Photodynamic therapy enhances liposomal doxorubicin distribution in tumors during isolated perfusion of rodent lungs.

BACKGROUND: Photodynamic therapy (PDT) at low drug-light conditions can enhance the transport of intravenously injected macromolecular therapeutics through the tumor vasculature. Here we determined the impact of PDT on the distribution of liposomal doxorubicin (Liporubicin™) administered by isolated lung perfusion (ILP) in sarcomas grown on rodent lungs. METHODS: A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the left lung of Fischer rats. Treatment schemes consisted in ILP alone (400 μg of Liporubicin), low-dose (0.0625 mg/kg Visudyne®, 10 J/cm(2) and 35 mW/cm(2)) and high-dose left lung PDT (0.125 mg/kg Visudyne, 10 J/cm(2) and 35 mW/cm(2)) followed by ILP (400 μg of Liporubicin). The uptake and distribution of Liporubicin in tumor and lung tissues were determined by high-performance liquid chromatography and fluorescence microscopy in each group. RESULTS: Low-dose PDT significantly improved the distribution of Liporubicin in tumors compared to high-dose PDT (p < 0.05) and ILP alone (p < 0.05). However, both PDT pretreatments did not result in a higher overall drug uptake in tumors or a higher tumor-to-lung drug ratio compared to ILP alone. CONCLUSIONS: Intraoperative low-dose Visudyne-mediated PDT enhances liposomal doxorubicin distribution administered by ILP in sarcomas grown on rodent lungs which is predicted to improve tumor control by ILP.

Consequences of smoking for body weight, body fat distribution, and insulin resistance

Our aim was to critically evaluate the relations among smoking, body weight, body fat distribution, and insulin resistance as reported in the literature. In the short term, nicotine increases energy expenditure and could reduce appetite, which may explain why smokers tend to have lower body weight than do nonsmokers and why smoking cessation is frequently followed by weight gain. In contrast, heavy smokers tend to have greater body weight than do light smokers or nonsmokers, which likely reflects a clustering of risky behaviors (eg, low degree of physical activity, poor diet, and smoking) that is conducive to weight gain. Other factors, such as weight cycling, could also be involved. In addition, smoking increases insulin resistance and is associated with central fat accumulation. As a result, smoking increases the risk of metabolic syndrome and diabetes, and these factors increase risk of cardiovascular disease. In the context of the worldwide obesity epidemic and a high prevalence of smoking, the greater risk of (central) obesity and insulin resistance among smokers is a matter of major concern

Fusion of Multi-Atlas Segmentations with Spatial Distribution Modeling

In recent years, multi-atlas fusion methods have gainedsignificant attention in medical image segmentation. Inthis paper, we propose a general Markov Random Field(MRF) based framework that can perform edge-preservingsmoothing of the labels at the time of fusing the labelsitself. More specifically, we formulate the label fusionproblem with MRF-based neighborhood priors, as an energyminimization problem containing a unary data term and apairwise smoothness term. We present how the existingfusion methods like majority voting, global weightedvoting and local weighted voting methods can be reframedto profit from the proposed framework, for generatingmore accurate segmentations as well as more contiguoussegmentations by getting rid of holes and islands. Theproposed framework is evaluated for segmenting lymphnodes in 3D head and neck CT images. A comparison ofvarious fusion algorithms is also presented.

21st century climate change threatens mountain flora unequally across Europe

Continental-scale assessments of 21st century global impacts of climate change on biodiversity have forecasted range contractions for many species. These coarse resolution studies are, however, of limited relevance for projecting risks to biodiversity in mountain systems, where pronounced microclimatic variation could allow species to persist locally, and are ill-suited for assessment of species-specific threat in particular regions. Here, we assess the impacts of climate change on 2632 plant species across all major European mountain ranges, using high-resolution (ca. 100 m) species samples and data expressing four future climate scenarios. Projected habitat loss is greater for species distributed at higher elevations; depending on the climate scenario, we find 36-55% of alpine species, 31-51% of subalpine species and 19-46% of montane species lose more than 80% of their suitable habitat by 2070-2100. While our high-resolution analyses consistently indicate marked levels of threat to cold-adapted mountain florae across Europe, they also reveal unequal distribution of this threat across the various mountain ranges. Impacts on florae from regions projected to undergo increased warming accompanied by decreased precipitation, such as the Pyrenees and the Eastern Austrian Alps, will likely be greater than on florae in regions where the increase in temperature is less pronounced and rainfall increases concomitantly, such as in the Norwegian Scandes and the Scottish Highlands. This suggests that change in precipitation, not only warming, plays an important role in determining the potential impacts of climate change on vegetation.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻&supl;³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Knowing the past to predict the future: land-use change and the distribution of invasive bullfrogs

Biological invasions and land-use changes are two major causes of the global modifications of biodiversity. Habitat suitability models are the tools of choice to predict potential distributions of invasive species. Although land-use is a key driver of alien species invasions, it is often assumed that land-use is constant in time. Here we combine historical and present day information, to evaluate whether land-use changes could explain the dynamic of invasion of the American bullfrog Rana catesbeiana (=Lithobathes catesbeianus) in Northern Italy, from the 1950s to present-day. We used maxent to build habitat suitability models, on the basis of past (1960s, 1980s) and present-day data on land-uses and species distribution. For example, we used models built using the 1960s data to predict distribution in the 1980s, and so on. Furthermore, we used land-use scenarios to project suitability in the future. Habitat suitability models predicted well the spread of bullfrogs in the subsequent temporal step. Models considering land-use changes predicted invasion dynamics better than models assuming constant land-use over the last 50 years. Scenarios of future land-use suggest that suitability will remain similar in the next years. Habitat suitability models can help to understand and predict the dynamics of invasions; however, land-use is not constant in time: land-use modifications can strongly affect invasions; furthermore, both land management and the suitability of a given land-use class may vary in time. An integration of land-use changes in studies of biological invasions can help to improve management strategies.

Health care supply, payment system and medical practice : evidence from obstetric practice

ABSTRACTA significant share of deliveries are performed by Cesarian section (C-section) in Europe and in many developed and developing countries. The aims of this thesis are to highlight the non medical, especially economic and financial, incentives that explain the use of C-section, as well as the medical consequences of C-section on women's health, in regard with other factors of ob¬stetrical care quality such as hospital concentration. Those diagnoses enable us to exhibit ways of improvement of obstetrical care quality in France. Our analysis focus on two countries, France and Switzerland. In the first part of the thesis, we show the influence of two non medical factors on the C-section use, namely the hospital payment system on the one hand and the obstetricians behaviour, especially their demand for leisure, on the other hand. With French data on the year 2003, we show firstly that the fee-for-service payment system of private for profit hospitals induces a higher probability of using C-section. Obstetricians play also a preeminent role in the decision to use a C-section, as the probability of a C-section rises with the number of obstetricians. We then focus on a French reform introduced in 2004, to investigate the impact of Prospective Payment System on obstetric practise. We show that the rise of C-section rate between 2003 and 2006 is mainly caused by changes in hospitals and patients features. Obstetricians practises do not vary a lot for patients with the same risk code. In the mean time however, the number of women coded with a high risk rises. This can be caused by improvements in the quality of coding, obstetricians chosing codes that match better the real health state of their patients. Yet, it can also show that obstetricians change their coding practises to justify the use of certain practises, such as C-section, with no regard to the health state of patients. Financial factors are not the only non medical fac¬tors that can influence the resort to C-section. Using Shelton Brown ΠΙ identification strategy, we focus on the potential impact of obstetricians leisure preference on the use of C-section. We use the distributions of days and hours of delivering and the types of C-section - planned or emergency C-sections - to show that the obstetricians demand for leisure has a significant impact on the resort to C-section, but only in emergency situations. The second part of the thesis deals with some ways to improve obstetric care quality. We use on the one hand swiss and french data to study the impact of C-section on the patients' probability of having an obstetric complication and on the other hand the influence of hospital concentration on the quality of obstetric care. We find the same results as former medical studies about the risks entailed by C-section on obstetric complications.These results prove women ought to be better informed of the medical consequences of C-section and that the slowing of C-section use should be a priority of public health policy. We finally focus on another way to improve obstetric care quality, that is hospital lmarket concentration. We investigate the impact of hospital concentration by integrating the Herfindahl-Hirschman index in our model, on health care quality, measured by the HCUP indicator. We find that hospital concentration has a negative impact on obstetric care quality, which undermines today's policy of hospital closings in France.JEL classification: 112; 118Keywords: Hospital; C-section; Payment System; Counterfactual Estimation; Quality of Care.RÉSUMÉUne part importante des accouchements sont réalisés par césarienne en Europe et dans de nom¬breux pays développés ou en développement. Les objectifs de cette thèse sont de mettre en évidence les déterminants non médicaux, notamment économiques et financiers, expliquant le développe¬ment de cette pratique, ainsi que ses conséquences sur la santé des femmes après Γ accouchement, en lien avec d'autres facteurs comme la concentration locale des structures hospitalières. Les résul¬tats exposés dans cette thèse éclairent les perspectives et voies d'amélioration de la qualité des soins en obstétriques.Notre analyse se concentre sur deux pays : la France et la Suisse. Dans la première partie de la thèse, nous mettons en évidence l'influence de deux déterminants non médicaux sur l'emploi de la césarienne : le système de paiement des hôpitaux d'une part, et le comportement des médecins obstétriciens d'autre part. En étudiant des données françaises de 2003, nous montrons d'abord que le financement à l'acte des établissements privés engendre une hausse de la proba¬bilité de pratiquer une césarienne. Le rôle de l'obstrétricien paraît également déterminant dans la décision d'opérer une césarienne, la probabilité d'employer cette technique augmentant avec le nombre d'obstétriciens. Nous nous intéressons ensuite à l'impact de la mise en place en 2004 du système de paiement prospectif sur l'évolution des pratiques obstétricales entre 2003 et 2006 en France. La hausse du taux de recours à la césarienne entre 2004 et 2006 peut ainsi être principa¬lement imputée aux évolutions des caractéristiques des hôpitaux et des patients, les pratiques des obstétriciens, pour un même codage de la situation du patient, variant peu. Dans le même temps cependant, les pratiques de codage des patients parles obstétriciens évoluent fortement, les femmes étant de plus en plus nombreuses à porter des codes correspondant à des situations à risques. Cette évolution peut indiquer que la qualité du codage en 2006 s'est améliorée par rapport à 2004, le codage correspondant de plus en plus à la situation réelle des patientes. H peut aussi indiquer que les pratiques de codage évoluent pour justifier un recours accru à la césarienne, sans lien avec l'état réel des patientes. Les facteurs financiers ne sont pas les seuls facteurs non médicaux à pouvoir expliquer le recours à la césarienne : nous nous intéressons, en suivant la stratégie d'identifica¬tion de Shelton Brown m, à l'impact potentiel de la demande de loisir des médecins obstétriciens sur la pratique de la césarienne. En utilisant la distribution des jours et heures d'accouchement, et en distinguant les césariennes planifiées de celles effectuées en urgence, nous constatons que la demande de loisir des obstétriciens influence significativement le recours à la césarienne, mais uni¬quement pour les interventions d'urgence. La deuxième partie de la thèse est consacrée à l'étude de la qualité des soins en obstétriques. Nous utilisons des données suisses et françaises pour analyser d'une part l'impact de la césarienne sur la survenue de complications obstétricales et d'autre part l'impact de la concentration des soins sur la qualité des soins en obstétrique. Nons confirmons les résultats antérieurs de la littérature médicale sur la dangerosité de la césarienne comme facteur de complications obstétricales. Ces conclusions montrent que les femmes ont besoin d'être informées des conséquences de la césarienne sur leur santé et que le ralentissement de l'augmentation de la pratique de la césarienne devrait être un objectif de la politique publique de santé. Nous nous in¬téressons à un autre facteur d'amélioration des soins en obstrétique, l'organisation des hôpitaux et particulièrement leur concentration. Nous estimons ainsi l'effet de la concentration sur la qualité des soins obstétriques en intégrant l'indice de Herfindahl-Hirschman dans notre modèle, la qualité des soins étant mesurée à l'aide de l'indicateur HCUP. Nous constatons que la concentration des naissances a un impact négatif sur la qualité des soins en obstétrique, résultat qui va dans le sens contraire des politiques de fermeture d'hôpitaux menées actuellement en France. JEL classification : 112 ; 118Mots-clés : Hôpital ; Césarienne ; Système de paiement ; Contrefactuels ; Qualité des soins, sur la qualité des soins en obstétrique.

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved in lipid metabolism and also play a role in adipocyte differentiation. We present the expression patterns of the PPAR subtypes in the adult rat, determined by in situ hybridization using specific probes for PPAR-alpha, -beta and -gamma, and by immunohistochemistry using a polyclonal antibody that recognizes the three rat PPAR subtypes. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, with relative levels varying between them from one cell type to the other. PPAR-alpha is highly expressed in hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPAR-beta is expressed ubiquitously and often at higher levels than PPAR-alpha and -gamma. PPAR-gamma is expressed predominantly in adipose tissue and the immune system. Our results suggest new potential directions to investigate the functions of the different PPAR subtypes.

Combining food web and species distribution models for improved community projections

The ability to model biodiversity patterns is of prime importance in this era of severe environmental crisis. Species assemblage along environmental gradient is subject to the interplay of biotic interactions in complement to abiotic environmental filtering. Accounting for complex biotic interactions for a wide array of species remains so far challenging. Here, we propose to use food web models that can infer the potential interaction links between species as a constraint in species distribution models. Using a plant-herbivore (butterfly) interaction dataset, we demonstrate that this combined approach is able to improve both species distribution and community forecasts. Most importantly, this combined approach is very useful in rendering models of more generalist species that have multiple potential interaction links, where gap in the literature may be recurrent. Our combined approach points a promising direction forward to model the spatial variation of entire species interaction networks. Our work has implications for studies of range shifting species and invasive species biology where it may be unknown how a given biota might interact with a potential invader or in future climate.

Differential distribution of tau proteins in developing cat cerebellum.

The differential distribution and phosphorylation of tau proteins in cat cerebellum was studied with two well characterized antibodies, TAU-1 and TAU-2. TAU-1 detects tau proteins in axons, and the epitope in perikarya and dendrites is masked by phosphorylation. TAU-2 detects a phosphorylation-independent epitope on tau proteins. The molecular composition of tau proteins in the range of 45 kD to 64 kD at birth changed after the first postnatal month to a set of several adult variants of higher molecular weights in the range of 59 kD to 95 kD. The appearance of tau proteins in subsets of axons corresponds to the axonal maturation of cerebellar local-circuit neurons in granular and molecular layers and confirms previous studies. Tau proteins were also identified in synapses by immunofluorescent double-staining with synapsin I, located in the pinceau around the Purkinje cells, and in glomeruli. Dephosphorylation of juvenile cerebellar tissue by alkaline phosphatase indicated indirectly the presence of differentially phosphorylated tau forms mainly in juvenile ages. Additional TAU-1 immunoreactivity was unmasked in numerous perikarya and dendrites of stellate cells, and in cell bodies of granule cells. Purkinje cell bodies were stained transiently at juvenile ages. During postnatal development, the intensity of the phosphate-dependent staining decreased, suggesting that phosphorylation of tau proteins in perikarya and dendrites may be essential for early steps in neuronal morphogenesis during cat cerebellum development.