Selective deletion of PPARβ/δ in fibroblasts causes dermal fibrosis by attenuated LRG1 expression.

Connective tissue diseases of the skin are characterized by excessive collagen deposition in the skin and internal organs. Fibroblasts play a pivotal role in the clinical presentation of these conditions. Nuclear receptor peroxisome-proliferator activated receptors (PPARs) are therapeutic targets for dermal fibrosis, but the contribution of the different PPAR subtypes are poorly understood. Particularly, the role of fibroblast PPARβ/δ in dermal fibrosis has not been elucidated. Thus, we generated a mouse strain with selective deletion of PPARβ/δ in the fibroblast (FSPCre- <i>Pparb/d</i> <sup>-/-</sup> ) and interrogated its epidermal and dermal transcriptome profiles. We uncovered a downregulated gene, leucine-rich alpha-2-glycoprotein-1 ( <i>Lrg1</i> ), of previously unknown function in skin development and architecture. Our findings suggest that the regulation of <i>Lrg1</i> by PPARβ/δ in fibroblasts is an important signaling conduit integrating PPARβ/δ and TGFβ1-signaling networks in skin health and disease. Thus, the FSPCre- <i>Pparb/d</i> <sup>-/-</sup> mouse model could serve as a novel tool in the current gunnery of animal models to better understand dermal fibrosis

Defining the 'Social' in 'Social Entrepreneurship': Altruism and Entrepreneurship

Abstract. What is social entrepreneurship? In, particular, what’s so social about it? Understanding what social entrepreneurship is enables researchers to study the phenomenon and policy-makers to design measures to encourage it. However, such an understanding is lacking partly because there is no universally accepted definition of entrepreneurship as yet. In this paper, we suggest a definition of social entrepreneurship that intuitively accords with what is generally accepted as entrepreneurship and that captures the way in which entrepreneurship may be altruistic. Based on this we provide a taxonomy of social entrepreneurship and identify a number of real cases from Asia illustrating the different forms it could take. Keywords: social entrepreneurship, definition, taxonomy, altruism Social entrepreneurship is a concept that has captured the imagination of many researchers and policy-makers in recent years. Social entrepreneurship suggests that entrepreneurship may be aimed at benefiting society rather than merely maximising individual profits. It appears to promise an altruistic form of capitalism that does not evaluate all human activities in business terms. It enables a bridge to be built between enterprise and benevolence (Roberts and Woods, 2005). The history of the term ‘social entrepreneurship ’ can be traced to the publication of a Demos thinktank report entitled The Rise of the Social Entrepreneur (Leadbeater, 1997) in the United Kingdom and probably a little earlier in the United States to the publication of New Social Entrepreneurs by the Roberts Foundation (Emerson and Twerksy, 1996). Prior to this, some of the activities under the rubric of social entrepreneurship were either termed ‘community development ’ or those in ‘social purpose organizations’. There is considerable use of the term in popular literature although academic literature on it is thin (Taylor, Hobbs, Nilsson, O’Halloran and Preisser, 2000). Recent interest saw a call for papers for a special issue on social entrepreneurship (Honig an

Validation of a new prognostic index score for disseminated nasopharyngeal carcinoma

Patients with metastatic nasopharyngeal carcinoma have variable survival outcomes. We previously designed a scoring system to better prognosticate these patients. Here, we report results on validation of this new prognostic index score in a separate cohort of patients. Clinical features and laboratory parameters were examined in 172 patients with univariate and multivariate analyses and a numerical score was derived for each independent prognostic variable. Significant independent prognostic variables and their scores assigned included poor performance status (score 5), haemoglobin <12 g dl−1 (score 4) and disease-free interval (DFI) (DFI⩽6 months (score 10) or metastases at initial diagnosis (score 1)). Maximum score was 19 and patients stratified into three prognostic groups: good, 0–3; intermediate, 4–8; poor, ⩾9. When applied to a separate cohort of 120 patients, 59 patients were good, 43 intermediate and 18 poor prognosis, with median survivals of 19.6 (95% CI 16.1, 23.1), 14.3 (95% CI 12.3, 16.2) and 7.9 (95% CI 6.6, 9.2) months, respectively. (logrank test: P=0.003). We have validated a new prognostic score with factors readily available in the clinics. This simple score will prove useful as a method to prognosticate and stratify patients as well as to promote consistent reporting among clinical trials

Factors determining the survival of nasopharyngeal carcinoma with lung metastasis alone: does combined modality treatment benefit?

<p>Abstract</p> <p>Background</p> <p>Nasopharyngeal carcinoma (NPC) with lung metastasis alone has been reported as a relatively favorable prognostic group, and combined modality treatment might be indicated for selected cases. However, the prognostic factors determining survival of this group and the indication of combined therapy have not been thoroughly studied.</p> <p>Methods</p> <p>We retrospectively reviewed 246 patients of NPC with lung metastasis(es) alone presented at diagnosis or as the first failure after primary treatment from 1993 to 2008 in an academic tertiary hospital. Univariate and multivariate survival analyses of post-metastasis survival (PMS) and overall survival (OS) were carried out to determine the prognostic factors.</p> <p>Results</p> <p>The 3-year, 5-year, and 10-year of PMS and OS for the whole cohort were 34.3%, 17.0%, 8.6% and 67.8%, 45.4%, 18.5%, respectively. The median PMS (45.6 months <it>vs</it>. 23.7 months) and OS (73.7 months <it>vs</it>. 46.2 months) of patients treated with combined therapy was significantly longer than that of those treated with chemotherapy alone (<it>P </it>< 0.001). Age, disease-free interval (DFI) and treatment modality were evaluated as independent prognostic factors of OS, while only age and treatment modality retain their independent significance in PMS analysis. In stratified survival analysis, compared to chemotherapy alone, combined therapy could benefit the patients with DFI > 1 year, but not those with DFI ≤ 1 year.</p> <p>Conclusions</p> <p>Age ≤ 45 years, DFI > 1 year, and the combined therapy were good prognostic factors for NPC patients with lung metastasis(es) alone. The combination of local therapy and the basic chemotherapy should be considered for these patients with DFI > 1 year.</p

Ethnic differences in the association between blood pressure components and chronic kidney disease in middle aged and older Asian adults

10.1186/1471-2369-14-86BMC Nephrology141

Reliable quantification of the potential for equations based on spot urine samples to estimate population salt intake: protocol for a systematic review and meta-analysis

Background: Methods based on spot urine samples (a single sample at one time-point) have been identified as a possiblealternative approach to 24-hour urine samples for determining mean population salt intake.Objective: The aim of this study is to identify a reliable method for estimating mean population salt intake from spot urinesamples. This will be done by comparing the performance of existing equations against one other and against estimates derivedfrom 24-hour urine samples. The effects of factors such as ethnicity, sex, age, body mass index, antihypertensive drug use, healthstatus, and timing of spot urine collection will be explored. The capacity of spot urine samples to measure change in salt intakeover time will also be determined. Finally, we aim to develop a novel equation (or equations) that performs better than existingequations to estimate mean population salt intake.Methods: A systematic review and meta-analysis of individual participant data will be conducted. A search has been conductedto identify human studies that report salt (or sodium) excretion based upon 24-hour urine samples and spot urine samples. Therewere no restrictions on language, study sample size, or characteristics of the study population. MEDLINE via OvidSP (1946-present),Premedline via OvidSP, EMBASE, Global Health via OvidSP (1910-present), and the Cochrane Library were searched, and tworeviewers identified eligible studies. The authors of these studies will be invited to contribute data according to a standard format.Individual participant records will be compiled and a series of analyses will be completed to: (1) compare existing equations forestimating 24-hour salt intake from spot urine samples with 24-hour urine samples, and assess the degree of bias according tokey demographic and clinical characteristics; (2) assess the reliability of using spot urine samples to measure population changesin salt intake overtime; and (3) develop a novel equation that performs better than existing equations to estimate mean populationsalt intake.Results: The search strategy identified 538 records; 100 records were obtained for review in full text and 73 have been confirmedas eligible. In addition, 68 abstracts were identified, some of which may contain data eligible for inclusion. Individual participantdata will be requested from the authors of eligible studies.Conclusions: Many equations for estimating salt intake from spot urine samples have been developed and validated, althoughmost have been studied in very specific settings. This meta-analysis of individual participant data will enable a much broaderunderstanding of the capacity for spot urine samples to estimate population salt intake

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia