Expanding the phenotype of anauxetic dysplasia caused by biallelic NEPRO mutations:A case report

The cartilage hair hypoplasia and anauxetic dysplasia (CHH-AD) spectrum encompasses a group of rare skeletal disorders, with anauxetic dysplasia (ANXD) at the most severe end of the spectrum. Biallelic variants in RMRP, POP1, and NEPRO (C3orf17) have previously been associated with the three currently recognized ANXD types. Generally, all types are characterized by severe short stature, brachydactyly, skin laxity, joint hypermobility and dislocations, and extensive skeletal abnormalities visible on radiological evaluation. Thus far, only five patients with type 3 anauxetic dysplasia (ANXD3) have been reported. Here, we describe one additional ANXD3 patient. We provide a detailed physical and radiological evaluation of this patient, in whom we identified a homozygous variant, c.280C &gt; T, p.(Arg94Cys), in NEPRO. Our patient presented with clinically relevant features not previously described in ANXD3: atlantoaxial subluxation, extensive dental anomalies, and a sagittal suture craniosynostosis resulting in scaphocephaly. We provide an overview of the literature on ANXD3 and discuss our patient's characteristics in the context of previously described patients. This study expands the phenotypic spectrum of ANXD, particularly ANXD3. Greater awareness of the possibility of atlantoaxial subluxation, dental anomalies, and craniosynostosis may lead to more timely diagnosis and treatment.</p

Examining the distribution and impact of single nucleotide polymorphisms in the capsular locus of Streptococcus pneumoniae serotype 19A

Streptococcus pneumoniae serotype 19A prevalence has increased after implementation of PCV7 and PCV10 vaccines. In this study, we have provided, with high accuracy, the genetic diversity of the 19A serotype in a cohort of Dutch invasive pneumococcal disease patients and asymptomatic carriers obtained in the period 2004-2016. Whole genomes of the 338 pneumococcal isolates in this cohort were sequenced and their capsule (cps) loci compared to examine the diversity and determine the impact on the production of CPS sugar precursors and CPS shedding. We discovered 79 types with a unique CPS locus sequence. Most variation was observed in the rmlB and rmlD genes of the TDP-Rha synthesis pathway, and in the wzg gene, of unknown function. Interestingly, gene variation in the cps locus was conserved in multiple alleles. Using RmlB and RmlD protein models, we predict that enzymatic function is not affected by the single nucleotide polymorphisms as identified. To determine if RmlB and RmlD function was affected, we analyzed nucleotide sugar levels using UHPLC-MS. CPS precursors differed between 19A cps locus subtypes, including TDP-Rha, but no clear correlation was observed. Also, a significant difference in multiple nucleotide sugar levels was observed between phylogenetically branched groups. Because of indications of a role for Wzg in capsule shedding, we analyzed if this was affected. No clear indication of a direct role in shedding was found. We thus describe genotypic variety in rmlB, rmlD and wzg in serotype 19A the Netherlands, for which we have not discovered an associated phenotype

Genetic determinants of cortical structure (thickness, surface area and volumes) among disease free adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

Injury markers predict time to dementia in subjects with MCI and amyloid pathology

OBJECTIVES: Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology. METHODS: We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of β-amyloid(1-42) (Aβ(1-42)) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models. RESULTS: We included 110 subjects with MCI with abnormal CSF Aβ(1-42) and a mean MMSE score of 26.3 ± 2.8. During a mean follow-up of 2.2 ± 1.0 (range 0.4-5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1-4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3-9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1-5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0-55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score. CONCLUSIONS: In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline

Energy efficient UV/H2O2 processes for conversion of pharmaceuticals in drinking water: effect of water quality

Previous research showed that surface water in the Netherlands may contain significant concentrations of organic micropollutants like pharmaceuticals. A model has been developed which can predict the conversion of a broad range of organic micropollutants in a UV/H2O2 process with low pressure UV lamps. This model also was applied to optimize UV reactors, which were tested at three Dutch locations, including two drinking water companies. It was observed that the model predictions were very accurate, that very high conversion could be obtained, and that the optimized UV reactors resulted in a 30-40% reduced energy demand of the process. Furthermore it was shown that the effect of pretreatment of the water, reducing the DOC content and increasing UV-T values, can improve reactor performance by 30-70%

A search for new MRI criteria for dissemination in space in subjects with a clinically isolated syndrome

The International Panel on the Diagnosis of Multiple Sclerosis (MS) incorporated the Barkhof/Tintoré (B/T) magnetic resonance criteria into their diagnostic scheme to provide evidence of dissemination in space of central nervous system lesions, a prerequisite for diagnosing MS in patients who present with clinically isolated syndromes (CIS). Although specific for MS, the B/T criteria were criticised for their low sensitivity and relative complexity in clinical use. We used lesion characteristics at onset from 349 CIS patients in logistic regression and recursive partitioning modelling in a search for simpler and more sensitive criteria, while maintaining current specificity. The resulting models, all based on the presence of periventricular and deep white matter lesions, performed roughly in agreement with the B/T criteria, but were unable to provide higher diagnostic accuracy based on information from a single scan. Apparently, findings from contrast-enhanced and follow-up magnetic resonance scans are needed to improve the diagnostic algorithm

Impact of T‐cell depletion strategies on outcomes following hematopoietic stem cell transplantation for idiopathic aplastic anemia: A study on behalf of the European blood and marrow transplant severe aplastic anemia working party

We retrospectively analyzed the outcomes of 1837 adults and children with severe aplastic anemia (SAA) who underwent matched sibling donor (MSD) and matched unrelated donor (MUD) hemopoietic stem cell transplantation (HSCT) between 2000 and 2013. Patients were grouped by transplant conditioning containing either anti‐thymocyte globulin (ATG) (n = 1283), alemtuzumab (n = 261), or no serotherapy (NS) (n = 293). The risks of chronic GvHD were significantly reduced when ATG or alemtuzumab were compared with NS (P = .021 and .003, respectively). Acute GVHD was significantly reduced in favor of alemtuzumab compared with ATG (P = .012) and NS (P < .001). By multivariate analysis, when compared with ATG, alemtuzumab was associated with a lower risk of developing acute (OR 0.262; 95% CI 0.14‐0.47; P < .001) and chronic GVHD (HR 0.58; 95% CI 0.35‐0.94; P = .027). OS was significantly better in ATG and alemtuzumab patients compared with NS (P = .010 and .025). Our data shows inclusion of serotherapy in MSD and MUD HSCT for patients with SAA reduces chronic GVHD and provides a survival advantage over patients not receiving serotherapy. Notably, alemtuzumab reduced the risk of acute and chronic GvHD compared with ATG and indicates that alemtuzumab might be the serotherapy of choice for MSD and MUD transplants for SAA

Marine spatial planning: risk or opportunity for fisheries in the North Sea?

The North Sea is one of the busiest marine areas in the world. It is also a major fisheries ground. Bordered by seven countries with their own spatial uses and claims, the stage is set for complex and demanding governance challenges. Recent decades have also seen user groups multiply, competition for space and resources increase, and the pressure on the marine environment and its living natural resources grow. As governments strive to balance conservation and economic development needs, they also have to deal with inter-as well as intra-national user conflicts. Marine Spatial Planning (MSP) has arrived as a new approach to these issues. It is argued that for North Sea fishing people and their communities MSP holds risks as well as opportunities, depending on which institutions are formed and what role they are allowed to play in the planning process

Mice co-administrated with partially hydrolysed whey proteins and prebiotic fibre mixtures show allergen-specific tolerance and a modulated gut microbiota

Non-breastfed infants at-risk of allergy are recommended to use a hydrolysed formula before the age of 6 months. The addition of prebiotics to this formula may reduce the allergy development in these infants, but clinical evidence is still inconclusive. This study evaluates (1) whether the exposure duration to different prebiotics alongside a partially hydrolysed whey protein (pHP) influences its' effectiveness to prevent allergy development and (2) whether the gut microbiota plays a role in this process. Mice orally sensitised with whey and/or cholera toxin were orally treated for six days before sensitization with phosphate buffered saline, whey or pHP to potentially induce tolerance. Two groups received an oligosaccharide diet only from day -7 until -2 (GFshort and GFAshort) whereas two other groups received their diets from day -15 until 37 (GFlong and GFAlong). On day 35, mice underwent an intradermal whey challenge, and the acute allergic skin response, shock score, and body temperatures were measured. At day 37, mice received whey orally and serum mouse mast cell protease-1, SLPI and whey-specific antibodies were assessed. Faecal samples were taken at day -15, -8 and 34. Feeding mice pHP alone during tolerance induction did not reduce ear swelling. The tolerance inducing mechanisms seem to vary according to the oligosaccharide-composition. GFshort, GFlong, and GFAlong reduced the allergic skin response, whereas GFAshort was not potent enough. However, in the treatment groups, the dominant Lactobacillus species decreased, being replaced by Bacteroidales family S24- 7 members. In addition, the relative abundance of Prevotella was significantly higher in the GFlong, GFAshort and GFAlong groups. Co-administration of oligosaccharides and pHP can induce immunological tolerance in mice, although tolerance induction was strongest in the animals that were fed oligosaccharides during the entire protocol. Some microbial changes coincided with tolerance induction, however, a specific mechanism could not be determined based on these data

‘To the land or to the sea' : diet and mobility in early medieval Frisia

This study investigated palaeodiet and population mobility in early medieval Frisia through the stable isotope analysis of individuals buried in the fifth–eighth century AD cemetery of Oosterbeintum, a terp site on the northern coast of the Netherlands. The results cast new light on the role of the northern Netherlands in trade and migration in the early medieval period, and have significance for the study of interaction and movement throughout the wider North Sea region. Bone collagen and tooth enamel from humans and animals were analyzed using carbon, nitrogen, oxygen, and strontium isotopes. δ13C and δ15N results indicated that the population had a terrestrial, C3-based diet. High δ15N values were observed in humans and fauna, which are probably related to the terp's salt-marsh location. The δ18O and 87Sr/86Sr data revealed a high proportion of non-locals buried at Oosterbeintum, some of whom had probably migrated from regions as distant and varied as Scandinavia and southern England. It is suggested that this immigration may be associated with Frisian maritime trading activities. New data are also presented from a small number of contemporaneous European sites