bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the Use of Innovation Performance Measurement to Build Innovation Capability in a Medical Device Company
Authors: Nilsson Susanne , Ritzén Sofia
Published: February 2014

In order to increase their innovation capability, many organizations make the effort to actively change theirR&Dworking practices. In parallel, measurement is an important issue with regard to managing innovation. In this paper, innovation management and measurement theory are combined with empirical investigations of experiences of using measurement as a support to the development of innovation capability in practice. The paper reports results from analysis of measurement data and a semi‐structured interview study, encompassing 19 interviews with managers and engineers involved in the current change activities of the case company. The study reveals that various innovation measurement mechanisms are used in different departments in theR&Dorganization, reflecting the diverse views of what constitutes innovation that dominate in each group, as well as the group's level of involvement in the on‐going building of innovation capability – from heavily involved (innovation leaders) to attentiveness from a distance (innovation laggards and progress evaluators). This, together with challenges related to identifying relevant metrics to support both incremental and radical innovation and managing existing reward and goal‐setting systems, is seen to have implications on the capability development in the organization requiring attention to how innovation measurement is designed, implemented and used in practice.
Array‐comparative genomic hybridization profiling of immunohistochemical subgroups of diffuse large B‐cell lymphoma shows distinct genomic alterations
Authors: Guo Ying , Takeuchi Ichiro , Karnan Sivasundaram , Miyata Tomoko , Ohshima Koichi , Seto Masao
Published: February 2014

Diffuse large B‐cell lymphoma (DLBCL) displays striking heterogeneity at the clinical, genetic and molecular levels. Subtypes include germinal center B‐cell‐like (GCB) DLBCL and activated B‐cell‐like (ABC) DLBCL, according to microarray analysis, and germinal center type or non‐germinal center type by immunohistochemistry. Although some reports have described genomic aberrations based upon microarray classification system, genomic aberrations based upon immunohistochemical classifications have rarely been reported. The present study aimed to ascertain the relationship between genomic aberrations and subtypes identified by immunohistochemistry, and to study the pathogenetic character of Chinese DLBCL. We conducted immunohistochemistry using antibodies against CD10, BCL6 and MUM1 in 59 samples of DLBCL from Chinese patients, and then performed microarray‐based comparative genomic hybridization for each case. Characteristic genomic differences were found between GCB and non‐GCB DLBCL from the array data. The GCB type was characterized by more gains at 7q (7q22.1, P < 0.05) and losses at 16q (P ≤ 0.05), while the non‐GCB type was characterized by gains at 11q24.3 and 3q13.2 (P < 0.05). We found completely different mutations in BCL6+ and BCL6− non‐GCB type DLBCL, whereby the BCL6− group had a higher number of gains at 1q and a loss at 14q32.13 (P ≤ 0.005), while the BCL6+ group showed a higher number of gains at 14q23.1 (P = 0.15) and losses at 6q (P = 0.07). The BCL6− group had a higher frequency of genomic imbalances compared to the BCL6+ group. In conclusion, the BCL6+ and BCL6− non‐GCB type of DLBCL appear to have different mechanisms of pathogenesis.
MKK7 mediates miR‐493‐dependent suppression of liver metastasis of colon cancer cells
Authors: Sakai Hiroaki , Sato Ai , Aihara Yuki , Ikarashi Yoshinori , Midorikawa Yutaka , Kracht Michael , Nakagama Hitoshi , Okamoto Koji
Published: February 2014

The prognosis of advanced colon cancer patients is profoundly affected by the presence or absence of liver metastasis. miR‐493 functions as a potent suppressor of liver metastasis, and low‐level miR‐493 expression in human primary colon cancer is associated with an elevated incidence of liver metastasis. We previously showed that IGF1R is a target gene of miR‐493, and that the inhibition of IGF1R partly explains how miR‐493 suppresses liver metastasis. However, major functional targets that mediate the antimetastatic activity of miR‐493 remain elusive. Here, we extended our search for target genes and identified MKK7, a mitogen‐activated protein kinase kinase, as a novel target of miR‐493. miR‐493 inhibits MKK7 expression by targeting the binding site at the 3′‐UTR of the mkk7 gene. MKK7 was expressed in six out of seven colon cancer cell lines examined but not in non‐transformed colon epithelial cells, and its expression was required for the activating phosphorylation of JNK. RNA interference‐mediated inhibition of MKK7 resulted in marked suppression of liver metastasis of colon cancer cells. A significant decrease of metastasized cells by the MKK7 knockdown was observed, even at early stages of the metastatic settlement, in accordance with a time course of the miR‐493‐mediated inhibition of the metastasis. Immunohistochemical examination in human primary colon tumors revealed that the occurrence of liver metastasis is associated with elevated levels of MKK7. Thus, MKK7 is a major functional target of miR‐493, and its suppression thwarts liver metastasis of colon cancer cells.
High proportions of FOXP3+CD25high T cells in neonates are positively associated with allergic sensitization later in childhood
Authors: Strömbeck A. , Rabe H. , Lundell A.‐C. , Andersson K. , Johansen S. , Adlerberth I. , Wold A. E. , Hesselmar B. , Rudin A.
Published: February 2014

Background

The role of FOXP3+ regulatory T cells in the prevention against sensitization and allergy development is controversial.

Objective

We followed 65 newborn Swedish children from farming and non‐farming families from birth to 3 years of age and investigated the relation between CD4+ T cell subsets in blood samples and development of sensitization and allergic disease.

Methods

The proportions of FOXP3+CD25high, CTLA‐4+CD25+, CD45RO+, HLA‐DR+, CCR4+ or α4β7+ within the CD4+ T cell population were examined by flow cytometry of blood samples at several time‐points. Mononuclear cells were isolated from blood and stimulated with birch allergen, ovalbumin or the mitogen PHA, and the levels of IL‐1β, IL‐6, TNF, IFN‐γ, IL‐5 and IL‐13 were measured. A clinical evaluation regarding the presence of allergen‐specific IgE and allergy was performed at 18 and 36 months of age.

Results

Multivariate discriminant analysis revealed that children who were sensitized at 18 or 36 months of age had higher proportions of FOXP3+CD25high T cells at birth and at 3 days of life than children who remained non‐sensitized, whereas allergy was unrelated to the neonatal proportions of these cells. The proportions of CTLA‐4+CD25+ T cells were unrelated to both sensitization and allergy. The association between higher proportions of FOXP3+CD25high T cells and sensitization persisted after exclusion of farmer's children. Finally, a farming environment was associated with lower proportions of FOXP3+CD25high T cells in early infancy and to a more prominent T cell memory conversion and cytokine production.

Conclusion & Clinical Relevance

Our results indicate that high proportions of FOXP3+CD25high T cells in neonates are not protective against later sensitization or development of allergy.
Inhibition of farnesyl pyrophosphate synthase prevents angiotensin II-induced cardiac fibrosis in vitro
Authors: Li Z , Bi X , Wang M , Zhang J , Song J , Shen X , Han J , Fu G , Ye Y
Published: February 2014

Farnesyl pyrophosphate synthase (FPPS)-catalysed isoprenoid intermediates are important for the activation of Ras homologue gene family, member A (RhoA) in angiotensin (Ang) II-induced cardiac fibrosis. This study was designed to investigate the specific role of FPPS in the development of cardiac fibrosis. We demonstrated that FPPS expression was elevated in both in-vivo and in-vitro models of Ang II-mediated cardiac fibrosis. FPPS inhibition by zolendronate and FPPS knock-down by a silencing lentivirus decreased the expression of cardiac fibrosis marker genes, including collagen I, collagen III and transforming growth factor (TGF)-β1. FPPS inhibition was reversed by geranylgeraniol (GGOH) and mimicked by RhoA knock-down with siRhoA. The antagonistic effect of GGOH on the zolendronate-mediated modulation of RhoA activation in Ang II-stimulated cardiac fibroblasts was demonstrated by a pull-down assay. Furthermore, FPPS knock-down also prevented RhoA activation by Ang II in vitro. In conclusion, FPPS and RhoA may be part of a signalling pathway that plays an important role in Ang II-induced cardiac fibrosis in vitro.
Prevention of acute liver allograft rejection by IL-10-engineered mesenchymal stem cells
Authors: Niu J , Yue W , Song Y , Zhang Y , Qi X , Wang Z , Liu B , Shen H , Hu X
Published: February 2014

Hepatic allograft rejection remains a challenging problem, with acute rejection episode as the major barrier for long-term survival in liver transplant recipients. To explore a strategy to prevent allograft rejection, we hypothesized that mesenchymal stem cells (MSCs) genetically engineered with interleukin-10 (IL-10) could produce beneficial effects on orthotopic liver transplantation (OLT) in the experimental rat model. Syngeneic MSCs transduced with IL-10 were delivered via the right jugular vein 30 min post-orthotopic transplantation in the rat model. To evaluate liver morphology and measure cytokine concentration, the blood and liver samples from each animal group were collected at different time-points (3, 5 and 7 days) post-transplantation. The mean survival time of the rats treated with MSCs–IL-10 was shown to be much longer than those treated with saline. According to Banff scheme grading, the saline group scores increased significantly compared with those in the MSCs–IL-10 group. Retinoid acid receptor-related orphan receptor gamma t (RORγt) expression was more increased in the saline group compared to those in the MSCs–IL-10 group in a time-dependent manner; forkhead box protein 3 (FoxP3) expression also decreased significantly in the saline group compared with those in the MSCs–IL-10 group in a time-dependent manner. The expression of cytokines [IL-17, IL-23, IL-6, interferon (IFN)-γ and tumour necrosis factor (TNF)-α] in the saline groups increased significantly compared with the time-point-matched MSCs–IL-10 group, whereas cytokine expression of (IL-10, TGF-β1) was deceased markedly compared to that in the MSCs–IL-10 group. These results suggest a potential role for IL-10-engineered MSC therapy to overcome clinical liver transplantation rejection.
Interleukin-37 ameliorates myocardial ischaemia/reperfusion injury in mice
Authors: Wu B , Meng K , Ji Q , Cheng M , Yu K , Zhao X , Tony H , Liu Y , Zhou Y , Chang C , Zhong Y , Zhu Z , Zhang W , Mao X , Zeng Q
Published: February 2014

Innate immune and inflammatory responses are involved in myocardial ischaemia/reperfusion (I/R) injury. Interleukin (IL)-37 is a newly identified member of the IL-1 family, and functions as a fundamental inhibitor of innate immunity and inflammation. However, its role in myocardial I/R injury remains unknown. I/R or sham operations were performed on male C57BL/6J mice. I/R mice received an injection of recombinant human IL-37 or vehicle, immediately before reperfusion. Compared with vehicle treatment, mice treated with IL-37 showed an obvious amelioration of the I/R injury, as demonstrated by reduced infarct size, decreased cardiac troponin T level and improved cardiac function. This protective effect was associated with the ability of IL-37 to suppress production of proinflammatory cytokines, chemokines and neutrophil infiltration, which together contributed to a decrease in cardiomyocyte apoptosis and reactive oxygen species (ROS) generation. In addition, we found that IL-37 inhibited the up-regulation of Toll-like receptor (TLR)-4 expression and nuclear factor kappa B (NF-kB) activation after I/R, while increasing the anti-inflammatory IL-10 level. Moreover, the administration of anti-IL-10R antibody abolished the protective effects of IL-37 in I/R injury. In-vitro experiments further demonstrated that IL-37 protected cardiomyocytes from apoptosis under I/R condition, and suppressed the migration ability of neutrophils towards the chemokine LIX. In conclusion, IL-37 plays a protective role against mouse myocardial I/R injury, offering a promising therapeutic medium for myocardial I/R injury.
Expression of interleukin (IL)-19 and IL-24 in inflammatory bowel disease patients: a cross-sectional study
Authors: Fonseca-Camarillo G , Furuzawa-Carballeda J , Granados J , Yamamoto-Furusho J K
Published: February 2014

Interleukin (IL)-19 and IL-24 belong to the IL-20 subfamily, and are involved in host defence against bacteria and fungi, tissue remodelling and wound healing. Nevertheless, no previous studies have explored their expression in Mexican mestizo patients with inflammatory bowel disease (IBD). The aim of the study was to characterize and to enumerate peripheral and tissue IL-19- and IL-24-producing cells, as well as gene expression in patients with IBD with regard to its clinical activity. We studied a total of 77 patients with ulcerative colitis (UC), 36 Crohn's disease (CD) and 33 patients as control group (without endoscopic evidence of intestinal inflammation). Gene expression was measured by real-time–polymerase chain reaction (RT–PCR). Protein expression was detected in biopsies by immunohistochemistry and in freshly isolated peripheral blood mononuclear cells by flow cytometry. IL-19 and IL-24 gene expression was elevated significantly in patients with active IBD versus the inactive disease and non-inflammatory control groups (P < 0·05). However, IL-19- and IL-24-producing cells were only increased in active CD versus active UC and non-inflammatory tissues (P < 0·05). IL-19 was produced conspicuously by circulating B cells and monocytes in patients with inactive disease (P < 0·05). Conversely, IL-24 was noticeably synthesized by peripheral B cells, CD4+ T cells, CD8+ T cells and monocytes in patients with active disease. In conclusion, IL-19- and IL-24-producing cells in active CD patients were increased compared with active UC and non-inflammatory tissues. These cytokines could significantly shape and differentiate inflammatory process, severity and tolerance loss between UC and CD pathophysiology.
High salt intake does not exacerbate murine autoimmune thyroiditis
Authors: Kolypetri P , Randell E , Van Vliet B N , Carayanniotis G
Published: February 2014

Recent studies have shown that high salt (HS) intake exacerbates experimental autoimmune encephalomyelitis and have raised the possibility that a HS diet may comprise a risk factor for autoimmune diseases in general. In this report, we have examined whether a HS diet regimen could exacerbate murine autoimmune thyroiditis, including spontaneous autoimmune thyroiditis (SAT) in non-obese diabetic (NOD.H2h4) mice, experimental autoimmune thyroiditis (EAT) in C57BL/6J mice challenged with thyroglobulin (Tg) and EAT in CBA/J mice challenged with the Tg peptide (2549–2560). The physiological impact of HS intake was confirmed by enhanced water consumption and suppressed aldosterone levels in all strains. However, the HS treatment failed to significantly affect the incidence and severity of SAT or EAT or Tg-specific immunoglobulin (Ig)G levels, relative to control mice maintained on a normal salt diet. In three experimental models, these data demonstrate that HS intake does not exacerbate autoimmune thyroiditis, indicating that a HS diet is not a risk factor for all autoimmune diseases.
Endogenous interleukin (IL)-17A promotes pristane-induced systemic autoimmunity and lupus nephritis induced by pristane
Authors: Summers S A , Odobasic D , Khouri M B , Steinmetz O M , Yang Y , Holdsworth S R , Kitching A R
Published: February 2014

Interleukin (IL)-17A is increased both in serum and in kidney biopsies from patients with lupus nephritis, but direct evidence of pathogenicity is less well established. Administration of pristane to genetically intact mice results in the production of autoantibodies and proliferative glomerulonephritis, resembling human lupus nephritis. These studies sought to define the role of IL-17A in experimental lupus induced by pristane administration. Pristane was administered to wild-type (WT) and IL-17A−/− mice. Local and systemic immune responses were assessed after 6 days and 8 weeks, and autoimmunity, glomerular inflammation and renal injury were measured at 7 months. IL-17A production increased significantly 6 days after pristane injection, with innate immune cells, neutrophils (Ly6G+) and macrophages (F4/80+) being the predominant source of IL-17A. After 8 weeks, while systemic IL-17A was still readily detected in WT mice, the levels of proinflammatory cytokines, interferon (IFN)-γ and tumour necrosis factor (TNF) were diminished in the absence of endogenous IL-17A. Seven months after pristane treatment humoral autoimmunity was diminished in the absence of IL-17A, with decreased levels of immunoglobulin (Ig)G and anti-dsDNA antibodies. Renal inflammation and injury was less in the absence of IL-17A. Compared to WT mice, glomerular IgG, complement deposition, glomerular CD4+ T cells and intrarenal expression of T helper type 1 (Th1)-associated proinflammatory mediators were decreased in IL-17A−/− mice. WT mice developed progressive proteinuria, but functional and histological renal injury was attenuated in the absence of IL-17A. Therefore, IL-17A is required for the full development of autoimmunity and lupus nephritis in experimental SLE, and early in the development of autoimmunity, innate immune cells produce IL-17A.
Effects of cigarette smoke on Toll-like receptor (TLR) activation of chronic obstructive pulmonary disease (COPD) macrophages
Authors: Metcalfe H J , Lea S , Hughes D , Khalaf R , Abbott-Banner K , Singh D
Published: February 2014

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal innate immune response. We have investigated the changes in the innate immune response of COPD alveolar macrophages exposed to both cigarette smoke and Toll-like receptor (TLR) stimulation. COPD and control alveolar macrophages were exposed to cigarette smoke extract (CSE) followed by TLR-2, -4 and -5 ligands [Pam3CSK4, lipopolysaccharide (LPS) and phase I flagellin (FliC), respectively] or non-typeable Haemophilus influenzae (NTHi). CSE exposure suppressed TLR-induced tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and regulated on activation, normal T cell expressed and secreted (RANTES) production in both COPD and control alveolar macrophages, but had no effect on interleukin 8 (CXCL8) production. Similarly, CSE suppressed NTHi-induced TNF-α but not NTHi-induced CXCL8 production in COPD alveolar macrophages. Gene expression analysis showed that CSE suppressed LPS-induced TNF-α transcription but not CXCL8 transcription in COPD alveolar macrophages. The dampening effect of CSE on LPS-induced cytokine production was associated with a reduction in p38, extracellular signal regulated kinase (ERK) and p65 activation. In conclusion, CSE caused a reduced innate immune response in COPD alveolar macrophages, with the exception of persistent CXCL8 production. This could be a mechanism by which alveolar macrophages promote neutrophil chemotaxis under conditions of oxidative stress and bacterial exposure.
Safety and immunogenicity of co-administered MF59-adjuvanted 2009 pandemic and plain 2009–10 seasonal influenza vaccines in rheumatoid arthritis patients on biologicals
Authors: Milanetti F , Germano V , Nisini R , Donatelli I , Di Martino A , Facchini M , Ferlito C , Cappella A , Crialesi D , Caporuscio S , Biselli R , Rossi F , Salemi S , D'Amelio R
Published: February 2014

Rheumatoid arthritis (RA) patients under immunosuppressive therapy are particularly susceptible to infections, mainly of the respiratory tract, thus vaccination may represent a strategy to reduce their incidence in this vulnerable population. In the 2009–10 influenza season, the safety and immunogenicity of co-administered non-adjuvanted seasonal and MF59-adjuvanted pandemic influenza vaccines were evaluated in this study in 30 RA patients under therapy with anti-tumour necrosis factor (TNF)-α agents or Abatacept and in 13 healthy controls (HC). Patients and HC underwent clinical and laboratory evaluation before (T0), 1 (T1) and 6 months (T2) after vaccinations. No severe adverse reactions, but a significant increase in total mild side effects in patients versus HC were observed. Both influenza vaccines fulfilled the three criteria of the Committee for Proprietary Medicinal Products (CPMP). Seroconversion rate for any viral strain in patients and HC was, respectively, 68 versus 45 for H1-A/Brisbane/59/07, 72 versus 81 for H3-A/Brisbane/10/07, 68 versus 54 for B/Brisbane/60/08 and 81 versus 54 for A/California/7/2009. A slight increase in activated interferon (IFN)-γ-, TNF-α- or interleukin (IL)-17A-secreting T cells at T1 compared to T0, followed by a reduction at T2 in both patients and HC, was registered. In conclusion, simultaneous administration of adjuvanted pandemic and non-adjuvanted seasonal influenza vaccines is safe and highly immunogenic. The largely overlapping results between patients and HC, in terms of antibody response and cytokine-producing T cells, may represent further evidence for vaccine safety and immunogenicity in RA patients on biologicals.
Adjuvant effects of aluminium hydroxide-adsorbed allergens and allergoids – differences in vivo and in vitro
Authors: Heydenreich B , Bellinghausen I , Lund L , Henmar H , Lund G , Adler Würtzen P , Saloga J
Published: February 2014

Allergen-specific immunotherapy (SIT) is a clinically effective therapy for immunoglobulin (Ig)E-mediated allergic diseases. To reduce the risk of IgE-mediated side effects, chemically modified allergoids have been introduced. Furthermore, adsorbance of allergens to aluminium hydroxide (alum) is widely used to enhance the immune response. The mechanisms behind the adjuvant effect of alum are still not completely understood. In the present study we analysed the effects of alum-adsorbed allergens and allergoids on their immunogenicity in vitro and in vivo and their ability to activate basophils of allergic donors. Human monocyte derived dendritic cells (DC) were incubated with native Phleum pratense or Betula verrucosa allergen extract or formaldehyde- or glutaraldehyde-modified allergoids, adsorbed or unadsorbed to alum. After maturation, DC were co-cultivated with autologous CD4+ T cells. Allergenicity was tested by leukotriene and histamine release of human basophils. Finally, in-vivo immunogenicity was analysed by IgG production of immunized mice. T cell proliferation as well as interleukin (IL)-4, IL-13, IL-10 and interferon (IFN)-γ production were strongly decreased using glutaraldehyde-modified allergoids, but did not differ between alum-adsorbed allergens or allergoids and the corresponding unadsorbed preparations. Glutaraldehyde modification also led to a decreased leukotriene and histamine release compared to native allergens, being further decreased by adsorption to alum. In vivo, immunogenicity was reduced for allergoids which could be partly restored by adsorption to alum. Our results suggest that adsorption of native allergens or modified allergoids to alum had no consistent adjuvant effect but led to a reduced allergenicity in vitro, while we observed an adjuvant effect regarding IgG production in vivo.
A case–control study of hyponatraemia as an independent risk factor for inpatient mortality
Authors: Tzoulis Ploutarchos , Bagkeris Emmanouil , Bouloux Pierre‐Marc
Published: February 2014

Objectives

Hyponatraemia is strongly associated with increased inpatient mortality, but it is unknown whether hyponatraemia per se contributes to excess mortality. Our hypothesis was that if hyponatraemic patients had significantly greater mortality compared with controls despite no difference with regard to gender, age, comorbidities and type of primary pathology, this would incriminate hyponatraemia as an independent predictor of mortality.

Design

Single‐centre, case–control study.

Patients

Cases (N = 139) were hospitalized patients with serum Na ≤ 128 mmol/l over 3 months. Controls were 254 age‐ and gender‐matched patients residing in the same hospital ward with serum Na > 128 mmol/l.

Measurements

Data were collected about age, gender, comorbidities, drug history, serum creatinine, intensive care unit (ICU) admission and length of hospitalization. The main outcome measure was inpatient mortality.

Results

Hyponatraemic patients had an inpatient mortality rate of 17·3% and were more than three times more likely to die during their hospital stay compared with controls (OR 3·33, 95% CI 1·68–6·58, P < 0·01) despite no statistically significant difference with respect to age, gender, comorbidities, use of common drugs, serum creatinine, ICU admission rate and length of hospitalization. Comparison of cases with the normonatraemic subgroup of controls demonstrated that cases were almost 12 times more likely to die during admission than normonatraemic controls (OR 11·89, 95% CI 2·75–51·51, P < 0·01).

Conclusions

This study showed that hyponatraemia is an independent predictor of mortality, and hyponatraemia per se is likely to contribute to excess mortality. Further studies are needed to examine whether correction of hyponatraemia can reduce mortality.
Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing's disease: results from a Phase III study
Authors: Pivonello Rosario , Petersenn Stephan , Newell‐Price John , Findling James W. , Gu Feng , Maldonado Mario , Trovato Andrew , Hughes Gareth , Salgado Luiz R. , Lacroix André , Schopohl Jochen , Biller Beverly M.K. ,   Pasireotide B2305 Study Group
Published: February 2014

Objective

Signs and symptoms of Cushing's disease are associated with high burden of illness. In this analysis, we evaluated the effect of pasireotide treatment on signs and symptoms in patients with Cushing's disease.

Design

Phase III study with double‐blind randomization of two pasireotide doses.

Methods

Patients (n = 162) with persistent/recurrent or de novo Cushing's disease and urinary free cortisol (UFC) levels ≥1·5× upper limit of normal (ULN) were randomized to receive subcutaneous pasireotide (600/900 μg bid). At month 3, patients with UFC ≤2 × ULN and not exceeding the baseline value continued their randomized dose; all others received 300 μg bid uptitration. At month 6, patients could enter an open‐label phase until month 12 with a maximal dose of 1200 μg bid. Changes in signs and symptoms of hypercortisolism over 12 months' treatment in patients still enroled in the study and with evaluable measurements were assessed in relation to degree of UFC control.

Results

Reductions in blood pressure were observed even without full UFC control and were greatest in patients who did not receive antihypertensive medications during the study. Significant reductions in total cholesterol and low‐density lipoprotein (LDL)‐cholesterol were observed in patients who achieved UFC control. Reductions in BMI, weight and waist circumference occurred during the study even without full UFC control. Adverse effects were typical of somatostatin analogues except for hyperglycaemia‐related events, which were experienced by 72·8% of patients.

Conclusions

In the largest Phase III study of medical therapy in Cushing's disease, significant improvements in signs and symptoms were seen during 12 months of pasireotide treatment, as UFC levels decreased.
Circulating microRNAs in autoimmune thyroid diseases
Authors: Yamada Hiroya , Itoh Mitsuyasu , Hiratsuka Izumi , Hashimoto Shuji
Published: February 2014

Context

Autoimmune thyroid diseases (AITDs), including Graves’ disease (GD) and Hashimoto's thyroiditis (HT), are the most common autoimmune diseases. MicroRNAs (miRNAs) are small noncoding RNAs, which can play pivotal roles in immune functions and development of autoimmunity. Recently, it has been recognized that identification of circulating miRNAs can provide important and novel information regarding disease pathogenesis and clinical condition. However, the role circulating miRNAs in AITD has not yet been described.

Objective

The aim of this study was to characterize the different circulating levels of miRNA in patients with AITD.

Design and methods

Sixty‐four participants who met the criteria for HT or GD and healthy subjects were recruited. Microarrays were used to analyse the expression patterns of miRNA in serum obtained from patients with HT and GD and healthy subjects. After analysing the microarray data, four interesting miRNAs (miR‐16, miR‐22, miR‐375 and miR‐451) were selected and validated by quantitative real‐time PCR.

Results

Several miRNAs were observed to be differently expressed in serum from patients with AITD compared with healthy subjects by microarray analysis. Further analysis consistently showed that serum levels of miR‐22, miR‐375 and miR‐451 were increased in patients with HT. On the other hand, the serum levels of miR‐16, miR‐22, miR‐375 and miR‐451 were increased in patients with GD compared with healthy subjects.

Conclusions

We revealed that different levels of serum miRNAs were associated with GD and HT, which may play a role in the pathogenesis of these diseases.
Why parents matter: exploring the impact of a hegemonic concern with the timetable for the child
Authors: Holt Kim , Kelly Nancy
Published: February 2014

In a climate of austerity, timescales and targets, this paper probes whether parents matter sufficiently within the current child protection system in England. Evidence suggests that achieving partnership working in the context of child protection has become increasingly illusive, particularly when parents are notified that the local authority is considering compulsory intervention to remove their children under the Children Act 1989. Recent changes to legislation, policy and practice ushered in with the aim of achieving earlier decisions within the time frame for the child are laudable, but there are consequences for both children and their parents. The aspirations of the Public Law Outline (2008) are well rehearsed, but the changes being introduced with the recent reform of the family justice system, alongside particular constructions of parenting, may be failing to recognize the potential of many parents, if offered appropriate support, to care safely for their children.
Open spaces, supple bodies? Considering the impact of agile working on social work office practices
Authors: Jeyasingham Dharman
Published: February 2014

There has been a shift towards social workers in many areas of the UK being based in large open plan offices and working more flexibly and remotely in space. This approach is commonly referred to as ‘agile working’. The paper explores the impact of agile working on social workers' practices and experiences in office spaces. It discusses data from an ethnographic study of children's safeguarding social work teams in two locations. One team was based in a large open plan office and was engaged in agile working, the other team was located in a much smaller office and was not using this approach. Data from observations of practice, analysis of material spaces, and interviews with social workers and those responsible for planning office space are examined. The paper concludes that there are qualitative differences between such spaces which are due to agile working arrangements and which are likely to impact significantly on social workers' experiences of practice, interactions with colleagues and development of practice knowledge. The data also suggest a lack of understanding in social work of the spatial requirements of practitioners and the significance that private and open space has for children's social work in the current UK context.
MicroRNAs in personalized cancer therapy
Authors: Sethi S. , Ali S. , Sethi S. , Sarkar F.H.
Published: February 2014

MicroRNAs (miRNAs) are small endogenous noncoding single‐stranded RNAs. They critically regulate the post‐transcriptional activity of several key physiological and pathological cell processes including cancer. Through their transcriptional regulatory functions, miRNAs control tumor proliferation, invasion and metastasis. The expression of miRNAs is altered in malignancies. It could be either upregulated or downregulated depending upon the role of a particular miRNA in the pathogenetic development of the tumor. The upregulated miRNAs exert an ‘oncogenic’ effect leading to tumor proliferation and metastasis. The downregulated miRNAs have ‘tumor suppressor’ effects. Recent studies have demonstrated that miRNAs have a role in the early diagnosis, prognosis and treatment outcome assessment of cancers. Every tumor has specific miRNA alterations, i.e. some are overexpressed and others are downregulated. These altered miRNAs can be used as a tumor‐specific ‘signature’ for potential clinical use in improving the accuracy of diagnosis, determining prognosis and as therapeutic targets for therapy. Specific miRNAs can be targeted using oligonucleotide sequences corresponding to the altered miRNAs. These are referred to as ‘antagomirs’. Depending upon the miRNA alterations in the tumor of an individual patient, one could design targeted therapies for personalized medicine in patients. Hence, miRNAs have an immense role in personalized cancer therapy.
Different acute cardiovascular stress in response to resistance exercise leading to failure versus not to failure in elderly women with and without hypertension – a pilot study
Authors: Tajra Vitor , Vieira Denis C. L. , Tibana Ramires A. , Teixeira Tatiane G. , Silva Alessandro O. , Farias Darlan L. , Nascimento Dahan da C. , de Sousa Nuno M. F. , Willardson Jeffrey , Prestes Jonato
Published: February 2014

Objective

The purpose of the present study was to compare the effects of resistance exercise (RE) leading to failure versus not to failure on 24‐h blood pressure (BP) and rate‐pressure product (RPP) responses in normotensive and hypertensive trained elderly women.

Methodology

Seven normotensive women and seven women with medically documented hypertension randomly performed three experimental sessions: (i) a non‐exercise control session that involved 30 min of seated rest, (ii) whole body RE leading to failure that involved three sets with an eight repetitions maximum (8RM) load and (iii) whole body RE not to failure that involved three sets with 70% of an 8RM load. Systolic BP (SBP), diastolic BP (DBP) and mean BP (MBP) responses during each hour of sleep and awake states were measured.

Results

Results of all subjects revealed that the RPP was higher (P≤0·05) during afternoon and night hours after the RE session leading to failure versus not to failure and the non‐exercise control session. For the hypertensive group during the night hours, SBP remained higher after the RE session not to failure (P = 0·047) versus non‐exercise control session. For the normotensive group, DBP remained higher after the RE session leading to failure over the 24‐h period (approximately 8 mmHg h−1, P = 0·044) and the period upon awaking (approximately 5 mmHg h−1, P = 0·044) versus the hypertensive group.

Conclusions

The normotensive elderly women of this pilot study presented a greater cardiovascular response to RE leading to failure, as a consequence of the higher training intensity.
Effect of positive end‐expiratory pressure on acoustic wave propagation in experimental porcine lung injury
Authors: Räsänen Jukka , Nemergut Michael E. , Gavriely Noam
Published: February 2014

To evaluate the effect of positive end‐expiratory pressure (PEEP) on sound propagation through injured lungs, we injected a multifrequency broad‐band sound signal into the airway of eight anesthetized, intubated and mechanically ventilated pigs, while recording transmitted sound at three locations bilaterally on the chest wall. Oleic acid injections effected a severe pulmonary oedema predominately in the dependent lung regions, with an average increase in venous admixture from 19 ± 15 to 59 ± 14% (P<0·001), and a reduction in dynamic respiratory system compliance from 34 ± 7 to 14 ± 4 ml cmH2O−1 (P<0·001). A concomitant decrease in sound transit time was seen in the dependent lung regions (P<0·05); no statistically significant change occurred in the lateral or non‐dependent areas. The application of PEEP resulted in a decrease in venous admixture, increase in respiratory system compliance and return of the sound transit time to pre‐injury levels in the dependent lung regions. Our results indicate that sound transmission velocity increases in lung tissue affected by permeability‐type pulmonary oedema in a manner reversible during alveolar recruitment with PEEP.
The impact of consecutive freshwater trimix dives at altitude on human cardiovascular function
Authors: Lozo Mislav , Madden Dennis , Gunjaca Grgo , Ljubkovic Marko , Marinovic Jasna , Dujic Zeljko
Published: February 2014

Self‐contained underwater breathing apparatus (SCUBA) diving is regularly associated with numerous asymptomatic changes in cardiovascular function. Freshwater SCUBA diving presents unique challenges compared with open sea diving related to differences in water density and the potential for dive locations at altitude. The aim of this study was to evaluate the impact of freshwater trimix diving at altitude on human cardiovascular function. Ten divers performed two dives in consecutive days at 294 m altitude with the surface interval of 24 h. Both dives were at a depth of 45 m with total dive time 29 and 26 min for the first and second dive, respectively. Assessment of venous gas embolization, hydration status, cardiac function and arterial stiffness was performed. Production of venous gas emboli was low, and there were no significant differences between the dives. After the first dive, diastolic blood pressure was significantly reduced, which persisted up to 24 h. Left ventricular stroke volume decreased, and heart rate increased after both dives. Pulse wave velocity was unchanged following the dives. However, the central and peripheral augmentation index became more negative after both dives, indicating reduced wave reflection. Ejection duration and round trip travel time were prolonged 24 h after the first dive, suggesting longer‐lasting suppression of cardiac and endothelial function. This study shows that freshwater trimix dives with conservative profiles and low venous gas bubble loads can result in multiple asymptomatic acute cardiovascular changes some of which were present up to 24 h after dive.
Travel for transplantation and transplant commercialism in Argentina: a 4‐decade experience from a University Hospital
Authors: Rodríguez‐Reimundes Ezequiel , Soler‐Pujol Gervasio , Díaz Carlos H. , Dávalos‐Michel Mario , Jost Luis J. , Laham Gustavo , Vilches Antonio R.
Published: February 2014

Travel for transplantation and transplant commercialism have become major issues in the last years, generating a passionate medical, legal, and ethical debate. We evaluated the general characteristics of patients who received a kidney transplant abroad and were subsequently followed in our institution. Then, we carried out a retrospective analysis of travelers' outcomes and compared them with a matched cohort of patients transplanted in our center. Between 1971 and 2008, 58 kidney transplants were performed outside Argentina and were subsequently followed up at our institution. The main destinations were the USA (32.8%), Bolivia (29.3%), and Brazil (17.2%). Deceased donor transplants were the most common (53.4%) followed by unrelated living donors (32.8%). No difference was observed between travelers and controls in terms of one‐month and one‐yr renal function and one‐yr and five‐yr graft survival. Travelers had significantly less time on dialysis before transplantation than controls. The major destination among all travelers was the USA, and the main destination for commercial transplants was Bolivia. The destination countries involved in our study and the apparent non‐inferiority of travelers graft outcomes differ from those of previous reports.
Mycology – an update. Part 1: Dermatomycoses: Causative agents, epidemiology and pathogenesis
Authors: Nenoff Pietro , Krüger Constanze , Ginter‐Hanselmayer Gabriele , Tietz Hans‐Jürgen
Published: February 2014

Dermatomycoses are caused most commonly by dermatophytes. The anthropophilic dermatophyte Trichophyton rubrum is still the most frequent causative agent worldwide. Keratinolytic enzymes, e.g. hydrolases and keratinases, are important virulence factors of T. rubrum. Recently, the cysteine dioxygenase was found as new virulence factor. Predisposing host factors play a similarly important role for the development of dermatophytosis of the skin and nails. Chronic venous insufficiency, diabetes mellitus, disorders of cellular immunity, and genetic predisposition should be considered as risk factors for onychomycosis. A new alarming trend is the increasing number of cases of onychomycosis – mostly due to T. rubrum – in infancy.

In Germany, tinea capitis is mostly caused by zoophilic dermatophytes, in particular Microsporum canis. New zoophilic fungi, primarily Trichophyton species of Arthroderma benhamiae, should be taken into differential diagnostic considerations of tinea capitis, tinea faciei, and tinea corporis. Source of infection are small household pets, particularly rodents, like guinea pigs. Anthropophilic dermatophytes may be introduced by families which immigrate from Africa or Asia to Europe. The anthropophilic dermatophytes T. violaceum, T. tonsurans (infections occurring in fighting sports clubs as “tinea gladiatorum capitis et corporis”) and M. audouinii are causing outbreaks of small epidemics of tinea corporis and tinea capitis in kindergartens and schools.

Superficial infections of the skin and mucous membranes due to yeasts are caused by Candida species. Also common are infections due to the lipophilic yeast fungus Malassezia. Today, within the genus Malassezia more than 10 different species are known. Malassezia globosa seems to play the crucial role in pityriasis versicolor.

Molds (also designated non‐dermatophyte molds, NDM) are increasingly found as causative agents in onychomycosis. Besides Scopulariopsis brevicaulis, several species of Fusarium and Aspergillus are found.
Benign hereditary chorea: more than meets the eye
Authors: Rice James
Published: February 2014

This commentary is on the original article by Peall et al. on pages 642–648 of this issue.
Development of a direct observation Measure of Environmental Qualities of Activity Settings
Authors: King Gillian , Rigby Patty , Batorowicz Beata , McMain‐Klein Margot , Petrenchik Theresa , Thompson Laura , Gibson Michelle
Published: February 2014

Aim

The aim of this study was to develop an observer‐rated measure of aesthetic, physical, social, and opportunity‐related qualities of leisure activity settings for young people (with or without disabilities).

Method

Eighty questionnaires were completed by sets of raters who independently rated 22 community/home activity settings. The scales of the 32‐item Measure of Environmental Qualities of Activity Settings (MEQAS; Opportunities for Social Activities, Opportunities for Physical Activities, Pleasant Physical Environment, Opportunities for Choice, Opportunities for Personal Growth, and Opportunities to Interact with Adults) were determined using principal components analyses. Test–retest reliability was determined for eight activity settings, rated twice (4–6wk interval) by a trained rater.

Results

The factor structure accounted for 80% of the variance. The Kaiser‐Meyer‐Olkin Measure of Sampling Adequacy was 0.73. Cronbach's alphas for the scales ranged from 0.76 to 0.96, and interrater reliabilities (ICCs) ranged from 0.60 to 0.93. Test–retest reliabilities ranged from 0.70 to 0.90.

Interpretation

Results suggest that theMEQAShas a sound factor structure and preliminary evidence of internal consistency, interrater, and test–retest reliability. TheMEQASis the first observer‐completed measure of environmental qualities of activity settings. TheMEQASallows researchers to assess comprehensively qualities and affordances of activity settings, and can be used to design and assess environmental qualities of programs for young people.
Early intervention after perinatal stroke: opportunities and challenges
Authors: Basu Anna P
Published: February 2014

Perinatal stroke is the most common cause of hemiplegic cerebral palsy. No standardized early intervention exists despite evidence for a critical time window for activity‐dependent plasticity to mould corticospinal tract development in the first few years of life. Intervention during this unique period of plasticity could mitigate the consequences of perinatal stroke to an extent not possible with later intervention, by preserving the normal pattern of development of descending motor pathways. This article outlines the broad range of approaches currently under investigation. Despite significant progress in this area, improved early detection and outcome prediction remain important goals.
Does early intensive multifactorial therapy reduce modelled cardiovascular risk in individuals with screen‐detected diabetes? Results from the ADDITION‐Europe cluster randomized trial
Authors: Black J. A. , Sharp S. J. , Wareham N. J. , Sandbæk A. , Rutten G. E. H. M. , Lauritzen T. , Khunti K. , Davies M. J. , Borch‐Johnsen K. , Griffin S. J. , Simmons R. K.
Published: February 2014

Aims

Little is known about the long‐term effects of intensive multifactorial treatment early in the diabetes disease trajectory. In the absence of long‐term data on hard outcomes, we described change in 10‐year modelled cardiovascular risk in the 5 years following diagnosis, and quantified the impact of intensive treatment on 10‐year modelled cardiovascular risk at 5 years.

Methods

In a pragmatic, cluster‐randomized, parallel‐group trial in Denmark, the Netherlands and the UK, 3057 people with screen‐detected Type 2 diabetes were randomized by general practice to receive (1) routine care of diabetes according to national guidelines (1379 patients) or (2) intensive multifactorial target‐driven management (1678 patients). Ten‐year modelled cardiovascular disease risk was calculated at baseline and 5 years using the UK Prospective Diabetes Study Risk Engine (version 3β).

Results

Among 2101 individuals with complete data at follow up (73.4%), 10‐year modelled cardiovascular disease risk was 27.3% (sd 13.9) at baseline and 21.3% (sd 13.8) at 5‐year follow‐up (intensive treatment group difference –6.9, sd 9.0; routine care group difference –5.0, sd 12.2). Modelled 10‐year cardiovascular disease risk was lower in the intensive treatment group compared with the routine care group at 5 years, after adjustment for baseline cardiovascular disease risk and clustering (–2.0; 95% CI –3.1 to –0.9).

Conclusions

Despite increasing age and diabetes duration, there was a decline in modelled cardiovascular disease risk in the 5 years following diagnosis. Compared with routine care, 10‐year modelled cardiovascular disease risk was lower in the intensive treatment group at 5 years. Our results suggest that patients benefit from intensive treatment early in the diabetes disease trajectory, where the rate of cardiovascular disease risk progression may be slowed.