Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency

BACKGROUND: Mucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I-IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described. METHODS: In this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis. RESULTS: The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS. CONCLUSION: Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X

Oncogenic human papillomavirus-associated nasopharyngeal carcinoma:an observational study of correlation with ethnicity, histological subtype and outcome in a UK population

BACKGROUND: Nasopharyngeal carcinoma (NPC) accounts for 0.6% of all cancers worldwide with the highest prevalence in South East Asia, Southern China and Northern Africa but the disease is uncommon in Europe with an annual incidence in this region of less than 1 per 100 000. Although the Epstein-Barr virus (EBV) is a well known causative agent in NPC, recent reports have implicated oncogenic Human Papillomavirus (HPV) in a subgroup of these tumours. The recent striking rise of oropharyngeal carcinoma has been attributed to HPV, but little is known about the prevalence and clinical significance of the virus in NPC. The aim of this study was to determine the prevalence of oncogenic HPV in NPC from tissue archives of two head and neck cancer centres in the UK. METHODS: Samples were available for 67 patients with clinically validated NPC. The detection of high-risk HPV was carried out by screening all cases for p16 using immunohistochemistry and HPV DNA by polymerase chain reaction (PCR) using GP5+/6+ primers. All cases with p16 over-expression or positive for HPV by PCR were then examined by high-risk HPV DNA in-situ hybridisation and genotype analysis by PCR. RESULTS: Eleven cases (11/67, 16.4%) showed concurrent over-expression of p16 and evidence of high-risk HPV DNA by in-situ hybridisation; the majority were HPV16 positive. Of these 11 cases, nine occurred in Whites and two in Blacks. Histologically, there were two keratinising squamous cell carcinoma and nine non-keratinising carcinomas (eight differentiated and one undifferentiated). None of the HPV-positive cases showed any co-infection with EBV. There was no statistically significant difference in overall survival outcome between patients with HPV-positive and HPV-negative NPC. CONCLUSION: The results of this study show that oncogenic HPV is associated with a subgroup of NPCs and is more likely to occur in Whites. However, unlike oropharyngeal carcinoma there was no significant difference in overall survival between patients with HPV-positive and HPV-negative NPC

Arithmetic learning in advanced age

<div><p>Acquisition of numerical knowledge and understanding of numerical information are crucial for coping with the changing demands of our digital society. In this study, we assessed arithmetic learning in older and younger individuals in a training experiment including brain imaging. In particular, we assessed age-related effects of training intensity, prior arithmetic competence, and neuropsychological variables on the acquisition of new arithmetic knowledge and on the transfer to new, unknown problems. Effects were assessed immediately after training and after 3 months. Behavioural results showed higher training effects for younger individuals than for older individuals and significantly better performance after 90 problem repetitions than after 30 repetitions in both age groups. A correlation analysis indicated that older adults with lower memory and executive functions at baseline could profit more from intensive training. Similarly, training effects in the younger group were higher for those individuals who had lower arithmetic competence and executive functions prior to intervention. In younger adults, successful transfer was associated with higher executive functions. Memory and set-shifting emerged as significant predictors of training effects in the older group. For the younger group, prior arithmetic competence was a significant predictor of training effects, while cognitive flexibility was a predictor of transfer effects. After training, a subgroup of participants underwent an MRI assessment. A voxel-based morphometry analysis showed a significant interaction between training effects and grey matter volume of the right middle temporal gyrus extending to the angular gyrus for the younger group relative to the older group. The reverse contrast (older group vs. younger group) did not yield any significant results. These results suggest that improvements in arithmetic competence are supported by temporo-parietal areas in the right hemisphere in younger participants, while learning in older people might be more widespread. Overall, our study indicates that arithmetic learning depends on the training intensity as well as on person-related factors including individual age, arithmetic competence before training, memory, and executive functions. In conclusion, we suggest that major progress can be also achieved by older participants, but that interventions have to take into account individual variables in order to provide maximal benefit.</p></div

Haste makes waste: Decision making in patients with restless legs syndrome with and without augmentation.

OBJECTIVES:To investigate decision making in patients with primary restless legs syndrome (RLS) with and without augmentation treated with dopaminergic medication. METHODS:A total of 64 non-demented RLS patients treated with dopaminergic medication with and without augmentation were included in this study. We used an information sampling task to assess how much evidence participants gather before making a decision. Performance was compared to the results of 21 healthy controls. RESULTS:All patients with and without augmentation gathered less information than healthy controls before making a decision (p<0.001), but there was no difference between the two patient groups (p = 1.0). Furthermore, both patient groups made more irrational decisions (e.g. decisions against the evidence they had at the time) than healthy controls (p≤0.002). In addition, RLS patients with augmentation made significantly more irrational decisions than RLS patients without augmentation (p = 0.037) and controls (p<0.001). CONCLUSIONS:Our results show that RLS patients treated with dopaminergic drugs, regardless of having augmentation or not, jumped to conclusions and decided significantly more often against the evidence they had at the time of their decision. However, those with augmentation performed worse than all other groups and made more often irrational decisions, a phenomenon which is also common in patients with substance abuse or behavioural addictions. Thus, jumping to conclusions and deciding with a higher degree of uncertainty as well as irrational decision making is more common in RLS patients treated with dopaminergic medication particularly in those with augmentation

High-Density Lipoprotein Function in Exudative Age-Related Macular Degeneration.

PURPOSE:High-density lipoproteins (HDL) have long been implicated in the pathogenesis of age-related macular degeneration (AMD). However, conflicting results have been reported with regard to the associations of AMD with HDL-cholesterol levels. The present study is the first to assess HDL composition and metrics of HDL function in patients with exudative AMD and control patients. METHODS:Blood samples were collected from 29 patients with exudative AMD and 26 age-matched control patients. Major HDL associated apolipoproteins were determined in apoB-depleted serum by immunoturbidimetry or ELISA, HDL-associated lipids were quantified enzymatically. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function, including cholesterol efflux capacity, anti-oxidative and anti-inflammatory activities using apoB-depleted serum from study participants. RESULTS:In our study, we observed that the HDL associated acute phase protein serum amyloid A (SAA) was significantly increased in AMD patients (p<0.01), whereas all other assessed apolipoproteins including ApoA-I, apoA-II, apoC-II, apoC-III and apoE as well as major HDL associated lipids were not altered. HDL efflux capacity, anti-oxidative capacity and arylesterase activity were not different in AMD patients when compared with the control group. The ability of apoB-depleted serum to inhibit monocyte NF-κB expression was significantly improved in AMD patients (mean difference (MD) -5.6, p<0.01). Moreover, lipoprotein-associated phospholipase A2 activity, a marker of vascular inflammation, was decreased in AMD subjects (MD -24.1, p<0.01). CONCLUSIONS:The investigated metrics of HDL composition and HDL function were not associated with exudative AMD in this study, despite an increased content of HDL associated SAA in AMD patients. Unexpectedly, anti-inflammatory activity of apoB-depleted serum was even increased in our study. Our data suggest that the investigated parameters of serum HDL function showed no significant association with exudative AMD. However, we cannot exclude that alterations in locally produced HDL may be part of the AMD pathogenesis

Descriptive statistics of the analysis of transfer effects.

<p>Descriptive statistics of the analysis of transfer effects.</p

Brain regions showing a positive correlation between training effects in response accuracy and brain volume for the younger group, and for the contrast younger group vs. older group.

<p>Brain regions showing a positive correlation between training effects in response accuracy and brain volume for the younger group, and for the contrast younger group vs. older group.</p

Schematisation of the study procedure.

<p>Schematisation of the study procedure.</p