Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases

Purpose: 153Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet®) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa®) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated. Methods: Patients with hormone-refractory prostate cancer were treated with 18.5 MBq/kg 153Sm-EDTMP in weeks 1 and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg zoledronic acid began in week 3 and continued every 4 weeks through week 23. In weeks 3 and 15, zoledronic acid was administered 2 days before 153Sm-EDTMP treatment. Urine was collected 48 h after injection of 153Sm-EDTMP, and whole-body images were obtained 6, 24 and 48 h post-injection. The effect of zoledronic acid on total bone uptake of 153Sm-EDTMP was measured indirectly by the cumulative activity excreted in the urine in weeks 1, 3 and 15. Biodistribution, safety, tolerability and effect on prostate-specific antigen level were also studied. Results: The urinary excretion in week 3 divided by the urinary excretion in week 1 (baseline) times 100% was mean 98.4±11.6% (median 96.2%). From week 1 to 15, after four zoledronic acid treatments, the mean ratio was 101.9±10.7% (median 101.8%). Bioequivalence could be concluded by using a two-sample t test for both perprotocol (n=13) and full-analysis sets (n=18). Toxicity was comparable to of monotherapy with 153Sm-EDTMP. Conclusion: Zoledronic acid treatment does not influence 153Sm-EDTMP skeletal uptake. Combined treatment is feasible and safe

Mitochondrial DNA methylation in metabolic associated fatty liver disease

INTRODUCTION: Hepatic lipid accumulation and mitochondrial dysfunction are hallmarks of metabolic associated fatty liver disease (MAFLD), yet molecular parameters underlying MAFLD progression are not well understood. Differential methylation within the mitochondrial DNA (mtDNA) has been suggested to be associated with dysfunctional mitochondria, also during progression to Metabolic Steatohepatitis (MeSH). This study further investigates whether mtDNA methylation is associated with hepatic lipid accumulation and MAFLD.METHODS: HepG2 cells were constructed to stably express mitochondria-targeted viral and prokaryotic cytosine DNA methyltransferases (mtM.CviPI or mtM.SssI for GpC or CpG methylation, respectively). A catalytically inactive variant (mtM.CviPI-Mut) was constructed as a control. Mouse and human patients' samples were also investigated. mtDNA methylation was assessed by pyro- or nanopore sequencing.RESULTS AND DISCUSSION: Differentially induced mtDNA hypermethylation impaired mitochondrial gene expression and metabolic activity in HepG2-mtM.CviPI and HepG2-mtM.SssI cells and was associated with increased lipid accumulation, when compared to the controls. To test whether lipid accumulation causes mtDNA methylation, HepG2 cells were subjected to 1 or 2 weeks of fatty acid treatment, but no clear differences in mtDNA methylation were detected. In contrast, hepatic Nd6 mitochondrial gene body cytosine methylation and Nd6 gene expression were increased in mice fed a high-fat high cholesterol diet (HFC for 6 or 20 weeks), when compared to controls, while mtDNA content was unchanged. For patients with simple steatosis, a higher ND6 methylation was confirmed using Methylation Specific PCR, but no additional distinctive cytosines could be identified using pyrosequencing. This study warrants further investigation into a role for mtDNA methylation in promoting mitochondrial dysfunction and impaired lipid metabolism in MAFLD.</p

Mitochondrial DNA methylation in metabolic associated fatty liver disease

IntroductionHepatic lipid accumulation and mitochondrial dysfunction are hallmarks of metabolic associated fatty liver disease (MAFLD), yet molecular parameters underlying MAFLD progression are not well understood. Differential methylation within the mitochondrial DNA (mtDNA) has been suggested to be associated with dysfunctional mitochondria, also during progression to Metabolic Steatohepatitis (MeSH). This study further investigates whether mtDNA methylation is associated with hepatic lipid accumulation and MAFLD.MethodsHepG2 cells were constructed to stably express mitochondria-targeted viral and prokaryotic cytosine DNA methyltransferases (mtM.CviPI or mtM.SssI for GpC or CpG methylation, respectively). A catalytically inactive variant (mtM.CviPI-Mut) was constructed as a control. Mouse and human patients’ samples were also investigated. mtDNA methylation was assessed by pyro- or nanopore sequencing.Results and discussionDifferentially induced mtDNA hypermethylation impaired mitochondrial gene expression and metabolic activity in HepG2-mtM.CviPI and HepG2-mtM.SssI cells and was associated with increased lipid accumulation, when compared to the controls. To test whether lipid accumulation causes mtDNA methylation, HepG2 cells were subjected to 1 or 2 weeks of fatty acid treatment, but no clear differences in mtDNA methylation were detected. In contrast, hepatic Nd6 mitochondrial gene body cytosine methylation and Nd6 gene expression were increased in mice fed a high-fat high cholesterol diet (HFC for 6 or 20 weeks), when compared to controls, while mtDNA content was unchanged. For patients with simple steatosis, a higher ND6 methylation was confirmed using Methylation Specific PCR, but no additional distinctive cytosines could be identified using pyrosequencing. This study warrants further investigation into a role for mtDNA methylation in promoting mitochondrial dysfunction and impaired lipid metabolism in MAFLD

Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample

We obtained conclusive linkage of Alzheimer disease (AD) with a candidate region of 19.7 cM at 7q36 in an extended multiplex family, family 1270, ascertained in a population-based study of early-onset AD in the northern Netherlands. Single-nucleotide polymorphism and haplotype association analyses of a Dutch patient-control sample further supported the linkage at 7q36. In addition, we identified a shared haplotype at 7q36 between family 1270 and three of six multiplex AD-affected families from the same geographical region, which is indicative of a founder effect and defines a priority region of 9.3 cM. Mutation analysis of coding exons of 29 candidate genes identified one linked synonymous mutation, g.38030G-->C in exon 10, that affected codon 626 of the PAX transactivation domain interacting protein gene (PAXIP1). It remains to be determined whether PAXIP1 has a functional role in the expression of AD in family 1270 or whether another mutation at this locus explains the observed linkage and sharing. Together, our linkage data from the informative family 1270 and the association data in the population-based early-onset AD patient-control sample strongly support the identification of a novel AD locus at 7q36 and re-emphasize the genetic heterogeneity of AD

Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate

Occupational therapy and return to work: a systematic literature review

<p>Abstract</p> <p>Background</p> <p>The primary aim of this review study was to gather evidence on the effectiveness in terms of return to work (RTW) of occupational therapy interventions (OTIs) in rehabilitation patients with non-congenital disorders. A secondary aim was to be able to select the most efficient OTI.</p> <p>Methods</p> <p>A systematic literature review of peer-reviewed papers was conducted using electronic databases (Cinahl, Cochrane Library, Ebsco, Medline (Pubmed), and PsycInfo). The search focussed on randomised controlled trials and cohort studies published in English from 1980 until September 2010. Scientific validity of the studies was assessed.</p> <p>Results</p> <p>Starting from 1532 papers with pertinent titles, six studies met the quality criteria. Results show systematic reviewing of OTIs on RTW was challenging due to varying populations, different outcome measures, and poor descriptions of methodology. There is evidence that OTIs as part of rehabilitation programs, increase RTW rates, although the methodological evidence of most studies is weak.</p> <p>Conclusions</p> <p>Analysis of the selected papers indicated that OTIs positively influence RTW; two studies described precisely what the content of their OTI was. In order to identify the added value of OTIs on RTW, studies with well-defined OT intervention protocols are necessary.</p

Job Resources and Matching Active Coping Styles as Moderators of the Longitudinal Relation Between Job Demands and Job Strain

Background: Only in a few longitudinal studies it has been examined whether job resources should be matched to job demands to show stress-buffering effects of job resources (matching hypothesis), while there are no empirical studies in which the moderating effect of matching personal characteristics on the stress-buffering effect of job resources has been examined. Purpose: In this study, both the matching hypothesis and the moderating effect of matching active coping styles were examined with respect to the longitudinal relation between job demands, job resources, and job strain.Method: The study group consisted of 317 beginning teachers from Belgium. The two-wave survey data with a 1-year time lag were analyzed by means of structural equation modeling and multiple group analyses. Results: Data did not support the matching hypothesis. In addition, no support was found for the moderating effect of specific active coping styles, irrespective of the level of match. Conclusion: To show stress-buffering effects of job resources, it seems to make no difference whether or not specific types of job demands and job resources are matched, and whether or not individual differences in specific active coping styles are taken into account

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal fring as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family signifcantly linked to 7q36. We identifed and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identifed signifcantly more rare variants—nonsense, frameshift, and missense—in early-onset Alzheimer’s disease (EOAD, p value=0.03, OR=2.21 95% CI 1.05–4.82) and frontotemporal dementia (FTD, p=0.006, OR=2.59, 95% CI 1.28–5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p<0.001 and p<0.0001) leading to a loss of protein. Reduced DPP6 and/or Kv4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to caus

Cereal yield gaps across Europe

peer-reviewedEurope accounts for around 20% of the global cereal production and is a net exporter of ca. 15% of that production. Increasing global demand for cereals justifies questions as to where and by how much Europe’s production can be increased to meet future global market demands, and how much additional nitrogen (N) crops would require. The latter is important as environmental concern and legislation are equally important as production aims in Europe. Here, we used a country-by-country, bottom-up approach to establish statistical estimates of actual grain yield, and compare these to modelled estimates of potential yields for either irrigated or rainfed conditions. In this way, we identified the yield gaps and the opportunities for increased cereal production for wheat, barley and maize, which represent 90% of the cereals grown in Europe. The combined mean annual yield gap of wheat, barley, maize was 239 Mt, or 42% of the yield potential. The national yield gaps ranged between 10 and 70%, with small gaps in many north-western European countries, and large gaps in eastern and south-western Europe. Yield gaps for rainfed and irrigated maize were consistently lower than those of wheat and barley. If the yield gaps of maize, wheat and barley would be reduced from 42% to 20% of potential yields, this would increase annual cereal production by 128 Mt (39%). Potential for higher cereal production exists predominantly in Eastern Europe, and half of Europe’s potential increase is located in Ukraine, Romania and Poland. Unlocking the identified potential for production growth requires a substantial increase of the crop N uptake of 4.8 Mt. Across Europe, the average N uptake gaps, to achieve 80% of the yield potential, were 87, 77 and 43 kg N ha−1 for wheat, barley and maize, respectively. Emphasis on increasing the N use efficiency is necessary to minimize the need for additional N inputs. Whether yield gap reduction is desirable and feasible is a matter of balancing Europe’s role in global food security, farm economic objectives and environmental targets.We received financial contributions from the strategic investment funds (IPOP) of Wageningen University & Research, Bill & Melinda Gates Foundation, MACSUR under EU FACCE-JPI which was funded through several national contributions, and TempAg (http://tempag.net/)

De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes

Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette's syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder