1.3. Definition of the parameter boundaries for GSA Setting the boundaries of the parameter space for GSA for large scale models represents a distinct task, as on the one hand, they should be relatively wide to justify the globality of the analysis, but on the other hand the boundaries should be reasonably Dabrafenib clinical trial narrow due to the limitations imposed by the resulting computational time and available CPU resources. Since our GSA implementation is specifically directed towards identification of appropriate drug targets and cancer-related biomarkers within signalling networks, the parameter ranges should be able to incorporate potential

effects of drugs and genetic modifications on the level of protein activities. In our analysis we assumed that up to a 10-fold reduction in parameter value could imitate an efficient suppression of the protein activity by an anti-cancer drug. It’s R428 nmr worth noting, that it is difficult to predict the real extent of the

inhibition of the protein activity by targeted drugs in vivo, since it depends on many factors – drug transformations within the body, efficiency of drug delivery to the target, etc. However, there is a good reason to believe that in vivo drugs cause not more than a 10-fold inhibition of targeted protein activity. For example, in our experiments pertuzumab caused up to 40% inhibition of ErbB3/2 dimer formation ( Faratian et al., 2009b). Recent findings of Gaborit et al. (2011) also confirmed that anti-ErbB2 drugs cause not more than 40–20% of reduction of ErbB2 heterodimerization, when used alone, and up to 70%, when combined with an EGFR inhibitor. These estimates have been made for drugs targeting cellular membrane receptors. For intracellular targets the level of inhibition may be even lower, Bay 11-7085 due to additional factors, limiting drug availability within the cell (e.g. due to inefficient drug transfer into

the cell). Similarly, we assumed that up to a 10-fold variation of parameter value above and below its nominal value (that in total provides effectively a 100-fold variation) could approximate modification of protein activity by the majority of mutations. For example, a PIK3CA mutation is thought to increase PI3K activity only two-fold (Carson et al., 2008), whereas lipid phosphatase activity of PTEN can differ up to 100-fold between different PTEN mutants, as assessed in (Rodriguez-Escudero et al., 2011). Importantly, in our analysis the parameters are varied within the 10-fold range around the nominal value, thus allowing us to consider many possible levels of protein inhibition/activation, including both weak and strong effects. Thus, for our ErbB2/3 network model the constraints for the majority of kinetic parameters were set to span one order of magnitude above and below the values obtained in one of our best data fits. In some cases the parameter ranges were adjusted to match the order of magnitude of other existing estimates (see Additional File 2 and Table S2).

University of Costa Rica, San José, Costa Rica—Enrique Freer (director, HPV diagnostics laboratory), José Bonilla (head, HPV immunology laboratory). United States National Cancer Institute, Bethesda, MD, USA—Allan Hildesheim (co-principal investigator & NCI co-project officer), Aimée R. Kreimer (co-investigator), Douglas R. Lowy (DRL; HPV virologist), Nora Macklin (trial coordinator),

Mark Schiffman (medical monitor & NCI Olaparib manufacturer co-project officer), John T. Schiller (JTS; HPV virologist), Mark Sherman (QC pathologist), Diane Solomon (medical monitor & QC pathologist), Sholom Wacholder (statistician). SAIC, NCI-Frederick, Frederick, MD, UDA—Ligia Pinto (head, HPV immunology laboratory), Troy Kemp (immunologist). Georgetown University, JAK2 inhibitors clinical trials Washington, DC, USA—Mary Sidawy (histopathologist). DDL Diagnostic Laboratory, Netherlands—Wim Quint (virologist, HPV DNA testing), Leen-Jan van Doorn (HPV DNA testing). F.S., G.C. and G.D. are employees of the GlaxoSmithKline group of companies. G.D. and F.S. receive stock options/restricted shares from the GlaxoSmithKline group of companies, and G.D. has previously received patent royalties

from Wyeth Vaccines. The other authors declare that they have no conflicts of interest. The NCI receives licensing fees for HPV vaccines. A.H. (NCI principal investigator), S.W. (NCI statistician) and R.H. (Costa Rica principal investigator) were responsible for the design and conduct of the study. From GlaxoSmithKline Vaccines, G.D. contributed to discussions regarding trial Adenylyl cyclase design and conduct. G.C. contributed toward data analyses and interpretation, and prepared the statistical analysis report submitted to the FDA. F.S. and G.D. critically reviewed the study report in close collaboration with NCI and Costa Rica co-principal investigators. A.H. wrote the manuscript, and all other

authors reviewed and commented on the initial and subsequent drafts. All authors had full access to the data and gave final approval before submission. The Costa Rica HPV vaccine trial is a long-standing collaboration between investigators in Costa Rica and the National Cancer Institute (NCI). The trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women’s Health, and done with the support from the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GlaxoSmithKline Biologicals, under a Clinical Trials Agreement with the NCI. GlaxoSmithKline Biologicals also provided support for aspects of the trial associated with regulatory submission needs of the company under US Food and Drug Administration BB-IND 7920. JTS and DRL report that they are named inventors on US Government-owned HPV vaccine patents that are licensed to GlaxoSmithKline and Merck. They are entitled to limited royalties as specified by federal law.

Extensive pre-administration piloting was conducted with a convenience sample of physicians

similar to the study population. A clear need to slim down the questionnaire emerged. Therefore, only questions concerning APC mutations were included among the knowledge items concerning the inherited forms of colorectal cancer, thus excluding questions regarding gene mutations associated with the Lynch syndrome. Other minor revisions included changes to the questionnaire item wording and format. Multiple logistic regression analysis was performed. Five models were built to identify the predictors of physicians knowledge of predictive genetic testing for breast and colorectal cancer (Models 1 and 2), attitudes (Model 3), and professional use of predictive genetic tests for breast and Buparlisib Onalespib cost colorectal cancer (Models 4 and 5). For purposes of analyses, the outcome variables “knowledge” and “attitudes” in Models 1–3, originally consisting of multiple categories, were collapsed into two levels. In brief, for the variable knowledge physicians were divided in those who agreed with all correct responses versus all others, while for attitudes responders were grouped into those who showed a positive attitude in at least 70% of the questions versus all others (see Table 3 for the details of dichotomization). The following physician characteristics were initially tested in all models as predictor variables:

location; gender; age; exposure to cancer genetic testing during graduate/postgraduate courses; attendance to postgraduate epidemiology and Evidence Based Medicine (EBM) courses; knowledge of the English language; internet access in the workplace; hours per week dedicated to continuing medical education; the average number of patients treated in a typical week; patient requests for genetic tests in the previous year; the presence of genetic testing laboratories in the geographical area of professional activity; and a personal or family history of breast or colorectal cancer. The variable “adequate knowledge” was also included in the model concerning

attitudes, and the variables “adequate knowledge” and “positive attitudes” were included in over the models concerning the professional use of predictive genetic tests (see Table 3 for the details of dichotomization). The model building strategy suggested by Hosmer and Lemeshow (2000) was used and included the following steps: (a) univariate analysis of each variable and inclusion if the p-value was lower than 0.25; (b) backward elimination of each variable that did not contribute to the model on the ground of the Likelihood Ratio Test using a cut-off of 0.05 level of significance; variables whose exclusion markedly altered the coefficient of the remaining variables were kept in the model; (c) testing of interaction terms using a cut-off of 0.15 level of significance.

By the chemical assignments obtained from the spectral studies, the compound is not identical with similar antibiotics described in literature. The antimicrobial compound is therefore identified as N-ethyl-2-(2-(3-hydroxybutyl)

phenoxy) acetamide and the probable structure is shown in ( Fig. 3). The purified compound showed broad spectrum of antimicrobial activity against selective Gram positive bacteria, Gram negative bacteria and fungi. The lowest MIC was recorded against E. coli and B. cereus (10 μg/ml) and highest against S. aureus (28 μg/ml). The MIC of fungi was lowest (35 μg/ml) for A. flavus and highest (86 μg/ml) for C. albicans ( Table 4). The results showed that, the growth and antimicrobial

compound production was highest EGFR inhibitor with glucose than that of other carbon PD0325901 order sources used in the study. The maximum yield was obtained with 10 g/l concentration of glucose in the medium, while at 12.5 g/l glucose concentration the metabolite yield was relatively close to that of 10 g/l glucose concentration but the growth was less (3 mg/ml). Further, increase or decrease in glucose concentration reduced the growth and yield. Nitrogen source in addition to the carbon source also play an important role in the antibiotic production. In comparison with organic nitrogen sources, inorganic nitrogen sources produced more metabolite. The Cediranib (AZD2171) maximum yield was obtained with NH4NO3 at 2.5 g/l concentration in the medium, other nitrogen

sources also favored good growth but the yield was less in comparison to NH4NO3. The results suggest that the level of antibiotic production may be greatly influenced by the nature and the type of the nitrogen source supplied in the culture medium. In addition to the carbon and nitrogen sources, addition of metal ions such as K2HPO4 at 2.0 g/l and MgSO4.7H2O at 1.0 g/l concentration strongly influenced the yield and enhanced the metabolite production. Further it is clear that above and below the critical concentrations of metal ions effect the growth and antibiotic production significantly. The isolate BTSS-301 showed a narrow range of incubation temperature for relatively good growth and production. The organism appeared to be mesophilic in nature with the optimum temperature of 30 °C. The balanced use of carbon and nitrogen sources form the basis for pH control as buffering capacity is providing by the proteins, peptides and amino acids in the medium. The results evidently suggest that the isolate is capable of producing antimicrobial compound, only with in the optimum pH range (6.8–7.6) although; the strains withstands a broad range of pH (5.2–10.0).10 The results indicated that the optimum incubation period and agitation for maximum production was 96 h at 180 rpm. The yield was decreased at both lower and higher agitation speeds.

Therefore, after treatment of the primary tumor, in the presence of only minimal residual disease and with little immune suppression, there is sufficient time to develop an effective immune response with adjuvant dendritic cell vaccination. Furthermore, patients with a high risk for relapse could be selected

based on monosomy 3 status. The presence of monosomy 3 in the primary tumor is accepted widely as the most simple and reliable prognostic parameter, identified in approximately 50% of patients with primary uveal melanoma.46 Long-term studies have shown a 3-year survival rate of 40% if monosomy 3 is present, whereas tumors with normal chromosome 3 status rarely give rise to metastatic disease

and have a 90% 3-year survival rate.47 To date, no adjuvant OSI744 therapy has shown survival benefit in uveal melanoma,48 and 49 and because immunologic responses are seen more frequently in patients before clinically detectable metastasis develop, dendritic cell vaccination may be a good candidate. We currently are investigating this strategy in a randomized study. In conclusion, we show that dendritic cell vaccination is feasible and safe in metastatic uveal melanoma. Our data suggest the potential of dendritic cell-based immunotherapy to INK1197 clinical trial enhance the host’s antitumor immunity and that it may be associated with longer than average overall survival times in metastatic uveal melanoma. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and Adenosine none were reported. Supported by Grants KUN2010-4722 and KUN2009-4402 from the Dutch Cancer Society, the Netherlands; Grant ENCITEHEALTH-F5-2008-201842 from the European Union; Grant NWO-Vidi-917.76.363 from The Netherlands Organization for Scientific Research, the Netherlands; the Nijmeegs Offensief Tegen Kanker Foundation, Nijmegen, the Netherlands; and the Stichting

Combined Ophthalmic Research Rotterdam and Stichting Wetenschappelijk Onderzoek het Oogziekenhuis, Rotterdam, the Netherlands. Dr Figdor received the Spinoza award of the Netherlands Organization for Scientific Research and Grant ERC-2010-AdG-269019-PATHFINDER from the European Research Council Advanced). Involved in Design and conduct of study (C.J.A.P., C.G.F., I.J.M.d.V.); Analysis and interpretation of data (K.F.B., H.W.M., E.H.J.G.A., G.S., J.E.E.K., P.G.C., A.d.K., C.J.A.P., D.P., C.G.F., I.J.M.d.V.); and Preparation (K.F.B., G.S., H.W.M., I.J.M.d.V.) and critical review and approval (K.F.B., H.W.M., E.H.J.G.A., G.S., J.E.E.K., P.G.C., A.d.K., C.J.A.P., D.P., C.G.F., I.J.M.d.V.) of manuscript.

Such

studies are also essential in higher age groups for better understanding of RV spread in the community. In our earlier study carried out to characterise RV infections in adolescents and adults, a rise in RVA infections in NVP-BGJ398 solubility dmso 2004–2007 as compared to 1993–1996 was reported [15]. Infections with uncommon G-P and mixed infections were higher in these age groups when compared to those in children. In the present study, the surveillance of RV infections was continued in the same age groups of patients with acute gastroenteritis to understand the temporal variations in the rate of RV infections and the strains during the 5 year period, 2008–2012. A total of 371 stool specimens were collected Dactolisib nmr from adolescent (10–18 years) and adult (>18 years) cases of acute gastroenteritis, admitted to or visiting out-patient departments

of local hospitals from Pune city during 2008–2012. The study was approved by the ethical committee of the National Institute of Virology. Epidemiologic data including age, gender, dates of diarrhoea onset and specimen collection were available from all patients. Ten percent (w/v) stool suspension of each of the specimens was prepared in 0.01 M phosphate buffered saline (PBS), pH 7.2 containing 0.01 M CaCl2. The suspensions were centrifuged at 805 g for 15 min to remove debris. The supernatants were stored in aliquots L-NAME HCl at -70 ̊C until tested for RVA antigen and genotypes. All specimens were tested for the presence of RV by using Generic Assay ELISA kit for rotavirus (Cat. No. 6001, Germany) as per manufacturer’s instructions. Specimens with optical density (OD) values above the cut-off value (0.2 + mean value of OD of negative control wells) were considered positive for rotavirus antigen. RVA dsRNA was extracted from stool specimens by using TRIZOL®LS reagent (Invitrogen, Carlsbad, CA) as per the manufacturer’s protocol. The VP7 and VP4 genes were genotyped by multiplex reverse transcription

(RT)-PCR using the methods described earlier [16] and [17] and modified thermal cycling programme [18]. The full-length NSP4 genes (751 bp) and VP6 gene subgrouping region (379 bp) were amplified using the NSP4-F and NSP4-R primers [19] and forward (F) VP6 and reverse (R) VP6 primers [20], respectively, with the one step RT-PCR kit (Qiagen, Hilden, Germany). The PCR conditions involved initial reverse transcription step of 30 min at 45̊C and 95̊C for 15 min followed by 40 cycles of 94̊C for 1 min, 50̊C for 1 min, 70̊C for 2.5 min with a final extension at 70̊C for 7 min. All PCR products, including those from the first-round and multiplex PCRs, were analysed by electrophoresis using Tris acetate EDTA (TAE) buffer, pH 8.3 on 2% agarose gels, containing ethidium bromide (0.5 ug/ml) and visualised under UV illumination.

Seven groups of eight 5-week old female C57BL/6 mice were purchased from Charles River Laboratory and maintained at Novartis Vaccines Animal Care. Mice received three subcutaneous immunizations at 14 days-interval with 200 μL/dose of 1 μg of conjugated OAg. Mice were bled before the first immunization (day 0) and two weeks after each immunization. All animal protocols were approved by

the local animal ethical committee (approval N. AEC201018) and by the Italian Minister of Health in accordance with Italian law. Serum IgG, IgM and IgA levels against both OAg and CRM197 were measured by ELISA (see SI) [28] and [30]; day 42 sera were additionally assessed for serum bactericidal activity (SBA) and binding capacity (flow cytometry) of two www.selleckchem.com/products/SP600125.html invasive clinical isolates (see SI). Statistical analysis of ELISA results was conducted using Kruskal–Wallis test, with Dunn’s post hoc this website analysis (α = 0.05). NaIO4-based

oxidation affects vicinal diols to generate two aldehyde groups, opening the sugar ring. In the case of S. Typhimurium OAg, this reactivity can involve Rha and glucose (Glc) residues ( Fig. 1a). The resulting aldehyde groups can then react with the amine group on lysine residues of the carrier protein to form a covalent C N linkage, which is subsequently reduced to a stable C N bond with NaBH3CN. A further reduction step with NaBH4 was introduced to quench unreacted C O groups (see SI). The first reaction conditions applied to 2192 OAg were derived from an optimization performed with the LT2 S. Typhimurium laboratory strain (see SI). The HPLC-SEC profile of the oxidized OAg in comparison with the underivatized OAg (average MW of 20.5 kDa) showed a shift of the main peak to a slightly lower MW ( Fig. 2a and b). By micro BCA, 14% of OAg repeating units were found to be derivatized (calculated as number of oxidized monomers/total OAg repeating units × 100). HPAEC-PAD analysis showed that 14% of the Rha and 6.4% of the Glc residues were oxidized,

with 15.5% of total repeating units modified. All CRM197 in the conjugation mixture became linked to OAg, while 36% of OAg was conjugated. HPLC-SEC analysis demonstrated a shift for the conjugate to a higher MW compared with free protein ( Fig. 3b and a) and was used for estimating conjugate MW distribution ( Table 1). Oxidation of 2192 OAg with TEMPO allowed random formation of aldehyde groups along the chain without opening the sugar rings, as oxidation with NaIO4 does. TEMPO oxidation targets primary alcohol groups. These are present in Man, Gal and Glc residues of S. Typhimurium OAg, with one per monosaccharide. The resulting aldehyde groups can then react with the lysine residues on the carrier protein by reductive amination as for derivatization with NaIO4 ( Fig. 1a). Oxidation of 2192 OAg with TEMPO was followed over time and the % of OAg monomers oxidized increased from 15% after 2 h to 36% after 12 h, as detected by micro BCA.

Choi and LeDoux (2003) had rodents learn to perform an instrumental shuttling response in the presence of a CS to avoid an imminent electric shock. A specific subset of ‘non-learners’ were unable to perform this avoidance response because of high levels of conditioned fear responses (i.e., freezing). However, Doxorubicin nmr after lesions to the CE, these animals were capable of adopting the avoidance strategy, indicating that excessive fear expression can impair the capacity to perform

actions that promote safety and reduce fear. This implies that higher levels of trait anxiety or acute exposure to stress may impair the capacity to acquire or retain avoidance strategies when confronted with threat. Of the limited studies that have directly assessed the effects of stress or stress hormones on avoidance learning, most have examined passive (i.e., inhibitory) avoidance learning. In contrast to active avoidance processes that requires the use of an instrumental response to prevent or terminate an aversive outcome, passive avoidance requires the suppression

of an innate behavior in order to successfully avoid an aversive outcome. A common way to test passive avoidance is to measure the latency with which an animal crosses from a naturally preferred FK228 manufacturer darkened chamber that has been paired with shock to a less preferred bright chamber that the animal has learned to associate with safety. Passive avoidance involves the amygdala as well as the hippocampus due to the contextual nature of the task (Ogren and Stiedl, 2010). As with other forms of aversive learning, passive avoidance is dependent on stress hormones to facilitate learning and consolidation.

For example, blocking noradrenaline systemically or within the LA or B after avoidance training disrupts its consolidation as measured by weaker subsequent retention (Ferry et al., 1999, Gallagher et al., 1977, Liang et al., 1986 and Quirarte et al., 1997). In contrast, enhancing noradrenaline after avoidance training enhances its retention (McGaugh et al., 2002 and McIntyre Adenylyl cyclase et al., 2002). Furthermore, infusion of glucocorticoid agonists into the LA directly after training on a fear avoidance and escape task enhances subsequent retention, while GR antagonists infused prior to training impaired retention. Notably, infusions at either time point into the CE had no effect on memory retrieval (Roozendaal and McGaugh, 1997). The effect of acute stress on passive avoidance was recently tested in rodents. Before training, animals were classified into high, medium and low anxiety based on the elevated plus-maze test; subsequently, half of the mice in each group then underwent an acute stress manipulation. Stress altered avoidance performance in the high anxiety group only.

7 and 8 The activity of angelicin has been checked by using

two experimental cell systems, the human leukemic K562 cell line and human erythroid progenitors from normal donors. It has been observed that angelicin is a potent inducer of erythroid differentiation, gamma globin gene expression and fetal hemoglobin (HbF) production, thereby making it useful in the treatment of beta-thalassemia. 7 Rapamycin is a macrocyclic fermented product produced by Streptomyces hygroscopicus. Initially, its role as an antitumor and antifungal agent was tested. As it possesses lymphopenic properties therefore it is known to be a useful immunosuppressant. 9 It is AG-014699 in vitro FDA (food and drug administration) approved agent used for the prevention of acute renal allograft rejection. Its activity was tested by using two cell systems, the human leukemia K562 cell line and human erythroid progenitors isolated from normal donors and beta-thalassemia patients. When K562 cells were cultured in the presence of rapamycin, it induced activation and differentiation of K562

cells. Differentiation of K562 cells is associated with an increased expression of γ globin mRNA. It has been observed that rapamycin is more efficient than hydroxyurea for stimulating the production of γ globin mRNA and increasing HbF level. Rapamycin was found to increase HbF level in beta-thalassemic patients. 10 FT (fruit of Trichosanthes kirilowii MAXIM) is one of the most commonly used Chinese STK38 herbs. According to the Chinese medicine theory, FT is useful in treating breast cancer, diabetes, leukemia and bronchial diseases. Trametinib manufacturer It has been reported that the ethanol extract of FT significantly increased γ-globin mRNA expression and HbF level in K562 cultured cells. Its inducing effect is due to up-regulation of

p38 MAPK (mitogen activated protein kinase) signaling pathway and down-regulation of ERK (extracellular regulated protein kinase) signaling pathway. An ethanolic extract of the FT increases the HbF level to 2.6 folds in beta-thalassemia cells. Its inducing effect has been found to be more as compared to hydroxyurea positive control cells. The component of FT extract responsible for inducing HbF level in cultured cells is still unknown. There is a need to find out the component responsible for HbF induction by checking the activity of all the components present in raw FT. In order to promote the usage of FT ethanol (FT-EtOH) extract for the treatment of thalassemia, there is a need to elucidate the effect of FT-EtOH on precursor cells obtained from normal and beta-thalassemic patients. The potency of the extract should be examined clinically and its toxic effect should be checked for ensuring its safety on human subject. 11 Bergamot (Citrus bergamia Risso) is the popular fruit of Reggio Calabria region, South Italy. The peel of the ripe fruit is the source of bergamot oil.

Une dénutrition (IMC < 20 kg/m2) est d’autant plus fréquente que le VEMS est abaissé et représente à elle seule un facteur de risque de mortalité toutes causes confondues et de mortalité par BPCO indépendant de la sévérité

de l’obstruction bronchique (VEMS) [1]. La réhabilitation est un moment privilégié pour l’éducation thérapeutique du patient mais cette dernière faisant partie du parcours de soin dans la BPCO doit être réalisée même en dehors de toute réhabilitation, par tous les professionnels de santé formés à l’éducation thérapeutique. Les objectifs sont définis avec le patient lors du diagnostic éducatif, parmi eux on peut citer la compréhension de la maladie et des symptômes avant-coureurs d’une exacerbation, le sevrage tabagique, l’explication des traitements de fond et de l’exacerbation avec mise en place d’un plan d’action personnalisé, les techniques d’utilisation des dispositifs d’inhalation des Ibrutinib cost médicaments, l’apprentissage de la gestion de l’effort, drainage,

activités de la vie journalière, éventuels dispositifs type oxygène, aérosol, ventilation non invasive. Enfin, la mise en place du maintien des acquis avec l’intégration dans le quotidien du patient après réhabilitation d’une activité physique personnalisée (vélo, marche, escaliers, voire chant, etc.), trois à cinq fois par semaine pendant 30 à 45 minutes. La pratique de ces activités physiques pourra être favorisée par les associations sport santé ou les associations de patients. Sans ce changement essentiel de comportement, le bénéfice de la réhabilitation

ne perdure que quelques mois [6]. CDK inhibitors in clinical trials En cas d’insuffisance respiratoire chronique, la nécessité d’une oxygénothérapie (-)-p-Bromotetramisole Oxalate de longue durée ou d’une ventilation non invasive doit être précisément évaluée par le pneumologue. L’indication de l’oxygénothérapie de longue durée est strictement codifiée (encadré 3) ; utilisée plus de 15 heures par jour, elle augmente la survie, d’où l’importance majeure de l’évaluation et du renforcement de l’observance par tous les professionnels de santé impliqués dans la prise en charge. Une étude récente suggère que la ventilation non invasive chez des patients souffrant d’une BPCO hypercapnique pourrait aussi réduire la mortalité [42]. L’oxygénothérapie et la ventilation non invasive ne seront pas détaillées plus avant dans cet article. Chez les malades atteints de BPCO, l’OLD est indiquée lorsque, à distance d’un épisode aigu, et sous réserve d’une prise en charge thérapeutique optimale (c’est-à-dire associant arrêt du tabac, bronchodilatateurs et kinésithérapie), la mesure des gaz du sang artériel en air ambiant, réalisée à deux reprises, a montré : • soit une PaO2 ≤ 55 mmHg ; Chez les patients souffrant de BPCO sévère avec handicap important et distension pulmonaire majeure, des techniques de réduction du volume pulmonaire peuvent être envisagées en milieu très spécialisé. Leur objectif est essentiellement symptomatique, via l’amélioration de la mécanique ventilatoire.