich die hämolytische Aktivität, die Thrombozytenzahl, die Nierenfunktion als auch der Blutdruck innerhalb einer Woche. Empfehlung und Schlussfolgerung Die Indikation zur Plasmapherese, Hämodialyse oder Eculizumab-Therapie muss möglicherweise schnell gestellt werden. Bei engmaschiger Überwachung der Laborparameter kann durch eine adäquate Therapie ein gutes Outcome erreicht werden. Daher sollte die GRT nur in Zentren durchgeführt werden, die neben der neuropädiatrischen Expertise auch über eine pädiatrische Nephrologie verfügen.

Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC.We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence.TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs.The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.

Objective: Alagille syndrome (AS) is a rare multisystem disease of the liver, heart, eyes, face, skeleton, kidneys, and vascular system. Occurrence of pseudotumor cerebri syndrome (PTCS) in AS is exceedingly rare and, thus far, continuous intracranial pressure (ICP) monitoring has never been utilized[for full text, please go to the a.m. URL], 72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie

Holzpellets der Qualitätsklasse A1 sind der derzeit am konsequentesten normierte Holzbrennstoff. Trotzdem weisen auch solche Pellets in der Feuerung ein deutlich unterschiedliches Emissions- und Ascheschmelzverhalten auf. Dies liegt vor allem daran, dass verschiedene Brennstoffkenndaten in der Normung gar nicht betrachtet werden. Doch deren verbrennungstechnische Bedeutung ist erheblich, sie wurde jetzt im Forschungsprojekt „FuturePelletSpec“ an mehreren Pelletfeuerungen nachgewiesen. Wenn daraus neue und erweiterte Brennstoffanforderungen abgeleitet werden sollen, sind entsprechende Schnellbestimmungsmethoden und vereinfachte Analyseverfahren erforderlich.

A key goal of neonatal neurocritical care is improved outcomes, and brain monitoring plays an essential role. The recent NEST trial(1) reported no outcome benefits using aEEG monitoring compared to clinical seizure identification among neonates treated for seizures. However, the study failed to prove the effects of monitoring on seizure treatment in the first place.

AIM Deficiency of antiquitin (α-aminoadipic semialdehyde dehydrogenase ), an enzyme involved in lysine degradation and encoded by ALDH7A1, is the major cause of vitamin B6 -dependent epilepsy (PDE-ALDH7A1). Despite seizure control with high dose pyridoxine (PN), developmental delay still occurs in approximately 70% of patients. We aimed to investigate metabolic perturbations due to possible previously unidentified roles of antiquitin, which may contribute to developmental delay, as well as metabolic effects of high dose pyridoxine supplementation reflecting the high doses used for seizure control in patients with PDE-ALDH7A1. METHODS Untargeted metabolomics by high resolution mass spectrometry (HRMS) was used to analyse plasma of patients with PDE-ALDH7A1 and two independently generated lines of cultured ReNcell CX human neuronal progenitor cells (NPCs) with CRISPR/Cas mediated antiquitin deficiency. Accumulation of lysine pathway metabolites in antiquitin-deficient NPCs and Western-blot analysisconfirmed knockdown of ALDH7A1. RESULTS Metabolomics analysis of antiquitin-deficient NPCs in conditions of lysine restriction and PN supplementation identified changes in metabolites related to the transmethylation and transsulfuration pathways and osmolytes, indicating a possible unrecognized role of antiquitin outside the lysine degradation pathway. Analysis of plasma samples of PN treated patients with PDE-ALDH7A1 and antiquitin-deficient NPCs cultured in conditions comparable to the patient plasma samples demonstrated perturbation of metabolites of the gamma-glutamyl cycle, suggesting potential oxidative stress-related effects in PN-treated patients with PDE-ALDH7A1. CONCLUSIONS We postulate that a model of human NPCs with CRISPR/Cas mediated antiquitin deficiency is well suited to characterise previously unreported roles of antiquitin, relevant to this most prevalent form of pyridoxine-dependent epilepsy. This article is protected by copyright. All rights reserved.

5q-associated spinal muscular atrophy is one of the most severe and common genetic diseases. In the last few years, innovative methods of therapy have been developed based on SMN2 gene modification, such as splicing, or replacement of the damaged SMN1 gene (gene replacement therapy, GRT). GRT is known to be accompanied by off target effects like temporary elevation of liver and cardiac enzymes usually without serious clinical relevance. We report a 4-year-old girl suffering from thrombotic microangiopathy (TMA) after GRT due to 5q- SMA.A 4-year-old girl developed TMA indicated by haemolytic anemia and thrombocytopenia in conjunction with renal failure 7 days after GRT with onasemnogene abeparvovec. The latter was characterized by a rise in serum creatinine, oliguria, hypertension, protein- and haematuria, and oedema. The patient was started on eculizumab and antihypertensives resulting in normalization of haemolytic activity, platelet count, kidney function and blood pressure within one week.SMA patients receiving GRT should undergo close monitoring for early detection of TMA. Adequate measures for TMA including eculizumab or plasmapheresis as well as renal replacement therapy should be available without delay in order to avoid progressive kidney disease or other severe complications in these patients. Careful follow-up including assessment of proteinuria and blood pressure is recommended since patients may require antihypertensive/nephroprotective treatment to avoid chronic kidney disease in later life. Therefore, GRT in SMA patients should only be performed at centers with neuropediatric and paediatric nephrology expertise.Die 5q-assoziierte spinale Muskelatrophie ist eine der schwersten und häufigsten genetischen Erkrankungen. In den letzten Jahren wurden innovative Therapiemethoden entwickelt, die auf der Modifikation des SMN2-Gens, z.B. mittels Spleißmodifikatoren oder dem Ersatz des geschädigten SMN1-Gens basieren (Genersatztherapie, GRT). Es ist bekannt, dass die GRT von Off-Target-Effekten wie einer vorübergehenden Erhöhung der Leber- und Herzenzyme begleitet wird, die in der Regel keine ernsthafte klinische Relevanz haben. Wir berichten über ein 4 Jahre altes Mädchen, das nach GRT bei 5q- SMA eine TMA entwickelte.Ein 4 Jahre altes Mädchen bildete 7 Tage nach einer GRT mit Onasemnogene-Abeparvovec eine TMA mit hämolytischer Anämie, Thrombozytopenie und Nierenversagen. Letzteres war gekennzeichnet durch eine Kreatinin-Erhöhung, Oligurie, Hypertonie, Protein- und Hämaturie und Ödeme. Nach Therapie mit Eculizumab und Gabe von Antihypertensiva normalisierten sich die hämolytische Aktivität, die Thrombozytenzahl, die Nierenfunktion als auch der Blutdruck innerhalb einer Woche.Die Indikation zur Plasmapherese, Hämodialyse oder Eculizumab-Therapie muss möglicherweise schnell gestellt werden. Bei engmaschiger Überwachung der Laborparameter kann durch eine adäquate Therapie ein gutes Outcome erreicht werden. Daher sollte die GRT nur in Zentren durchgeführt werden, die neben der neuropädiatrischen Expertise auch über eine pädiatrische Nephrologie verfügen.

Background The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.

Pellet boilers and pellet stoves are widely used for heat production. But in most cases, only specific wood pellets with a low ash content are approved due to the increased risk of slagging and lim ...

The aim of this study was the modification of agricultural biofuels to allow for low emission combustion in domestic biomass boilers without slagging or other ash related problems. Four agricultural biomasses were additivated with kaolin. Fuel blends were produced from wheat straw and woody biomass. All fuels were combusted in a 30 kW biomass boiler while emissions and slag formation were measured. Due to additivation or fuel blending, total particle and CO emissions were reduced by 53–77% and 69–95%, respectively. At the same time, slag formation (determined as the mass of agglomerates > 3.15 mm) strongly declined. For fuels containing high amounts of sulphur or chlorine, kaolin additivation may lead to increased HCl and SOx emissions. Moreover, NOx-formation may be higher during combustion of additivated fuels (up to 21%). Overall, additivation with kaolin or blending of fuels might be an interesting option for the utilization of agricultural biomasses. The selection of the optimal upgrading method should consider the chemical and physical biomass properties and address the minimum amount of additive or blending ratio to achieve a sufficient reduction of emissions and slagging.

Wood chip quality is essential for failure-free and low-emission combustion in automatically stoked small-scale biomass boilers (

Within six case studies, different drying and sieving process steps were employed for the removal of adhering soil and other extraneous impurities from wood chips. Consequently, it was systematically investigated to which extent this strategy can be used to jointly mitigate the risk of bottom ash slagging and high pollutant emission levels during combustion in an automatically stoked small-scale boiler. Throughout all combustion tests, slag and emission formation were recorded. Formation of agglomerates in the bottom ash was not observed in the fuel bed. However, fuel processing resulted in an increase of the ash shrinking–softening range up to 230 K indicating a lower slagging risk in the bottom ash. An asymptotic trend for the ash melting temperatures was observed as a function of the molar (Si + P + K)/(Ca + Mg) ratio. It was also found that potassium is less efficiently retained in the bottom ash with lower Si content in the fuel. Lower moisture contents in the wood chips typically resulted in lower CO emissions and higher boiler efficiencies for the investigated range of moisture content. The sieving of the unprocessed wood chips reduced NOx emission levels up to 28%. However, fuel processing did not necessarily reduce the level of particulate matter emissions.

The brain imaging findings in children with neurological complications associated with influenza A infections are presented and analyzed and pathological imaging changes including atypical intracerebral hemorrhages in these patients are discussed. Neuroimaging findings in six children with influenza encephalopathy following influenza A infection between 2012–2017 were retrospectively investigated. Of these five underwent magnetic resonance imaging (MRI) and one computed tomography (CT). Gene analysis was performed in two cases with acute necrotizing encephalitis of childhood (ANEC). The MRI findings of one child were concordant with mild encephalopathy with a reversible splenial lesion (MERS); this patient recovered but remained aphasic. In two cases MRI showed typical bilateral thalamic lesions as a feature of ANEC; genetic testing facilitated the diagnosis in one case. One of the patients died, the other showed little improvement. The remaining three patients had multiple diffuse cerebral hemorrhages predominantly affecting the supratentorial white matter after influenza A infection complicated by pneumonia, rhabdomyolysis and sepsis requiring extracorporeal membrane oxygenation (ECMO). Neurological complications in children associated with influenza A infection may include MERS and ANEC. Additionally, atypical disseminated intracerebral hemorrhages as a complication of influenza A infection is reported.

Ashes from biomass heat (and power) plants that apply untreated woody biofuels may be suitable for use as fertilizers if certain requirements regarding pollutant and nutrient contents are met. The aim of this study was to examine if both bottom and cyclone ashes from 17 Bavarian heating plants and one ash collection depot are suitable as fertilizers (n = 50). The range and average values of relevant nutrients and pollutants in the ashes were analyzed and evaluated for conformity with the German Fertilizer Ordinance (DüMV). Approximately 30% of the bottom ashes directly complied with the heavy metal limits of the Fertilizer Ordinance. The limits were exceeded for chromium(VI) (62%), cadmium (12%) and lead (4%). If chromium(VI) could be reduced by suitable treatment, 85% of the bottom ashes would comply with the required limit values. Cyclone ashes were high in cadmium, lead, and zinc. The analysis of the main nutrients showed high values for potassium and calcium in bottom ashes, but also relevant amounts of phosphorus, making them suitable as fertilizers if pollutant limits are met. Quality assurance systems should be applied at biomass heating plants to improve ash quality if wood ashes are used as fertilizers in agriculture.

New genetic testing technologies have revolutionized medicine within the past years. It is foreseeable that the development will continue with the introduction of new techniques. Nevertheless, despite improved technology, an exact clinical description of the phenotype is still necessary and it is important to critically question findings, both before initiating genetic testing and when interpreting the results. We present four brief case vignettes to point out difficulties associated with correctly interpreting genetic findings.

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal–fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal–fetal transfer of Contactin-associated protein-like 2, N-methyl-d-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of alpha-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.

Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G&gt, T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.

Long-term treatment with 6-thioguanine (6-TG) for pediatric acute lymphoblastic leukemia (ALL) is associated with high rates of hepatic sinusoidal obstruction syndrome (SOS). Nevertheless, current treatment continues to use short-term applications of 6-TG with only sparse information on toxicity. 6-TG is metabolized by thiopurine methyltransferase (TPMT) which underlies clinically relevant genetic polymorphism. We analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term 6-TG application in 3983 pediatric ALL patients treated on trial AIEOP-BFM ALL 2000 (derivation cohort) and defined the role of TPMT genotype in this relationship. We identified 17 patients (0.43%) with hepatic SOS, 13 of which with short-term exposure to 6-TG (P TPMT variants, resulting in a 22.4-fold (95% confidence interval 7.1–70.7; P ≤ 0.0001) increased risk of hepatic SOS for heterozygotes in comparison to TPMT wild-type patients. Results were supported by independent replication analysis. All patients with hepatic SOS after short-term 6-TG recovered and did not demonstrate residual symptoms. Thus, hepatic SOS is associated with short-term exposure to 6-TG during treatment of pediatric ALL and SOS risk is increased for patients with low-activity TPMT genotypes.

Purpose Ketogenic diets (KDs) are used to treat epilepsies resistant to pharmacotherapy or some inborn errors of metabolism. For prolonged anesthesia, use of balanced electrolyte solutions (BESs) supplemented with 0.5% glucose has been advocated to maintain ketosis while preventing hypoglycemia. Unfortunately, there is no BES containing 0.5% glucose available from pharmacies. In a laboratory study, we investigated the physical and chemical stability of different BES mixtures containing 0.5% glucose. Methods In total, six approaches were chosen to create a BES with 0.5% glucose: three different glucose-free BESs were supplemented with glucose. Additionally, commercially available BES containing 1% glucose was diluted with three different glucose-free BESs to obtain a solution containing 0.5% glucose. Turbidity, pH, electrical conductivity, and macroscopic appearance of these solutions were measured immediately, at 24 hours, and after 7 days, and were compared with the original BES. Results Turbidity, pH, and electrical conductivity, as well as macroscopic appearance did not exceed the changes of the controls. Conclusions No signs of incompatibility reactions could be observed in a 1-week time period. Our study supports the stability of the examined BES containing 0.5% glucose for prolonged anesthesia in patients on KD. Clinical studies are needed to evaluate if BES containing 0.5% glucose is superior in patients on KDs.