tbuckley/cabot-search huggingface dataset:
Podocyte-Specific Loss of Cdc42 Leads to Congenital Nephropathy
Authors: Rizaldy P. Scott, Steve P. Hawley, Julie Ruston, Jianmei Du, Cord Brakebusch, Nina Jones, Tony Pawson
Journal: Journal of the American Society of Nephrology (2012)

Rho family GTPases are molecular switches best known for their pivotal role in dynamic regulation of the actin cytoskeleton. The prototypic members of this family are Cdc42, Rac1, and RhoA; these GTPases contribute to the breakdown of glomerular filtration and the resultant proteinuria, but their functions in normal podocyte physiology remain poorly understood. Here, mice lacking Cdc42 in podocytes developed congenital nephropathy and died as a result of renal failure within 2 weeks after birth. In contrast, mice lacking Rac1 or RhoA in podocytes were overtly normal and lived to adulthood. Kidneys from Cdc42-mutant mice exhibited protein-filled microcysts with hallmarks of collapsing glomerulopathy, as well as extensive effacement of podocyte foot processes with abnormal junctional complexes. Furthermore, we observed aberrant expression of several podocyte markers and cell polarity proteins in the absence of Cdc42, indicating a disruption of the slit diaphragm. Kidneys from Rac1- and RhoA-mutant mice, however, had normal glomerular morphology and intact foot processes. A nephrin clustering assay suggested that Cdc42 deficiency, but not Rac1 or RhoA deficiency, impairs the polymerization of actin at sites of nephrin aggregates. Taken together, these data highlight the physiological importance of Cdc42, but not Rac1 or RhoA, in establishing podocyte architecture and glomerular function.
A4.11 Combination of TNF-α and IL-17a promotes osteogenic differentiation, but increases schnurri 3 in isolated human mesenchymal stem cells
Authors: Bilal Osta, Assia Eljaafari, Fabien Lavocat, Pierre Miossec
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Rheumatoid arthritis (RA) is characterised by defective bone repair and excessive bone destruction, and ankylosing spondylitis (AS) by increased ectopic bone formation. Since TNF-α and IL-17A are involved in the pathogenesis of both diseases, the aim of this study was to investigate their effects on the osteogenic differentiation of isolated human bone marrow derived mesenchymal stem cells (hMSCs). <h3>Materials and Methods</h3> Differentiation of hMSCs into osteoblasts was induced in the presence or absence of TNF-α and/or IL-17A. Matrix mineralization was evaluated by alizarin red staining and alkaline phosphatase activity measurement. mRNA expression was measured by qRT-PCR for the osteogenesis associated genes BMP2 and RUNX2, for DKK1 the negative regulator of osteogenesis, and for Shn3 and RANKL, genes associated with the cross-talk with osteoclasts. <h3>Results</h3> Exposure of isolated hMSCs to TNF-α resulted in a significant acceleration of matrix mineralization, which was potentiated by IL-17A (TNF-α, <i>p = </i>0.03; TNF-α + IL-17A, <i>p</i> = 0.001 vs. induction medium at day 17). This was associated with a significant increase of alkaline phosphatase activity and an acceleration of its kinetics (TNF-α, p = 0.05; IL-17A, p = 0.01; TNF-α + IL-17A 1, p = 0.01 vs. induction). TNF-α but not IL-17A induced significant a early increase of BMP2 mRNA expression (TNF-α, <i>p</i> = 0.007 vs. induction at 6hrs). The combination of TNF-α and IL-17A induced a strong and sustained significant decrease of DKK1 (<i>p</i> = 0.03 vs. induction at 72hr) and RANKL (<i>p</i> = 0.002 vs. induction at 6hr) mRNA expression, but an early significant increase of Schnurri-3 (TNF-α, <i>p</i> = 0.03; TNF-α + IL-17A, <i>p</i> = 0.007 vs. induction at 6hr). On the contrary, Runx2 gene expression was not affected in any conditions. <h3>Conclusions</h3> The combined action of TNF-α and IL-17A increased hMSCs osteogenesis, via increasing BMP2 and reducing RANKL and DKK1 gene expression. This could be involved in ectopic bone formation as observed in AS, where osteoclasts are not present. Conversely, increase of Schnurri-3 may activate osteoclasts and bone destruction as observed in RA.
Treatment of post pneumonectomy pleural empyema by open window thoracostomy
Authors: PE Postmus, JM Kerstjens, WJ de Boer, JN Homan van der Heide, GH Koeter
Journal: European Respiratory Journal (1989)

In 13 patients an open window thoracostomy (OWT) was performed for post pneumonectomy pleural empyema. The operation, and life with an OWT cavity, were tolerated well. Early closure of an OWT is not advisable because of a high chance of recurrence of the infection and, in lung cancer patients also the risk of tumour relapse within two years after tumour surgery.
Myocardial Pitx2 Differentially Regulates the Left Atrial Identity and Ventricular Asymmetric Remodeling Programs
Authors: Alessandra Tessari, Mara Pietrobon, Antonella Notte, Giuseppe Cifelli, Philip J. Gage, Michael D. Schneider, Giuseppe Lembo, Marina Campione
Journal: Circulation Research (2008)

The Pitx2 gene regulates left-right (L/R) asymmetrical cardiac morphogenesis. Constitutive Pitx2 knock out (ko) mice die before birth and display, among other defects, right atrial isomerism, atrial and ventricular septal defects, and double outlet right ventricle. The myocardial role of the gene has not been dissected. In particular, how Pitx2 regulates the differential L/R cardiac identity program is not clear. Additionally, the relation between Pitx2 ko ventricular defects and the gene expression pattern is not understood. In this article we analyze Pitx2 myocardial function during mouse heart development. By in situ hybridization analysis we show that myocardial Pitx2 expression delineates the remodeling of the left atrioventricular canal, the inner curvature, the ventral part of the interventricular ring, and the ventral portion of the right and left ventricle. By genetic analysis using an allelic series of Pitx2 mutants, among which a myocardial specific ko (ko(myo)) we show it has a crucial role in this process. Pitx2 ko(myo) mutants survive to adulthood, when they present strong cardiac morphological and functional defects. Confocal analysis of embryonic Pitx2 ko(myo) hearts reveals delayed cardiomyocyte development in the ventricular but not in the atrial Pitx2 null areas. Conversely, selective left atrial BMP10 mRNA downregulation which normally occurs at fetal stages is not found in the Pitx2 ko(myo) mice. This is the first evidence for distinct Pitx2 action in mediating L/R atrial identity and asymmetrical ventricular remodeling.
What is the relationship between epidermal growth factor-like domain 7 and RhoC in metastasis of hepatocellular carcinoma?
Authors: Na Liu, Hongbo Zhang, Kaichun Wu, Daiming Fan
Journal: Hepatology (2009)

We read with great interest the article written by Yang et al.1 in which they showed for the first time that epidermal growth factor-like domain 7 (Egfl7) promotes metastasis of hepatocellular carcinoma (HCC) by enhancing cell motility through epidermal growth factor receptor (EGFR)-dependent focal adhesion kinase (FAK) phosphorylation. They suggested Egfl7 as a novel prognostic marker for metastasis of HCC and a potential therapeutic target. Very interestingly, the same group demonstrated in previous work that RhoC also plays a critical role in metastasis of HCC,2, 3 which is consistent with our result of RhoC in gastric cancer.4 So what is the relationship between Egfl7 and RhoC in metastasis of HCC? Yang et al. showed in figures 4C and 5B that recombinant Egfl7 protein stimulated the reorganization of actin, leading to the formation of stress-fiber–like structures in HCCLM3Egfl7RNAi+ cells and EGFR inhibitor could inhibit this effect. It is known that RhoC protein plays an important role in controlling stress fiber and focal adhesion contact formation.4 In another article from the same group, Yang et al. also observed that inhibition of RhoC in HCCLM3 (hepatocellular carcinoma lung metastasis 3rd selection) cells blocked autotoxin-induced stress fiber formation.2 So, is RhoC involved in the cytoskeletal change induced by Egfl7 protein? The authors interpreted this change due to FAK phosphorylation stimulated by Egfl7 protein, but we found some reports demonstrating that RhoC can activate FAK.5, 6 One group indicated that RhoC promotes tumor metastasis in prostate cancer by sequential activation of Pyk2 (Proline-rich tyrosine kinase 2), FAK, MAPK (mitogen-activated protein kinase), and Akt followed by the up-regulation of matrix metalloproteinase 2(MMP2) and MMP9, which results in the stimulation of invasiveness of tumor cells.5 So, can we hypothesize that Egfl7 activates FAK through RhoC protein in HCC cells? We also noticed one article from the same group showing that overexpression of RhoC in HCC tissues was highly correlated with tumor invasion and poor prognosis,3 which is similar with the results of Egfl7.4 The HCC specimens used in the article regarding Egfl7 were from 112 patients with HCC in Xiangya Hospital of Central South University between 1998 and 2005,1 and specimens used in the RhoC article were collected from the same hospital between 1994 and 2002,3 so the period from 1998 to 2002 was overlapped. If the expression pattern of RhoC in these specimens is strongly correlated with that of Egfl7, it will further confirm our hypothesis. Na Liu*, Hongbo Zhang*, Kaichun Wu*, Daiming Fan*, * State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Top-Accessed Article: Text-Message Reminders to Improve Sunscreen Use
Authors: Melody J. Eide
Journal: JAMA Dermatology (2013)

campaign by the IT industry and continue to inform their patients about the risks of IT and the existence of potentially misleading information from the ASA and other organizations.Scientists and clinicians have a duty to remain cognizant of such issues and to voice concerns when agenda-based research is presented in order to "defend and promote" a product with potentially devastating health consequences.
Hydroperoxides in Plasma Are Reduced by Intensified Insulin Treatment: A randomized controlled study of IDDM patients with microalbuminuria
Authors: Tore Julsrud Berg, Jaffar Nourooz-Zadeh, Simon P Wolff, Hans J Tritschler, Hans-Jacob Bangstad, Kristian F Hanssen
Journal: Diabetes Care (1998)

An association between reactive oxygen species and diabetic micro- and macrovascular complications has been proposed. In the present study, we have examined the effect of an improved blood glucose control on plasma levels of hydroperoxides in patients with IDDM.Subjects included 30 young IDDM patients with microalbuminuria who were randomized to receive either continuous subcutaneous insulin infusion (CSII) by a portable insulin pump (n = 15) or conventional insulin treatment (CIT) (n = 15) for 24 months. Plasma levels of hydroperoxides were measured by the ferrous oxidation with Xylenol Orange, version 2 (FOX2) assay. This method measures total lipid hydroperoxides and, unlike other methods, does not suffer from extraction losses.The mean HbA1c level was lower in the CSII group at the end of the study than in the CIT group: (mean [95% CI]) 8.6 (8.1-9.1) vs. 9.6 (9.0-10.3)%, respectively (P < 0.002). The level of plasma hydroperoxides was very similar at the start of the study but was significantly lower in the CSII group compared with the CIT group at the end of the study: 2.9 (2.1-3.7) vs. 4.3 (3.2-5.4) mumol/l, respectively (P < 0.02). In the CSII group, hydroperoxides were reduced by 31% from baseline (P < 0.001), whereas there was no change in levels of hydroperoxides in the CIT group. Mean hydroperoxide levels correlated with mean HbA1c during the study (r = 0.39, P < 0.04). Hydroperoxide levels were associated with the levels of microalbuminuria (r = 0.45, P < 0.02).This study provides support for the hypothesis that hyperglycemia is an important factor in the generation of hydroperoxides, and, thus, reactive oxygen species, in the circulation of IDDM patients.
Pharmacogenetics in Cancer Treatment
Authors: R. Nagasubramanian, F. Innocenti, M. J. Ratain
Journal: Annual Review of Medicine (2003)

Interindividual variability in the efficacy and toxicity of drug therapy is associated with polymorphisms in genes encoding drug-metabolizing enzymes, transporters, or drug targets. Pharmacogenetics aims to identify individuals predisposed to high risk of toxicity from conventional doses of cancer chemotherapeutic agents. We review the role of genetic polymorphisms in UGT1A1 and TPMT, as well as mutations in DPD, in influencing drug disposition and toxicity. Recent studies show that pharmacogenetic determinants may also influence treatment outcomes. We discuss the clinical significance of polymorphisms in TS, MTHFR, and FCGR3A, as well as the polymorphic DNA repair genes XPD and XRCC1, in influencing response to chemotherapy and survival outcomes. Finally, the potential implications of transporter pharmacogenetics in influencing drug bioavailability are addressed.
Thermal signature analysis as a novel method for evaluating inflammatory arthritis activity
Authors: Max Brenner, Chris Braun, Mike Oster, Percio S. Gulko
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To examine the potential usefulness of a novel thermal imaging technique to evaluate and monitor inflammatory arthritis activity in small joints using rat models, and to determine whether thermal changes can be used to detect preclinical stages of synovitis. <b>Methods:</b> Three different rat strains were studied in a model of inflammatory arthritis of the ankle induced by an intra-articular (IA) injection of complete Freund's adjuvant (CFA), compared with the contralateral ankle injected with normal saline. Arthritis activity and severity scores, ankle diameters, pain related posture scores, and thermal images were obtained at 10 different times between 0 h (before induction) and day 7. The pristane induced arthritis (PIA) model was used to study preclinical synovitis. Thermal images were obtained at each time point using the TSA ImagIR system and were digitally analysed. <b>Results:</b> Rats developed similar ankle arthritis detected six hours after the IA injection of CFA, which persisted for seven days. All ankle clinical indices, including arthritis activity and severity scores, correlated significantly with ankle thermal imaging changes in the monoarthritis model (p&lt;0.003). No thermal imaging changes were detected in preclinical stages of PIA. However, PIA onset coincided with increased ankle thermal signature. <b>Conclusions:</b> Thermal measurements correlated significantly with arthritis activity and severity indices. The technique was highly sensitive and could measure directly two cardinal signs of inflammation (warmth and oedema, based on ankle diameter) in an area (ankle) that is less than half the size of a human interphalangeal joint, suggesting a potential use in drug trials or clinical practice.
Age at childhood infections and risk of atopy
Authors: P Bager
Journal: Thorax (2002)

Background: It has been proposed that early age at exposure to common childhood infections is associated with a decreased risk of allergy. Previous studies on the possible association between allergy and infection with measles, mumps, rubella, and varicella have not been conclusive as most did not include information on exact age at exposure. The objective of our study was to investigate whether early age at exposure to these infections was associated with a decreased risk of atopy using information on exact age at infection. Methods: The study population consisted of 889 pregnant women who participated in a national birth cohort study in Denmark and for whom detailed information on history of measles, rubella, varicella, and mumps before school entry (age 7 years) was available from school health records from Copenhagen. Atopic status was assessed serologically by a specific response to 11 common inhalant allergens using serum samples obtained from the women during pregnancy. Results: Measles in the first year of life was associated with a higher risk of atopy than no measles before age 7 years (OR 3.36, 95% CI 1.47 to 7.68). There was no association between atopy and mumps, rubella, or varicella in the first 7 years of life or with measles acquired after the first year of life. The risk of atopy increased significantly with increasing number of childhood infections in the first 2 years of life (p<sub>trend</sub>=0.01). Conclusions: These findings do not support the suggestion that childhood exposure to measles, rubella, varicella, or mumps protects against atopy, even if acquired very early in life.
Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii.
Authors: O Liesenfeld, J Kosek, J S Remington, Y Suzuki
Journal: The Journal of Experimental Medicine (1996)

Since there is a remarkable difference in susceptibility to peroral infection with Toxoplasma gondii among inbred strains of mice, we performed studies to examine the mechanism(s) of this difference in susceptibility. After peroral infection with the ME49 strain of T. gondii, C57BL/6 (B6) mice all died whereas BALB/c mice all survived. At day 7 of infection (when B6 mice began dying), massive necrosis of the villi and mucosal cells in the ilea were observed in B6 but not in BALB/c mice. To analyze the role of T cells in resistance against death and development of necrosis in the ilea after infection, studies were performed using athymic nude and euthymic control B6 and BALB/c mice. Athymic B6 mice all died after infection, but surprisingly, they survived significantly longer than control B6 mice, indicating that T cells predispose to early death in these mice. Necrosis in the ilea was observed in control B6 but not in athymic B6 mice; however, significantly less numbers of tachyzoites were observed in the ilea of the former than the latter mice. These results indicate that necrosis in the ilea of the B6 mice was not due to destruction of tissue by tachyzoites but was mediated by T cells. This deleterious effect of T cells appears to contribute to early death in these mice. In contrast, T cells conferred resistance against death in BALB/c mice but did not cause necrosis in their ilea. To analyze the T cell subset(s) that induces necrosis of the ilea in B6 mice, we examined histological changes of the small intestines after infection of mutant mice deficient in different T cell subsets (with the same H-2b haplotype as B6 mice). Mice deficient in alpha/beta or CD4+ T cells did not develop necrosis in the ilea, whereas wild-type control mice and mice deficient in gamma/delta or CD8+ T cells did, suggesting that the cells that induce necrosis in the ilea after infection are CD4+ alpha/beta T cells. Since interferon (IFN)-gamma has been shown to be critical for survival of BALB/c mice after infection with T. gondii, we examined the role of this cytokine in resistance/susceptibility of infected B6 mice. Treatment of B6 mice with anti-IFN-gamma monoclonal antibody shortly before they developed illness prolonged time to death and prevented necrosis in the ilea in these mice. These results indicate that IFN-gamma mediates necrosis in the ilea of B6 mice after infection. This CD4+ T cell-dependent, IFN-gamma-mediated necrosis of the small intestines appears to be a mechanism that underlies the genetic susceptibility of B6 mice to peroral infection with T. gondii, whereas the same cytokine plays a critical role in the resistance of genetically resistant BALB/c mice.
Effect of autogenic training and mental imagery on the trait anxiety of the hockey players
Authors: Chitra Dhiman, Harneet Shallu Bedi
Journal: British Journal of Sports Medicine (2010)

The present research investigation was an attempt to enhance the performance of the hockey players by regulating their trait anxiety level through implementing autogenic training and mental imagery. Pre- and post-test design was used for this purpose. Sample of the study included 31 hockey players of Netaji Subhas National Institute of Sports, Patiala. The trait anxiety test (Spielberger 1973) was used to assess trait anxiety of the participants in pre- and post-test conditions. In order to analyse pre- and post-test data t test was applied. The findings revealed that the trait anxiety of the hockey players was significantly reduced, t-ratio = 3.84**, p&lt;0.01, in post-test condition (mean = 29.55) as compared to the pretest condition (mean = 36.81). The concerned coaches had observed improvement in the performance of the hockey players.
Predicting risk for early infantile atopic dermatitis by hereditary and environmental factors
Authors: H-J. Wen, P-C. Chen, T-L. Chiang, S-J. Lin, Y-L. Chuang, Y-L. Guo
Journal: British Journal of Dermatology (2009)

Hereditary and environmental factors contribute to the occurrence of atopic dermatitis (AD). However, the interaction of these two factors is not totally understood.To evaluate the early risk factors for infantile AD at the age of 6 months and to develop a predictive model for the development of AD.In 2005, a representative sample of mother and newborn pairs was obtained by multistage, stratified systematic sampling from the Taiwan national birth register. Information on hereditary and environmental risk factors was collected by home interview when babies were 6 months old. Multivariate regression analysis was applied to determine the risk factors for AD in the infants.A total of 20 687 pairs completed the study satisfactorily. AD was diagnosed in 7.0% of 6-month-old infants by physicians. Parental asthma, atopic dermatitis and allergic rhinitis, and maternal education levels were risk factors for AD in infants. Among environmental factors, fungus on walls at home and renovation/painting in the house during pregnancy were significantly associated with early infantile AD. Using these factors, the probability of having infantile AD was estimated and grouped into low, high and very high. With five runs of tests in mutually exclusive subsets of this population, the likelihood of AD for 6-month-old infants was consistent in all the groups with the predictive model. The highest predicted probability of AD was 70.1%, among boys with maternal education levels > 12 years, both parents with AD, renovation and painting of the house during pregnancy and fungus on walls at home. The lowest probability was 3.1%, among girls with none of the above factors.This investigation provides a technique for predicting the risk of infantile AD based on hereditary and environmental factors, which could be used for developing a preventive strategy against AD, especially among those children with a family history of atopy.