Maximizing lentiviral vector gene transfer in the CNS.

Gene transfer is a widely developed technique for studying and treating genetic diseases. However, the development of therapeutic strategies is challenging, due to the cellular and functional complexity of the central nervous system (CNS), its large size and restricted access. We explored two parameters for improving gene transfer efficacy and capacity for the selective targeting of subpopulations of cells with lentiviral vectors (LVs). We first developed a second-generation LV specifically targeting astrocytes for the efficient expression or silencing of genes of interest, and to better study the importance of cell subpopulations in neurological disorders. We then made use of the retrograde transport properties of a chimeric envelope to target brain circuits affected in CNS diseases and achieve a broad distribution. The combination of retrograde transport and specific tropism displayed by this LV provides opportunities for delivering therapeutic genes to specific cell populations and ensuring high levels of transduction in interconnected brain areas following local administration. This new LV and delivery strategy should be of greater therapeutic benefit and opens up new possibilities for the preclinical development of gene therapy for neurodegenerative diseases

Incidence of anogenital warts in Germany: a population-based cohort study

<p>Abstract</p> <p>Background</p> <p>Human papilloma virus (HPV) types 6 and 11 account for 90 percent of anogenital warts (AGW). Assessment of a potential reduction of the incidence of AGW following introduction of HPV vaccines requires population-based incidence rates. The aim of this study was to estimate incidence rates of AGW in Germany, stratified by age, sex, and region. Additionally, the medical practitioner (gynaecologist, dermatologist, urologist etc.) who made the initial diagnosis of AGW was assessed.</p> <p>Methods</p> <p>Retrospective cohort study in a population aged 10 to 79 years in a population-based healthcare insurance database. The database included more than 14 million insurance members from all over Germany during the years 2004-2006. A case of AGW was considered incident if a disease-free period of twelve months preceded the diagnosis. To assess regional variation, analyses were performed by federal state.</p> <p>Results</p> <p>The estimated incidence rate was 169.5/100,000 person-years for the German population aged 10 to 79 years. Most cases occurred in the 15 to 40 years age group. The incidence rate was higher and showed a peak at younger ages in females than in males. The highest incidence rates for both sexes were observed in the city-states Berlin, Hamburg and Bremen. In females, initial diagnosis of AGW was most frequently made by a gynaecologist (71.7%), whereas in males, AGW were most frequently diagnosed by a dermatologist (44.8%) or urologist (25.1%).</p> <p>Conclusions</p> <p>Incidence of AGW in Germany is comparable with findings for other countries. As expected, most cases occurred in the younger age groups. The frequency of diagnoses of AGW differs between sexes and women and men receive treatment by doctors of different specialties.</p

The influence of lean mass in trabecular and cortical bone in juvenile onset systemic lupus erythematosus

The aim of this study was to evaluate risk factors for low bone mineral density (BMD) and vertebral fractures, in juvenile systemic lupus (JSLE). Thirty-one consecutive patients with JSLE were compared with 31 gender- and age-matched healthy controls. BNID and body composition from all participants were measured using dual-energy X-ray absorptiometry. Vertebral fractures were defined as a reduction of >= 20% of the vertebral height for all patients. Lumbar spine and total femur BMD was significantly decreased in patients compared with controls (P = 0.021 and P = 0.023, respectively). A high frequency of vertebral fractures (22.58%) was found in patients with JSLE. Analysis of body composition revealed lower lean mass (P = 0.033) and higher fat mass percentage (P = 0.003) in patients than in controls. Interestingly, multiple linear regression using BMD as a dependent variable showed a significant association with lean mass in lumbar spine (R(2) = 0.262; P = 0.004) and total femur (R(2) = 0.419, P = 0.0001), whereas no association was observed with menarche age, SLE Disease Activity Index, Systemic Lupus International Collaborating Clinics/American College of Rheumatology, and glucocorticoid. This study indicates that low BMD and vertebral fractures are common in JSLE, and the former is associated with low lean mass, suggesting that muscle rehabilitation may be an additional target for bone therapeutic approach

Serum from children with polyarticular juvenile idiopathic arthritis (pJIA) inhibits differentiation, mineralization and may increase apoptosis of human osteoblasts in vitro

We examined the effects of polyarticular juvenile idiopathic arthritis (pJIA) serum on proliferation, differentiation, mineralization, and apoptosis of human osteoblast cells (hOb) in culture. the hOb were cultured with 10% serum from active pJIA and healthy controls (CT) and were tested for DNA synthesis, alkaline phosphatase (AP) activity, osteocalcin (OC) secretion, calcium levels, caspase 3 activity, and DNA fragmentation. None of the patients had used glucocorticoids for at least 1 month before the study, or any other drug that can affect bone mineral metabolism. Human inflammatory cytokine levels (IL-6, IL-8, IL-10, IL-1 beta, TNF-alpha, and IL-12p70) were measured in pJIA and CT sera. Low levels of AP activity was observed in pJIA cultures compared with CT cultures (67.16 +/- 53.35 vs 100.11 +/- 50.64 mu mol p-nitrophenol/h(-1) mg(-1) protein, P=0.008). There was also a significant decrease in OC secretion (9.23 +/- 5.63 vs 12.82 +/- 7.02 ng/mg protein, P=0.012) and calcium levels (0.475 +/- 0.197 vs 0.717 +/- 0.366 mmol/l, P=0.05) in pJIA hOb cultures. No difference was observed in cell proliferation (323.56 +/- 108.23 vs 328.91 +/- 88.03 dpm/mg protein, P=0.788). Osteoblasts cultured with JIA sera showed lower levels of DNA and increased fragmentation than osteoblasts cultured with CT sera. pJIA sera showed higher IL-6 values than CT (21.44 +/- 9.31 vs 3.58 +/- 2.38 pg/ml, P<0.001), but no difference was observed related to IL-8, IL-10, IL-1 beta, TNF-alpha, and IL-12p70 between pJIA and controls. This study suggests that serum from children with pJIA inhibits differentiation, mineralization and may increase apoptosis of hOb cultures, and inflammatory cytokines such as IL-6 might be a mechanism in this find. These results may represent an alternative therapeutic target for prevention and treatment of bone loss in JIA.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)PIBIC fellowshipUniv São Paulo, Fac Med, BR-01246903 São Paulo, BrazilUniv São Paulo, Div Rheumatol, Sch Med, BR-01246903 São Paulo, BrazilUniv São Paulo, Sch Med, Dept Orthoped, BR-01246903 São Paulo, BrazilUniv São Paulo, Sch Med, Dept Pediat, BR-01246903 São Paulo, BrazilFAPESP: 01/13835-6PIBIC fellowship: 80.30.70/87.0Web of Scienc

Developments in the Dutch Urban System on the Basis of Flows

Limtanakool N., Schwanen T. and Dijst M. Developments in the Dutch urban system on the basis of flows, Regional Studies. In this study, the 1992, 1995, 1999, and 2002 Netherlands National Travel Surveys are employed to examine the change in the configuration of the urban system on the basis of commute and leisure flows between 23 daily urban systems (DUSs). The results for commuting flows provide some evidence of smaller differences in the importance of DUSs in the system over the ten-year period in the Dutch urban system. Leisure flows, however, do not reveal clear evidence of such development. It is found that the development process occurs very slowly and the developments between DUSs in close proximity to one another take place at a faster pace than between those located further away. [image omitted] Limtanakool N., Schwanen T. et Dijst M. Le developpement du systeme urbain neerlandais sur la base des flux, Regional Studies. A partir des enquetes de 1992, 1995, 1999 et 2002 sur les trajets quotidiens aux Pays-Bas, menees au niveau national, cette etude cherche a examiner l'evolution de l'ossature du systeme urbain sur la base des migrations quotidiennes entre vingt-trois Daily Urban Systems (DUS; systemes urbains quotidiens) pour se rendre au travail et au loisir. Pour ce qui est des migrations quotidiennes pour se rendre a la zone de travail. Les resultats laissent voir de faibles differences quant a l'importance des DUS dans le systeme urbain neerlandais sur une periode de dix annees. Cependant, les migrations quotidiennes pour se rendre a la zone de loisir ne font pas preuve d'un tel developpement. Il s'avere que le processus de developpement evolue tres lentement et que les developpements entre DUS a proximite evoluent plus rapidement que ne le font ceux qui sont entre DUS a plus grande distance. Systeme urbain Flux urbains Polycentrisme Pays-Bas Limtanakool N., Schwanen T. und Dijst M. Entwicklungen im hollandischen urbanen System auf der Grundlage von Stromen, Regional Studies. In dieser Studie werden mit Hilfe der nationalen Verkehrserhebungen in den Niederlanden von 1992, 1995, 1999 und 2002 die Veranderungen in der Konfiguration der urbanen Systeme anhand der Verkehrsstrome zu Arbeits- und Freizeitzwecken zwischen 23 Einzugsgebieten untersucht. Die Ergebnisse bei den Verkehrsstromen von Berufspendlern liefern einige Anzeichen fur kleinere Unterschiede hinsichtlich der Bedeutung der Einzugsgebiete im System uber den zehnjahrigen Zeitraum des hollandischen urbanen Systems. Bei den Verkehrsstromen zu Freizeitzwecken werden hingegen keine klaren Anzeichen fur eine solche Entwicklung sichtbar. Wir stellen fest, dass der Entwicklungsprozess ausserst langsam vonstatten geht und dass sich die Entwicklungen zwischen nahe beieinander liegenden Einzugsgebieten schneller vollziehen als die zwischen weiter voneinander entfernt liegenden Gebieten. Urbanes System Urbane Verkehrsstrome Polyzentrismus Niederlande Limtanakool N., Schwanen T. y Dijst M. Desarrollo en el sistema urbano holandes segun los flujos, Regional Studies. Con ayuda de las encuestas nacionales sobre el trafico en los Paises Bajos de 1992, 1995, 1999 y 2002, en este ensayo analizamos el cambio en la configuracion del sistema urbano en funcion de los flujos de desplazamiento por motivos laborales y de ocio entre veintitres sistemas urbanos de movimientos pendulares diarios. En los resultados de los flujos de desplazamientos por motivos laborales se observan pequenas diferencias en cuanto a la importancia de los sistemas urbanos diarios en el sistema durante un periodo de diez anos en el sistema urbano holandes. Sin embargo, los flujos de ocio no indican una clara evidencia de tal desarrollo. Observamos que el proceso de desarrollo ocurre muy lentamente y los desarrollos entre los sistemas urbanos diarios que estan proximos entre ellos tienen lugar a un ritmo mas rapido que entre los que estan mas lejos. Sistema urbano Flujos urbanos Policentrismo Los Paises BajosUrban system, Urban flows, Polycentrism, the Netherlands,

Simultaneous PET-MR-EEG: Technology, Challenges and Application in Clinical Neuroscience

Due to technological developments in positron emission tomography (PET) detectors and PET-MR integration, the simultaneous measurement of PET-MR-EEG has become feasible, offering the possibility of exploring the complementary information provided by each modality. Studies have already shown the benefits of simultaneous measurement using PET-MR, however, such achievements come with different technical and practical challenges. In this context, we aim to give an overview of the technical challenges involved in integrating electroencephalography with hybrid PET-MR scanners and demonstrate possible solutions. When acquiring simultaneous data from multiple modalities, the data acquisition protocol should be optimized in order to utilize time and complementary information most effectively. Thus, practical considerations with regard to protocol optimization are also discussed, alongside relevant examples. In addition to simultaneous data acquisition, another major challenge is the integration of the multimodal data, which is also addressed. Finally, a clinical application with a strong focus on neuro-psychiatry is shown. This clinical application is discussed with relevant examples from an ongoing clinical study. Finally, the possibility of utilizing the PET-MR-EEG data in search for new biomarkers for individualized medicine in clinical neuroscience is briefly explored

Physical activity and amyotrophic lateral sclerosis : a European population-based case-control study

Objective To assess whether physical activity is a risk factor for amyotrophic lateral sclerosis (ALS). Methods From February 2008 to April 2012, 652 patients with ALS from European population-based registries (France, Ireland, Italy, United Kingdom, Serbia) and 1,166 population controls (matched for age, sex, and residency) were assessed. Upon direct interview, data were collected on occupation and history of sport and leisure activities, physical activity, and accidental injuries. Physical exercise was defined as having spent time doing activities that caused an individual to breath hard at least once per month and was coded as none, job-related, and/or sport-related. Sport-related and work-related physical exercise were quantified using metabolic equivalents (METs). Risks were calculated using conditional logistic regression models (adjusting for age, country, trauma, and job-related physical activity) and expressed as odds ratios (ORs) and adjusted ORs (Adj ORs) with 95% confidence intervals (CIs). Results Overall physical activity was associated with reduced odds of having ALS (Adj OR = 0.65, 95% CI = 0.48-0.89) as were work-related physical activity (Adj OR = 0.56, 95% CI = 0.36-0.87) and organized sports (Adj OR = 0.49, 95% CI = 0.32-0.75). An inverse correlation was observed between ALS, the duration of physical activity (p = 0.0041), and the cumulative MET scores, which became significant for the highest exposure (Adj OR = 0.34, 95% CI = 0.21-0.54). An inverse correlation between ALS and sport was found in women but not in men, and in subjects with repeated traumatic events. Interpretation Physical activity is not a risk factor for ALS and may eventually be protective against the disease

Urban energy transitions: places, processes and politics of socio-technical change

International audienc