Répercussions de l'agression sur le métabolisme et la composition corporelle chez l'individu obèse : Nutrition de l'obèse agressé. [Repercussions of injury on metabolic and body composition factors in obese individuals : Nutrition and obese critical patients]

La réponse métabolique de l'obèse apparemment « sainen situation d'agression aiguë (polytraumatisés, traumatisés crâniens, patients chirurgicaux, grands brûlés, opérations électives) ne se distingue pas ou peu de celle de l'individu non-obèse. Cependant, les complications médicales liées à l'agression (insuffisances respiratoire et cardiaque, bronchopneumonie, infections de plaies, thrombophlébites et embolies) demeurent plus importantes chez l'obèse morbide que chez l'individu de poids normal. Grâce à l'inflation de ses réserves énergétiques, l'obèse apparemment sain est avantagé, par rapport au sujet mince, au cours d'une agression nutritionnelle chronique telle que le jeûne prolongé. Le facteur fonctionnel limitant la survie dépend avant tout de la composition corporelle initiale et du degré d'adaptation métabolique (et comportementale) en particulier du degré de conservation de la masse maigre par rapport à la masse grasse. La mobilisation accrue de la masse grasse associée à la perte de poids chez l'obèse (par rapport à son homologue non-obèse) est favorable à une prolongation de la vie, car, en brûlant davantage de graisse corporelle, la part des protéines corporelles endogènes utilisée à des fins énergétiques est plus faible. Il s'ensuit chez l'obèse qu'un niveau de masse maigre critique pour la survie n'est atteint qu'après une réduction très marquée de ses réserves énergétiques. En revanche, le sujet mince perd davantage de masse maigre lors de l'amaigrissement et, par conséquent, son métabolisme de repos diminuera plus rapidement que celui du sujet obèse. Cela peut constituer un avantage énergétique évident en termes d'économie d'énergie consécutive à l'adaptation métabolique, mais un inconvénient majeur quant à la durée de la survie. The metabolic response of « apparently healthyobese individuals following acute injury (multiple trauma, head injury and surgical patients, extended burns, elective surgery) is not dramatically different from that of a non-obese individuals. However, the medical complications following the injury (respiratory and cardiac insufficiency, broncho-pneumonia, infections of wounds, trombophlebitis and embolism) are more prevalent in morbid obese patients than in individuals of normal body weight. Because of a large increase in their individuals energy store, "apparently healthy" obese individuals have an advantage over very lean subjects when exposed to a chronic nutritional aggression such as total fasting. The functional limiting factor for survival depends primarily on initial body composition and the magnitude of metabolic adaptation (including behavioral adaptation). The key factor is the extent to which the fat-free mass is maintained (versus to the fat mass) during weight loss. The increased proportion of body fat mobilized during weight loss in obese patients, compared with their non-obese counterparts, favors prolonged survival, because more adipose tissue is burned off, the fraction of body protein endogenously utilized for energy purpose individuals, is smaller. This implies that obese individuals do not reach a fat-free mass "critical" for their survival until their energy stores reach very low values. In contrast, lean subject tend to lose more fat-free mass during weight loss than obese subjects and, as a result, their energy expenditure drops more rapidly. This may offer a potential advantage in terms of energy economy (more energy saving) but a major disadvantage in terms of duration of survival.

Endovascular treatment of symptomatic intracranial arterial stenosis: six-year experience in a single-center series of 42 consecutive patients with acute and mid-term results.

BACKGROUND: The limitations of the medical management of symptomatic intracranial arterial stenosis encourage the development of new therapeutic strategies such as intracranial stenting. OBJECTIVE: To report and analyze the results of a series of 42 patients treated with 3 different endovascular techniques: isolated angioplasty, balloon-expandable coronary stents, and the Wingspan self-expandable intracranial stent system. METHODS: Forty-two patients presenting with symptomatic intracranial arterial stenosis were treated with one of these techniques. Computed tomography angiography was performed 6 months after the procedure, and the clinical neurological statuses were categorized using the modified Rankin Scale and the National Institutes of Health Stroke Scale. RESULTS: A total of 42 lesions were treated: 9 with isolated angioplasty, 14 with balloon-expandable coronary stents, and 19 with Wingspan self-expandable intracranial stents. The mean patient age was 62.9 years, and the mean arterial diameter stenosis was 73.9%. Technical success was achieved in 97.6% of the patients. The overall incidence of procedural complications was 21.4%, and the postoperative permanent morbidity/mortality rate was 7.1%. There were 3 cases of in-stent thrombosis (1 fatal) and 5 cases of asymptomatic restenosis (11.9%), 3 in the isolated angioplasty group and 2 in the Wingspan self-expandable intracranial stent group (mean follow-up 20.4 months). The rate of restenosis was higher in the angioplasty group (33%) than in the coronary (0%) and Wingspan stent (10.5%) groups. CONCLUSION: Endovascular treatment of symptomatic intracranial stenosis has significant overall morbidity and mortality rates. Nevertheless, the very critical natural history of severe refractory lesions and the relatively favorable postoperative evolution suggest that it should be considered the first alternative strategy in cases in which medical therapy has failed.

Determination of the critical activities of a public-private intermediary organization with the help of value chain analysis

Tämän diplomityön tavoitteena oli selvittää arvoketjuanalyysin avulla toiminnot, joilla voittoatavoittelemattoman, julkisen osakeyhtiön toimintaa voitaisiin kuvata. Tarkoituksena oli selvittää mainitut toiminnot yleisesti ja luoda malli kohdeyrityksen arvoketjusta ja sen toiminnoista. Tutkielma jakautuu teoreettiseen ja empiiriseen osaan. Ensimmäinen pohjautuu aikaisempaan tutkimukseen ja kirjallisuuteen sidosryhmistä, arvon muodostumisesta ja arvoketjuanalyysistä. Jälkimmäinen on laadullista tapaustutkimusta. Empiriassa mallinnettiin Lappeenranta Innovation Oy:nsisäisiä toimintoja ja sidosryhmien odotuksia. Empiirinen tutkimus perustui kohdeyrityksen omistajille ja henkilöstölle tehtyihin haastatteluihin sekä yrityksen toiminnan päivittäiseen seurantaan. Johtopäätöksenätodettiin, että julkisen, voittoa tavoittelemattoman yrityksen toiminnot on mahdollista kuvata arvoketjuanalyysin avulla. Alan ja yrityksen asettamat erityispiirteet toivat haasteita määrittelylle, mutta silti arvoketju antoi selkeän tavan kohdeyrityksen toimintojen mallintamiselle.

Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation.

Although canonical Notch signaling regulates multiple hematopoietic lineage decisions including T cell and marginal zone B cell fate specification, the downstream molecular mediators of Notch function are largely unknown. We showed here that conditional inactivation of Hes1, a well-characterized Notch target gene, in adult murine bone marrow (BM) cells severely impaired T cell development without affecting other Notch-dependent hematopoietic lineages such as marginal zone B cells. Competitive mixed BM chimeras, intrathymic transfer experiments, and in vitro culture of BM progenitors on Delta-like-expressing stromal cells further demonstrated that Hes1 is required for T cell lineage commitment, but dispensable for Notch-dependent thymocyte maturation through and beyond the beta selection checkpoint. Furthermore, our data strongly suggest that Hes1 is essential for the development and maintenance of Notch-induced T cell acute lymphoblastic leukemia. Collectively, our studies identify Hes1 as a critical but context-dependent mediator of canonical Notch signaling in the hematopoietic system.

Effects of particulate matters on inflammatory markers in the general adult population

Summary: Particulate air pollution is associated with increased cardiovascular risk. The induction of systemic inflammation following particle inhalation represents a plausible mechanistic pathway. The purpose of this study was to assess the associations of short-term exposure to ambient particulate matters of aerodynamic diameter less than 10 μm (PM10) with circulating inflammatory markers in 6183 adults in Lausanne, Switzerland. The results show that short-term exposure to PM10 was associated with higher levels of circulating IL-6 and TNF-α. The positive association of PM10 with markers of systemic inflammation materializes the link between air pollution and cardiovascular risk. Background: Variations in short-term exposure to particulate matters (PM) have been repeatedly associated with daily all-cause mortality. Particle-induced inflammation has been postulated to be one of the important mechanisms for increased cardiovascular risk. Experimental in-vitro, in-vivo and controlled human studies suggest that interleukin 6 (IL-6) and tumor-necrosis-factor alpha (TNF-α) could represent key mediators of the inflammatory response to PM. The associations of short-term exposure to ambient PM with circulating inflammatory markers have been inconsistent in studies including specific subgroups so far. The epidemiological evidence linking short-term exposure to ambient PM and systemic inflammation in the general population is scarce. So far, large-scale population-based studies have not explored important inflammatory markers such as IL-6, IL-1β or TNF-α. We therefore analyzed the associations between short-term exposure to ambient PM10 and circulating levels of high-sensitive CRP (hs-CRP), IL-6, IL-1β and TNF-α in the population-based CoLaus study. Objectives: To assess the associations of short-term exposure to ambient particulate matters of aerodynamic diameter less than 10 μm (PM10) with circulating inflammatory markers, including hs-CRP, IL-6, IL-1β and TNF-α, in adults aged 35 to 75 years from the general population. Methodology: All study subjects were participants to the CoLaus study (www.colaus.ch) and the baseline examination was carried out from 2003 to 2006. Overall, 6184 participants were included. For the present analysis, 6183 participants had data on at least one of the four measured circulating inflammatory markers. The monitoring data was obtained from the website of Swiss National Air Pollution Monitoring Network (NABEL). We analyzed data on PM10 as well as outside air temperature, pressure and humidity. Hourly concentrations of PM10 were collected from 1 January 2003 to 31 December 2006. Robust linear regression (PROC ROBUSTREG) was used to evaluate the relationship between cytokine inflammatory and PM10. We adjusted all analyses for age, sex, body mass index, smoking status, alcohol consumption, diabetes status, hypertension status, education levels, zip code, and statin intake. All data were adjusted for the effects of weather by including temperature, barometric pressure, and season as covariates in the adjusted models. We performed simple and multiple logistic regression analyses. Descriptive statistical analysis used the Wilcoxon rank sum test (for medians). All data analyses were performed using SAS software (version 9.2; SAS Institute Inc., Cary, NC, USA), and a two-sided significance level of 5% was used. Results: PM10 levels averaged over 24 hours were significantly and positively associated with continuous IL-6 and TNF-α levels, in the whole study population both in unadjusted and adjusted analyses. For each cytokine, there was a similar seasonal pattern, with wider confidence intervals in summer than during the other seasons, which might partly be due to the smaller number of participants examined in summer. The associations of PM10 with IL-6 and TNF-α were also found after having dichotomized these cytokines into high versus low levels, which suggests that the associations of PM10 with the continuous cytokine levels are very robust to any distributional assumption and to potential outlier values. In contrast with what we observed for continuous IL-1β levels, high PM10 levels were significantly associated with high IL-1β. PM10 was significantly associated with IL-6 and TNF-α in men, but with TNF-α only in women. However, there was no significant statistical interaction between PM10 and sex. For IL-6 and TNF-α, the associations tended to be stronger in younger people, with a significant interaction between PM10 and age groups for IL-6. PM10 was significantly associated with IL-6 and TNF-α in the healthy group and also in the "non-healthy" group, although the statistical interaction between healthy status and PM10 was not significant. Conclusion: In summary, we found significant independent positive associations of short-term exposure to PM10 with circulating levels of IL-6 and TNF-α in the adult population of Lausanne. Our findings strongly support the idea that short-term exposure to PM10 is sufficient to induce systemic inflammation on a broad scale in the general population. From a public health perspective, the reported association of elevated inflammatory cytokines with short-term exposure to PM10 in a city with relatively clean air such as Lausanne supports the importance of limiting urban air pollution levels.

Neuromonitorage après coma aigu aux soins intensifs [Multimodal neuromonitoring for the critical care management of acute coma].

Management of neurocritical care patients is focused on the prevention and treatment of secondary brain injury, i.e. the number of pathophysiological intracerebral (edema, ischemia, energy dysfunction, seizures) and systemic (hyperthermia, disorders of glucose homeostasis) events that occur following the initial insult (stroke, hemorrhage, head trauma, brain anoxia) that may aggravate patient outcome. The current therapeutic paradigm is based on multimodal neuromonitoring, including invasive (intracranial pressure, brain oxygen, cerebral microdialysis) and non-invasive (transcranial doppler, near-infrared spectroscopy, EEG) tools that allows targeted individualized management of acute coma in the early phase. The aim of this review is to describe the utility of multimodal neuromonitoring for the critical care management of acute coma.

Developmental critical period in genetic redox dysregulation: animal and human studies in schizophrenia

Converging evidence favors an abnormal susceptibility to oxidative stress in schizophrenia. Decreased levels of glutathione (GSH), the major cellular antioxidant and redox regulator, was observed in cerebrospinal-fluid and prefrontal cortex of patients. Importantly, abnormal GSH synthesis of genetic origin was observed: Two case-control studies showed an association with a GAG trinucleotide repeat (TNR) polymorphism in the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) catalytic subunit (GCLC) gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/8 was three times more frequent in patients. The disease associated genotypes (35% of patients) correlated with decreased GCLC protein, GCL activity and GSH content. Similar GSH system anomalies were observed in early psychosis patients. Such redox dysregulation combined with environmental stressors at specific developmental stages could underlie structural and functional connectivity anomalies. In pharmacological and knock-out (KO) models, GSH deficit induces anomalies analogous to those reported in patients. (a) morphology: spine density and GABA-parvalbumine immunoreactivity (PV-I) were decreased in anterior cingulate cortex. KO mice showed delayed cortical PV-I at PD10. This effect is exacerbated in mice with increased DA from PD5-10. KO mice exhibit cortical impairment in myelin and perineuronal net known to modulate PV connectivity. (b) physiology: In cultured neurons, NMDA response are depressed by D2 activation. In hippocampus, NMDA-dependent synaptic plasticity is impaired and kainate induced g-oscillations are reduced in parallel to PV-I. (c) cognition: low GSH models show increased sensitivity to stress, hyperactivity, abnormal object recognition, olfactory integration and social behavior. In a clinical study, GSH precursor N-acetyl cysteine (NAC) as add on therapy, improves the negative symptoms and decreases the side effects of antipsychotics. In an auditory oddball paradigm, NAC improves the mismatched negativity, an evoked potential related to pre-attention and to NMDA receptors function. In summary, clinical and experimental evidence converge to demonstrate that a genetically induced dysregulation of GSH synthesis combined with environmental insults in early development represent a major risk factor contributing to the development of schizophrenia

MRE11-RAD50-NBS1 is a critical regulator of FANCD2 stability and function during DNA double-strand break repair.

Monoubiquitination of the Fanconi anaemia protein FANCD2 is a key event leading to repair of interstrand cross-links. It was reported earlier that FANCD2 co-localizes with NBS1. However, the functional connection between FANCD2 and MRE11 is poorly understood. In this study, we show that inhibition of MRE11, NBS1 or RAD50 leads to a destabilization of FANCD2. FANCD2 accumulated from mid-S to G2 phase within sites containing single-stranded DNA (ssDNA) intermediates, or at sites of DNA damage, such as those created by restriction endonucleases and laser irradiation. Purified FANCD2, a ring-like particle by electron microscopy, preferentially bound ssDNA over various DNA substrates. Inhibition of MRE11 nuclease activity by Mirin decreased the number of FANCD2 foci formed in vivo. We propose that FANCD2 binds to ssDNA arising from MRE11-processed DNA double-strand breaks. Our data establish MRN as a crucial regulator of FANCD2 stability and function in the DNA damage response.

On the molecular basis of ion permeation in the epithelial Na+ channel.

The epithelial Na+ channel (ENaC) is highly selective for Na+ and Li+ over K+ and is blocked by the diuretic amiloride. ENaC is a heterotetramer made of two alpha, one beta, and one gamma homologous subunits, each subunit comprising two transmembrane segments. Amino acid residues involved in binding of the pore blocker amiloride are located in the pre-M2 segment of beta and gamma subunits, which precedes the second putative transmembrane alpha helix (M2). A residue in the alpha subunit (alphaS589) at the NH2 terminus of M2 is critical for the molecular sieving properties of ENaC. ENaC is more permeable to Li+ than Na+ ions. The concentration of half-maximal unitary conductance is 38 mM for Na+ and 118 mM for Li+, a kinetic property that can account for the differences in Li+ and Na+ permeability. We show here that mutation of amino acid residues at homologous positions in the pre-M2 segment of alpha, beta, and gamma subunits (alphaG587, betaG529, gammaS541) decreases the Li+/Na+ selectivity by changing the apparent channel affinity for Li+ and Na+. Fitting single-channel data of the Li+ permeation to a discrete-state model including three barriers and two binding sites revealed that these mutations increased the energy needed for the translocation of Li+ from an outer ion binding site through the selectivity filter. Mutation of betaG529 to Ser, Cys, or Asp made ENaC partially permeable to K+ and larger ions, similar to the previously reported alphaS589 mutations. We conclude that the residues alphaG587 to alphaS589 and homologous residues in the beta and gamma subunits form the selectivity filter, which tightly accommodates Na+ and Li+ ions and excludes larger ions like K+.

Role of seipin in lipid droplet morphology and hepatitis C virus life cycle.

Infectious hepatitis C virus (HCV) particle assembly starts at the surface of lipid droplets, cytoplasmic organelles responsible for neutral fat storage. We analysed the relationship between HCV and seipin, a protein involved in lipid droplet maturation. Although seipin overexpression did not affect the total mean volume occupied by lipid droplets nor the total triglyceride and cholesterol ester levels per cell, it caused an increase in the mean diameter of lipid droplets by 60 %, while decreasing their total number per cell. The latter two effects combined resulted in a 34 % reduction of the total outer surface area of lipid droplets per cell, with a proportional decrease in infectious viral particle production, probably due to a defect in particle assembly. These results suggest that the available outer surface of lipid droplets is a critical factor for HCV release, independent of the neutral lipid content of the cell.

Effect of physico-chemical conditions and operating parameters on flux and retention of different components in ultrafiltration and nanofiltration fractionation of sweet whey

Tässä väitöstutkimuksessa tutkittiin fysikaaliskemiallisten olosuhteiden ja toimintaparametrien vaikutusta juustoheran fraktiointiin. Kirjallisuusosassa on käsitelty heran ympäristövaikutusta, heran hyödyntämistä ja heran käsittelyä kalvotekniikalla. Kokeellinen osa on jaettu kahteen osaan, joista ensimmäinen käsittelee ultrasuodatusta ja toinen nanosuodatusta juustoheran fraktioinnissa. Ultrasuodatuskalvon valinta tehtiin perustuen kalvon cut-off lukuun, joka oli määritetty polyetyleeniglykoliliuoksilla olosuhteissa, joissa konsentraatiopolariosaatioei häiritse mittausta. Kriittisen vuon konseptia käytettiin sopivan proteiinikonsentraation löytämiseksi ultrasuodatuskokeisiin, koska heraproteiinit ovat tunnetusti kalvoa likaavia aineita. Ultrasuodatuskokeissa tutkittiin heran eri komponenttien suodattumista kalvon läpi ja siihen vaikuttavia ominaisuuksia. Herapermeaattien peptidifraktiot analysoitiin kokoekskluusiokromatografialla ja MALDI-TOF massaspektrometrillä. Kokeissa käytettävien nanosuodatuskalvojen keskimääräinen huokoskoko analysoitiin neutraaleilla liukoisilla aineilla ja zeta-potentiaalit virtauspotentiaalimittauksilla. Aminohappoja käytettiin malliaineina tutkittaessa huokoskoon ja varauksen merkitystä erotuksessa. Aminohappojen retentioon vaikuttivat pH ja liuoksen ionivahvuus sekä molekyylien väliset vuorovaikutukset. Heran ultrasuodatuksessa tuotettu permeaatti, joka sisälsi pieniä peptidejä, laktoosia ja suoloja, nanosuodatettiin happamassa ja emäksisessä pH:ssa. Emäksisissä oloissa tehdyssä nanosuodatuksessa foulaantumista tapahtui vähemmän ja permeaattivuo oli parempi. Emäksisissä oloissa myös selektiivisyys laktoosin erotuksessa peptideistä oli parempi verrattuna selektiivisyyteen happamissa oloissa.

A Study on Fractionation and Ultrafiltration of Proteins with Characterized Modified and Unmodified Membranes

Membrane filtration has become increasingly attractive in the processing of both foodand biotechnological products. However, the poor selectivity of the membranes and fouling are the critical factors limiting the development of UF systems for the specific fractionation of protein mixtures. This thesis gives an overview on fractionation of proteins from model protein solutions or from biological solutions. An attempt was made to improve the selectivity of the available membranes by modifying the membranes and by exploiting the different electrostatic interactions between the proteins and the membrane pore surfaces. Fractionation and UF behavior of proteins in the model solutions and in the corresponding biological solutions were compared. Characterization of the membranes and protein adsorptionto the membrane were investigated with combined flux and streaming potential studies. It has been shown that fouling of the membranes can be reduced using "self-rejecting" membranes at pH values where electrostatic repulsion is achieved between the membrane and the proteins in solution. This effect is best shown in UF of dilute single protein solutions at low ionic strengths and low pressures. Fractionation of model proteins in single, binary, and ternary solutionshas been carried out. The results have been compared to the results obtained from fractination of biological solutions. It was generally observed that fractination of proteins from biological solutions are more difficult to carry out owingto the presence of non studied protein components with different properties. Itcan be generally concluded that it is easier to enrich the smaller protein in the permeate but it is also possible to enrich the larger protein in the permeateat pH values close to the isoelectric point of the protein. It should be possible to find an optimal flux and modification to effectively improve the fractination of proteins even with very similar molar masses.

Effluent particle removal by microirrigation system filters

La distribución del número y del volumen de partículas, y la eficiencia de eliminación de las partículas y los sólidos en suspensión de diferentes efluentes y sus filtrados, fueron analizadas para estudiar si los filtros más usuales en los sistemas de riego localizado eliminan las partículas que pueden obturar los goteros. En la mayoría de los efluentes y filtrados fue mínimo el número de partículas con diámetros superiores a 20 μm. Sin embargo, al analizar la distribución del volumen de las partículas, en los filtrados aparecieron partículas de dimensiones superiores a la luz de los filtros de anillas y malla, siendo el filtro de arena el que retuvo las partículas de mayor diámetro. La eficiencia de los filtros para retener partículas se debió más al tipo de efluente que al filtro. Se verificó también que la distribución del número de partículas sigue una relación de tipo potencial. Analizando el exponente β de la ley potencial, se halló que los filtros no modificaron significativamente la distribución del número de partículas de los efluentes.