Clinical and biochemical response to neridronate treatment in a patient with osteoporosis-pseudoglioma syndrome (OPPG)

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive syndrome characterized by juvenile-onset osteoporosis and ocular abnormalities due to a low-density lipoprotein receptor-related protein 5 (LRP5) gene mutation. Treatment with bisphosphonates, particularly with pamidronate and risedronate, has been reported to be of some efficacy in this condition. We report on a patient with OPPG due to an LRP5 gene mutation, who showed an encouraging response after a 36-month period of neridronate therapy. We report a case of a patient treated with bisphosphonates. Bisphosphonates should be administered in OPPG patients as a first-line therapy during early childhood

Molecular Mechanism of DNA Topoisomerase I-Dependent rDNA Silencing: Sir2p Recruitment at Ribosomal Genes

Saccharomyces cerevisiae sir2Δ or top1Δ mutants exhibit similar phenotypes involving ribosomal DNA, including (i) loss of transcriptional silencing, resulting in non-coding RNA hyperproduction from cryptic RNA polymerase II promoters; (ii) alterations in recombination; and (iii) a general increase in histone acetylation. Given the distinct enzymatic activities of Sir2 and Top1 proteins, a histone deacetylase and a DNA topoisomerase, respectively, we investigated whether genetic and/or physical interactions between the two proteins could explain the shared ribosomal RNA genes (rDNA) phenotypes. We employed an approach of complementing top1Δ cells with yeast, human, truncated, and chimeric yeast/human TOP1 constructs and of assessing the extent of non-coding RNA silencing and histone H4K16 deacetylation. Our findings demonstrate that residues 115–125 within the yeast Top1p N-terminal domain are required for the complementation of the top1Δ rDNA phenotypes. In chromatin immunoprecipitation and co-immunoprecipitation experiments, we further demonstrate the physical interaction between Top1p and Sir2p. Our genetic and biochemical studies support a model whereby Top1p recruits Sir2p to the rDNA and clarifies a structural role of DNA topoisomerase I in the epigenetic regulation of rDNA, independent of its known catalytic activity

1H NMR Characterization of Organic and Inorganic Nanoparticles

Drug delivery employing nano-object as liposomes, polymer conjugates, and nanoparticles suspended in solution is a subject of high current interest [1]. The characterization of the size and the surface functionalization of these nanoparticles is of primary importance. Microscopy techniques give information on deposited colloidal samples, after solvent evaporation, so that the correspondence with the nature of the species in solution is not granted. Dynamic Light Scattering (DLS), which is usually used to estimate the size of a colloidal sample in solution, can overestimate the radii of very small nanoparticles [2]. Diffusion NMR, and in particular Pulsed gradient spin-echo (PGSE) technique, has recently emerged as a valuable tool for colloids characterization [3], complementary to DLS from the point of view of the size evaluation, being highly reliable for the measurement of the smallest particles. Moreover, NMR provide information not only on the size, but also on the interaction between the capping ligands and the nanoparticle surface. In this work, we present the characterization through 1H PGSE NMR measurements of the size of spherical and rod-like TiO2/oleic acid nanoparticles and of conjugates between Re complexes and polyamidoamine nanoparticles. Moreover, by 1H NMR experiments the interaction between TiO2 and the capping oleic acid (OA) has been characterized. [1] a) A. H. Faraji, P. Wipf, Bioorganic and Medicinal Chemistry 2009, 17, 2950-2962; b) S. M. Garg, A. V. Deshmukh, Nano Science and Nano Technology 2007, 1(2), 45-58; c) C. Khemtong, C. W. Kessinger, J. Gao, Chem. Commun. 2009, 3497-3510. [2] C. Sanna, C. La Mesa, L. Mannina, P. Stano, S. Viel, A. Segre, Langmuir 2006, 22, 6031-6041. [3] a) F. Ribot, V. Escax, C. Roiland, C. Sanchez, J. C. Martins, M. Biesemans, I. Verbruggen, R. Willem, Chem. Commun. 2005, 1019-1021; b) M. Valentini, A. Vaccaro, A. Rehor, A. Napoli, J. A. Hubbell, N. Tirelli, J. Am. Chem. Soc. 2004, 126, 2142-2147

A proxy cost model for tramway services

In this paper, we build a proxy cost model for tramway services. we estimate separately: (i) transport services production costs; (ii) infrastructure costs; (iii) maintenance costs; (iv) administrative and general costs and (v) the cost of capital. we apply the proposed methodology to estimate the standard cost of italian tramway services. detailed data about costs, technical and environmental characteristics were collected by means of questionnaires sent to italian companies providing 100% of tramway services in 2012. we perform a simulation study in order to highlight the marginal impact of efficiency gains obtained by manipulating cost-driving variables both under the control of the operators (trains and drivers productivity) and of the local authority who assigns the service (number of train revenue kilometers (trK) assigned within the service contract, average fleet age). the simulations show how the local authority should allocate extra resources if it wants to increase the quality-quantity mix of tramway services. our results might help the decision-maker to define the maximum economic compensation (auction base) in competitive tendering procedures or a benchmark for the bargaining with the local monopolist

Polymorphisms in the dopaminergic receptor D3 gene correlate with disease progression rate in relapsing–remitting multiple sclerosis patients

Background: Multiple sclerosis (MS) is a common chronic autoimmune disease of the central nervous system. In MS, disability progresses unpredictably. Dopamine (DA) is a modulator of immune functions, and compelling evidence supports its involvement in both pathogenesis and treatment of MS. Although single nucleotide polymorphisms (SNPs) in dopaminergic receptor (DR) genes have been extensively studied, their role in MS progression remains unexplored. Therefore, the aim of this explorative study is to investigate the potential association between functional SNPs in DR genes and MS progression. Methods: Caucasian patients with relapsing-remitting (RR) MS were enrolled, and disease progression assessed by the Multiple Sclerosis Severity Score (MSSS). Results: Out of the 59 RRMS patients enrolled, those with the G/G genotype for rs6280 and rs1800828 SNPs in DRD3 showed significantly higher MSSSs compared to those with ancestral and heterozygous genotypes. Conclusions: If confirmed in a larger prospective study, the reported findings could contribute to a better understanding of MS pathophysiological mechanisms, opening the way for the identification of marker(s) for assessing MS progression as well as novel therapeutic strategies. A personalized approach to MS management has the potential to improve the overall well-being of MS patients and alleviate the burden on their caregivers

Metal(loid)s role in the pathogenesis of amyotrophic lateral sclerosis: Environmental, epidemiological, and genetic data

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. The etiology is still unknown and the pathogenesis remains unclear. ALS is familial in the 10% of cases with a Mendelian pattern of inheritance. In the remaining sporadic cases, a multifactorial origin is supposed in which several predisposing genes interact with environmental factors. The etiological role of environmental factors, such as pesticides, exposure to electromagnetic fields, and metals has been frequently investigated, with controversial findings. Studies in the past two decades have highlighted possible roles of metals, and ionic homeostasis dysregulation has been proposed as the main trigger to motor-neuron degeneration. This study aims at evaluating the possible role of environmental factors in etiopathogenesis of ALS, with a particular attention on metal contamination, focusing on the industrial Briga area in the province of Novara (Piedmont region, North Italy), characterized by: i) a higher incidence of sporadic ALS (sALS) in comparison with the entire province, and ii) the reported environmental pollution. Environmental data from surface, ground and discharge waters, and from soils were collected and specifically analyzed for metal content. Considering the significance of genetic mechanisms in ALS, a characterization for the main ALS genes has been performed to evaluate the genetic contribution for the sALS patients living in the area of study. The main findings of this study are the demonstration that in the Briga area the most common metal contaminants are Cu, Zn, Cr, Ni (widely used in tip-plating processes), that are above law limits in surface waters, discharge waters, and soil. In addition, other metals and metalloids, such as Cd, Pb, Mn, and As show a severe contamination in the same area. Results of genetic analyses show that sALS patients in the Briga area do not carry recurrent mutations or an excess of mutations in the four main ALS causative genes (SOD1, TARDBP, FUS, C9ORF72) and for ATXN2 CAG repeat locus. This study supports the hypothesis that the higher incidence of sALS in Briga area may be related to environmental metal(loid)s contamination, along with other environmental factors. Further studies, implementing analysis of genetic polymorphisms, as well as investigation with long term follow-up, may yield to key aspects into the etiology of ALS. The interplay between different approaches (environmental, chemical, epidemiological, genetic) of our work provides new insights and methodology to the comprehension of the disease etiology

Targeted next-generation sequencing for the identification of genetic predictors of radiation-induced late skin toxicity in breast cancer patients: A preliminary study

Normal tissue radiosensitivity is thought to be influenced by an individual’s genetic back-ground. However, the specific genetic variants underlying the risk of late skin reactions following radiotherapy for breast cancer remain elusive. To unravel the genetic basis for radiation-induced late skin toxicity, we carried out targeted next-generation sequencing of germline DNA samples from 48 breast cancer patients with extreme late skin toxicity phenotypes, consisting of 24 cases with grade 2–3 subcutaneous fibrosis and/or grade 2–3 telangiectasia (LENT-SOMA scales) and 24 controls with grade 0 fibrosis and grade 0 telangiectasia. In this exploratory study, a total of five single-nucleotide variants (SNVs) located in three genes (TP53, ERCC2, and LIG1) reached nominal levels of statistical significance (p C, Pro72Arg) in the replication cohort had an effect (OR per C allele: 1.52, 95%CI: 0.82–2.83, p = 0.186) in the same direction as in the exploratory cohort (OR per C allele: 4.70, 95%CI: 1.51–14.6, p = 0.007) and was found be nominally associated to the risk of radiation-induced late skin toxicity in the overall combined cohort (OR per C allele: 1.79, 95%CI: 1.06–3.02, p = 0.028). These results raise the possibility of an association between TP53 rs1042522 and risk of radiation-induced late skin toxicity in breast cancer patients; however, large replication studies are warranted for conclusive evidence

Perceptions of a group of elderly on the fact of not seeing the dentist regularly

Ainda existe no imaginário coletivo a ideia de que idosos não necessitam de assistência odontológica, pois são em sua maioria desdentados e usuários de dentaduras. Assim, a pergunta desta pesquisa é: Qual o motivo que faz com que muitos idosos não consultem regularmente o cirurgião-dentista? O objetivo foi levantar e analisar os motivos que fazem com que idosos cadastrados em uma Unidade de Saúde da Família não consultem regularmente o dentista. Trata-se de uma pesquisa descritiva exploratória de abordagem metodológica quanti-qualitativa realizada por meio de entrevistas domiciliares semiestruturadas aplicadas em 149 idosos cadastrados em uma Unidade de Saúde da Família na cidade de Ribeirão Preto,SP. Os dados foram analisados e sistematizados por meio da técnica da Análise de Conteúdo, e para a análise quantitativa foram realizadas análises bivariadas com associações significantes baseadas em valor de p<0,05. Houve associação estatisticamente significante entre visita ao dentista e idade (p=0,025), e observou-se que idosos com idades mais avançadas relataram ir menos ao dentista. Alguns dos motivos alegados foram: medo, dificuldade financeira, falta de tempo, além de falta de sintomatologia dolorosa nos dentes devido ao uso de dentaduras. Concluiu-se que os motivos alegados estão associados a aspectos sociais e culturais que devem ser analisados frente ao cuidado na atenção primária à saúde

Development of a Moderated Online Intervention to Treat Social Anxiety in First-Episode Psychosis.

Background: It is well established that social anxiety disorder (SAD) is a significant clinical problem for individuals with a psychotic disorder. Comorbid social anxiety in individuals with psychosis has been associated with poorer premorbid functioning, increased depression, and a reduced quality of life. Cognitive behavior therapy (CBT) is recommended for people with psychosis as a first-line psychological treatment; however, its focus and evaluation primarily revolves around reducing psychotic symptoms and not necessarily targeting comorbid social anxiety symptoms. We developed a novel online social cognitive behavioral intervention (entitled EMBRACE) specifically designed to treat social anxiety symptoms in first episode psychosis (FEP). Methods: The key clinical and engagement features of the intervention were established through integrating evidence-based material derived from 1) CBT-based treatment models for SAD, 2) relevant literature findings related to psychosis and its clinical correlates (e.g., shame, social rank, and its relationship with social anxiety and paranoia), 3) feedback from youth focus groups in order to inform a user-centered intervention design, and 4) a highly multidisciplinary collaborative development approach to design therapy comics. Results: A detailed description of the final version of the 12-week online social intervention to treat social anxiety in FEP is presented. Conclusion: The EMBRACE intervention was designed to provide young people with the necessary skills and confidence to overcome social anxiety within a supportive, safe online space. By design, it allows young people the opportunity to practice their newly learnt skills to connect with others and in doing so, learn to embrace their true authentic selves