bluuebunny/crossref_metadata_2025 huggingface dataset:
P2Y2receptor activation decreases blood pressure and increases renal Na+excretion
Authors: Rieg Timo , Gerasimova Maria , Boyer José L. , Insel Paul A. , Vallon Volker
Published: May 2011

ATP and UTP are endogenous agonists of P2Y2/4receptors. To define the in vivo effects of P2Y2receptor activation on blood pressure and urinary excretion, we compared the response to INS45973, a P2Y2/4receptor agonist and UTP analog, in wild-type (WT) and P2Y2receptor knockout (P2Y2−/−) mice. INS45973 was administered intravenously as a bolus injection or continuous infusion to determine effects on blood pressure and renal function, respectively. Within seconds, bolus application of INS45973 (0.1 to 3 mg/kg body wt) dose-dependently decreased blood pressure in WT (maximum response −35 ± 2 mmHg) and to a similar extent in endothelial nitric oxide synthase knockout mice. By contrast, blood pressure increased in P2Y2−/− (maximum response +18 ± 1 mmHg) but returned to basal levels within 60 s. Continuous infusion of INS45973 (25 to 750 μg·min−1·kg−1body wt) dose-dependently increased urinary excretion of Na+in WT (maximum response +46 ± 15%) but reduced Na+excretion in P2Y2−/− (maximum responses of −45 ± 15%) mice. In renal clearance experiments, INS45973 did not affect glomerular filtration rate but lowered blood pressure and increased fractional excretion of fluid, Na+, and K+in WT relative to P2Y2−/− mice. The blood pressure responses to INS45973 are consistent with P2Y2receptor-mediated NO-independent vasodilation and implicate responses to endothelium-derived hyperpolarizing factor, and P2Y2receptor-independent vasoconstriction, probably via activation of P2Y4receptors on smooth muscle. Systemic activation of P2Y2receptors thus lowers blood pressure and inhibits renal Na+reabsorption, effects suggesting the potential utility of P2Y2agonism in the treatment of hypertension.
Maternal vasodilation in pregnancy: the emerging role of relaxin
Authors: Conrad Kirk P.
Published: May 2011

Pregnancy is a unique physiological condition of profound maternal renal and systemic vasodilation. Our goal has been to unveil the reproductive hormones mediating this remarkable vasodilatory state and the underlying molecular mechanisms. In addition to advancing our knowledge of pregnancy physiology, reaching this goal may translate into therapeutics for pregnancy pathologies such as preeclampsia and for diseases associated with vasoconstriction and arterial stiffness in nonpregnant women and men. An emerging player is the 6 kDa corpus luteal hormone relaxin, which circulates during pregnancy. Relaxin administration to rats and humans induces systemic and renal vasodilation regardless of sex, thus mimicking the pregnant condition. Immunoneutralization or elimination of the source of circulating relaxin prevents renal and systemic vasodilation in midterm pregnant rats. Infertile women who become pregnant by donor eggs (IVF with embryo transfer) lack a corpus luteum and circulating relaxin, and they show a markedly subdued gestational increase in glomerular filtration rate. These data implicate relaxin as one of the vasodilatory reproductive hormones of pregnancy. There are different molecular mechanisms underlying the so-called rapid and sustained vasodilatory actions of relaxin. The former is mediated by Gαi/oprotein coupling to phosphatidylinositol-3 kinase/Akt (protein kinase B)-dependent phosphorylation and activation of endothelial nitric oxide synthase, the latter by vascular endothelial and placental growth factors, and increases in arterial gelatinase(s) activity. The gelatinases, in turn, hydrolyze big endothelin (ET) at a gly-leu bond to form ET1–32, which activates the endothelial ETBreceptor/nitric oxide vasodilatory pathway.
Evidence for NHE3-mediated Na transport in sheep and bovine forestomach
Authors: Rabbani Imtiaz , Siegling-Vlitakis Christiane , Noci Bardhyl , Martens Holger
Published: May 2011

Na absorption across the cornified, multilayered, and squamous rumen epithelium is mediated by electrogenic amiloride-insensitive transport and by electroneutral Na transport. High concentrations of amiloride (>100 μM) inhibit Na transport, indicating Na+/H+exchange (NHE) activity. The underlying NHE isoform for transepithelial Na absorption was characterized by mucosal application of the specific inhibitor HOE642 for NHE1 and S3226 for NHE3 in Ussing chamber studies with isolated epithelia from bovine and sheep forestomach. S3226 (1 μM; NHE3 inhibitor) abolished electroneutral Na transport under control conditions and also the short-chain fatty acid-induced increase of Na transport via NHE. However, HOE642 (30 μM; NHE1 inhibitor) did not change Na transport rates. NHE3 was immunohistochemically localized in membranes of the upper layers toward the lumen. Expression of NHE1 and NHE3 has been previously demonstrated by RT-PCR, and earlier experiments with isolated rumen epithelial cells have shown the activity of both NHE1 and NHE3. Obviously, both isoforms are involved in the regulation of intracellular pH, pHi. However, transepithelial Na transport is only mediated by apical uptake via NHE3 in connection with extrusion of Na by the basolaterally located Na-K-ATPase. The missing involvement of NHE1 in transepithelial Na transport suggests that the proposed “job sharing” in epithelia between these two isoforms probably also applies to forestomach epithelia: NHE3 for transepithelial transport and NHE1 for, among others, pHiand volume regulation.
Loss of poly(ADP-ribose) polymerase 1 attenuates renal fibrosis and inflammation during unilateral ureteral obstruction
Authors: Kim Jinu , Padanilam Babu J.
Published: May 2011

Poly(ADP-ribose) polymerase 1 (PARP1) contributes to necrotic cell death and inflammation in several disease models; however, the role of PARP1 in fibrogenesis remains to be defined. Here, we tested whether PARP1 was involved in the pathogenesis of renal fibrosis using the unilateral ureteral obstruction (UUO) mouse model. UUO was performed by ligation of the left ureter near the renal pelvis in Parp1-knockout (KO) and wild-type (WT) male mice. After 10 days of UUO, renal PARP1 expression and activation were strongly increased by 6- and 13-fold, respectively. Interstitial fibrosis induced by UUO was significantly attenuated in Parp1-KO kidneys compared with that in WT kidneys at 10 days, but not at 3 days, based on collagen deposition, α-smooth muscle actin (α-SMA), and fibronectin expression. Intriguingly, the UUO kidneys in Parp1-KO mice showed a dramatic decrease in infiltration of neutrophil and reduction in expression of proinflammatory proteins including intercellular adhesion molecule-1, tumor necrosis factor-α, inducible nitric oxide synthase, and toll-like receptor 4 as well as phosphorylation of nuclear factor-κB p65, but not transforming growth factor-β1 (TGF-β1) at both 3 and 10 days. Pharmacological inhibition of PARP1 in rat renal interstitial fibroblast (NRK-49F) cell line or genetic ablation in primary mouse embryonic fibroblast cells did not affect TGF-β1-induced de novo α-SMA expression. Parp1 deficiency significantly attenuated UUO-induced histological damage in the kidney tubular cells, but not apoptosis. These data suggest that PARP1 induces necrotic cell death and contributes to inflammatory signaling pathways that trigger fibrogenesis in obstructive nephropathy.
High sodium intake increases HCO3−absorption in medullary thick ascending limb through adaptations in basolateral and apical Na+/H+exchangers
Authors: Good David W. , George Thampi , Watts Bruns A.
Published: May 2011

A high sodium intake increases the capacity of the medullary thick ascending limb (MTAL) to absorb HCO3−. Here, we examined the role of the apical NHE3 and basolateral NHE1 Na+/H+exchangers in this adaptation. MTALs from rats drinking H2O or 0.28 M NaCl for 5–7 days were perfused in vitro. High sodium intake increased HCO3−absorption rate by 60%. The increased HCO3−absorptive capacity was mediated by an increase in apical NHE3 activity. Inhibiting basolateral NHE1 with bath amiloride eliminated 60% of the adaptive increase in HCO3−absorption. Thus the majority of the increase in NHE3 activity was dependent on NHE1. A high sodium intake increased basolateral Na+/H+exchange activity by 89% in association with an increase in NHE1 expression. High sodium intake increased apical Na+/H+exchange activity by 30% under conditions in which basolateral Na+/H+exchange was inhibited but did not change NHE3 abundance. These results suggest that high sodium intake increases HCO3−absorptive capacity in the MTAL through 1) an adaptive increase in basolateral NHE1 activity that results secondarily in an increase in apical NHE3 activity; and 2) an adaptive increase in NHE3 activity, independent of NHE1 activity. These studies support a role for NHE1 in the long-term regulation of renal tubule function and suggest that the regulatory interaction whereby NHE1 enhances the activity of NHE3 in the MTAL plays a role in the chronic regulation of HCO3−absorption. The adaptive increases in Na+/H+exchange activity and HCO3−absorption in the MTAL may play a role in enabling the kidneys to regulate acid-base balance during changes in sodium and volume balance.
Renal effects of prolonged high protein intake and COX2 inhibition on hypertensive rats with altered renal development
Authors: Reverte Virginia , Tapia Antonio , Moreno Juan Manuel , Rodríguez Leocadio , Salazar Francisco , Llinás M. Teresa , Salazar F. Javier
Published: May 2011

Cyclooxygenase 2 (COX2) is involved in regulating renal hemodynamics after renal ablation. It is also known that high protein intake (HPI) leads to a deterioration of renal function when there is preexisting renal disease and that there are important gender differences in the regulation of renal function. This study tested the hypothesis that the role of COX2 in regulating renal function and the renal hemodynamic effects elicited by HPI are enhanced when nephrogenesis is altered during renal development. It was also expected that the role of COX2 and the effects elicited by HPI are age and sex dependent. Newborn Sprague-Dawley rats were treated with an AT1 ANG II receptor antagonist during the nephrogenic period (ARAnp). Experiments were performed at 3–4 and 10–11 mo of age. Arterial pressure was elevated ( P < 0.05) at both ages and in both sexes of ARAnp-treated rats. Renal COX2 expression was only elevated ( P < 0.05) at 10–11 mo of age in both sexes of ARAnp-treated rats. COX2 inhibition induced greater renal vasoconstriction in male and female hypertensive than in normotensive rats at both ages. HPI did not induce glomerular filtration rate (GFR) in the youngest hypertensive rats and in the oldest female hypertensive rats. However, the GFR decreased during HPI (0.63 ± 0.07 to 0.19 ± 0.05 ml/min) in the oldest male hypertensive rats. The HPI-induced increment in proteinuria was greater ( P < 0.05) in male (99 ± 22 mg/day) than in female (30 ± 8 mg/day) hypertensive rats. These results show that COX2 plays an important role in the regulation of renal function when renal development is altered and that prolonged HPI can lead to a renal insufficiency in males but not in females with reduced nephron endowment.
GLUT1 enhances mTOR activity independently of TSC2 and AMPK
Authors: Buller Carolyn L. , Heilig Charles W. , Brosius Frank C.
Published: May 2011

Enhanced GLUT1 expression in mesangial cells plays an important role in the development of diabetic nephropathy by stimulating signaling through several pathways resulting in increased glomerular matrix accumulation. Similarly, enhanced mammalian target of rapamycin (mTOR) activation has been implicated in mesangial matrix expansion and glomerular hypertrophy in diabetes. We sought to examine whether enhanced GLUT1 expression increased mTOR activity and, if so, to identify the mechanism. We found that levels of GLUT1 expression and mTOR activation, as evidenced by S6 kinase (S6K) and 4E-BP-1 phosphorylation, changed in tandem in cell lines exposed to elevated levels of extracellular glucose. We then showed that increased GLUT1 expression enhanced S6K phosphorylation by 1.7- to 2.9-fold in cultured mesangial cells and in glomeruli from GLUT1 transgenic mice. Treatment with the mTOR inhibitor, rapamycin, eliminated the GLUT1 effect on S6K phosphorylation. In cells lacking functional tuberous sclerosis complex (TSC) 2, GLUT1 effects on mTOR activity persisted, indicating that GLUT1 effects were not mediated by TSC. Similarly, AMP kinase activity was not altered by enhanced GLUT1 expression. Conversely, enhanced GLUT1 expression led to a 2.4-fold increase in binding of mTOR to its activator, Rheb, and a commensurate 2.1-fold decrease in binding of Rheb to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) consistent with mediation of GLUT1 effects by a metabolic effect on GAPDH. Thus, GLUT1 expression appears to augment mesangial cell growth and matrix protein accumulation via effects on glycolysis and decreased GAPDH interaction with Rheb.
Role of local field potentials in encoding hand movement kinematics
Authors: Witte Matthias
Published: May 2011

How the brain orchestrates the musculoskeletal system to produce complex three-dimensional movements is still poorly understood. Despite first promising results in brain-machine interfaces that translate cortical activity to control output, there is an ongoing debate about which brain signals provide richest information related to movement planning and execution. Novel results by Bansal and colleagues (2011) now suggest that neuronal spiking and local field potentials jointly encode kinematics during skilled reach and grasp movements.
Collocation Method via Jacobi Polynomials for Solving Nonlinear Ordinary Differential Equations
Authors: Imani Ahmad , Aminataei Azim , Imani Ali
Published: May 2011

We extend a
collocation method for solving a nonlinear
ordinary differential
equation (ODE) via Jacobi polynomials. To date, researchers
usually use Chebyshev or Legendre collocation method for solving
problems in chemistry, physics, and so forth, see the works of (Doha and Bhrawy 2006, Guo 2000, and Guo et al. 2002). Choosing the optimal polynomial for solving every ODEs problem
depends on many factors, for example, smoothing continuously and
other properties of the solutions. In this paper, we show
intuitionally that in some problems choosing other members of
Jacobi polynomials gives better result compared to Chebyshev or
Legendre polynomials.
Poly(ADP-Ribose) Polymerase Inhibition Synergizes with 5-Fluorodeoxyuridine but not 5-Fluorouracil in Ovarian Cancer Cells
Authors: Huehls Amelia M. , Wagner Jill M. , Huntoon Catherine J. , Geng Liyi , Erlichman Charles , Patel Anand G. , Kaufmann Scott H. , Karnitz Larry M.
Published: May 2011

5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, and both agents undergo intracellular processing to active metabolites that disrupt RNA and DNA metabolism. These agents cause imbalances in deoxynucleotide triphosphate levels and the accumulation of uracil and 5-FU in the genome, events that activate the ATR- and ATM-dependent checkpoint signaling pathways and the base excision repair (BER) pathway. Here, we assessed which DNA damage response and repair processes influence 5-FU and FdUrd toxicity in ovarian cancer cells. These studies revealed that disabling the ATM, ATR, or BER pathways using small inhibitory RNAs did not affect 5-FU cytotoxicity. In stark contrast, ATR and a functional BER pathway protected FdUrd-treated cells. Consistent with a role for the BER pathway, the poly(ADP-ribose) polymerase (PARP) inhibitors ABT-888 (veliparib) and AZD2281 (olaparib) markedly synergized with FdUrd but not with 5-FU in ovarian cancer cell lines. Furthermore, ABT-888 synergized with FdUrd far more effectively than other agents commonly used to treat ovarian cancer. These findings underscore differences in the cytotoxic mechanisms of 5-FU and FdUrd and suggest that combining FdUrd and PARP inhibitors may be an innovative therapeutic strategy for ovarian tumors. Cancer Res; 71(14); 4944–54. ©2011 AACR.
Berberine Suppresses Androgen Receptor Signaling in Prostate Cancer
Authors: Li Jing , Cao Bo , Liu Xichun , Fu Xueqi , Xiong Zhenggang , Chen Li , Sartor Oliver , Dong Yan , Zhang Haitao
Published: May 2011

The androgen receptor (AR) is critical in the normal development and function of the prostate, as well as in prostate carcinogenesis. Androgen deprivation therapy is the mainstay in the treatment of advanced prostate cancer; however, after an initial response, the disease inevitably progresses to castration-resistant prostate cancer (CRPC). Recent evidence suggests that continued AR activation, sometimes in a ligand-independent manner, is commonly associated with the development of CRPC. Thus, novel agents targeting the AR are urgently needed as a strategic step in developing new therapies for this disease state. In this study, we investigated the effect of berberine on AR signaling in prostate cancer. We report that berberine decreased the transcriptional activity of AR. Berberine did not affect AR mRNA expression, but induced AR protein degradation. Several ligand-binding, domain-truncated AR splice variants have been identified, and these variants are believed to promote the development of CRPC in patients. Interestingly, we found that these variants were more susceptible to berberine-induced degradation than the full-length AR. Furthermore, although the growth of LNCaP xenografts in nude mice was inhibited by berberine, and AR expression was reduced in the tumors, the morphology and AR expression in normal prostates were not affected. This study is the first to show that berberine suppresses AR signaling and suggests that berberine, or its derivatives, presents a promising agent for the prevention and/or treatment of prostate cancer. Mol Cancer Ther; 10(8); 1346–56. ©2011 AACR.
Push-Back Technique Facilitates Ultra-Low Anterior Resection without Nerve Injury in Total Mesorectal Excision for Rectal Cancer
Authors: Inoue Yasuhiro , Hiro Junichiro , Toiyama Yuji , Tanaka Koji , Uchida Keiichi , Miki Chikao , Kusunoki Masato
Published: May 2011

Aims: To describe our push-back approach to ultra-low anterior resection using the concept of the mucosal stump. Methods: We mobilize the rectum using an abdominal approach, and perform mucosal cutting circumferentially at the dentate line. The mucosal stump is closed, and the internal sphincteric muscle resected partially or totally according to tumor location. Perianal dissection is performed along the medial plane of the external sphincteric muscles, and the hiatal ligament is dissected posteriorly. To resect the entire rectum, the closed rectal stump is pushed back to the abdominal cavity using composed gauze. This prevents injury to the autonomic nerve. Results: We performed colonic J-pouch anal anastomosis using our mucosal stump approach in 58 patients with rectal cancer located <4 cm from the anal verge. According to the Wexner score, 7% of patients were fully continent, 71% had acceptable function with minor continence problems, and 22% were incontinent. No patients required intermittent self-catheterization during follow-up. After a median follow-up of 49 months, there was only 1 case of local recurrence after surgery. Conclusion: Our push-back approach for internal sphincter resection produces satisfactory functional and oncological results in ultra-low anterior rectal cancer.
Effect of Shunt Operation on Idiopathic Normal Pressure Hydrocephalus Patients in Reducing Caregiver Burden: Evidence from SINPHONI
Authors: Kazui Hiroaki , Mori Etsuro , Hashimoto Masaaki , Ishikawa Masatsune , Hirono Nobutsugu , Takeda Masatoshi
Published: May 2011

Background/Aims: Patients with idiopathic normal pressure hydrocephalus (iNPH) are often given shunt operations to reduce the triad symptoms (cognitive impairment, gait disturbance and urinary disturbance). We examined whether they also reduce caregiver burden. Methods: The personal strain (PS) and role strain (RS) factors, which are related to the stress and constraints, respectively, on the caregivers of 81 iNPH patients were evaluated with the Zarit burden interview (ZBI) and each of the triad symptoms was evaluated with the iNPH grading scale (iNPHGS) before and 1 year after the shunt operation. Results: Each of the iNPHGS scores, the total ZBI score and PS factor significantly improved after the shunt operation, but the RS factor did not. The improvement of cognitive impairment was the major factor in reducing caregiver burden. Conclusion: Shunt operations reduced the caregiver burden of iNPH patients.
Functional mapping of factor VIII C2 domain
Authors: Pellequer Jean-Luc , Chen Shu-wen W. , Saboulard Didier , Delcourt Marc , Négrier Claude , Plantier Jean-Luc
Published: May 2011

The factor VIII (FVIII) is a cofactor of the coagulation cascade. The FVIII C2 domain is a critical domain that participates in the interactions with the von Willebrand factor and the phospholipidic surfaces. To assess the importance of each residue of this domain in the maintenance of the structure and the function of FVIII, a number (n=139) of mutants were generated by substituting the original residues, from Ser2173 to Gly2325, by an alanine. Mutants were built within a complete B domain- deleted FVIII and expressed in COS-1 cells. Mutant antigen levels and procoagulant activities were measured. Two in silico analyses, a sliding average procedure and an analysis of the mutation energy cost were conducted in parallel on the FVIII structure. Both results were in agreement with the functional data, and illustrated the benefit of using such strategies prior to targeting specific residues in the aim of generating active recombinant molecules. The functional assays identify the residues that are important to maintaining the structure of the C2 domain, mainly those forming β-sheet, and those that can afford substitution, establishing a detailed functional relation with the available crystallographic data. This study provided a comprehensive functional mapping of the FVIII C2 domain and discussed the implication of specific residues in respect to the maintenance in the activity and structure stability, the efficiency in secretion, the binding to phospholipids and the formation of epitope.
Myocardial infarction, ischaemic stroke and pulmonary embolism before and after breast cancer hospitalisation
Authors: Shantakumar Sumitra , Kamphuisen Pieter W. , Beest Fernie J. A. Penning-van , Herings Ron M. C. , Herk-Sukel Myrthe P. P. van
Published: May 2011

We studied the occurrence of myocardial infarction (MI), ischaemic stroke (IS) and pulmonary embolism (PE) before and after breast cancer hospitalisation compared with cancer-free controls. For this, women with a first breast cancer hospitalisation during 2000–2007 were selected from the PHARMO Record Linkage System, including drug use and hospitalisations of three million inhabitants in the Netherlands, and matched 1:10 by age to cancer-free women. The occurrence of MI, IS and PE were assessed in the 12 months before and after breast cancer hospitalisation. The study included 11,473 breast cancer patients, with a mean (± SD) age of 59 (± 14) years. Breast cancer patients were two to three times as likely as their cancer-free controls to have had a hospitalisation for PE, MI or IS in the 12 months before diagnosis, though prevalence was <1% in all groups. Breast cancer patients experienced an extreme high risk of PE in the first six months after diag- nosis (hazard ratio [HR] 23.5, 95% confidence interval [CI] 11.1–49.7 compared to controls), which declined gradually to a four times increased risk (HR 3.6, 95%CI 2.4–5.5) more than 12 months after breast cancer hospitalisation. However, incidence was low: less than five events per 1,000 person years during all time periods. For MI and IS we did not observe significant increased HRs after breast cancer hospitalisation compared to controls. Breast cancer patients seem to have a higher risk profile to develop MI and IS, and receive treatment that increases the risk of PE compared to cancer-free controls, although the frequency of hospitalisations was low.
Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy
Authors: Angiolillo Dominick J. , Capranzano Piera , Ferreiro Jose Luis , Ueno Masafumi , Capodanno Davide , Dharmashankar Kodlipet , Darlington Andrew , Sumner Sabrina , Desai Bhaloo , Charlton Ronald K. , Box Lyndon C. , Zenni Martin M. , Guzman Luis A. , Bass Theodore A.
Published: May 2011

Cilostazol is a platelet inhibitor which when added to aspirin and clopidogrel has shown to reduce the risk of recurrent ischaemic events without an increase in bleeding. These clinical benefits have shown to be more pronounced in patients with diabetes mellitus (DM). However, it remains unknown whether cilostazol exerts different pharmacodynamic effects in patients with and without DM. This was a randomised, double-blind, placebo-controlled, cross-over pharmacodynamic study comparing platelet function in patients with and without DM on aspirin and clopidogrel therapy. Patients (n=111) were randomly assigned to either cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment for another 14 days. Platelet function was performed at baseline, 14 days post-randomisation, and 14 days post-cross-over. Functional testing to assess P2Y12 signalling included flow cytometric analysis of phosphorylation status of vasodilatorstimulated phosphoprotein measured by P2Y12 reactivity index (PRI), light transmittance aggregometry and VerifyNow. Thrombin generation processes were also studied using thrombelastography. Significantly lower PRI values were observed following treatment with cilostazol compared with placebo both in DM and non-DM groups (p < 0.0001). The absolute between-treatment differences of PRI between groups was a 35.1% lower in patients with DM (p=0.039). Similar results were obtained using all other functional measures assessing P2Y12 signalling. Thrombin generation was not affected by cilostazol. Cilostazol reduces platelet reactivity both in patients with and without DM, although these pharmacodynamic effects are enhanced in patients with DM. Despite the marked platelet inhibition, cilostazol does not alter thrombin-mediated haemostatic processes, which may explain its ischaemic benefit without the increased risk of bleeding.
Knockout of Toll-Like Receptor-2 Attenuates Both the Proinflammatory State of Diabetes and Incipient Diabetic Nephropathy
Authors: Devaraj Sridevi , Tobias Peter , Kasinath Balakuntalam S. , Ramsamooj Rajendra , Afify Alaa , Jialal Ishwarlal
Published: May 2011

Objective—

Type 1 diabetes (T1DM) is a proinflammatory state and confers an increased risk for vascular complications. Toll-like receptors (TLR) could participate in diabetic vasculopathies. Whether TLR activation contributes to the proinflammatory state of T1DM and the pathogenesis of diabetic nephropathy remains unknown.

Methods and Results—

We induced T1DM in TLR2 knockout mice (TLR2−/−) and wild-type littermates (C57BL/6J-WT) using streptozotocin (STZ). Fasting blood, peritoneal macrophages, and kidneys were obtained for flow cytometry, Western blot, microscopy, and cytokine assays at 6 and 14 weeks after induction of diabetes. Macrophage TLR2 expression and MyD88-dependent signaling were increased in diabetic mice (WT+STZ) compared with nondiabetic WT mice. These biomarkers were attenuated in diabetic TLR2−/− macrophages. WT+STZ mice showed increased kidney:body weight ratio due to cell hypertrophy, increased albuminuria, decreased kidney nephrin, podocin, and podocyte number and increased transforming growth factor-β and laminin compared with WT mice. Nephrin, podocin, and podocyte number and effacement were restored, and transforming growth factor-β and laminin levels were decreased in TLR2−/−+ STZ mice kidneys versus WT+STZ. Peritoneal and kidney macrophages were predominantly M1 phenotype in WT+STZ mice; this was attenuated in TLR2−/−+STZ mice.

Conclusion—

These data support a role for TLR2 in promoting inflammation and early changes of incipient diabetic nephropathy, in addition to albuminuria and podocyte loss.
Arginase I Attenuates Inflammatory Cytokine Secretion Induced by Lipopolysaccharide in Vascular Smooth Muscle Cells
Authors: Wang Xu-ping , Chen Yu-guo , Qin Wei-dong , Zhang Wei , Wei Shu-jian , Wang Juan , Liu Fu Qiang , Gong Lei , An Feng Shuang , Zhang Yun , Chen Zhe-Yu , Zhang Ming-Xiang
Published: May 2011

Objective—

Inflammation plays an important role in atherosclerosis. Arginase I (Arg I) promotes the proliferation of vascular smooth muscle cells; however, the effect of Arg I on inflammation remains unknown. The present study investigated the role of Arg I in inflammation in vitro and in vivo.

Methods and Results—

Quantitative reverse transcription–polymerase chain reaction and Western blot analysis demonstrated that Arg I inhibited tumor necrosis factor-α production induced by lipopolysaccharide in human aortic smooth muscle cells. Inducible nitric oxide synthase substrate competition and nuclear factor-κB activation were main contributors to lipopolysaccharide-mediated inflammatory cytokine generation. However, Arg I could attenuate the function of inducible nitric oxide synthase and inhibit the subsequent nuclear factor-κB activation, leading to inhibition of tumor necrosis factor-α generation. Furthermore, upregulation of Arg I significantly decreased macrophage infiltration and inflammation in atherosclerotic plaque of rabbits, whereas downregulation of Arg I aggravated these adverse effects.

Conclusion—

The results indicate the antiinflammatory effects of Arg I and suggest an unexpected beneficial role of Arg I in inflammatory disease.
Interactions Between Ankyrin-G, Plakophilin-2, and Connexin43 at the Cardiac Intercalated Disc
Authors: Sato Priscila Y. , Coombs Wanda , Lin Xianming , Nekrasova Oxana , Green Kathleen J. , Isom Lori L. , Taffet Steven M. , Delmar Mario
Published: May 2011

Rationale:

The early description of the intercalated disc defined 3 structures, all of them involved in cell-cell communication: desmosomes, gap junctions, and adherens junctions. Current evidence demonstrates that molecules not involved in providing a physical continuum between cells also populate the intercalated disc. Key among them is the voltage-gated sodium channel complex. An important component of this complex is the cytoskeletal adaptor protein Ankyrin-G (AnkG).

Objective:

To test the hypothesis that AnkG partners with desmosome and gap junction molecules and exerts a functional effect on intercellular communication in the heart.

Methods and Results:

We used a combination of microscopy, immunochemistry, patch-clamp, and optical mapping to assess the interactions between AnkG, Plakophilin-2, and Connexin43. Coimmunoprecipitation studies from rat heart lysate demonstrated associations between the 3 molecules. With the use of siRNA technology, we demonstrated that loss of AnkG expression caused significant changes in subcellular distribution and/or abundance of PKP2 and Connexin43 as well as a decrease in intercellular adhesion strength and electric coupling. Regulation of AnkG and of Na
v
1.5 by Plakophilin-2 was also demonstrated. Finally, optical mapping experiments in AnkG-silenced cells demonstrated a shift in the minimal frequency at which rate-dependence activation block was observed.

Conclusions:

These experiments support the hypothesis that AnkG is a key functional component of the intercalated disc at the intersection of 3 complexes often considered independent: the voltage-gated sodium channel, gap junctions, and the cardiac desmosome. Possible implications to the pathophysiology of inherited arrhythmias (such as arrhythmogenic right ventricular cardiomyopathy) are discussed.
Community-Based Participatory Research
Authors: Skolarus Lesli E. , Zimmerman Marc A. , Murphy Jillian , Brown Devin L. , Kerber Kevin A. , Bailey Sarah , Fowlkes Sophronia , Morgenstern Lewis B.
Published: May 2011

Background and Purpose—

Acute stroke treatments are underutilized primarily because of delayed hospital arrival. Using a community-based participatory research approach, we explored stroke self-efficacy, knowledge, and perceptions of stroke among a predominately African American population in Flint, Michigan.

Methods—

In March 2010, a survey was administered to youth and adults after religious services at 3 churches and during 1 church health day. The survey consisted of vignettes (12 stroke, 4 nonstroke) to assess knowledge of stroke warning signs and behavioral intent to call 911. The survey also assessed stroke self-efficacy, personal knowledge of someone who had experienced a stroke, personal history of stroke, and barriers to calling 911. Linear regression models explored the association of stroke self-efficacy with behavioral intent to call 911 among adults.

Results—

Two hundred forty-two adults and 90 youths completed the survey. Ninety-two percent of adults and 90% of youth respondents were African American. Responding to 12 stroke vignettes, adults would call 911 in 72% (SD, 0.26) of the vignettes, whereas youths would call 911 in 54% of vignettes (SD, 0.29;
P
<0.001). Adults correctly identified stroke in 51% (SD, 0.32) of the stroke vignettes and youth correctly identified stroke in 46% (SD, 0.28) of the stroke vignettes (
P
=0.28). Stroke self-efficacy predicted behavioral intent to call 911 (
P
=0.046).

Conclusions—

In addition to knowledge of stroke warning signs, behavioral interventions to increase both stroke self-efficacy and behavioral intent may be useful for helping people make appropriate 911 calls for stroke. A community-based participatory research approach may be effective in reducing stroke disparities.
Are Teachers' Unions Really to Blame? Collective Bargaining Agreements and Their Relationships with District Resource Allocation and Student Performance in California
Authors: Strunk Katharine O.
Published: May 2011

Increased spending and decreased student performance have been attributed in part to teachers' unions and to the collective bargaining agreements (CBAs) they negotiate with school boards. However, only recently have researchers begun to examine impacts of specific aspects of CBAs on student and district outcomes. This article uses a unique measure of contract restrictiveness generated through the use of a partial independence item response model to examine the relationships between CBA strength and district spending on multiple areas and district-level student performance in California. I find that districts with more restrictive contracts have higher spending overall, but that this spending appears not to be driven by greater compensation for teachers but by greater expenditures on administrators' compensation and instruction-related spending. Although districts with stronger CBAs spend more overall and on these categories, they spend less on books and supplies and on school board–related expenditures. In addition, I find that contract restrictiveness is associated with lower average student performance, although not with decreased achievement growth.
Teacher Mobility, School Segregation, and Pay-Based Policies to Level the Playing Field
Authors: Clotfelter Charles T. , Ladd Helen F. , Vigdor Jacob L.
Published: May 2011

Research has consistently shown that teacher quality is distributed very unevenly among schools, to the clear disadvantage of minority students and those from low-income families. Using North Carolina data on the length of time individual teachers remain in their schools, we examine the potential for using salary differentials to overcome this pattern. We conclude that salary differentials are a far less effective tool for retaining teachers with strong preservice qualifications than for retaining other teachers in schools with high proportions of minority students. Consequently large salary differences would be needed to level the playing field when schools are segregated. This conclusion reflects our finding that teachers with stronger qualifications are both more responsive to the racial and socioeconomic mix of a school's students and less responsive to salary than are their less-qualified counterparts when making decisions about remaining in their current school, moving to another school or district, or leaving the teaching profession.
Laws of Attraction
Authors: Rao Hayagreeva , Yue Lori Qingyuan , Ingram Paul
Published: May 2011

Past research recognizes that firms exploit regulatory variations to their advantage but depicts such regulatory arbitrage as a dyadic process between firms and regulators. We extend this account by including a firm’s non-market rivals and suggest that firms view regulatory differences as part of a corporate political opportunity structure and exploit regulatory variations to disadvantage their rivals. Empirically, we focus on variations in right-to-work (RTW) laws that signal the pro-business climate in a state; these laws exist in 22 U.S. states. Using a spatial-regression discontinuity design, we analyze how Walmart locates new stores in the face of anti-Walmart activists and exploits regulatory discontinuities on the borders between RTW and non-RTW states. We find that Walmart is more likely to propose new stores, and to open those stores even if they are protested, at the borders of RTW states, compared with the borders of neighboring non-RTW states. We conclude with a discussion of implications for the study of regulation, social movements, and organizations.
Nonmarital Childbearing, Union History, and Women’s Health at Midlife
Authors: Williams Kristi , Sassler Sharon , Frech Adrianne , Addo Fenaba , Cooksey Elizabeth
Published: May 2011

Despite high rates of nonmarital childbearing in the United States, little is known about the health of women who have nonmarital births. We use data from the NLSY79 to examine differences in age 40 self-assessed health between women who had a premarital birth and those whose first birth occurred within marriage. We then differentiate women with a premarital first birth according to their subsequent union histories and estimate the effect of marrying or cohabiting versus remaining never-married on midlife self-assessed health. We pay particular attention to the paternity status of a mother’s partner and the stability of marital unions. To partially address selection bias, we employ multivariate propensity score techniques. Results suggest that premarital childbearing is negatively associated with midlife health for white and black women, but not for Hispanic women. We find no evidence that the negative health consequences of nonmarital childbearing are mitigated by either marriage or cohabitation for black women. For other women, only enduring marriage to the child’s biological father is associated with better health than remaining unpartnered.
The International Diffusion of Democracy
Authors: Elkink Johan A.
Published: May 2011

The idea that democracy is contagious, that democracy diffuses across the world map, is now well established among policy makers and political scientists alike. The few theoretical explanations of this phenomenon focus exclusively on political elites. This article presents a theoretical model and accompanying computer simulation that explains the diffusion of democracy based on the dynamics of public opinion and mass revolutions. On the basis of the literature on preference falsification, cascading revolutions, and the social judgment theory, an agent-based simulation is developed and analyzed. The results demonstrate that the diffusion of attitudes, in combination with a cascading model of revolutions, is indeed a possible theoretical explanation of the spatial clustering of democracy.
Modernization and its impact on Chinese older people’s perception of their own image and status
Authors: Chow Nelson , Xue Bai
Published: May 2011

This article represents an attempt to look at the impact of modernization on how older people in China perceive their own image and status. Findings from a study conducted in Wuhan, China reveal that modernization has tarnished the image and lowered the status of older people, who still welcome their country’s modernization as it has made marked improvements in their standard of living. Differences in reactions towards modernization are also found to exist between urban and rural older residents — an issue that the Chinese Government must redress to promote positive ageing.
Open-Mindedness and Defensiveness in Multisource Feedback Processes
Authors: Taylor Scott N. , Bright David S.
Published: May 2011

Multisource Feedback Assessment (MSF or 360-degree feedback) used for employee development has become ubiquitous in many organizations. From an organization development (OD) perspective, this article presents a conceptual model to explain reactions to MSF in feedback recipients. In the ideal mode, MSF recipients react to MSF data with open-mindedness, a strong willingness to evaluate self-perceptions by learning from others’ perspectives. In the converse mode of defensiveness, MSF recipients are likely to be closed to and dismissive of others’ perspectives. The usefulness of the model for testing alternative MSF approaches is illustrated through a discussion of two MSF techniques: the Self–Other Comparison (SOC) approach and the Predicted–Other Comparison (POC) approach. Approaches that foster a mode of open-mindedness over defensiveness are more likely to produce the intended learning benefits.
Managing Threat, Cost, and Incentive to Kill
Authors: Kathman Jacob D. , Wood Reed M.
Published: May 2011

How do third-party interventions affect the severity of mass killings? The authors theorize that episodes of mass killing are the consequence of two factors: (1) the threat perceptions of the perpetrators and (2) the cost of implementing genocidal policies relative to other alternatives. To reduce genocidal hostilities, interveners must address these factors. Doing so requires that interveners alter the genocidaire’s expectation of a successful extermination policy, which in turn requires a demonstration of the third party’s resolve. This cannot be achieved immediately upon intervention, and, given the perpetrator’s strategic response to third-party involvement, the authors expect intervention to increase hostilities in the short term. With time, however, the authors contend that the characteristics of impartial interventions offer the greatest opportunity for reducing the violence in the long term. A statistical analysis of the 1955–2005 period supports the theoretical expectations.
“Brother, Can You Spare Some Time, or a Dime?”
Authors: Cai Deborah A. , Fink Edward L. , Xie Xiaoying
Published: May 2011

This study investigates the role that culture plays in the effect of intimacy, relationship type, and resources on obligations. Participants ( n = 144 U.S. undergraduates and n = 122 Chinese undergraduate and graduate students) were asked about their obligations to another person. Chinese, as compared to Americans, reported greater obligation and greater likelihood to expend money to help another. Americans reported greater intimacy with others and greater likelihood of expending time talking. Chinese are willing to “spare a dime” (i.e., help with money), whereas Americans are willing to “spare some time” (i.e., help with time). Americans exhibited a greater degree of transitivity, as assessed by the extent to which obligations to a person known directly are transferred to the person known indirectly.
Retribution or Reconciliation: Young Americans’ Attitudes Toward Peaceful Transitions of Power
Authors: Gallay Leslie , Flanagan Constance A. , Duo Samuel
Published: May 2011

This exploratory study assessed the associations of age, gender, and a school climate of solidarity and pride with adolescents’ endorsements of democratic regime change. Middle- and high-school students ( N = 273) in the United States responded to three vignettes concerning how a society should transition from dictatorship to democracy and specifically, what should happen to the leaders, supporters, and opponents of the (former) dictatorship. Open-ended responses were coded for references to reconciliation, retribution, and reward. Older students were more likely to provide codable responses and the majority endorsed reconciliation for the leaders, supporters, and opponents of the old (dictatorship) regime. Males were more likely than females to endorse retribution against the leaders. Students were more likely to endorse reconciliation if they perceived that group solidarity and pride characterized the climate at their school. Discussion focuses on the potential of schools to develop feelings of membership and commitments to democratic norms in younger generations.
Effects of Everyday Romantic Goal Pursuit on Women’s Attitudes Toward Math and Science
Authors: Park Lora E. , Young Ariana F. , Troisi Jordan D. , Pinkus Rebecca T.
Published: May 2011

The present research examined the impact of everyday romantic goal strivings on women’s attitudes toward science, technology, engineering, and math (STEM). It was hypothesized that women may distance themselves from STEM when the goal to be romantically desirable is activated because pursuing intelligence goals in masculine domains (i.e., STEM) conflicts with pursuing romantic goals associated with traditional romantic scripts and gender norms. Consistent with hypotheses, women, but not men, who viewed images (Study 1) or overheard conversations (Studies 2a-2b) related to romantic goals reported less positive attitudes toward STEM and less preference for majoring in math/science compared to other disciplines. On days when women pursued romantic goals, the more romantic activities they engaged in and the more desirable they felt, but the fewer math activities they engaged in. Furthermore, women’s previous day romantic goal strivings predicted feeling more desirable but being less invested in math on the following day (Study 3).
Union Type and Depressive Symptoms Among Mexican Adults
Authors: Schmeer Kammi K. , Kroeger Rhiannon A.
Published: May 2011

Diversity in union type is increasing around the world as cohabitation and higher order unions become more prevalent in developing and developed countries. This necessitates a more nuanced understanding of how different union types relate to individual well-being across social settings. In this study, the authors analyze nationally-representative data from Mexico in cross-sectional and change models to evaluate differences in depressive symptoms across union type (marital vs. cohabiting and first vs. higher order unions) among Mexican men and women. The findings suggest that cohabiting unions do not provide the same mental health benefits as marital unions (especially for men). Repartnering is also associated with higher depressive symptoms (especially for women), which indicates possible lasting mental health disadvantages of divorce/separation or entrance into lower quality second unions. These results suggest that the changing family context in Mexico, which includes increasing cohabitation and union instability, may have important consequences for individuals’ psychological well-being.