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Prader-Willi syndrome is a genetic disorder that is associated with short stature, partial growth hormone deficiency, small hands and feet, learning and behavioural problems, and hyperphagia leading to severe, often morbid, obesity. Growth hormone therapy is associated with an improvement in height and body composition. We evaluated the efficacy and safety of long-term growth hormone treatment in a retrospective observational multinational study of 41 prepubertal children (mean age 3.8 ± 3.0 years) with genetically diagnosed Prader-Willi syndrome treated with growth hormone (0.03-0.06 mg/kg/ day) for > 12 months [mean duration 4.1 (range 0.9-9.5) years]. Height, weight, and body composition measurements were recorded at baseline and at 6 month intervals until last observation. Mean (SD) gain in height at 12 months was 0.9 (0.2) SD score (p < 0.0001). At last observation (after approximately 6 years) mean gain in height was 1.3 (0.3) (p = 0.0001) with 85 % of children achieving height > - 2 SD score. Body composition improved during treatment with an estimated 9.1 % increase in lean body mass and 9.1 % decrease in fat mass at last observation (p = 0.019). Scoliosis was reported in 3 patients at baseline and 8 patients at last observation. Sleep apnoea was recorded in 3 (7.3 %) patients. There were no other severe adverse events reported. Long-term growth hormone treatment of prepubertal children with Prader-Willi syndrome was associated with significant improvements in height and body composition. Treatment was well tolerated. The development of scoliosis warrants monitoring by an orthopaedic specialist. [ABSTRACT FROM AUTHOR]

Patients with Down's syndrome are at higher risk for developing autoimmune diseases than those of the general population. Autoimmune diseases like Hashimoto's thyroiditis, Graves' disease, diabetes mellitus type I, celiac disease, autoimmune chronic active hepatitis, alopecia, vitiligo and hypoparathyroidism are recognized associations with Down's syndrome. We describe the case of a very young boy with Down's syndrome who was diagnosed with diabetes mellitus type I, Hashimoto's thyroiditis and celiac disease before 8 yr of age. Unspecific symptoms like weight loss, unstable blood sugar with high amplitudes, behavioural problems and dry skin were suspicious for other endocrine disorders or celiac disease in our case. The boy was showing the typical human leukocyte antigen profile for these autoimmune diseases. The prevalence of these autoimmune diseases is higher in Down's syndrome than in general population. Therefore, we advice to follow children with Down's syndrome who develop more than two autoimmune diseases very carefully. [ABSTRACT FROM AUTHOR]

Ketogenic diet therapy (KDT) is well established for the treatment of early epileptic encephalopathies and specific aetiologies; however, the impact on growth in infancy remains controversial. Our aim was to examine the influence of early KDT on growth velocity and height percentiles completing two tasks. First, we systematically reviewed the literature on growth in infants younger than 12 months. Second, we analysed data from our prospective database, including infants <12 months (n = 63) treated with KDT. The literature review (n = 7) remains descriptive and includes growth percentiles and z-scores as growth velocity was not described. Studies up to 2010 used fasting, calorie restrictions, and ratios >3:1. In individual cases, significant growth delays were found; other authors did not find any changes in growth parameters. Study endpoints in our own cohort included z-scores of growth velocity, standard deviation (SD) of height, weight, BMI, deviation from individual height percentile, and daily macronutrient intake. The median z-score of growth velocity was 1.03 (first year of life). After three months, median daily intake of protein and energy was 1.68 g/kg and 85 kcal/kg. Until the age of one year, neither growth velocity nor individual growth percentiles decreased. Infants showed distinct growth improvements at three months, likely due to continuous nutritional monitoring and reduction in seizures. In the second year of life, z-scores of growth velocity decreased in patients still receiving KDT (from 1.03 at 12 months to -1.5 at 24 months). Furthermore, younger age at epilepsy onset and at KDT start correlated with slower growth velocities in the first year of life. With appropriate nutritional intake and monitoring, KDT does not reduce growth in the first year of life. Future directions might be to study the impact of KDT on growth velocity and growth hormones throughout childhood., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recombinant human growth hormone (rhGH, somatropin) therapy is approved in children with Prader-Willi syndrome (PWS)., Objectives: To report safety and effectiveness data for children with PWS treated with biosimilar rhGH (Omnitrope ® , Sandoz) in the PAtients TReated with Omnitrope (PATRO) Children study., Design: PATRO Children was a multicenter, non-interventional, postmarketing surveillance study., Methods: Children with PWS received Omnitrope according to standard clinical practice. Adverse events (AEs) were monitored for the duration of Omnitrope treatment. Effectiveness outcomes were also assessed, including height standard deviation (SD) scores (HSDS)., Results: As of July 2020 (study completion), 235 patients with PWS had been enrolled. At baseline, 95.7% ( n  = 225) of patients were prepubertal and 86.4% ( n  = 203) were rhGH treatment-naïve. At analysis, the median (range) treatment duration in the study was 56.8 (2.9-155.8) months. AEs were reported in 192 patients (81.7%) and were suspected as treatment-related in 39 patients (16.6%). Serious AEs (SAEs) were reported in 96 patients (40.9%) and were suspected as treatment-related in 22 patients (9.4%). The most frequent treatment-related SAEs were sleep apnea syndrome ( n  = 11; 4.7%), tonsillar hypertrophy ( n  = 4; 1.7%), and adenoidal hypertrophy ( n  = 4; 1.7%). Development of scoliosis was considered treatment-related in two patients; development of impaired glucose tolerance in one patient and type 2 diabetes mellitus in another patient were considered treatment-related. Effectiveness outcomes were primarily assessed in 153 patients who completed 3 years of treatment. Among the 151 prepubertal patients (135 treatment-naïve), mean (SD) change from baseline in HSDS after 3 years was +1.50 (1.07) across all patients and +1.57 (1.07) for treatment-naïve patients., Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in patients with PWS managed in real-life clinical practice. Patients with PWS should continue to be closely monitored for well-known safety issues (including respiratory, sleep, and glucose metabolism disorders, and scoliosis) during rhGH treatment., (© The Author(s), 2024.)

Transamination of Sn(NMe 2 ) 4 with H 2 NMes (Mes is 2,4,6-tri-methyl-phenyl, C 9 H 11 ) led to the formation of the title compound, [Sn(C 9 H 12 N) 4 ] or Sn(NHMes) 4 , which crystallizes in the tetra-gonal space group P 2 1 c , with four formula units per unit cell. The mol-ecular structure consists of a central tin(IV) atom, which is surrounded by four NHMes groups. Sn(NHMes) 4 possesses crystallographically imposed symmetry. The SnN 4 coordination polyhedron is best described as a compressed bis-phenoid., (© Lämmer and Merzweiler 2024.)

Previous studies have described the association of onchocerciasis (caused by Onchocerca volvulus) with epilepsy, including nodding syndrome, although a clear etiological link is still missing. Cases are found in different African countries (Tanzania, South Sudan, Uganda, Democratic Republic of the Congo, Central African Republic and Cameroon). In our study we investigated immunological parameters (cytokine, chemokine, immunoglobulin levels) in individuals from the Mahenge area, Tanzania, presenting with either epilepsy or nodding syndrome with or without O. volvulus infection and compared them to O. volvulus negative individuals from the same endemic area lacking neurological disorders. Additionally, cell differentiation was performed using blood smears and systemic levels of neurodegeneration markers, leiomodin-1 and N-acetyltyramine-O, β-glucuronide (NATOG) were determined. Our findings revealed that cytokines, most chemokines and neurodegeneration markers were comparable between both groups presenting with epilepsy or nodding syndrome. However, we observed elevated eosinophil percentages within the O. volvulus positive epilepsy/nodding syndrome patients accompanied with increased eosinophilic cationic protein (ECP) and antigen-specific IgG levels in comparison to those without an O. volvulus infection. Furthermore, highest levels of NATOG were found in O. volvulus positive nodding syndrome patients. These findings highlight that the detection of distinct biomarkers might be useful for a differential diagnosis of epilepsy and nodding syndrome in O. volvulus endemic areas. Trial-registration: NCT03653975., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Arndts et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The filarial nematode Onchocerca volvulus causes onchocerciasis (river blindness), a neglected tropical disease affecting 21 million people, mostly in Sub-Saharan Africa. Targeting the endosymbiont Wolbachia with antibiotics leads to permanent sterilization and killing of adult worms. The gold standard to assess Wolbachia depletion is the histological examination of adult worms in nodules beginning at 6 months post-treatment. However, nodules can only be used once, limiting the time points to monitor Wolbachia depletion. A diagnostic to longitudinally monitor Wolbachia depletion from microfilariae (MF) at more frequent intervals < 6 months post-treatment would accelerate clinical trials of antiwolbachials. We developed a TaqMan qPCR amplifying the single-copy gene wOvftsZ to quantify Wolbachia from as few as one MF that had migrated from skin biopsies and compared quantification using circular and linearized plasmids or synthetic dsDNA (gBlock®). qPCR for MF from the rodent nematode Litomosoides sigmodontis was used to support the reproducibility and validate the principle. The qPCR using as few as 2 MF from O. volvulus and L. sigmodontis reproducibly quantified Wolbachia. Use of a linearized plasmid standard or synthesized dsDNA resulted in numbers of Wolbachia/MF congruent with biologically plausible estimates in O. volvulus and L. sigmodontis MF. The qPCR assay yielded a median of 48.8 (range 1.5-280.5) Wolbachia/O. volvulus MF. The qPCR is a sensitive tool for quantifying Wolbachia in a few MF from skin biopsies and allows for establishing the qPCR as a surrogate parameter for monitoring Wolbachia depletion in adult worms of new antiwolbachial candidates., (© 2022. The Author(s).)

Current efforts to eliminate the neglected tropical diseases onchocerciasis and lymphatic filariasis, caused by the filarial nematodes Onchocerca volvulus and Wuchereria bancrofti or Brugia spp., respectively, are hampered by lack of a short-course macrofilaricidal-adult-worm killing-treatment. Anti-wolbachial antibiotics, e.g. doxycycline, target the essential Wolbachia endosymbionts of filariae and are a safe prototype adult-worm-sterilizing and macrofilaricidal regimen, in contrast to standard treatments with ivermectin or diethylcarbamazine, which mainly target the microfilariae. However, treatment regimens of 4-5 weeks necessary for doxycycline and contraindications limit its use. Therefore, we tested the preclinical anti-Wolbachia drug candidate Corallopyronin A (CorA) for in vivo efficacy during initial and chronic filarial infections in the Litomosoides sigmodontis rodent model. CorA treatment for 14 days beginning immediately after infection cleared >90% of Wolbachia endosymbionts from filariae and prevented development into adult worms. CorA treatment of patently infected microfilaremic gerbils for 14 days with 30 mg/kg twice a day (BID) achieved a sustained reduction of >99% of Wolbachia endosymbionts from adult filariae and microfilariae, followed by complete inhibition of filarial embryogenesis resulting in clearance of microfilariae. Combined treatment of CorA and albendazole, a drug currently co-administered during mass drug administrations and previously shown to enhance efficacy of anti-Wolbachia drugs, achieved microfilarial clearance after 7 days of treatment at a lower BID dose of 10 mg/kg CorA, a Human Equivalent Dose of 1.4 mg/kg. Importantly, this combination led to a significant reduction in the adult worm burden, which has not yet been published with other anti-Wolbachia candidates tested in this model. In summary, CorA is a preclinical candidate for filariasis, which significantly reduces treatment times required to achieve sustained Wolbachia depletion, clearance of microfilariae, and inhibition of embryogenesis. In combination with albendazole, CorA is robustly macrofilaricidal after 7 days of treatment and fulfills the Target Product Profile for a macrofilaricidal drug., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Achim Hoerauf, Kenneth Pfarr, Andrea Schiefer, Stefan Kehraus and Gabriele M. König hold the following patents for the use of Corallopyronin A for filarial infections - US 9168244 B2, US 9687470 B2, EP 2704708 B1; Rolf Müller holds the following patent for the heterologous production of Corallopyronin A - EP2994535B1.

Treating Mansonella perstans is challenged by the low efficacy of registered antihelminthics. Wolbachia endobacteria provide an alternative treatment target because depletion results in amicrofilaremia in filarial infections with Wuchereria bancrofti and Onchocerca volvulus infections. This open-label, randomized study sought to confirm that i) Wolbachia are present in M. perstans in Ghana and ii) doxycycline treatment will deplete Wolbachia and cause a slow, sustained decline in microfilariae (MF). Two hundred and two Ghanaians with M. perstans infection were randomized into early (immediate) and delayed (6 months deferred) treatment groups, given doxycycline 200 mg/day for 6 weeks, and monitored for MF and Wolbachia levels at baseline, 4, 12, and 24 months after the study onset (= time of randomization and start of treatment for the early group). Per protocol analysis revealed that the median MF/mL in the early group declined from 138 at baseline to 64 at month 4 and further to 0 at month 12. In the delayed group, MF load did not change from a baseline median of 97 to 102 at month 4 but declined to 42 at month 12, that is, 6 months after receiving treatment, trailing the early group as expected. By month 24, both treatment groups had reached a median MF level of 0. After treatment, Wolbachia were depleted from MF by ≥ 1-log drop compared with baseline levels. We conclude that M. perstans in Ghana harbor Wolbachia that are effectively depleted by doxycycline with subsequent reduction in MF loads, most likely because of interruption of fertility of adult worms.

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303&#95;Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/βII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303&#95;Leu2305dup) and p.(Arg2308&#95;Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Filarial infections causing lymphatic filariasis or onchocerciasis (river blindness) can be treated with antibiotics (e.g. doxycycline) targeting the essential endosymbiotic Wolbachia bacteria. The depletion of Wolbachia inhibits worm development and causes worm death. Available antibiotics have restrictions for use in children and pregnant or breastfeeding women. Therefore, alternative antibiotics are needed that can be given to all members of the population and that are active with a shorter therapy time. Antibiotics of the acyldepsipeptide class have been shown to inhibit the growth of bacteria by overactivating the peptidase ClpP. The novel mode of action of this class of antibiotics could lead to faster killing of intracellular bacteria., Objectives: To characterize acyldepsipeptide activity against the Wolbachia ClpP., Methods: The activity of acyldepsipeptides was investigated against Wolbachia in vitro in insect cells and also against worms in culture. In addition, structural effects were investigated by fluorescence microscopy and electron microscopy. The activity of ClpP was also investigated in vitro., Results: We show that acyldepsipeptides are active against recombinant Wolbachia ClpP and endobacteria resident within insect cells in vitro, and some derivatives were also active against filarial worms in culture. As a consequence of treatment, the worms became immotile and died, the latter confirmed by a viability assay., Conclusions: The mode of action of the acyldepsipeptides in Wolbachia is the dysregulation of ClpP, causing the uncontrolled degradation of proteins, including the cell division protein FtsZ. Our results demonstrate that wolbachial ClpP is a target for further antifilarial antibiotic discovery.

Doxycycline and rifampicin deplete essential Wolbachia from filarial nematodes that cause lymphatic filariasis or onchocerciasis, resulting in blocked worm development and death. However, doxycycline is contraindicated for children and pregnant/breastfeeding women, as is rifampicin in the latter group with the additional specter of possible resistance development in Mycobacterium spp. Novel antibiotics with a narrower spectrum would aid in eliminating filarial diseases. Corallococcus coralloides synthesizes corallopyronin A, a noncompetitive inhibitor of RNA polymerase ineffective against Mycobacterium spp. Corallopyronin A depleted Wolbachia from infected insect cells (1.89 Thus the antibiotic is effective against intracellular bacteria despite the many intervening surfaces (blood vessels, pleura, worm cuticle) and membranes (worm cell, vesicle, Wolbachia inner and outer membranes). Corallopyronin A is an antibiotic to develop further for filariasis elimination without concern for cross-resistance development in tuberculosis.

Background: Life expectance and life quality have markedly changed in PWS patients within the last 10-15 years. A strict diet, improved physical activity and an additive growth hormone treatment have led to these changes. Growth hormone therapy decreases body fat and improves final height. But growth hormone also antagonizes insulin and therefore increases the diabetic potential. The purpose of our study was to investigate incidence and multiple dependencies of development of impaired carbohydrate metabolism in patients with PWS under growth hormone therapy and to determine suitable parameters for the work-up., Patients and Methods: 34 patients with genetically approved PWS have been treated with growth hormone for at least 0.5 years. The mean duration of growth hormone treatment was 2.15 years (0.5-4.51). At the start of growth hormone treatment patients were 1.33 to 16.47 years old. The clinical picture and the nutritional situation of children with PWS change age-dependent and can be divided up into three phases. The patients were duty subdivided into three age-groups at the beginning of growth hormone treatment. Group 1: 15 PWS patients, mean age 2.62 years (1.33-3.78). Group 2: 10 PWS patients, mean age 5.54 years (4.08-7.61). Group 3: 9 PWS patients, mean age 11.35 years (8.89-16.47). Data were collected within 0.3-0.38 years before start of treatment and every 6 months throughout the treatment period. Anthropometrical data, fat mass by bioelectric impedance analysis (BIA), fasting insulin, HbA1c, C-peptide, blood fats and the blood sugar profile in oral glucose tolerance tests (OGT/1.75 g glucose/kg body mass) were obtained. Growth hormone therapy was started with an average dose of 0.031 mg/kg body mass in all groups. Insulin resistance was based on Homeostasis Model Assessment-Test (HOMA)., Result: No IR or pathological OGT were detected when growth hormone therapy started before the 4th year of life. When therapy started between the 4th and 8th year, PWS patients with normal weight did not develop an IR under GH therapy. 6% developed a glucose tolerance (IGT) disorder and 4% developed an increased fasting glucose (IFG). 5 of 9 PWS patients older than 8 years at therapystart showed a transient disorder of glucose metabolism: 11% of the results obtained in these patients presented an IR with no pathological OGT, 13% showed an IR with IGT, 7% showed an IR with IFG, and 2% showed an IR with transient diabetes. For 4% the IFG persisted with no IR, for 4% the IGT persisted with no IR. These patients differed from younger ones by an increased average BMI, an increase fat body ratio and an increase fasting insulin as well as an already reached puberty. No difference was found in C-peptide, HbA1c or GH dose/kg/body mass., Conclusion: Transient glucose metabolism disorders with no development of manifest insulin resistance are shown by PWS patients with normal weight starting from 4th year under GH therapy. Changes in the glucose metabolism with and with no development of IR appear after start of puberty and weight increase. Changes persisted partially for 18 months. GH therapy was not interrupted for any patient, whereby physical training and dietetic measurements were increased for all patients. HOMA-index and OGT shall be used in parallel to monitor glucose metabolism as both show independently distinctive features. HbA1c and C-peptide are not suitable parameters for monitoring carbohydrate metabolism in PWS patients under GH treatment.