The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood

HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2

Polyglutamine expansion in huntingtin is the underlying mutation leading to neurodegeneration in Huntington disease. This mutation influences the interaction of huntingtin with different proteins, including huntingtin-interacting protein I (HIP(), in which affinity to bind to mutant huntingtin is profoundly reduced. Here we demonstrate that HIP( colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP( binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276-335. This region, which contains consensus clathrin- and AP2-binding sites, functions in conjunction with the coiled-coil domain to target HIP( to CCVs. Expression of various HIP1 fragments leads to a potent block of clathrin-mediated endocytosis. Our findings demonstrate that HIP1 is a novel component of the endocytic machinery

Lesion bacterial communities in American lobsters with diet-induced shell disease

In southern New England, USA, shell disease affects the profitability of the American lobster Homarus americanus fishery. In laboratory trials using juvenile lobsters, exclusive feeding of herring Clupea harengus induces shell disease typified initially by small melanized spots that progress into distinct lesions. Amongst a cohabitated, but segregated, cohort of 11 juvenile lobsters fed exclusively herring, bacterial communities colonizing spots and lesions were investigated by denaturing gradient gel electrophoresis of 16S rDNA amplified using 1 group-specific and 2 universal primer sets. The Bacteroidetes and Proteobacteria predominated in both spots and lesions and included members of the orders Flavobacteriales (Bacteriodetes), Rhodobacterales, Rhodospirillales and Rhizobiales (Alphaproteobacteria), Xanthomonadales (Gammaproteobacteria) and unclassified Gammaproteobacteria. Bacterial communities in spot lesions displayed more diversity than communities with larger (older) lesions, indicating that the lesion communities stabilize over time. At least 8 bacterial types persisted as lesions developed from spots. Aquimarina ‘homaria’, a species commonly cultured from lesions present on wild lobsters with epizootic shell disease, was found ubiquitously in spots and lesions, as was the ‘Candidatus Kopriimonas aquarianus’, implicating putative roles of these species in diet-induced shell disease of captive lobsters

Exposures of Homarus americanus Shell to Three Bacteria Isolated from Naturally Occurring Epizootic Shell Disease Lesions

Epizootic shell disease (ESD) is an emerging form of shell disease of the American lobster (Homarus americanus) that has had detrimental effects on the fishery in southern New England. Three bacteria commonly isolated from lesions of wild lobsters with ESD—a novel Aquimarina sp. (A. ‘homaria’ I32.4), a novel Rhodobacteraceae species (‘Thalassobius’ sp. I31.1) and a Pseudoalteromonas sp. (Pseudoalteromonas ‘gracilis’ ISA7.3)—were applied directly to normal and abraded juvenile lobster carapaces, and then monitored for persistence over time and for the development of shell-disease lesions at 3 different temperatures (10°C, 15°C, and 20°C). Without abrasion of the carapace, no lesions developed in the exposures. After abrasion and exposure with a pure culture of A. ‘homaria’ I32.4, lesions developed at all 3 temperature and A. ‘homaria’ was detected in the lesions of all animals tested. Surprisingly, ‘Thalassobius’ sp. I31.1 also colonized these lesions. A coexposure with all 3 bacteria also demonstrated lesion development and the persistence of A. ‘homaria’ I32.4 and ‘Thalassobius’ sp. I31.1. The bacterium P. ‘gracilis’ ISA7.3 was not able to persist in any of the challenged lesions. Abraded areas of the cuticle with no bacteria added directly were also colonized by A. ‘homaria’ and ‘Thalassobius’ sp., and moderate lesions developed; however, the directly exposed lesions were significantly more severe (P \u3c 0.05). The bacterium A. ‘homaria’, but not ‘Thalassobius’ sp., was detected in spontaneous lesions that developed independent of any abrasion and/or bacterial exposures. A novel bacterium, ‘Candidatus Kopriimonas aquarianus’ was also detected in spontaneous lesions. This study shows that 2 bacteria isolated from ESD lesions of wild lobsters are able to persist in and act together as important components of lesion development on abraded surfaces of American lobsters. This indicates that they are likely major contributors to lesion development in the ESD polymicrobial infection and may represent significant pathogens of the American lobster

Mass Spectral Charting of Neuropeptidomic Expression in the Stomatogastric Ganglion at Multiple Developmental Stages of the Lobster <i>Homarus americanus</i>

The stomatogastric nervous system (STNS) of the American lobster <i>Homarus americanus</i> serves as a useful model for studies of neuromodulatory substances such as peptides and their roles in the generation of rhythmic behaviors. As a central component of the STNS, the stomatogastric ganglion (STG) is rich in neuropeptides and contains well-defined networks of neurons, serving as an excellent model system to study the effect of neuropeptides on the maturation of neural circuits. Here, we utilize multiple mass spectrometry (MS)-based techniques to study the neuropeptide content and abundance in the STG tissue as related to the developmental stage of the animal. Capillary electrophoresis (CE)-MS was employed to unambiguously identify low abundance neuropeptide complements, which were not fully addressed using previous methods. In total, 35 neuropeptides from 7 different families were detected in the tissue samples. Notably, 10 neuropeptides have been reported for the first time in this study. In addition, we utilized a relative quantitation method to compare neuropeptidomic expression at different developmental stages and observed sequential appearance of several neuropeptides. Multiple isoforms within the same peptide family tend to show similar trends of changes in relative abundance during development. We also determined that the relative abundances of tachykinin peptides increase as the lobster grows, suggesting that the maturation of circuit output may be influenced by the change of neuromodulatory input into the STG. Collectively, this study expands our knowledge about neuropeptides in the crustacean STNS and provides useful information about neuropeptide expression in the maturation process