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Exercise training (ExTr) is largely used to improve functional capacity in patients with chronic obstructive pulmonary disease (COPD). However, ExTr only partially restores muscle function in patients with COPD, suggesting that confounding factors may limit the efficiency of ExTr. In the present study, we hypothesized that skeletal muscle adaptations triggered by ExTr could be compromised in hypoxemic patients with COPD. Vastus lateralis muscle biopsies were obtained from patients with COPD who were either normoxemic ( n = 15, resting arterial Po2 = 68.5 ± 1.5 mmHg) or hypoxemic ( n = 8, resting arterial Po2 = 57.0 ± 1.0 mmHg) before and after a 2-mo ExTr program. ExTr induced a significant increase in exercise capacity both in normoxemic and hypoxemic patients with COPD. However, ExTr increased citrate synthase and lactate dehydrogenase enzyme activities only in skeletal muscle of normoxemic patients. Similarly, muscle fiber cross-sectional area and capillary-to-fiber ratio were increased only in patients who were normoxemic. Expression of atrogenes (MuRF1, MAFbx/Atrogin-1) and autophagy-related genes (Beclin, LC3, Bnip, Gabarapl) remained unchanged in both groups. Phosphorylation of Akt (Ser473), GSK-3β (Ser9), and p70S6k (Thr389) was nonsignificantly increased in normoxemic patients in response to ExTr, but it was significantly decreased in hypoxemic patients. We further showed on C2C12 myotubes that hypoxia completely prevented insulin-like growth factor-1-induced phosphorylation of Akt, GSK-3β, and p70S6K. Together, our observations suggest a role for hypoxemia in the adaptive response of skeletal muscle of patients with COPD in an ExTr program.

After highlighting the difficulties encountered while implementing a supervisor on actual industrial controllers and different approaches already suggested to tackle them, this paper presents a signal-interpreted approach to the Supervisory Control Theory (SCT) framework. This work focuses on further developments of this approach for reactive systems. Due to fundamental differences between event- and signal-based approaches, new algorithms have to be implemented to apply an SCT approach on the basis of signal-interpreted Boolean finite automata extended with variables. Also, compared to a previous version of this approach, partially controllable signals are introduced.

Sepsis induced loss of muscle mass and function contributes to promote physical inactivity and disability in patients. In this experimental study, mice were sacrificed 1, 4, or 7 days after cecal ligation and puncture (CLP) or sham surgery. When compared with diaphragm, locomotor muscles were more prone to sepsis-induced muscle mass loss. This could be attributed to a greater activation of ubiquitin-proteasome system and an increased myostatin expression. Thus, this study strongly suggests that the contractile activity pattern of diaphragm muscle confers resistance to atrophy compared to the locomotor gastrocnemius muscle. These data also suggest that a strategy aimed at preventing the activation of catabolic pathways and preserving spontaneous activity would be of interest for the treatment of patients with sepsis-induced neuromyopathy.

The regenerative and immunomodulatory activity of mesenchymal stromal cells (MSCs) is partially mediated by secreted vesicular factors. Extracellular vesicles (EVs) exocytosed by MSCs are gaining increased attention as prospective non-cellular therapeutics for a variety of diseases. However, the lack of suitable in vitro assays to monitor the therapeutic potential of EVs currently restricts their application in clinical studies. We have evaluated a dual in vitro immunomodulation potency assay that reproducibly reports the inhibitory effect of MSCs on induced T-cell proliferation and the alloantigen-driven mixed leukocyte reaction of pooled peripheral blood mononuclear cells in a dose-dependent manner. Phytohemagglutinin-stimulated T-cell proliferation was inhibited by MSC-derived EVs in a dose-dependent manner comparable to MSCs. In contrast, inhibition of alloantigen-driven mixed leukocyte reaction was only observed for MSCs, but not for EVs. Our results support the application of a cell-based in vitro potency assay for reproducibly determining the immunomodulatory potential of EVs. Validation of this assay can help establish reliable release criteria for EVs for future clinical studies.

This paper describes the design of a system to monitor floor vibrations in an office building and an analysis of several months worth of collected data. Floors of modern office buildings are prone to occupant-induced vibrations. The contributing factors include long spans, slender and flexible designs, use of lightweight materials and low damping. As a result, resonant frequencies often fall in the range easily excited by normal footfall loading, creating potential serviceability problems due to undesirable levels of vibrations. This study investigates in-situ performance of a non-composite timber-concrete floor located in a recently constructed innovative multi-storey office building. The floor monitoring system consists of several displacement transducers to measure long-term deformations due to timber and concrete creep and three accelerometers to measure responses to walking forces, the latter being the focus of this paper. Floor response is typically complex and multimodal and the optimal accelerometer locations were decided with the help of the effective independence-driving point residue (EfI-DPR) technique. A novel approach to the EfI-DPR method proposed here uses a combinatorial search algorithm that increases the chances of obtaining the globally optimal solution. Several months worth of data collected by the monitoring system were analyzed using available industry guidelines, including ISO2631-1:1997(E), ISO10137:2007(E) and SCI Publication P354. This enabled the evaluation of the floor performance under real operating conditions.

To make good communication choices for their children who are deaf or hard of hearing, hearing parents must develop their understanding of hearing loss.

A low cost and low temperature MEMS transfer process is presented. The process is based on adhesion control of molded electroplated Ni microstructures on donor wafer by using plasma deposited fluorocarbon film. Adhesive bonding of the microstructures on the target wafer using BCB sealing enables mechanical tearing out from the donor wafer. This proposed process has allowed us to realize from 7 µm down to 700 nm thick Ni patterns on Si, Pyrex glass wafers and Kapton foils. Multiple transfers lead to Ni stacked microstructures. Because this process is simple and only involves a low temperature (250°C) heating of the host wafer, it is highly versatile and suitable for various applications and brings new perspectives towards 3D integration of MEMS/NEMS.

Zusammenfassung: Der ELISA-Mikrotest wurde in der Diagnostik von drei tiefen Mykosen verwendet: Aspergillose, Cryptococcose und Candidose. Insgesamt untersuchten wir mehr als 600 Seren. In jedem Falle verwendeten wir metabolische und somatische Antigene und benutzten eine in Grenoble entwickelte modifizierte Technik (Mikro-ELISA-Test, bei dem das Konjugat mit Peroxydase markiert wird. Die Sichtbarmachung erfolgt unter Verwendung von Orthotolidine). Die Resultate wurden in Einheiten der optischen Dichte (OD) bei 630 nm abgelesen. Der diagnostische Wert dieses Tests scheint sehr gut zu sein: Bei der Aspergillose findet sich eine vollstandige Ubereinstimmung mit der Immunelektrophorese und bei der Candidose werden gleichwertige Ergebnisse wie in der Immunfluoreszenz erhalten. Bei der Cryptococcose sind die ubrigen serologischen Tests nicht verwertbar. Dagegen wurde mit dem ELISA-Mikro-Test in zwei Fallen einer nachgewiesenen Cryptococcose die Diagnose serologisch bestatigt. Der gleiche Test wurde auch fur den Nachweis von zirkulierenden Antigenen bei 3 Fallen einer bestatigten Candida-Septikamie benutzt. Gegenwartig wird dieses Verfahren auch bei der Cryptococcose untersucht. Summary: Micro-test ELISA was used for the diagnosis of three visceral mycoses: Aspergillosis, Cryptococcosis und Candidosis. We have studied more than 600 sera. We used for each case metabolic and somatic antigens and a modified technic used for the first time in Grenoble (micro ELISA where the conjugate is labelled with peroxydase, revealed by orthotolidine). Results were expressed as the optical density at 630 nm. The diagnostic value of the test seems to be very good: for Aspergillosis a perfect concordance with immunoelectrophoresis and for Candidosis the results are the same as those obtained by immunofluorescence. In cryptococcosis – all the serological tests are unable to be used: Meanwhile microtest ELISA confirmed 2 proved cases. The same test has been used for the detection of circulating antigens in 3 cases of confirmed invasive Candida infections. The same type of procedure is actually studied for cryptococcosis.

A survey was conducted with state level chapters from Family Voices, Parent Training and Information Centers, and Parent–to-Parent USA to understand their current activities support families of children with hearing-related concerns and to identify gaps in their ability to support families of children who are D/HH. these organizations reported that they are contacted with parent requests for information in regard to family support opportunities, early intervention, referral sources pertaining to hearing concerns, financial help, and providing information about legal rights. Results showed that the greatest challenges for these organizations were related to needing to connect families to financial resources pertaining to hearing-related needs, engaging families of children who are deaf/hard of hearing in their organization's activities, having resources available in other languages, and 4) identifying pediatric providers that serve D/HH children. Potential ways to strengthen the capacity of these organizations to meet the needs of families with hearing-related concerns as well as increasing their awareness of partnerships with the EHDI system are discussed.

Objectifs Apres estimation de la qualite de vie post-operatoire tardive de patients pris en charge par notre equipe oto-neurochirurgicale, nous avons recherche les facteurs susceptibles d’expliquer l’alteration de la qualite de vie. Materiel Notre etude retrospective porte sur 104 patients operes d’un schwannome vestibulaire unilateral entre 1991 et 2000 ayant un recul d’au moins un an. Les patients ont ete interroges par un auto-questionnaire : la version francaise du SF-36. Resultats Nous avons obtenu 68 % de reponses soit 71 patients sur les 104 sollicites. La qualite de vie des patients operes est plus alteree que celle de la population generale, notamment sur la dimension psychique. Cette alteration est comparable, quels que soient l’âge des patients, le stade tumoral, la voie d’abord ou le recul post-operatoire. Les seuls criteres significatifs majorant cette alteration sont les re-interventions et le sexe. Outre l’alteration des dimensions psychiques, les femmes semblent etre plus genees dans les dimensions physiques. Conclusion Il n’y a pas de difference, si l’on regarde la seule qualite de la vie des malades operes, entre ceux qui l’ont ete pour une petite tumeur et ceux qui l’ont ete pour une tumeur de volume plus important. Les femmes apparaissent avoir une qualite de vie plus alteree que les hommes et, de ce fait, necessitent plus d’informations pre operatoires et un suivi postoperatoire plus attentif.

Analysis of circulating cell-free fetal DNA (cffDNA) in maternal plasma is very promising for early diagnosis of monogenic diseases. However, this approach is not yet available for routine use and remains technically challenging because of the low concentration of cffDNA, which is swamped by the overwhelming maternal DNA.To make clinical applications more readily accessible, we propose a new approach based on mutant enrichment with 3′-modified oligonucleotides (MEMO) PCR along with real-time PCR to selectively amplify from the maternal blood the paternally inherited fetal allele that is not present in the maternal genome.The first proof of concept of this strategy was displayed for cystic fibrosis by the accuracy of our detection of the p.Gly542* mutation used as the initial developmental model. Subsequently, a retrospective study of plasmas originating from two pregnant women carrying a fetus with private mutation confirmed the effectiveness of our method. We confirmed the presence of cffDNA in the studied samples by the identification of a tri-allelic DNA profile using a miniSTR kit.This new non-invasive prenatal diagnosis test offers numerous advantages over current methods: it is simple, cost effective, time efficient and does not require complex equipment or bioinformatics settings. Moreover, our assays for different private mutations demonstrate the viability of this approach in clinical settings for monogenic disorders.

Objective: Improvement of neurosurgical techniques with a more detailed description of brain tumors and their functional environment. Methods: We performed: (1) anatomical magnetic resonance imaging (MRI) for reference, (2) functional sequences dedicated to the adjacent cortical structures (sensorimotor, visual, language paradigms), and (3) thallium 201 cerebral tomoscintigraphy to visualize active tumor invasion. Data were transferred to a workstation for automatic registration. Results: All data were combined into one synthetic image showing the foci of high proliferative activity, which have to be completely resected, and the peritumoral functional structures, which have to be spared in order to minimize postoperative sequelae. This trimodal image is entered into a surgical neuronavigation computer for preoperative planning in order to outline tumoral target and functional risk areas. All this information is displayed in the operative microscope (Zeiss MKM) optically linked to MR images. This multimodality technique diminishes operative time by reducing electrocorticography and improves the operative short-term outcome. Conclusion: Multimodal imaging is useful for optimization of neurosurgical tumor resection.

Background and Purpose— Loss of muscle mass and function is a severe complication in patients with stroke that contributes to promoting physical inactivity and disability. The deleterious consequences of skeletal muscle mass loss underline the necessity to identity the molecular mechanisms involved in skeletal muscle atrophy after cerebral ischemia. Methods— Transient focal cerebral ischemia (60 minutes) was induced by occlusion of the right middle cerebral artery in C57BL/6J male mice. Skeletal muscles were removed 3 days later and analyzed for the regulation of critical determinants of muscle mass homeostasis (Akt/mammalian target of rapamycin pathway, myostatin-Smad2/3 and bone morphogenetic protein-Smad1/5/8 signaling pathways, ubiquitin-proteasome and autophagy-lysosome proteolytic pathways). Results— Cerebral ischemia induced severe sensorimotor deficits associated with muscle mass loss of the paretic limbs. Mechanistically, cerebral ischemia repressed Akt/mammalian target of rapamycin pathway and increased expression of key players of ubiquitin-proteasome pathway (MuRF1 [muscle RING finger-1], MAFbx [muscle atrophy F-box], Musa1 [muscle ubiquitin ligase of SCF complex in atrophy-1]), together with a marked increase in myostatin expression, in both paretic and nonparetic skeletal muscles. The Smad1/5/8 pathway was also activated. Conclusions— Our data fit with a model in which a repression of Akt/mammalian target of rapamycin pathway and an increase in the expression of key players of ubiquitin-proteasome pathway are critically involved in skeletal muscle atrophy after cerebral ischemia. Cerebral ischemia also caused an activation of bone morphogenetic protein-Smad1/5/8 signaling pathway, suggesting that compensatory mechanisms are also concomitantly activated to limit the extent of skeletal muscle atrophy.

Times Cited: 0; International audience; In skeletal muscle, autophagy is activated in multiple physiological and pathological conditions, notably through the transcriptional regulation of autophagy-related genes by FoxO3. However, recent evidence suggests that autophagy could also be regulated by post-transcriptional mechanisms. The purpose of the study was therefore to determine the temporal regulation of transcriptional and post-transcriptional events involved in the control of autophagy during starvation (4 h) and nutrient restoration (4 h) in C2C12 myotubes. Starvation was associated with an activation of autophagy (decrease in mTOR activity, increase in AMPK activity and Ulk1 phosphorylation on Ser467), an increase in autophagy flux (increased LC3B-II/LC3B-I ratio, LC3B-II level and LC3B-positive punctate), and an increase in the content of autophagy-related proteins (Ulk1, Atg13, Vps34, and Atg5-Atg12 conjugate). Our data also indicated that the content of autophagy-related proteins was essentially maintained when nutrient sufficiency was restored. By contrast, mRNA level of Ulk1, Atg5, Bnip3, LC3B and Gabarapl1 did not increase in response to starvation. Accordingly, binding of FoxO3 transcription factor on LC3B promoter was only increased at the end of the starvation period, whereas mRNA levels of Atrogin1/MAFbx and MuRF1, two transcriptional targets of FoxO involved in ubiquitin-proteasome pathway, were markedly increased at this time. Together, these data provide evidence that target genes of FoxO3 are differentially regulated during starvation and that starvation of C2C12 myotubes is associated with a post-transcriptional regulation of autophagy.

Newborn screening (NBS) for cystic fibrosis (CF) was implemented throughout France in 2002. It involves a four-tiered procedure: immunoreactive trypsin (IRT)/DNA/IRT/sweat test was implemented throughout France in 2002. The aim of this study was to assess the performance of molecular CFTR gene analysis from the French NBS cohort, to evaluate CF incidence, mutation detection rate, and allelic heterogeneity. During the 8-year period, 5,947,148 newborns were screened for cystic fibrosis. The data were collected by the Association Francaise pour le Depistage et la Prevention des Handicaps de l’Enfant. The mutations identified were classified into four groups based on their potential for causing disease, and a diagnostic algorithm was proposed. Combining the genetic and sweat test results, 1,160 neonates were diagnosed as having cystic fibrosis. The corresponding incidence, including both the meconium ileus (MI) and false-negative cases, was calculated at 1 in 4,726 live births. The CF30 kit, completed with a comprehensive CFTR gene analysis, provides an excellent detection rate of 99.77% for the mutated alleles, enabling the identification of a complete genotype in 99.55% of affected neonates. With more than 200 different mutations characterized, we confirmed the French allelic heterogeneity. The very good sensitivity, specificity, and positive predictive value obtained suggest that the four-tiered IRT/DNA/IRT/sweat test procedure may provide an effective strategy for newborn screening for cystic fibrosis. Genet Med 17 2, 108–116.

Resume L’importante heterogeneite allelique de la mucoviscidose represente la principale difficulte pour l’etablissement de son diagnostic genotypique. De nombreuses etudes ont montre pour certaines mutations du gene CFTR des variations de frequence allelique parfois considerables entre des populations d’origine geographique et ethnique differentes. Materiel et methodes. – Nous avons analyse les genotypes de 207 enfants atteints de mucoviscidose et residant dans le Sud-Ouest de la France. Resultats. – Nous montrons que parmi les 50 mutations identifiees, certaines ont une frequence significativement differente de celle habituellement observee. Ces variations apparaissent plus clairement pour les alleles typiquement originaires du Sud-Ouest de la France. Ainsi, la mutation 1811+1,6kbA>G, rarement observee dans les autres regions ( Conclusion. – Nous montrons qu’il existe dans le Sud-Ouest de la France un spectre mutationnel specifique. Nous considerons que ces donnees regionales sont importantes pour ameliorer la sensibilite du test genetique et preciser le conseil genetique de la mucoviscidose en France.

The spectrum of CFTR mutations in three South African populations is presented. To date. a total of 192 white patients (384 chromosomes) with confirmed CF have been tested. deltaF508 accounts for 76% of the CF chromosomes in this group, with 3272-26A-->G, 394delTT and G542X occurring at the following frequencies: 4, 3.6 and 1.3%, respectively. A further 11 mutations account for 6% of CF chromosomes. A total of 91% of the CF-causing mutations can now be detected in the South African white population. Haplotype analysis suggests a founder effect in South Africans of European origin for the two common CFTR mutations, 3272-26A-->G and 394delTT. The diagnosis of CF has been confirmed in 14 coloured and 12 black CF patients. In the coloured population, both the deltaF508 and 3120 + 1G-->A mutations occur at appreciable frequencies of 43 and 29%, respectively. In the black population, the most common CF-causing mutation, the 3120 + 1G-->A mutation, occurs at an estimated frequency of 46%. Four other mutations have been detected, resulting in the identification of a total of 62.5% of mutations in this population.

The Marion Downs National Center for Infant Hearing was established in 1996 through a Maternal and Child Health Grant awarded to the University of Colorado. The goals of the grant are to implement statewide systems of newborn hearing screening, audiologic assessment, and early intervention in 19 states. Newborn hearing screening alone will not assure early identification or positive outcomes for the development of communication and language. Therefore, the staff at the Marion Downs National Center developed comprehensive goals for all participating states. These goals are described in this article.

Contradictory results have been reported on the effects and role of IL-6 on proteoglycan (PG) synthesis. Having shown recently that in vitro IL-6 depends on the presence of soluble IL-6 receptor alpha (sIL-6Ralpha) to fully exert its effects on chondrocytes, we conducted the present study to analyse the effects of IL-6 on PG synthesis by human articular chondrocytes in the presence of sIL-6Ralpha. PG synthesis was quantified by specific ELISA using a monoclonal antibody (MAB) raised against the keratan sulphate region of PG as a capture antibody, and a MAB to the acid binding region as a detector. It proved specific for PG from primary (differentiated) chondrocytes. In the absence of sIL-6Ralpha, IL-6 had a slight inhibitory effect on PG synthesis by articular chondrocytes. sIL-6Ralpha alone also had slight but consistent inhibitory effects. When adding sIL-6Ralpha at concentrations of 50 ng/ml corresponding to levels found in synovial fluid, the effects of IL-6 increased consistently. However, even at optimal concentrations (30-100 ng/ml of IL-6sR per 100 ng/ml of IL-6), maximal inhibition (48%) did not equal the degree of inhibition achieved by IL-1 at 1 ng/ml (66%). Similar effects, although slightly weaker, were observed on osteoarthritic cells. Dexamethasone, over a wide range of concentrations, markedly enhanced proteoglycan synthesis and completely reversed the downregulatory effects of IL-1 and IL-6 + sIL-6Ralpha. The effects of IL-1 were partially inhibited by an anti-IL-6 antibody. Finally, unlike IL-1, IL-6 + sIL-6Ralpha only weakly stimulated nitric oxide (NO) synthesis. In conclusion, sIL-6Ralpha potentiates the inhibitory effect of IL-6 on PG synthesis by articular chondrocytes, but the overall effect of IL-6 + IL-6sR is moderate compared to the effects of IL-1.

Cellular immune responses decrease with aging. Lymphocytes of aged individuals do not perform as well as cells from young subjects in a number of in vitro assays including cell proliferation, cytokine production, and protection against apoptosis. Here, we have tested the hypothesis that a decrease in T cell responses in tymphocytes from elderly subjects could parallel a decrease in the activity of protein tyrosine kinases (PTK) associated with signal transduction in T lymphocytes. We report that anti-CD3-triggered T lymphocyte proliferation was significantly decreased in T lymphocytes from elderly subjects, but the decrease was not due to an alteration of the percentage or mean fluorescence intensities of CD3, CD4, and CD45. Of significance, the activities of p56lck and ZAP-70 in vitro were significantly decreased in T lymphocytes from elderly subjects compared to young individuals. However, the level of expression of the two kinases did not change with aging. The activity of p59fyn did not show changes with aging, suggesting that p59fyn did not compensate for the decreased activity of p56lck. We also found that the extent of tyrosine phosphorylation of the adaptor protein p95vav was similar in activated T lymphocytes from elderly and young subjects. Our results suggest that the altered cellular immune responses observed in T lymphocytes with aging may be the result, at least in part, of an alteration in early events associated with signal transduction through the TcR/CD3 complex that translates into decreased activities of p56lck and ZAP-70. Impairment in the activities of these twokey components of T cell signaling may contribute to reduced immune functions associated with aging.

Benign neurogenic tumours originating from lumbar plexus or roots are rare. Two cases are reported. Resection, often possible with another localisation, may result in neurological deficit in these cases. Enucleation, the best choice, is not always feasible. Hollowing-out is therefore a procedure worth understanding.

Cachexia is a muscle-wasting syndrome that contributes significantly to morbidity and mortality of many patients with advanced cancers. However, little is understood about how the severe loss of skeletal muscle characterizing this condition occurs. In the current study, we tested the hypothesis that the muscle protein myostatin is involved in mediating the pathogenesis of cachexia-induced muscle wasting in tumor-bearing mice. Myostatin gene inactivation prevented the severe loss of skeletal muscle mass induced in mice engrafted with Lewis lung carcinoma (LLC) cells or in ApcMin/+ mice, an established model of colorectal cancer and cachexia. Mechanistically, myostatin loss attenuated the activation of muscle fiber proteolytic pathways by inhibiting the expression of atrophy-related genes, MuRF1 and MAFbx/Atrogin-1, along with autophagy-related genes. Notably, myostatin loss also impeded the growth of LLC tumors, the number and the size of intestinal polyps in ApcMin/+ mice, thus strongly increasing survival in both models. Gene expression analysis in the LLC model showed this phenotype to be associated with reduced expression of genes involved in tumor metabolism, activin signaling, and apoptosis. Taken together, our results reveal an essential role for myostatin in the pathogenesis of cancer cachexia and link this condition to tumor growth, with implications for furthering understanding of cancer as a systemic disease. Cancer Res; 74(24); 7344–56. ©2014 AACR.

Objective. To examine growth factor responses of human articular chondrocytes in aging and development. We have previously established a growth factor response profile for adult human articular chondrocytes and shown that transforming growth factor β (TGFβ) is the most potent mitogen among a variety of factors tested. Methods. Chondrocytes were isolated from human articular cartilage obtained from donors ages 11–83 years and tested in primary culture for proliferative responses to serum and recombinant preparations of the major chondrocyte growth factors. Proliferation was measured by 3H-thymidine incorporation and cell counting. Skeletal maturity of the young donors was determined by radiographic assessment of Risser's index. Results. Chondrocytes showed a continuous age-related decline in the proliferative response to serum. Analysis of recombinant growth factors showed that with increasing donor age, there was a decrease in the levels of DNA synthesis in response to all factors tested. In chondrocytes from adult donors, there was no change in the relative potencies of the different growth factors. The decrease in the levels of DNA synthesis as measured by 3H-thymidine incorporation corresponded to a reduced rate of in vitro cell replication with increasing donor age. In addition to the quantitative changes in the proliferative responses of chondrocytes with increasing age, there was a qualitative change in the pattern of growth factor responses during development. Cells from young donors (ages 10–20) responded better to platelet-derived growth factor, AA chain homodimer (PDGF-AA) than to TGFβ1, while the inverse pattern was seen in cells from adult donors. This decrease in the response to PDGF-AA was significantly correlated with increasing skeletal maturity. Conclusion. Chondrocyte growth factor responsiveness shows qualitative changes during development, and after skeletal maturity, there is a profound decline in the levels of DNA synthesis and cell replication in response to the known chondrocyte growth factors.

An innovative three-story timber building, using self-centering, post-tensioned timber shear walls as the main horizontal load resisting system and lightweight non-composite timber-concrete floors, has recently been completed in Nelson, New Zealand. It is expected to be the trailblazer for similar but taller structures to be more widely adopted. Performance based standards require an advanced understanding of building responses and in order to meet the need for in-situ performance data the building has been subjected to forced vibration testing and instrumented for continuous monitoring using a total of approximately 90 data channels to capture its dynamic and long-term responses. The first part of the paper presents a brief discussion of the existing research on the seismic performance of timber frame buildings and footfall induced floor vibrations. An outline of the building structural system, focusing on the novel design solutions, is then discussed. This is followed by the description of the monitoring system. The analysis of monitoring results starts with a discussion of the monitoring of long-term deformations. Next, the assessment of the floor vibration serviceability performance is outlined. Then, the forced vibration tests conducted on the whole building at different construction stages are reviewed. The system identification results from seismic shaking records are also discussed. Finally, updating of a finite element model of the building is conducted.

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Purpose The aim of this study was to investigate parent experiences with the infant diagnostic hearing evaluation process. Method This study used a cross-sectional survey design. Surveys were distributed via parent support organizations in December 2009 to parents of children with hearing loss. A total of 416 completed surveys were received from 43 states. Results The median age of diagnosis of hearing loss has decreased over time from 11 months of age to 2 months. For babies born between 2006 and 2009, the most frequently reported challenge to obtaining a diagnostic hearing evaluation by 3 months of age was a delay in appointment availability (36%). Just >¼ (27%) of parents reported that they did not feel comfortable in knowing what they needed to do next after talking with the audiologist at the time their child was diagnosed with hearing loss. Conclusion Significant progress has been made over the past 2 decades in reducing the age of hearing loss identification. However, many parents in this study experienced challenges that resulted in delays that exceeded Joint Committee on Infant Hearing (2007) recommendations of diagnosis by 3 months of age. The parent-reported experiences provide valuable information about areas that need further investigation to improve the early hearing detection and intervention process for children with hearing loss.

Background Muscle atrophy associated with various pathophysiological conditions represents a major health problem, because of its contribution to the deterioration of patient status and its effect on mortality. Although the involvement of pro-inflammatory cytokines in this process is well recognized, the role of sphingolipid metabolism alterations induced by the cytokines has received little attention. Results We addressed this question both in vitro using differentiated myotubes treated with TNF-α, and in vivo in a murine model of tumor-induced cachexia. Myotube atrophy induced by TNF-α was accompanied by a substantial increase in cell ceramide levels, and could be mimicked by the addition of exogenous ceramides. It could be prevented by the addition of ceramide-synthesis inhibitors that targeted either the de novo pathway (myriocin), or the sphingomyelinases (GW4869 and 3-O-methylsphingomyelin). In the presence of TNF-α, ceramide-synthesis inhibitors significantly increased protein synthesis and decreased proteolysis. In parallel, they lowered the expression of both the Atrogin-1 and LC3b genes, involved in muscle protein degradation by proteasome and in autophagic proteolysis, respectively, and increased the proportion of inactive, phosphorylated Foxo3 transcription factor. Furthermore, these inhibitors increased the expression and/or phosphorylation levels of key factors regulating protein metabolism, including phospholipase D, an activator of mammalian target of rapamycin (mTOR), and the mTOR substrates S6K1 and Akt. In vivo, C26 carcinoma implantation induced a substantial increase in muscle ceramide, together with drastic muscle atrophy. Treatment of the animals with myriocin reduced the expression of the atrogenes Foxo3 and Atrogin-1, and partially protected muscle tissue from atrophy. Conclusions Ceramide accumulation induced by TNF-α or tumor development participates in the mechanism of muscle-cell atrophy, and sphingolipid metabolism is a logical target for pharmacological or nutritional interventions aiming at preserving muscle mass in pathological situations.

XeCl excimer lasers could be potentially very relevant in the field of neurosurgery since they can be used for resection and for diagnostic. In this paper we describe the first in vivo demonstration that small, well defined cuts can be obtained in the brain with a stereotactical ly implanted optical fibre. We also relate a preliminary in vitro study which shows that 308 nm laser-induced autofluorescence spectra of normal and malignant human brain tissues are different enough for diagnosis. Finally, we give very recent in vivo results concerning evoked responses produced by the XeCl excitation of a bundle of central nervous fibres in the rat. These two last diagnostic methods could be used during stereotactical laser resection procedures to localise the distal tip of the optical fiber and to determine the pathological state of the irradiated tissue.

In order to characterize the non-delta F508 mutations that account for 36% of cystic fibrosis (CF) chromosomes in Southern France in a sample of 137 patients, we have systematically screened the entire coding region and adjacent sequences of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by the single strand conformation polymorphism (SSCP) technique followed by direct sequencing of the mutant DNAs. We identified 13 novel mutations (9 reported in this paper) and 4 novel rare nucleotide sequence variations. Forty different mutations including delta F508, located in 15 exons, account for only 91.2% of mutants in a population originating from Southern France, in contrast with a recent report on the Celtic population of Brittany demonstrating that 90% of mutations can be detected with only three mutations. We present a very large spectrum of different CF mutations identified in a small geographical area.

Recently, engineers have been studying on-payload networks for fast communication paths. Using intrasystem networks as a means to connect devices together allows for a flexible payload design that does not rely on dedicated communication paths between devices. In this manner, the data flow architecture of the system can be dynamically reconfigured to allow data routes to be optimized for the application or configured to route around devices that are temporarily or permanently unavailable. To use intrasystem networks, devices will need network controllers and switches. These devices are likely to be affected by single-event effects, which could affect data communication. In this paper, we will present radiation data and performance analysis for using a Broadcom network controller in a neutron environment.

Although ∼95% of US newborns are now screened for hearing loss at birth, more than half of those who do not pass the screen lack a documented diagnosis. In an effort to improve the quality of the follow-up process, teams from 8 states participated in a breakthrough-series learning collaborative. Teams were trained in the Model for Improvement, a quality-improvement approach that entails setting clear aims, tracking results, identifying proven or promising change strategies, and the use of small-scale, rapid-cycle plan-do-study-act tests of these changes. Parents acted as equal partners with professionals in guiding system improvement. Teams identified promising change strategies including ensuring the correct identification of the primary care provider before discharge from the birthing hospital; obtaining a second contact number for each family before discharge; “scripting” the message given to families when an infant does not pass the initial screening test; and using a “roadmap for families” as a joint communication tool between parents and professionals to demonstrate each family's location on the “diagnostic journey.” A learning-collaborative approach to quality improvement can be applied at a state-system level. Participants reported that the collaborative experience allowed them to move beyond a focus on improving their own service to improving connections between services and viewing themselves as part of a larger system of care. Ongoing quality-improvement efforts will require refinement of measures used to assess improvement, development of valid indicators of system performance, and an active role for families at all levels of system improvement.