Impact of infection on the prognosis of critically ill cirrhotic patients: results from a large worldwide study.

BACKGROUND: Infections are a leading cause of death in patients with advanced cirrhosis, but there are relatively few data on the epidemiology of infection in intensive care unit (ICU) patients with cirrhosis. AIMS: We used data from the Extended Prevalence of Infection in Intensive Care (EPIC) II 1-day point-prevalence study to better define the characteristics of infection in these patients. METHODS: We compared characteristics, including occurrence and types of infections in non-cirrhotic and cirrhotic patients who had not undergone liver transplantation. RESULTS: The EPIC II database includes 13,796 adult patients from 1265 ICUs: 410 of the patients had cirrhosis. The prevalence of infection was higher in cirrhotic than in non-cirrhotic patients (59 vs. 51%, P < 0.01). The lungs were the most common site of infection in all patients, but abdominal infections were more common in cirrhotic than in non-cirrhotic patients (30 vs. 19%, P < 0.01). Infected cirrhotic patients more often had Gram-positive (56 vs. 47%, P < 0.05) isolates than did infected non-cirrhotic patients. Methicillin-resistant Staphylococcus aureus (MRSA) was more frequent in cirrhotic patients. The hospital mortality rate of cirrhotic patients was 42%, compared to 24% in the non-cirrhotic population (P < 0.001). Severe sepsis and septic shock were associated with higher in-hospital mortality rates in cirrhotic than in non-cirrhotic patients (41% and 71% vs. 30% and 49%, respectively, P < 0.05). CONCLUSIONS: Infection is more common in cirrhotic than in non-cirrhotic ICU patients and more commonly caused by Gram-positive organisms, including MRSA. Infection in patients with cirrhosis was associated with higher mortality rates than in non-cirrhotic patients.

Large fluctuations in the disassembly rate of microtubules revealed by atomic force microscopy.

Atomic force microscopy (AFM) in situ has been used to observe the cold disassembly dynamics of microtubules at a previously unrealised spatial resolution. Microtubules either electrostatically or covalently bound to aminosilane surfaces disassembled at room temperature under buffer solutions with no free tubulin present. This process was followed by taking sequential tapping-mode AFM images and measuring the change in the microtubule end position as a function of time, with an spatial accuracy down to +/-20nm and a temporal accuracy of +/-1s. As well as giving average disassembly rates on the order of 1-10 tubulin monomers per second, large fluctuations in the disassembly rate were revealed, indicating that the process is far from smooth and linear under these experimental conditions. The surface bound rates measured here are comparable to the rates for GMPCPP-tubulin microtubules free in solution, suggesting that inhibition of tubulin curvature through steric hindrance controls the average, relatively low disassembly rate. The large fluctuations in this rate are thought to be due to multiple pathways in the kinetics of disassembly with differing rate constants and/or stalling due to defects in the microtubule lattice. Microtubules that were covalently bound to the surface left behind the protofilaments covalently cross-linked to the aminosilane via glutaraldehyde during the disassembly process. Further work is needed to quantitatively assess the effects of surface binding on protofibril disassembly rates, reveal any differences in disassembly rates between the plus and minus ends and to enable assembly as well as disassembly to be imaged in the microscope fluid cell in real-time.

Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics.

Alterations of the p53 pathway are among the most frequent aberrations observed in human cancers. We have performed an exhaustive analysis of TP53, p14, p15, and p16 status in a large series of 143 soft tissue sarcomas, rare tumors accounting for around 1% of all adult cancers, with complex genetics. For this purpose, we performed genomic studies, combining sequencing, copy number assessment, and expression analyses. TP53 mutations and deletions are more frequent in leiomyosarcomas than in undifferentiated pleomorphic sarcomas. Moreover, 50% of leiomyosarcomas present TP53 biallelic inactivation, whereas most undifferentiated pleomorphic sarcomas retain one wild-type TP53 allele (87.2%). The spectrum of mutations between these two groups of sarcomas is different, particularly with a higher rate of complex mutations in undifferentiated pleomorphic sarcomas. Most tumors without TP53 alteration exhibit a deletion of p14 and/or lack of mRNA expression, suggesting that p14 loss could be an alternative genotype for direct TP53 inactivation. Nevertheless, the fact that even in tumors altered for TP53, we could not detect p14 protein suggests that other p14 functions, independent of p53, could be implicated in sarcoma oncogenesis. In addition, both p15 and p16 are frequently codeleted or transcriptionally co-inhibited with p14, essentially in tumors with two wild-type TP53 alleles. Conversely, in TP53-altered tumors, p15 and p16 are well expressed, a feature not incompatible with an oncogenic process.

Generic approach for the sensitive absolute quantification of large undigested peptides in plasma using a particular liquid chromatography-mass spectrometry setup.

A generic LC-MS approach for the absolute quantification of undigested peptides in plasma at mid-picomolar levels is described. Nine human peptides namely, brain natriuretic peptide (BNP), substance P (SubP), parathyroid hormone 1-34 (PTH), C-peptide, orexines A and B (Orex-A and -B), oxytocin (Oxy), gonadoliberin-1 (gonadothropin releasing-hormone or luteinizing hormone-releasing hormone, LHRH) and α-melanotropin (α-MSH) were targeted. Plasma samples were extracted via a 2-step procedure: protein precipitation using 1vol of acetonitrile followed by ultrafiltration of supernatants on membranes with a MW cut-off of 30 kDa. By applying a specific LC-MS setup, large volumes of filtrates (e.g., 2×750 μL) were injected and the peptides were trapped on a 1mm i.d.×10 mm length C8 column using a 10× on-line dilution. Then, the peptides were back-flushed and a second on-line dilution (2×) was applied during the transfer step. The refocalized peptides were resolved on a 0.3mm i.d. C18 analytical column. Extraction recovery, matrix effect and limits of detection were evaluated. Our comprehensive protocol demonstrates a simple and efficient sample preparation procedure followed by the analysis of peptides with limits of detection in the mid-picomolar range. This generic approach can be applied for the determination of most therapeutic peptides and possibly for endogenous peptides with latest state-of-the-art instruments.

Développement de l'irrigation et évolution des régimes fonciers dans la région de Gaya (Niger)

Since the mid 90's, international actors as well as governmental actors have raised their interest into the development of irrigation's potential that is still largely unexploited in Niger. It seems all the more interesting as it could answer the needs of a fast growing population (3.3% per year). However, if everyone agrees on the need to development this system, the current implementation triggers questions on the process itself and its side effects. National and international policies on this matter were build upon an historical process through colonial, post-colonial and then the late 1980's neoliberal structures, leading to a business model that reveals a discrepancy between the state logic and the farming one. This business model asks for a high capacity of mobilization of resources unachievable for many, especially when they want to address small-scale irrigation (area large potential of accessible water resources that allowed an extensive production of fruits and vegetables since the 1980's. These productions were developed at first by the local farmers, but the high value added engendered then attracted external players as well, such as civil servants and merchants. The World Bank supported this momentum through the development of a business type project. Unfortunately, it reached mostly the new external players and local elites rather than the small farmers, notably due to the high illiteracy rate among farmers. In terms of land tenure analysis, the project excluded all farmers cultivating land on a loan or lease agreement and all those for whom it was difficult to obtain a title of ownership. However, this new interest for small-scale irrigation exerted by the project and the new players triggered the commoditization of land. As a matter of fact, the demographic constraints and the fragmentation of the familial land ownership led to a more individual production system, where the customary relation to land tenure is weakened or even overcome. This makes it easier for the new players who need to settle their small-scale irrigation projects to purchase land. When there are only few areas available for selling, the. purchasing processes are undermining the farmers with insecure rights. If the withdrawal of lands is supposed to be smoothened by social measures, such as replacement of the land and primary offers to purchase the land, those measures are often not attractive. The proposed land of replacement is frequently too far away located or lesser fertile to be of any use and the economic capacity of purchasing is too little, eventually leading the farmers to leave their terroirs. Those in charge of the application of the Rural Code have succeeding in answering the need of written secured land tenure, but have difficulty to meet the challenge of doing the same to secure rights for farmers with loans or lease agreements. The small-scale irrigation could bring an answer for their financial needs to buy the land, but it would require mobilizing resources to invest or an easier access to supportive projects. The economic benefice from small-scale irrigation is now widely recognized, but we have to take also into account the risks of marginalization of part of the small farmers. For a more widely spread exploitation of small-scale irrigation, the mechanism of land regulation as well as the process to access the financial and technical support of projects must be revised in order to reach more small farmers. Développement de l'irrigation et évolution des régimes fonciers dans la région de Gaya (Niger) - Le secteur de l'irrigation a bénéficié d'un regain d'intérêt de la part des acteurs internationaux du développement et de l'Etat nigérien depuis le milieu des années 1990. Cet intérêt est à la hauteur du potentiel en terres irrigables (300Ό00 ha environ) du pays, largement sous-exploité alors que les besoins alimentaires sont grandissants, la population augmentant de 3.3% par an. Si le diagnostic est correct, les stratégies mises en oeuvre en matière d'irrigation posent question. Les interventions, aussi bien publiques qu'internationales, reposent sur un modèle entrepreneurial qui parachève une longue trajectoire historique. Initiée par l'Etat colonial, poursuivie par l'Etat post-colonial et transformé par les politiques néolibérales des années 1980, elle se caractérise par un hiatus constant entre logiques étatiques et logiques paysannes. En matière de petite irrigation privée (surfaces < 1-2 ha, technologies à faible coût), ce modèle présuppose une mobilisation de ressources (économiques, sociales, éducationnelles et foncières) inégalement réparties au sein de la population rurale. Cette recherche s'est intéressée à expliciter les liens qui existent entre le développement de la petite irrigation privée et l'évolution des régimes fonciers. Les trois questionnements qui ont guidé l'analyse empirique portent sur la sécurisation foncière, les dynamiques de marchandisation de la terre et l'accès à la terre pour tous les producteurs. Le Département de Gaya dispose d'un potentiel très important en ressources hydriques, facilement mobilisables. Les productions maraîchères et fruitières ont connu un essor très important à partir des années 1980. Initialement pratiquées par les cultivateurs, elles ont progressivement attiré l'attention d'acteurs externes au monde rural (fonctionnaires, commerçants), du fait de leur haute valeur ajoutée. La Banque mondiale a fortement soutenu cette dynamique à travers un projet à vocation entrepreneuriale, qui s'est pourtant révélé hors de portée de la majorité des petits paysans et a principalement bénéficié à ces acteurs extra-ruraux ainsi qu'à certaines élites locales. Au plan foncier, il a en particulier exclu tous les emprunteurs des terres, qui ne sont pas à même de produire des documents écrits confirmant leurs droits sur la terre. Ce projet, et plus largement l'intérêt que les acteurs extra-ruraux portent à la petite irrigation, ont contribué à alimenter la marchandisation de la terre. Sans ancrage familial dans les terroirs villageois, ces acteurs sont obligés d'acheter la terre pour faire de l'irrigation. Leur demande vient s'inscrire dans un contexte général où la pression démographique et le morcellement successif des capitaux fonciers familiaux ont progressivement individualisé la relation entre les producteurs et la terre, au point d'affaiblir ou de faire tomber les interdits coutumiers en matière de vente. Dans les espaces disposant de faibles réserves foncières, les ventes se font principalement au détriment des acteurs qui, comme les emprunteurs, disposent de droits fonciers peu stables et sécurisés. Si le retrait de la terre est socialement encadré (terre en remplacement, possibilité d'acheter la terre qui va être vendue), il pose également des contraintes agronomiques (sols de moindre qualité) et économiques (nécessité de disposer des liquidités pour racheter la terre) qui peuvent, en dernier ratio, obligent les acteurs concernés à quitter les terroirs. Les instances du Code rural, qui ont su apporter des réponses satisfaisantes à la demande de sécurisation foncière par l'établissement de documents écrits, rencontrent aujourd'hui de grandes difficultés à en faire de même pour les droits de prêt. Dans ce contexte, l'irrigation peut apporter les sommes nécessaires à l'achat des terres. Encore faut-il que ces emprunteurs disposent des ressources financières propres pour la développer ou qu'ils puissent y avoir accès grâce à l'appui d'un projet. Si l'intérêt économique de la petite irrigation privée est indiscutable, les risques de marginalisation d'une partie de producteurs ruraux qu'elle peut produire sont bien réels. Pour en faire une activité accessible au plus grand nombre, il faut revoir les mécanismes de régulation foncière, ainsi que les montages techniques et financiers qui supportent le développement de ce secteur d'activité très prometteur.

Acvbp Versus Acvbp Plus Rituximab For Young Patients With Localized Low-Risk Diffuse Large B-Cell Lymphoma: A Study By The Groupe D'etude Des Lymphomes De L'adulte

Introduction: In a prior study, we demonstrated that ACVBP + consolidation was superior to 3 cycles of CHOP + radiotherapy in young patients (pts) with localized aggressive lymphoma (Reyes F et al. N Engl J Med 2005;352:1197). This randomized trial compared in these pts ACVBP vs. ACVBP + a short course of rituximab (R-ACVBP).Methods: untreated pts between 18 and 65y with stage I/II DLBCL and no adverse prognostic factors according to the aa-IPI were eligible. ACVBP consisted of 3 induction cycles given every 2 weeks: doxorubicin (75 mg/m2) day 1, cyclophosphamide (1.2g/m2) day 1, vindesine (2 mg/m2) day 1 and 5, bleomycin (10 mg) day 1 and 5, prednisone (60 mg/m2) day 1 to 5 followed by consolidation with metothrexate, ifosfamide, VP-16 and cytarabine. R-ACVBP consisted of the same regimen combined with 4 doses of rituximab (375 mg/m2) on day 1, 15, 29 and 43. Primary objective was EFS.Results: From 01/04 to 03/08, 223 pts were randomized, 113 in ACVBP and 110 in R-ACVBP arm. Characteristics were: median age 49y (18-65), stage I 63%, extranodal involvement 45%, bulky disease 4%. CR was 94% in ACVBP and 97% in ACVBP arm (ns). With a median follow-up of 43 months, the 3-y EFS was 82% (95% CI, 73% to 88%) in ACVBP and 93% (95% CI, 87% to 97%) in R-ACVBP group (P=0.0487). The 3-y PFS was 83% (95% CI, 74% to 89%) and 95% (95% CI, 89% to 98%) respectively (P=0.0205). OS did not significantly differ with a 3-y estimates of 97% (95% CI, 90% to 99%) for ACVBP and 98% (95% CI, 92% to 100%) for R-ACVBP (P=0.686). In multivariate analysis, a longer PFS was associated with R-ACVBP arm (P=0.0302) and lower b2-m level (P=0.0164). The same proportion of pts (27%) experienced at least 1 SAE in both groups. There were 4 deaths in each arm, with 1 treatment-related death in R-ACVBP (pneumocystis jiroveci pneumonia).Conclusion: the addition of only 4 doses of rituximab to ACVBP significantly improves EFS and PFS in younger pts with low-risk localized DLBCL.

Risk assessment of herbicide mixtures in a large European lake

Lake Geneva is one of the largest European lakes with a surface area of 580 km2. Its catchment area covers 7400 km2, of which approximately 20% is arable land. Monitoring campaigns have been carried out in 2004 and 2005 to determine the contamination of the lake by pesticides. The results highlight the widespread presence of herbicides in water, the measured concentrations for most substances remaining constant in 2004 and 2005. However, for some individual herbicides the concentrations increased drastically (e.g., the herbicide foramsulfuron). We assessed the environmental risk of the herbicides detected in the lake using water quality criteria recently determined for the Swiss environmental protection agency. Furthermore, we assessed the risk of herbicide mixtures, grouped based upon their mode of action. Generally, the risk estimated for all single substances is low, except for some sulfonylurea compounds. For these substances, the measured concentrations are higher than the predicted no-effect concentration. Impact on the flora of the lake can therefore not be excluded. When mixtures of pesticides with similar mode of action are taken into account, the risk remains lower than the mixture water quality criteria for all groups, but can reach as high as one third of this quality criteria. A further step would therefore be to assess the risk of the total pesticide mixture, including similar and dissimilar modes of action

A large deletion in the adRP gene PRPF31: evidence that haploinsufficiency is the cause of disease.

PURPOSE: To report a large deletion that encompasses more than 90% of PRPF31 gene and two other neighboring genes in their entirety in an adRP pedigree that appears to show only the typical clinical features of retinitis pigmentosa. METHODS: To identify PRPF31 mutation in a dominant RP family (ADRP2) previously linked to the RP11 locus, the 14 exons of PRPF31 were screened for mutations by direct sequencing. To investigate the possibility of a large deletion, microsatellite markers near PRPF31 gene were analyzed by non-denaturing PAGE. RESULTS: Initial screening of PRPF31 gene in the ADRP2 family did not reveal an obvious mutation. A large deletion was however suspected due to lack of heterozygosity for nearly all PRPF31 intragenic single nucleotide polymorphysm (SNPs). In order to estimate the size of the deletion, SNPs and microsatellite markers spanning and flanking PRPF31 were analyzed in the entire ADRP2 family. Haplotype analysis with the above markers suggested a deletion of approximately 30 kb that included the putative promoter region of a novel gene OSCAR, the entire genomic content of genes NDUFA3, TFPT and more than 90% of PRPF31 gene. Sequence analysis of the region flanking the potential deletion showed a high presence of Alu elements implicating Alu mediated recombination as the mechanism responsible for this event. CONCLUSIONS: This mutation provides evidence that haploinsufficiency rather than aberrant function of mutated proteins is the cause of disease in these adRP patients with mutations in PRPF31 gene.

Latissimus dorsi muscle-flap over Gore-Tex patch for coverage of large thoracic defects in paediatric Ewing sarcoma.

Primary rib involvement accounts for 16% of paediatric Ewing sarcoma (ES). Neo-adjuvant chemotherapy and surgical tumor resection may leave large thoracic wall defects requiring complex reconstruction in a growing individual. We report our experience in three children aged 3, 10, and 12 years, in whom single-stage resection and reconstruction were performed using a Gore-Tex Dualmesh patch, covered by a latissimus dorsi rotation flap harvested in continuity with the thoracolumbar fascia. The youngest patient also had a vertical expandable prosthetic titanium rib (VEPTR) anchored to help prevent subsequent scoliosis throughout growth.

Stable isotope ecology of Miocene large mammals from Sandelzhausen, southern Germany

The carbon, oxygen, and strontium isotope composition of enamel from teeth of large Miocene herbivorous mammals from Sandelzhausen (MN5, late Early/early Middle Miocene) in the North Alpine foreland basin, were analyzed to infer diet and habitat. The mean enamel delta(13)C value of -11.4 +/- 1.0% (n = 53) for the nine taxa analyzed (including proboscideans, cervids, suids, chalicotheres, equids, rhinocerotids) indicates a pure C(3) plant diet for all mammals. (87)Sr/(86)Sr ratios of similar to 0.710 higher than those from teeth of the western Molasse Basin (0.708-0.709) seem to indicate preferential feeding of the mammals in the northeastern Molasse Basin. The sympatric herbivores have different mean delta(13)C and delta(18)O values which support diet partitioning and/or use of different habitats within a C(3) plant ecosystem. Especially the three sympatric rhinoceroses Plesiaceratherium fahlbuschi, Lartetotherium sansaniense, and Prosantorhinus germanicus show clear partitioning of plants and/or habitats. The palaeomerycid Germanomeryx fahlbuschi was a canopy folivore in moderately closed environments whereas Metaschizotherium bavaricum (Chalicotheriidae) and P. germanicus (Rhinocerotidae) were browsers in more closed forest environments. The horse Anchitherium aurelianense was probably a more generalized feeder than assumed from its dental morphology. The forest hog Hyotherium soemmeringi has the highest delta(13)C and lowest delta(18)O value of all analyzed taxa, possibly related to a frugivorous diet. Most taxa were water-dependent browsers that record meteoric water delta(18)O values of about -5.6 +/- 0.7% Vienna Standard Mean Ocean Water (VSMOW). Using a modern-day mean annual air temperature (MAT)-delta(18)OH(2)O relation a MAT of 19.3 +/- 1.5 degrees C can be reconstructed for Sandelzhausen. A Gomphotherium subtapiroideum tusk serially sampled for delta(18)O values does not record a clear pattern of seasonality. Thus most taxa were C(3) browsers in a forested and humid floodplain environment in the Molasse Basin, which experienced a warm-temperate to subtropical climate and possibly low seasonality.