SBH17: Benchmark Database of Barrier Heights for Dissociative Chemisorption on Transition Metal Surfaces.

Accurate barriers for rate controlling elementary reactions on metal surfaces are key to understanding, controlling, and predicting the rate of heterogeneously catalyzed processes. While barrier heights for gas phase reactions have been extensively benchmarked, dissociative chemisorption barriers for the reactions of molecules on metal surfaces have received much less attention. The first database called SBH10 and containing 10 entries was recently constructed based on the specific reaction parameter approach to density functional theory (SRP-DFT) and experimental results. We have now constructed a new and improved database (SBH17) containing 17 entries based on SRP-DFT and experiments. For this new SBH17 benchmark study, we have tested three algorithms (high, medium, and light) for calculating barrier heights for dissociative chemisorption on metals, which we have named for the amount of computational effort involved in their use. We test the performance of 14 density functionals at the GGA, GGA+vdW-DF, and meta-GGA rungs. Our results show that, in contrast with the previous SBH10 study where the BEEF-vdW-DF2 functional seemed to be most accurate, the workhorse functional PBE and the MS2 density functional are the most accurate of the GGA and meta-GGA functionals tested. Of the GGA+vdW functionals tested, the SRP32-vdW-DF1 functional is the most accurate. Additionally, we found that the medium algorithm is accurate enough for assessing the performance of the density functionals tested, while it avoids geometry optimizations of minimum barrier geometries for each density functional tested. The medium algorithm does require metal lattice constants and interlayer distances that are optimized separately for each functional. While these are avoided in the light algorithm, this algorithm is found not to give a reliable description of functional performance. The combination of relative ease of use and demonstrated reliability of the medium algorithm will likely pave the way for incorporation of the SBH17 database in larger databases used for testing new density functionals and electronic structure methods.

The role of TET-mediated DNA hydroxymethylation in prostate cancer.

Ten-eleven translocation (TET) proteins are recently characterized dioxygenases that regulate demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further derivatives. The recent finding that 5hmC is also a stable and independent epigenetic modification indicates that these proteins play an important role in diverse physiological and pathological processes such as neural and tumor development. Both the genomic distribution of (hydroxy)methylation and the expression and activity of TET proteins are dysregulated in a wide range of cancers including prostate cancer. Up to now it is still unknown how changes in TET and 5(h)mC profiles are related to the pathogenesis of prostate cancer. In this review, we explore recent advances in the current understanding of how TET expression and function are regulated in development and cancer. Furthermore, we look at the impact on 5hmC in prostate cancer and the potential underlying mechanisms. Finally, we tried to summarize the latest techniques for detecting and quantifying global and locus-specific 5hmC levels of genomic DNA.

Treatment-induced changes in the androgen receptor axis: Liquid biopsies as diagnostic/prognostic tools for prostate cancer.

Prostate cancer progression and treatment relapse is associated with changes in the androgen receptor axis, and analysis of alternations of androgen receptor signaling is valuable for prognostics and treatment optimization. The profile of androgen receptor axis is currently obtained from biopsy specimens, which are not always easy to obtain. Moreover, the information acquired only provides a snapshot of the tumor biology, with strict spatial and temporal limitations. On the other hand, circulation is easily accessible source of both circulating tumor cells and circulating tumor DNA, which can be sampled at numerous time points. This Review will explore the potential use of androgen receptor axis alternations detectable in the blood in therapeutic decision-making and precision medicine for advancing metastatic castration-resistant prostate cancer.

Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

Hospital-based cluster randomised controlled trial to assess effects of a multi-faceted programme on influenza vaccine coverage among hospital healthcare workers and nosocomial influenza in the Netherlands, 2009 to 2011.

Nosocomial influenza is a large burden in hospitals. Despite recommendations from the World Health Organization to vaccinate healthcare workers against influenza, vaccine uptake remains low in most European countries. We performed a pragmatic cluster randomised controlled trial in order to assess the effects of implementing a multi-faceted influenza immunisation programme on vaccine coverage in hospital healthcare workers (HCWs) and on in-patient morbidity. We included hospital HCWs of three intervention and three control University Medical Centers (UMCs), and 3,367 patients. An implementation programme was offered to the intervention UMCs to assess the effects on both vaccine uptake among hospital staff and patient morbidity. In 2009/10, the coverage of seasonal, the first and second dose of pandemic influenza vaccine as well as seasonal vaccine in 2010/11 was higher in intervention UMCs than control UMCs (all p<0.05). At the internal medicine departments of the intervention group with higher vaccine coverage compared to the control group, nosocomial influenza and/or pneumonia was recorded in 3.9% and 9.7% of patients of intervention and control UMCs, respectively (p=0.015). Though potential bias could not be completely ruled out, an increase in vaccine coverage was associated with decreased patient in-hospital morbidity from influenza and/or pneumonia.

Somatic mosaicism in a mother of two children with Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, unusual face and breathing abnormalities and can be caused by haploinsufficiency of TCF4. The majority of cases are sporadic. Somatic mosaicism was reported infrequently. We report on a proband with typical manifestations of PTHS and his younger brother with a less striking phenotype. In both, a heterozygous frameshift mutation (c.1901_1909delinsA, p.Ala634AspfsX67) was found in exon 19 of TCF4. The same mutation was found at low levels in DNA extracted from the mother's blood, urine and saliva. This report of familial recurrence with somatic mosaicism in a healthy mother has important consequences for genetic counseling. We suggest careful studies in parents of other patients with PTHS to determine the frequency of germline and somatic mosaicism for TCF4 mutations.

Aging in Rett syndrome: a longitudinal study.

Little is known about the aging process of people with specific syndromes, like Rett syndrome (RTT). Recognition of the clinical and behavioral characteristics of the adult RTT is needed in order to improve future management of the RTT girl and counseling of parents. In association with the Dutch RTT parent association, a 5-year longitudinal study was carried out. The study population consisted of 53 adult women with a clinical diagnosis of RTT. Postal questionnaires were sent, including demographic features, skills, physical and psychiatric morbidity. At the time of the second measurement seven women had died. In 2012, 80% of the questionnaires (37/46) were returned. Mean age of the women was 31.4 years. Molecular confirmation was possible for 83% of the women for whom analyses were carried out. The adult RTT woman has a more or less stable condition. The general disorder profile is that of a slow on-going deterioration of gross motor functioning in contrast to a better preserved cognitive functioning, less autonomic and epileptic features and good general health. This is the first longitudinal cohort study about aging in RTT. Continuing longitudinal studies are needed to gain more insight into the aging process in RTT.

Rett Syndrome.

Rett syndrome is one of the most common causes of complex disability in girls. It is characterized by early neurological regression that severely affects motor, cognitive and communication skills, by autonomic dysfunction and often a seizure disorder. It is a monogenic X-linked dominant neurodevelopmental disorder related to mutation in MECP2, which encodes the methyl-CpG-binding protein MeCP2. There are several mouse models either based on conditional knocking out of the Mecp2 gene or on a truncating mutation. We discuss the clinical aspects with special emphasis on the behavioral phenotype and we review current perspectives in clinical management alongside with perspectives in altering gene expression.

Von Willebrand factor deficiency and atherosclerosis.

Von Willebrand factor (VWF) is a large multimeric glycoprotein that plays a major role in haemostasis, illustrated by the bleeding tendency in von Willebrand disease (VWD), the most common hereditary bleeding disorder caused by VWF deficiency or dysfunction. Elevated VWF levels are strongly associated with an increased risk of ischemic cardiovascular events. Whether this relation is causal, or whether increased VWF levels reflect disturbances of endothelial function remains to be elucidated. One possibility is that VWF participates in the process of atherogenesis. The aim of the current review is to determine whether VWF deficiency provides protection against the development of atherosclerosis in humans and animals. Results from animal studies suggest that, at arterial branch point predilection sites, VWF deficiency or blockage has a protective effect against atherosclerosis. Based on the available evidence, this potential protective effect of VWF deficiency can most likely be tracked to the VWF-platelet interaction. Sites involved in this interaction could prove attractive targets in future treatment and prevention of cardiovascular disease, an option that is already being explored in humans. An unequivocal protective effect of VWD on atherosclerosis has not been demonstrated in humans. However the interpretation of these results is hampered by several methodological weaknesses. In conclusion, VWF is probably a significant player in the multifaceted interaction between the haemostatic system and the atherosclerotic process which deserves further study.

Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a combination of neurological symptoms and hamartomatous growths, and caused by mutations in the TSC1 and TSC2 genes. Overall, TSC2 mutations are associated with a more severe disease phenotype. We identified the c.3598C>T (R1200W) change in the TSC2 gene in seven different families. The clinical phenotypes in the families were mild, characterized by mild skin lesions, remitting epilepsy and a lack of severe mental retardation or major organ involvement. Functional analysis of the TSC2 R1200W variant, and four other TSC2 missense variants associated with a mild TSC phenotype, confirmed that the changes disrupted the TSC1-TSC2 function. Interestingly however, in each case, the TSC1-TSC2 interaction was not affected by the amino acid substitution.

Determination of factors required to increase uptake of influenza vaccination among hospital-based healthcare workers.

A questionnaire study was performed in all eight University Medical Centers in The Netherlands to determine the predictors of influenza vaccination compliance in hospital-based healthcare workers (HCWs). Demographical, behavioural and organisational determinants were assessed based on behavioural and implementation models. Multivariable regression analysis was applied to assess the independent predictors for influenza vaccine uptake. Age >40 years, the presence of a chronic illness, awareness of personal risk and awareness of risk of infecting patients, trust in the effectiveness of the vaccine to reduce the risk of infecting patients, the HCWs' duty to do no harm and their duty to ensure continuity of care, finding vaccination useful despite the constant flow of visitors and having knowledge of the Health Council's advice, social influence and convenient time for vaccination were all independently associated with vaccine uptake. The accuracy of the prediction model was very high (area under the receiver operating curve: 0.95). Intervention programmes to increase influenza vaccine uptake among HCWs should target the relevant determinants identified in this study.

Updating the profile of C-terminal MECP2 deletions in Rett syndrome.

OBJECTIVES: This study aimed to compare the phenotype of Rett syndrome cases with C-terminal deletions to that of cases with different MECP2 mutations and to examine the phenotypic variation within C-terminal deletions. METHODS: Cases were selected from InterRett, an international database and from the population-based Australian Rett Syndrome Database. Cases (n=832) were included if they had a pathogenic MECP2 mutation in which the nature of the amino acid change was known. Three severity scale systems were used, and individual aspects of the phenotype were also compared. RESULTS: Lower severity was associated with C-terminal deletions (n=79) compared to all other MECP2 mutations (e.g. Pineda scale C-terminals mean 15.0 (95% CI 14.0-16.0) vs 16.2 (15.9-16.5). Cases with C-terminal deletions were more likely to have a normal head circumference (odds ratio 3.22, 95% CI 1.53 - 6.79) and weight (odds ratio 2.97, 95% CI 1.25-5.76). Onset of stereotypies tended to be later (median age 2.5 years vs 2 years, p<0.001 from survival analysis), and age of learning to walk tended to be earlier (median age 1.6 years vs 2 years, p=0.002 from survival analysis). Those with C-terminal deletions occurring later in the region had lower average severity scores than those occurring earlier in the region. CONCLUSION: In terms of overall severity C-terminal deletion cases would appear to be in the middle of the range. In terms of individual aspects of phenotype growth and ability to ambulate appear to be particular strengths. By pooling data internationally this study has achieved the case numbers to provide a phenotypic profile of C-terminal deletions in Rett syndrome.

Genetic diversity of methicillin-resistant Staphylococcus aureus in a tertiary hospital in The Netherlands between 2002 and 2006.

The aim of this study was to investigate the methicillin-resistant Staphylococcus aureus (MRSA) clones isolated in a Dutch university hospital, situated near the borders of Belgium and Germany, between 2002 and 2006. MRSA strains (n = 175) were characterized using spa and SCCmec typing. The presence of Panton Valentine leukocidin (PVL) was determined. Between 2002 and 2005, ST5-MRSA-IV was predominant, and the spa type of ST5-MRSA-IV changed from t002 to t447. ST5-MRSA-I, ST5-MRSA-II, ST228-MRSA-I, and ST247-MRSA-I were also observed in this period. From 2004, the MRSA genetic background became more diverse, and in 2006, ST5-MRSA-IV was only sporadically observed. From 2005, ST5-MRSA-II, ST8-MRSA-IV, ST22-MRSA-IV, and ST45-MRSA-IV were increasingly observed. Several other MRSA clones, such as ST239-MRSA-III, were found sporadically. Four PVL-positive MRSA isolates were observed, associated with ST80-MRSA-IV and ST8-MRSA-IV. ST5-MRSA-I, ST5-MRSA-II, ST5-MRSA-IV, and ST228-MRSA-I have not been described previously in The Netherlands.

The velo-cardio-facial syndrome: the spectrum of psychiatric problems and cognitive deterioration at adult age.

The velo-cardio-facial syndrome: the spectrum of psychiatric problems and cognitive deterioration at adult age: Deletion 22q11.2 syndrome, or the velo-cardio-facial syndrome (VCFS), is a syndrome with a known but varied clinical and behavioral phenotype. We report 7 patients with 22q11.2 deletion syndrome and an intellectual disability. Aside from the described behavioral phenotype in literature, a moderate, severe or profound intellectual disability may be present. Special attention should be given to cognitive deterioration.

Cost of the meticillin-resistant Staphylococcus aureus search and destroy policy in a Dutch university hospital.

Costs related to a search and destroy policy and treatment for Staphylococcus aureus bacteraemia in the University Hospital Maastricht were calculated for the period 2000 and 2004. The financial cost-benefit break-even point of the search and destroy policy was determined by modelling. On average 22,412 patients were admitted per year for an average of 8.7 days. Each year 246 patients were screened for meticillin-resistant Staphylococcus aureus (MRSA) and 74 patients were decolonised and nursed in preventive isolation. The prevalence of MRSA in the University Hospital Maastricht was 0.7%, as calculated from positive blood cultures, and mean length of stay for all patients with S. aureus bloodstream infections was 39.9 days. The annual cost of pro-active searching for MRSA in the University Hospital Maastricht was euro 1,383,200, and euro 2,736,762 for MRSA prevention and treatment of S. aureus bloodstream infections. Simulation of a variety MRSA/meticillin-susceptible S. aureus (MSSA) ratios showed that even if the MRSA prevalence reaches 8%, prevention costs are still lower than the cost of treating S. aureus infections. In conclusion, the total cost of a search and destroy policy is lower than the cost of treating S. aureus bloodstream infections in the University Hospital Maastricht. At an MRSA prevalence of

Subtelomeric chromosome aberrations: still a lot to learn.

Subtelomeric chromosome aberrations: still a lot to learn.Cryptic subtelomeric chromosome aberrations are a significant cause of mental retardation (MR). More than 4000 patients have been investigated, and the mean overall prevalence of subtelomeric rearrangements has been found to be 5.2%. In order to contribute to knowledge on the clinical presentation of subtelomeric rearrangements, we retrospectively studied patients with unexplained MR who had been evaluated for subtelomeric abnormalities by different fluorescence in situ hybridization (FISH) techniques. Hundred and two patients had an unexplained combination of MR with dysmorphism, congenital anomalies, and/or a positive family history and were investigated by total subtelomeric (TS) FISH (89/102), or by total painting (TP) in an obligate carrier in the case of familial MR (13/102). In 59 additional patients, a sequence-specific FISH was performed on clinical indication. In the 102 patients studied by TS or TP, six pathogenic aberrations (5.9%) were found in addition to one polymorphism. In total, eight clinically significant subtelomeric aberrations were found in the 161 index patients; four of these eight aberrations were familial. We report on the clinical presentation of all patients with an aberration and review the relevant literature. Factors complicating the interpretation of subtelomeric rearrangements are discussed, such as the occurrence of variants, clinical variability, and limited knowledge of the phenotype.

Rett syndrome in females with CTS hot spot deletions: a disorder profile.

From a series of 107 females with Rett syndrome (RTT), we describe the long-term history of ten females with a deletion in the C-terminus of the MECP2 gene. We observed that their disorder profile is clinically recognizable with time and different from other atypical and milder RTT phenotypes. In females with hot spot deletions in the C-terminus, dystonia is present from childhood and results in a serious spine deformation in spite of preventive measures. Their adaptive behavior is surprisingly better preserved and in contrast with the typical decline in motor functioning. The delineation of disorder profiles by long-term clinical observation can teach us about genotype/phenotype relationships and eventually about the effect of epigenetic phenomena on the final phenotype.

Hypotriploidy 68,XX: a new case report and review of earlier cases.

We report a prematurely born patient with a 68,XX karyotype. She presented with syndactyly of 2nd and 3rd toes, minor facial features, microcephaly, slender hands, bicuspid aortic valve, patent ductus arteriosus and hypotonia. Comparison with other reported cases is given.