Evolution de l'incidence des cancers et des polypes colorectaux dans le canton de Vaud entre 1983 et 2007. [Trends in incidence of colorectal cancers and polyps in the Swiss canton of Vaud 1983-2007].

Colorectal cancer is the second most frequent cancer at death and third most common neoplasm in Switzerland, with about 1600 deaths and 4000 new cases per year, respectively. This study describes the recent trends in colorectal polyps and cancers in the canton of Vaud where a rare population-based series on polyps has been available since 1983. The most salient results are the exponential increase in the detection rates of polyps since the late 19805, associated with a doubling in the proportion of right-sided polyps, whereas colorectal cancer incidence remained constant over the last 25 years. The apparent paradox between the strong increase in detection and resection of polyps, largely due to screening activity, and the absence of reduction in colorectal cancer incidence in the Vaud population is discussed.

Quantitative estimation of foot-flat and stance phase of gait using foot-worn inertial sensors.

Time periods composing stance phase of gait can be clinically meaningful parameters to reveal differences between normal and pathological gait. This study aimed, first, to describe a novel method for detecting stance and inner-stance temporal events based on foot-worn inertial sensors; second, to extract and validate relevant metrics from those events; and third, to investigate their suitability as clinical outcome for gait evaluations. 42 subjects including healthy subjects and patients before and after surgical treatments for ankle osteoarthritis performed 50-m walking trials while wearing foot-worn inertial sensors and pressure insoles as a reference system. Several hypotheses were evaluated to detect heel-strike, toe-strike, heel-off, and toe-off based on kinematic features. Detected events were compared with the reference system on 3193 gait cycles and showed good accuracy and precision. Absolute and relative stance periods, namely loading response, foot-flat, and push-off were then estimated, validated, and compared statistically between populations. Besides significant differences observed in stance duration, the analysis revealed differing tendencies with notably a shorter foot-flat in healthy subjects. The result indicated which features in inertial sensors' signals should be preferred for detecting precisely and accurately temporal events against a reference standard. The system is suitable for clinical evaluations and provides temporal analysis of gait beyond the common swing/stance decomposition, through a quantitative estimation of inner-stance phases such as foot-flat.

Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort

Abstract Background and aims. Limited data from large cohorts are available on tumor necrosis factor (TNF) antagonists (infliximab, adalimumab, certolizumab pegol) switch over time. We aimed to evaluate the prevalence of switching from one TNF antagonist to another and to identify associated risk factors. Methods. Data from the Swiss Inflammatory Bowel Diseases Cohort Study (SIBDCS) were analyzed. Results. Of 1731 patients included into the SIBDCS (956 with Crohn's disease [CD] and 775 with ulcerative colitis [UC]), 347 CD patients (36.3%) and 129 UC patients (16.6%) were treated with at least one TNF antagonist. A total of 53/347 (15.3%) CD patients (median disease duration 9 years) and 20/129 (15.5%) of UC patients (median disease duration 7 years) needed to switch to a second and/or a third TNF antagonist, respectively. Median treatment duration was longest for the first TNF antagonist used (CD 25 months; UC 14 months), followed by the second (CD 13 months; UC 4 months) and third TNF antagonist (CD 11 months; UC 15 months). Primary nonresponse, loss of response and side effects were the major reasons to stop and/or switch TNF antagonist therapy. A low body mass index, a short diagnostic delay and extraintestinal manifestations at inclusion were identified as risk factors for a switch of the first used TNF antagonist within 24 months of its use in CD patients. Conclusion. Switching of the TNF antagonist over time is a common issue. The median treatment duration with a specific TNF antagonist is diminishing with an increasing number of TNF antagonists being used.

Philemon and Baucis deaths: case reports and postmortem biochemistry contribution.

The death of a person as a reaction to the death of another is known as Philemon and Baucis death and may represent a difficult challenge for pathologists, especially due to the decompositional changes that often characterized these situations. In this article, we describe two cases of Philemon and Baucis deaths, the first concerning a married couple and the second concerning a father and son. Postmortem investigations including radiology and biochemistry were performed. Based on the results of all investigations, deaths were attributed to natural causes. Third-party involvement could be excluded in both situations. In one case, biochemical analysis results revealed potentially contributing causes of death. The reported cases emphasize the importance of correlating findings from different postmortem investigations to identify causes of death, precipitating conditions and predisposing disorders, thus allowing the conclusion of natural death to be reached and third-party involvement to be excluded.

mTOR Inhibition and the Tumor Vasculature

Abstract: Blocking tumor growth by targeting the tumor vasculature is a promising approach in cancer therapy. Both, disrupting tumor vessels as well as normalization of tumor vessel abnormalities have shown anti-cancer efficacy. A plethora of agents that act on the tumor vasculature have been developed; however, so far few have shown clinical benefits. Among the successful agents, inhibitors of the mammalian target of rapamycin (mTOR) are able to reduce tumor growth by targeting tumor vessels. mTOR inhibition exerts at least three different effects on the tumor vasculature. First, it reduces tumor angiogenesis. Second it normalizes the tumor vasculature and third, it promotes the formation of thrombosis in tumor vessels. The characterization of the molecular functions regulated by mTOR and of relevance to the tumor vasculature is therefore important in order to further identify biological mechanisms involved in the tumor vascular network as well as to improve the efficacy of these inhibitors. Here, we will first enumerate the evidences for the anti-angiogenic activities of mTOR inhibitors and describe the molecular mechanisms involved. We will further analyze the effects of mTOR inhibition on vascular normalization and also describe how mTOR inhibition promotes thrombosis formation specifically in tumor vessels. Finally, we will describe a new generation of mTOR inhibitors and examine their effects on the tumor vasculature

Role of prohormone convertases in pro-neuropeptide Y processing: coexpression and in vitro kinetic investigations.

Proneuropeptide Y (ProNPY) undergoes cleavage at a single dibasic site Lys38-Arg39 resulting in the formation of 1-39 amino acid NPY which is further processed successively by carboxypeptidase-like and peptidylglycine alpha-amidating monooxygenase enzymes. To investigate whether prohormone convertases are involved in ProNPY processing, a vaccinia virus derived expression system was used to coexpress recombinant ProNPY with each of the prohormone convertases PC1/3, PC2, furin, and PACE4 in Neuro2A and NIH 3T3 cell lines as regulated neuroendocrine and constitutive prototype cell lines, respectively. The analysis of processed products shows that only PC1/3 generates NPY in NIH 3T3 cells while both PC1/3 and PC2 are able to generate NPY in Neuro2A cells. The convertases furin and PACE4 are unable to process ProNPY in either cell line. Moreover, comparative in vitro cleavage of recombinant NPY precursor by the enzymes PC1/3, PC2 and furin shows that only PC1/3 and PC2 are involved in specific cleavage of the dibasic site. Kinetic studies demonstrate that PC1/3 cleaves ProNPY more efficiently than PC2. The main difference between the cleavage efficiency is observed in the Vmax values whereas no major difference is observed in Km values. In addition the cleavage by PC1/3 and PC2 of two peptides reproducing the dibasic cleavage site with different amino acid sequence lengths namely (20-49)-ProNPY and (28-43)-ProNPY was studied. These shortened ProNPY substrates, when recognized by the enzymes, are more efficiently cleaved than ProNPY itself. The shortest peptide is not cleaved by PC2 while it is by PC1/3. On the basis of these observations it is proposed, first, that the constitutive secreted NPY does not result from the cleavage carried out by ubiquitously expressed enzymes furin and PACE4; second, that PC1/3 and PC2 are not equipotent in the cleavage of ProNPY; and third, substrate peptide length might discriminate PC1/3 and PC2 processing activity.

Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort.

Abstract Background and aims. Limited data from large cohorts are available on tumor necrosis factor (TNF) antagonists (infliximab, adalimumab, certolizumab pegol) switch over time. We aimed to evaluate the prevalence of switching from one TNF antagonist to another and to identify associated risk factors. Methods. Data from the Swiss Inflammatory Bowel Diseases Cohort Study (SIBDCS) were analyzed. Results. Of 1731 patients included into the SIBDCS (956 with Crohn's disease [CD] and 775 with ulcerative colitis [UC]), 347 CD patients (36.3%) and 129 UC patients (16.6%) were treated with at least one TNF antagonist. A total of 53/347 (15.3%) CD patients (median disease duration 9 years) and 20/129 (15.5%) of UC patients (median disease duration 7 years) needed to switch to a second and/or a third TNF antagonist, respectively. Median treatment duration was longest for the first TNF antagonist used (CD 25 months; UC 14 months), followed by the second (CD 13 months; UC 4 months) and third TNF antagonist (CD 11 months; UC 15 months). Primary nonresponse, loss of response and side effects were the major reasons to stop and/or switch TNF antagonist therapy. A low body mass index, a short diagnostic delay and extraintestinal manifestations at inclusion were identified as risk factors for a switch of the first used TNF antagonist within 24 months of its use in CD patients. Conclusion. Switching of the TNF antagonist over time is a common issue. The median treatment duration with a specific TNF antagonist is diminishing with an increasing number of TNF antagonists being used.

The empirical assessment of agency accountability: A regime approach and an application to the German Bundesnetzagentur

Regulation has in many cases been delegated to independent agencies, which has led to the question of how democratic accountability of these agencies is ensured. There are few empirical approaches to agency accountability. We offer such an approach, resting upon three propositions. First, we scrutinize agency accountability both de jure (accountability is ensured by formal rights of accountability 'fora' to receive information and impose consequences) and de facto (the capability of fora to use these rights depends on resources and decision costs that affect the credibility of their sanctioning capacity). Second, accountability must be evaluated separately at political, operational and managerial levels. And third, at each level accountability is enacted by a system of several (partially) interdependent fora, forming together an accountability regime. The proposed framework is applied to the case of the German Bundesnetzagentur's accountability regime, which shows its suitability for empirical purposes. Regulatory agencies are often considered as independent, yet accountable. This article provides a realistic framework for the study of accountability 'regimes' in which they are embedded. It emphasizes the need to identify the various actors (accountability fora) to which agencies are formally accountable (parliamentary committees, auditing bodies, courts, and so on) and to consider possible relationships between them. It argues that formal accountability 'on paper', as defined in official documents, does not fully account for de facto accountability, which depends on the resources possessed by the fora (mainly information-processing and decision-making capacities) and the credibility of their sanctioning capacities. The article applies this framework to the German Bundesnetzagentur.

The fourth extracellular loop of the alpha subunit of Na,K-ATPase. Functional evidence for close proximity with the second extracellular loop.

Na,K-ATPase is the main active transport system that maintains the large gradients of Na(+) and K(+) across the plasma membrane of animal cells. The crystal structure of a K(+)-occluding conformation of this protein has been recently published, but the movements of its different domains allowing for the cation pumping mechanism are not yet known. The structure of many more conformations is known for the related calcium ATPase SERCA, but the reliability of homology modeling is poor for several domains with low sequence identity, in particular the extracellular loops. To better define the structure of the large fourth extracellular loop between the seventh and eighth transmembrane segments of the alpha subunit, we have studied the formation of a disulfide bond between pairs of cysteine residues introduced by site-directed mutagenesis in the second and the fourth extracellular loop. We found a specific pair of cysteine positions (Y308C and D884C) for which extracellular treatment with an oxidizing agent inhibited the Na,K pump function, which could be rapidly restored by a reducing agent. The formation of the disulfide bond occurred preferentially under the E2-P conformation of Na,K-ATPase, in the absence of extracellular cations. Using recently published crystal structure and a distance constraint reproducing the existence of disulfide bond, we performed an extensive conformational space search using simulated annealing and showed that the Tyr(308) and Asp(884) residues can be in close proximity, and simultaneously, the SYGQ motif of the fourth extracellular loop, known to interact with the extracellular domain of the beta subunit, can be exposed to the exterior of the protein and can easily interact with the beta subunit.

Secondary contact zones and hybridizations: the case of the lesser white-toothed shrew (Crocidura suaveolens group, Soricidae)

In the present study, we analyzed 58 samples of the lesser white-toothed shrew group (Crocidura suaveolens) from eastern Europe and Turkey, where, according to previous publications, three different mitochondrial and nuclear lineages are present. We sequenced 799 bp of the nuclear BRCA1 gene and 400 bp of the mitochondrial cytochrome b gene to: (1) determine a potential contact zone between the lineages; (2) detect hybridizations and introgressions between them; and (3) comment on the level of reproductive isolation of the different lineages. We revealed two zones of hybridization in Turkey, of which the first occurred west of the Bosphorus Straits (three hybrids) and the second in Anatolia (twelve hybrids). In the latter, the nuclear markers revealed a large zone of hybridization, of approximately 600 km. It also revealed that hybrids of first, second, and later generations are present within the populations, and therefore that the reproductive isolation between the different lineages is weak.

Theoretical study of the electrostatically driven step of receptor-G protein recognition.

This study proposes a theoretical model describing the electrostatically driven step of the alpha 1 b-adrenergic receptor (AR)-G protein recognition. The comparative analysis of the structural-dynamics features of functionally different receptor forms, i.e., the wild type (ground state) and its constitutively active mutants D142A and A293E, was instrumental to gain insight on the receptor-G protein electrostatic and steric complementarity. Rigid body docking simulations between the different forms of the alpha 1 b-AR and the heterotrimeric G alpha q, G alpha s, G alpha i1, and G alpha t suggest that the cytosolic crevice shared by the active receptor and including the second and the third intracellular loops as well as the cytosolic extension of helices 5 and 6, represents the receptor surface with docking complementarity with the G protein. On the other hand, the G protein solvent-exposed portions that recognize the intracellular loops of the activated receptors are the N-terminal portion of alpha 3, alpha G, the alpha G/alpha 4 loop, alpha 4, the alpha 4/beta 6 loop, alpha 5, and the C-terminus. Docking simulations suggest that the two constitutively active mutants D142A and A293E recognize different G proteins with similar selectivity orders, i.e., G alpha q approximately equal to G alpha s > G alpha i > G alpha t. The theoretical models herein proposed might provide useful suggestions for new experiments aiming at exploring the receptor-G protein interface.

The additive genetic variance after bottlenecks is affected by the number of loci involved in epistatic interactions.

We investigated the role of the number of loci coding for a neutral trait on the release of additive variance for this trait after population bottlenecks. Different bottleneck sizes and durations were tested for various matrices of genotypic values, with initial conditions covering the allele frequency space. We used three different types of matrices. First, we extended Cheverud and Routman's model by defining matrices of "pure" epistasis for three and four independent loci; second, we used genotypic values drawn randomly from uniform, normal, and exponential distributions; and third we used two models of simple metabolic pathways leading to physiological epistasis. For all these matrices of genotypic values except the dominant metabolic pathway, we find that, as the number of loci increases from two to three and four, an increase in the release of additive variance is occurring. The amount of additive variance released for a given set of genotypic values is a function of the inbreeding coefficient, independently of the size and duration of the bottleneck. The level of inbreeding necessary to achieve maximum release in additive variance increases with the number of loci. We find that additive-by-additive epistasis is the type of epistasis most easily converted into additive variance. For a wide range of models, our results show that epistasis, rather than dominance, plays a significant role in the increase of additive variance following bottlenecks.

Trends in the main diseases in an internal medicine ward, 2003-2011

Introduction : Population aging leads to a considerable increase in the prevalence of specific diseases. We aimed to assess if those changes were already reflected in an Internal Medicine ward. Methods : Anonymous data was obtained from the administrative database of the department of internal medicine of the Lausanne University Hospital (CHUV). All hospitalizations of adult (>=18 years) patients occurring between 2003 and 2011 were included. Infections, cancers and diseases according to body system (heart, lung...) were defined by the first letter of the ICD-10 code for the main cause of hospitalization. Specific diseases (myocardial infarction, heart failure...) were defined by the first three letters of the ICD-10 codes for the main cause of hospitalization. Results : Data from 32,741 hospitalizations occurring between 2003 and 2011 was analyzed. Cardiovascular (ICD-10 code I) and respiratory (ICD-10 code J) diseases ranked first and second, respectively, and their ranks did not change during the study period (figure). Digestive and endocrine diseases decreased while psychiatric diseases increased from rank 9 in 2003 to rank 6 in 2011 (figure). Among specific diseases, pneumonia (organism unspecified, code J18) ranked first in 2003 and second in 2011. Acute myocardial infarction (code I21) ranked second in 2003 and third in 2011. Chronic obstructive pulmonary disease with acute lower respiratory infection (code J44) ranked third in 2003 and decreased to rank 8 in 2011. Conversely, heart failure (code I50) increased from rank 8 in 2003 to rank 1 in 2011 and delirium (not induced by alcohol and other psychoactive substances, code F05) increased from below rank 20 in 2003 to rank 4 in 2011. For more details, see table. Conclusion : In less than 10 years, considerable changes occurred in the presentation of patients attending an Internal Medicine ward. The changes in diseases call for adaptations in hospital staff and logistics.

Reoperative Roux-En-Y Gastric Bypass Provides Similar Long-Term Results as Primary Surgery

Background: The increasing prevalence of obesity worldwide is associated with a massive increase in the number of yearly performed bariatric procedures, many of them purely restrictive. Consequently, a growing number of surgical revisions are necessary, and conversion to Roux-en-Y gastric bypass (RYGBP) is a common option. So far, few series including mostly patients reoperated using open surgery,and limited follow-up, have been reported.Patients and methods: Retrospective analysis of prospectively collected data of all patients undergoing revisional RYGBP in our two departments.Results: Between June 1999 and February 2011, 186 patients were submitted to revisional RYGBP, 161 women and 25 men with a mean age of 43 years. Their mean initial BMI was 45,3 kg/m2, their mean nadir BMI between the index operation and revision was 34, and their mean pre-revision BMI was 38,5. The initial procedure was gastric banding in 134 (72 %) patients, VBG in 48 (25,8 %), RYGBP in 5 (2,7 %), and others in 3. The main indications for revision were complications from the primary procedure with or without weight regain. A laparoscopic approach was usedin 137 (73,7 %) cases. Overall early morbidity was 18,8 %, and major morbidity was 3,2 %. Comparing patients in the first, second and last third of our experience, the percentage of patients operated using a laparoscopic approach increased from 53,2 % to 71 % and finally 96,7 %, and overall morbidity decreased from 27,4 % to 24,2 % and then 4,8 %. There were more wound infections after laparotomy (22,4 versus 2,9 %, p<0,001). There was no mortality. The mean BMI remained between 30 and 32 up to nine years after revision. Up to this limit, a BMI of <35 was maintained in between 75 and 83 % of the patients.Conclusions: Revisional RYGBP proves to be an effective and safe procedure. It can be performed by laparoscopy in most cases, especially as experience increases., It is associated with an acceptable morbidity, though higher than with primary RYGBP. Long-term results are equivalent to those of primary RYGBP, and can be considered as very satisfactory considering the fact that, on average, patients requiring redo surgery represent a sub-selection of difficult bariatric patients.

Mechanical and elemental characterization of solder joints and welds using a gold-palladium alloy

Purpose. This study was conducted to determine whether newer infrared or laser welding technologies created joints superior to traditional furnace or torch soldering methods of joining metals. It was designed to assess the mechanical resistance, the characteristics of the fractured surfaces, and the elemental diffusion of joints obtained by four different techniques: (1) preceramic soldering with a propane-oxygen torch, (2) postceramic soldering with a porcelain furnace, (3) preceramic and (4) postceramic soldering with an infrared heat source, and (5) laser welding. Material and methods. Mechanical resistance was determined by measuring the ultimate tensile strength of the joint and by determining their resistance to fatigue loading. Elemental diffusion to and from the joint was assessed with microprobe tracings. Scanning electron microscopy micrographs of the fractured surface were also obtained and evaluated. Results. Under monotonic tensile stress, three groups emerged: The laser welds were the strongest, the preceramic joints ranged second, and the postceramic joints were the weakest. Under fatigue stress, the order was as follows: first, the preceramic joints, and second, a group that comprised both postceramic joints and the laser welds. Inspection of the fractographs revealed several fracture modes but no consistent pattern emerged. Microprobe analyses demonstrated minor diffusion processes in the preceramic joints, whereas significant diffusion was observed in the postceramic joints. Clinical Implications. The mechanical resistance data conflicted as to the strength that could be expected of laser welded joints. On the basis of fatigue resistance of the joints, neither infrared solder joints nor laser welds were stronger than torch or furnace soldered joints.