Experience of 170 cases of ductal carcinoma in ' (DCIS)

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Identification of na\uefve HCV-1 patients with chronic hepatitis who may benefit from dual therapy with peg-interferon and ribavirin

Background & Aims The pool of HCV genotype 1 patients likely to be cured by peg-interferon and ribavirin remains to be quantified. Methods In 1045 patients treated with peg-interferon and ribavirin, two therapeutic strategies were confronted: the first one evaluated only baseline variables associated with sustained virological response (SVR), and the second one included the rapid virologic response (RVR) in addition to baseline predictors. An 80% SVR rate was the threshold to retain a strategy as clinically relevant. Results Overall, 414 patients (39.6%) attained SVR. In the first strategy, the hierarchy of features independently associated with SVR was IL28B CC genotype (OR 5.082; CI 3.637-7.101), low (80% SVR threshold. Only 26.6% of no-RVR patients attained SVR. Among the 255 RVR patients, the likelihood of SVR was 61.8% in those with unfavorable predictors, 80% in the presence of a single predictor, and 100% when both predictors were present. By using this model, 200 patients (19.1%) were predicted to have an 80% chance of being cured with dual therapy. Conclusions A consistent subset of na\uefve HCV-1 patients, identified by some baseline characteristics and RVR, may benefit from dual treatment with peg-interferon and ribavirin. \ua9 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

Transcriptional responses of Burkholderia cenocepacia to polymyxin B in isogenic strains with diverse polymyxin B resistance phenotypes

<p>Abstract</p> <p>Background</p> <p><it>Burkholderia cenocepacia </it>is a Gram-negative opportunistic pathogen displaying high resistance to antimicrobial peptides and polymyxins. We identified mechanisms of resistance by analyzing transcriptional changes to polymyxin B treatment in three isogenic <it>B. cenocepacia </it>strains with diverse polymyxin B resistance phenotypes: the polymyxin B-resistant parental strain K56-2, a polymyxin B-sensitive K56-2 mutant strain with heptoseless lipopolysaccharide (LPS) (RSF34), and a derivative of RSF34 (RSF34 4000B) isolated through multiple rounds of selection in polymyxin B that despite having a heptoseless LPS is highly polymyxin B-resistant.</p> <p>Results</p> <p>A heptoseless LPS mutant of <it>B. cenocepacia </it>was passaged through multiple rounds of selection to regain high levels of polymyxin B-resistance. This process resulted in various phenotypic changes in the isolate that could contribute to polymyxin B resistance and are consistent with LPS-independent changes in the outer membrane. The transcriptional response of three <it>B. cenocepacia </it>strains to subinhibitory concentrations of polymyxin B was analyzed using microarray analysis and validated by quantitative Real Time-PCR. There were numerous baseline changes in expression between the three strains in the absence of polymyxin B. In both K56-2 and RSF34, similar transcriptional changes upon treatment with polymyxin B were found and included upregulation of various genes that may be involved in polymyxin B resistance and downregulation of genes required for the synthesis and operation of flagella. This last result was validated phenotypically as both swimming and swarming motility were impaired in the presence of polymyxin B. RSF34 4000B had altered the expression in a larger number of genes upon treatment with polymyxin B than either K56-2 or RSF34, but the relative fold-changes in expression were lower.</p> <p>Conclusions</p> <p>It is possible to generate polymyxin B-resistant isolates from polymyxin B-sensitive mutant strains of <it>B. cenocepacia</it>, likely due to the multifactorial nature of polymyxin B resistance of this bacterium. Microarray analysis showed that <it>B. cenocepacia </it>mounts multiple transcriptional responses following exposure to polymyxin B. Polymyxin B-regulated genes identified in this study may be required for polymyxin B resistance, which must be tested experimentally. Exposure to polymyxin B also decreases expression of flagellar genes resulting in reduced swimming and swarming motility.</p

Mesoglycan connects Syndecan-4 and VEGFR2 through Annexin A1 and formyl peptide receptors to promote angiogenesis in vitro.

Mesoglycan is a mixture of glycosaminoglycans (GAG) with fibrinolytic effects and the potential to enhance skin wound repair. Here, we have used endothelial cells isolated from Wild Type (WT) and Syndecan-4 null (Sdc4-/-) C57BL/6 mice to demonstrate that mesoglycan promotes cell motility and in vitro angiogenesis acting on the co-receptor Syndecan-4 (SDC4). This latter is known to participate in the formation and release of extracellular vesicles (EVs). We characterized EVs released by HUVECs and assessed their effect on angiogenesis. Particularly, we focused on Annexin A1 (ANXA1) containing EVs, since they may contribute to tube formation via interactions with Formyl peptide receptors (FPRs). In our model, the bond ANXA1-FPRs stimulates the release of vascular endothelial growth factor (VEGF-A) that interacts with vascular endothelial receptor-2 (VEGFR2) and activates the pathway enhancing cell motility in an autocrine manner, as shown by Wound-Healing/invasion assays, and the induction of Endothelial to Mesenchymal Transition (EndMT). Thus, we have shown for the first time that mesoglycan exerts its pro-angiogenic effects in the healing process triggering the activation of the three interconnected molecular axis: mesoglycan-SDC4, EVs-ANXA1-FPRs and VEGF-A-VEGFR2

Physiotherapists' experiences of physiotherapy interventions in scientific physiotherapy publications focusing on interventions for children with cerebral palsy: a qualitative phenomenographic approach

Background: Physiotherapy research concerning interventions for children with CP is often focused on collecting evidence of the superiority of particular therapeutic methods or treatment modalities. Articulating and documenting the use of theory, instrumentation and research design and the assumptions underlying physiotherapy research interventions are important. Physiotherapy interventions focusing on children with Cerebral Palsy should, according to the literature, be based on a functional and environmental perspective with task-specific functional activity, motor learning processes and Family-Centred Service i.e. to enhance motor ability and improve capacity so that the child can perform the tasks necessary to participate actively in everyday life. Thus, it is important to coordinate the norms and values of the physiotherapist with those of the family and child. The aim of this study was to describe how physiotherapists' experiences physiotherapy interventions for children with CP in scientific physiotherapy publications written by physiotherapists. Methods: A qualitative phenomenographic approach was used. Twenty-one scientific articles, found in PubMed, strategically chosen according to year of publication (2001-2009), modality, journals and country, were investigated. Results: Three qualitatively different descriptive categories were identified: A: Making it possible a functional-based intervention based on the biopsychosocial health paradigm, and the role of the physiotherapist as collaborative, interacting with the child and family in goal setting, intervention planning and evaluation, B: Making it work an impairment-based intervention built on a mixed health paradigm (biomedical and biopsychosocial), and the role of the physiotherapist as a coach, leading the goal setting, intervention planning and evaluation and instructing family members to carry out physiotherapist directed orders, and; C: Making it normal an impairment-based intervention built on a biomedical health paradigm, and the role of the physiotherapist as an authoritative expert who determine goals, intervention planning and evaluation. Conclusions: Different paradigms of health and disability lead to different approaches to physiotherapy which influence the whole intervention process regarding strategies for the assessment and treatment, all of which influence Family-Centred Service and the child's motor learning strategies. The results may deepen physiotherapists' understanding of how different paradigms of health influence the way in which various physiotherapy approaches in research seek to solve the challenge of CP

Metabolic disorders across hepatocellular carcinoma in Italy

BACKGROUND: Metabolic disorders are well-known risk factors for HCC. Conversely, their impact on the natural history of HCC is not established. This study aimed at evaluating the impact of metabolic disorders on clinical features, treatment and survival of HCC patients regardless of its aetiology. METHODS: We analysed the ITA.LI.CA database regarding 839 HCC patients prospectively collected. The following metabolic features were analysed: BMI, diabetes, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. According to these features, patients were divided into 3 groups: 0-1, 2 and 3-5 metabolic features. RESULTS: As compared with patients with 0-1 metabolic features, patients with 3-5 features showed lower percentage of HCC diagnosis on surveillance (P = .021), larger tumours (P = .038), better liver function (higher percentage of Child-Pugh class A [P = .007] and MELD &lt; 10 [P = .003]), higher percentage of metastasis (P = .024) and lower percentage of portal vein thrombosis (P = .010). The BCLC stage and treatment options were similar among the 3 groups, with the exception of a less frequent access to loco-regional therapies for BCLC stage B patients with 3-5 features (P = .012). Overall survival and survival according to BCLC stage and/or treatment did not significantly differ among the 3 groups. Only using a probabilistic sensitivity analysis, diabetic patients showed a lower survival (P = .046). MELD score, HCC morphology, nodule size, BCLC stage, portal vein thrombosis and metastasis were independent predictors of lead-time adjusted survival. CONCLUSIONS: Our "real world" study suggests that metabolic disorders shape the clinical presentation of HCC but do not seem to play a major role in setting patient survival.Background: Metabolic disorders are well-known risk factors for HCC. Conversely, their impact on the natural history of HCC is not established. This study aimed at evaluating the impact of metabolic disorders on clinical features, treatment and survival of HCC patients regardless of its aetiology. Methods: We analysed the ITA.LI.CA database regarding 839 HCC patients prospectively collected. The following metabolic features were analysed: BMI, diabetes, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. According to these features, patients were divided into 3 groups: 0-1, 2 and 3-5 metabolic features. Results: As compared with patients with 0-1 metabolic features, patients with 3-5 features showed lower percentage of HCC diagnosis on surveillance (P&nbsp;=.021), larger tumours (P&nbsp;=.038), better liver function (higher percentage of Child-Pugh class A [P&nbsp;=.007] and MELD&nbsp;&lt;&nbsp;10 [P&nbsp;=.003]), higher percentage of metastasis (P&nbsp;=.024) and lower percentage of portal vein thrombosis (P&nbsp;=.010). The BCLC stage and treatment options were similar among the 3 groups, with the exception of a less frequent access to loco-regional therapies for BCLC stage B patients with 3-5 features (P&nbsp;=.012). Overall survival and survival according to BCLC stage and/or treatment did not significantly differ among the 3 groups. Only using a probabilistic sensitivity analysis, diabetic patients showed a lower survival (P&nbsp;=.046). MELD score, HCC morphology, nodule size, BCLC stage, portal vein thrombosis and metastasis were independent predictors of lead-time adjusted survival. Conclusions: Our \u201creal world\u201d study suggests that metabolic disorders shape the clinical presentation of HCC but do not seem to play a major role in setting patient survival

High Confidence Prediction of Essential Genes in Burkholderia Cenocepacia

BACKGROUND: Essential genes are absolutely required for the survival of an organism. The identification of essential genes, besides being one of the most fundamental questions in biology, is also of interest for the emerging science of synthetic biology and for the development of novel antimicrobials. New antimicrobial therapies are desperately needed to treat multidrug-resistant pathogens, such as members of the Burkholderia cepacia complex. METHODOLOGY/PRINCIPAL FINDINGS: We hypothesize that essential genes may be highly conserved within a group of evolutionary closely related organisms. Using a bioinformatics approach we determined that the core genome of the order Burkholderiales consists of 649 genes. All but two of these identified genes were located on chromosome 1 of Burkholderia cenocepacia. Although many of the 649 core genes of Burkholderiales have been shown to be essential in other bacteria, we were also able to identify a number of novel essential genes present mainly, or exclusively, within this order. The essentiality of some of the core genes, including the known essential genes infB, gyrB, ubiB, and valS, as well as the so far uncharacterized genes BCAL1882, BCAL2769, BCAL3142 and BCAL3369 has been confirmed experimentally in B. cenocepacia. CONCLUSIONS/SIGNIFICANCE: We report on the identification of essential genes using a novel bioinformatics strategy and provide bioinformatics and experimental evidence that the large majority of the identified genes are indeed essential. The essential genes identified here may represent valuable targets for the development of novel antimicrobials and their detailed study may shed new light on the functions required to support life

Thermal modeling of lesion growth with radiofrequency ablation devices

BACKGROUND: Temperature is a frequently used parameter to describe the predicted size of lesions computed by computational models. In many cases, however, temperature correlates poorly with lesion size. Although many studies have been conducted to characterize the relationship between time-temperature exposure of tissue heating to cell damage, to date these relationships have not been employed in a finite element model. METHODS: We present an axisymmetric two-dimensional finite element model that calculates cell damage in tissues and compare lesion sizes using common tissue damage and iso-temperature contour definitions. The model accounts for both temperature-dependent changes in the electrical conductivity of tissue as well as tissue damage-dependent changes in local tissue perfusion. The data is validated using excised porcine liver tissues. RESULTS: The data demonstrate the size of thermal lesions is grossly overestimated when calculated using traditional temperature isocontours of 42°C and 47°C. The computational model results predicted lesion dimensions that were within 5% of the experimental measurements. CONCLUSION: When modeling radiofrequency ablation problems, temperature isotherms may not be representative of actual tissue damage patterns