bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal development of cortical thickness, folding, and fiber density networks in the first 2 years of life
Authors: Nie Jingxin , Li Gang , Wang Li , Shi Feng , Lin Weili , Gilmore John H. , Shen Dinggang
Published: December 2013

Quantitatively characterizing the development of cortical anatomical networks during the early stage of life plays an important role in revealing the relationship between cortical structural connection and high‐level functional development. The development of correlation networks of cortical‐thickness, cortical folding, and fiber‐density is systematically analyzed in this article to study the relationship between different anatomical properties during the first 2 years of life. Specifically, longitudinal MR images of 73 healthy subjects from birth to 2 year old are used. For each subject at each time point, its measures of cortical thickness, cortical folding, and fiber density are projected to its cortical surface that has been partitioned into 78 cortical regions. Then, the correlation matrices for cortical thickness, cortical folding, and fiber density at each time point can be constructed, respectively, by computing the inter‐regional Pearson correlation coefficient (of any pair of ROIs) across all 73 subjects. Finally, the presence/absence pattern (i.e., binary pattern) of the connection network is constructed from each inter‐regional correlation matrix, and its statistical and anatomical properties are adopted to analyze the longitudinal development of anatomical networks. The results show that the development of anatomical network could be characterized differently by using different anatomical properties (i.e., using cortical thickness, cortical folding, or fiber density). Hum Brain Mapp 35:3726–3737, 2014. © 2013 Wiley Periodicals, Inc.
MYO5B and Bile Salt Export Pump Contribute to Cholestatic Liver Disorder in Microvillous Inclusion Disease
Authors: Girard Muriel , Lacaille Florence , Verkarre Virginie , Mategot Raphael , Feldmann Gerard , Grodet Alain , Sauvat Frédérique , Irtan Sabine , Davit-Spraul Anne , Jacquemin Emmanuel , Ruemmele Frank , Rainteau Dominique , Goulet Olivier , Colomb Virginie , Chardot Christophe , Henrion-Caude Alexandra , Debray Dominique
Published: December 2013

Microvillous inclusion disease (MVID) is a congenital disorder of the enterocyte related to mutations in the

MYO5B

gene, leading to intractable diarrhea often necessitating intestinal transplantation (ITx). Among our cohort of 28 MVID patients, 8 developed a cholestatic liver disease akin to progressive familial intrahepatic cholestasis (PFIC). Our aim was to investigate the mechanisms by which MYO5B mutations affect hepatic biliary function and lead to cholestasis in MVID patients. Clinical and biological features and outcome were reviewed. Pretransplant liver biopsies were analyzed by immunostaining and electron microscopy. Cholestasis occurred before (n = 5) or after (n = 3) ITx and was characterized by intermittent jaundice, intractable pruritus, increased serum bile acid (BA) levels, and normal gamma-glutamyl transpeptidase activity. Liver histology showed canalicular cholestasis, mild-to-moderate fibrosis, and ultrastructural abnormalities of bile canaliculi. Portal fibrosis progressed in 5 patients. No mutation in

ABCB11/BSEP

or

ATP8B1/FIC1

genes were identified. Immunohistochemical studies demonstrated abnormal cytoplasmic distribution of MYO5B, RAB11A, and BSEP in hepatocytes. Interruption of enterohepatic BA cycling after partial external biliary diversion or graft removal proved the most effective to ensure long-term remission.

Conclusion :

MVID patients are at risk of developing a PFIC-like liver disease that may hamper outcome after ITx. Our results suggest that cholestasis in MVID patients results from (1) impairment of the MYO5B/RAB11A apical recycling endosome pathway in hepatocytes, (2) altered targeting of BSEP to the canalicular membrane, and (3) increased ileal BA absorption. Because cholestasis worsens after ITx, indication of a combined liver ITx should be discussed in MVID patients with severe cholestasis. Future studies will need to address more specifically the effect of

MYO5B

dysfunction in BA homeostasis. (Hepatology 2014;60:301–310)
Mesenchymal Stem Cell Therapy Ameliorates Diabetic Hepatocyte Damage in Mice by Inhibiting Infiltration of Bone Marrow–Derived Cells
Authors: Nagaishi Kanna , Ataka Koji , Echizen Eijiro , Arimura Yoshiaki , Fujimiya Mineko
Published: December 2013

Although mesenchymal stem cells (MSCs) have been implicated in hepatic injury, the mechanism through which they contribute to diabetic liver disease has not been clarified. In this study, we investigated the effects of MSC therapy on diabetic liver damage with a focus on the role of bone-marrow–derived cells (BMDCs), which infiltrate the liver, and elucidated the mechanism mediating this process. Rat bone-marrow (BM)-derived MSCs were administered to high-fat diet (HFD)-induced type 2 diabetic mice and streptozotocin (STZ)-induced insulin-deficient diabetic mice. MSC-conditioned medium (MSC-CM) was also administered to examine the trophic effects of MSCs on liver damage. Therapeutic effects of MSCs were analyzed by assessing serum liver enzyme levels and histological findings. Kinetic and molecular profiles of BMDCs in the liver were evaluated using BM-chimeric mice. Curative effects of MSC and MSC-CM therapies were similar because both ameliorated the aggravation of aspartate aminotransferase and alanine aminotransferase at 8 weeks of treatment, despite persistent hyperlipidemia and hyperinsulinemia in HFD-diabetic mice and persistent hyperglycemia in STZ-diabetic mice. Furthermore, both therapies suppressed the abnormal infiltration of BMDCs into the liver, reversed excessive expression of proinflammatory cytokines in parenchymal cells, and regulated proliferation and survival signaling in the liver in both HFD- and STZ-diabetic mice. In addition to inducing hepatocyte regeneration in STZ-diabetic mice, both therapies also prevented excessive lipid accumulation and apoptosis of hepatocytes and reversed insulin resistance (IR) in HFD-diabetic mice.

Conclusion :

MSC therapy is a powerful tool for repairing diabetic hepatocyte damage by inhibiting inflammatory reactions induced by BMDCs and IR. These effects are likely the result of humoral factors derived from MSCs. (Hepatology 2014;59:1816–1829)
Hepatocyte-Specific High-Mobility Group Box 1 Deletion Worsens the Injury in Liver Ischemia/Reperfusion: A Role for Intracellular High-Mobility Group Box 1 in Cellular Protection
Authors: Huang Hai , Nace Gary W. , McDonald Kerry-Ann , Tai Sheng , Klune John R. , Rosborough Brian R. , Ding Qing , Loughran Patricia , Zhu Xiaorong , Beer-Stolz Donna , Chang Eugene B. , Billiar Timothy , Tsung Allan
Published: December 2013

High-mobility group box 1 (HMGB1) is an abundant chromatin-associated nuclear protein and released into the extracellular milieu during liver ischemia-reperfusion (I/R), signaling activation of proinflammatory cascades. Because the intracellular function of HMGB1 during sterile inflammation of I/R is currently unknown, we sought to determine the role of intracellular HMGB1 in hepatocytes after liver I/R. When hepatocyte-specific HMGB1 knockout (HMGB1-HC-KO) and control mice were subjected to a nonlethal warm liver I/R, it was found that HMGB1-HC-KO mice had significantly greater hepatocellular injury after I/R, compared to control mice. Additionally, there was significantly greater DNA damage and decreased chromatin accessibility to repair with lack of HMGB1. Furthermore, lack of hepatocyte HMGB1 led to excessive poly(ADP-ribose)polymerase 1 activation, exhausting nicotinamide adenine dinucleotide and adenosine triphosphate stores, exacerbating mitochondrial instability and damage, and, consequently, leading to increased cell death. We found that this was also associated with significantly more oxidative stress (OS) in HMGB1-HC-KO mice, compared to control. Increased nuclear instability led to a resultant increase in the release of histones with subsequently more inflammatory cytokine production and organ damage through activation of Toll-like receptor 9.

Conclusion :

The lack of HMGB1 within hepatocytes leads to increased susceptibility to cellular death after OS conditions. (Hepatology 2014;59:1984–1997)
Serum Immunoglobulin G4 and Immunoglobulin G1 for Distinguishing Immunoglobulin G4-Associated Cholangitis From Primary Sclerosing Cholangitis
Authors: Boonstra Kirsten , Culver Emma L. , de Buy Wenniger Lucas Maillette , van Heerde Marianne J. , van Erpecum Karel J. , Poen Alexander C. , van Nieuwkerk Karin M.J. , Spanier Marcel B.W. , Witteman Ben J.M. , Tuynman Hans A.R.E. , van Geloven Nan , van Buuren Henk , Chapman Roger W. , Barnes Eleanor , Beuers Ulrich , Ponsioen Cyriel Y.
Published: December 2013

The recent addition of immunoglobulin (Ig)G4-associated cholangitis (IAC), also called IgG4-related sclerosing cholangitis (IRSC), to the spectrum of chronic cholangiopathies has created the clinical need for reliable methods to discriminate between IAC and the more common cholestatic entities, primary (PSC) and secondary sclerosing cholangitis. The current American Association for the Study of Liver Diseases practice guidelines for PSC advise on the measurement of specific Ig (sIg)G4 in PSC patients, but interpretation of elevated sIgG4 levels remains unclear. We aimed to provide an algorithm to distinguish IAC from PSC using sIgG analyses. We measured total IgG and IgG subclasses in serum samples of IAC (n = 73) and PSC (n = 310) patients, as well as in serum samples of disease controls (primary biliary cirrhosis; n = 22). sIgG4 levels were elevated above the upper limit of normal (ULN = >1.4 g/L) in 45 PSC patients (15%; 95% confidence interval [CI]: 11-19). The highest specificity and positive predictive value (PPV; 100%) for IAC were reached when applying the 4× ULN (sIgG4 > 5.6 g/L) cutoff with a sensitivity of 42% (95% CI: 31-55). However, in patients with a sIgG4 between 1× and 2× ULN (n = 38/45), the PPV of sIgG4 for IAC was only 28%. In this subgroup, the sIgG4/sIgG1 ratio cutoff of 0.24 yielded a sensitivity of 80% (95% CI: 51-95), a specificity of 74% (95% CI: 57-86), a PPV of 55% (95% CI: 33-75), and a negative predictive value of 90% (95% CI: 73-97).

Conclusion :

Elevated sIgG4 (>1.4 g/L) occurred in 15% of patients with PSC. In patients with a sIgG4 >1.4 and <2.8 g/L, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved PPV and specificity. We propose a new diagnostic algorithm based on IgG4/IgG1 ratio that may be used in clinical practice to distinguish PSC from IAC. (Hepatology 2014;59:1954–1963)
IL-12/Th1 and IL-23/Th17 Biliary Microenvironment in Primary Biliary Cirrhosis: Implications for Therapy
Authors: Yang Chen-Yen , Ma Xiong , Tsuneyama Koichi , Huang Shanshan , Takahashi Toru , Chalasani Naga P. , Bowlus Christopher L. , Yang Guo-Xiang , Leung Patrick S.C. , Ansari Aftab A. , Wu Linda , Coppel Ross L. , Gershwin Eric M.
Published: December 2013

The interleukin (IL)-12/IL-23-mediated Th1/Th17 signaling pathway has been associated with the etiopathogenesis of primary biliary cirrhosis (PBC). To address the cytokine microenvironment specifically in the liver, we examined the localized expression of cytokine subunits and their corresponding receptors using previously optimized immunohistochemistry with an extensive panel of antibodies directed at IL-12p70, IL-12p35, interferon-gamma (IFN-γ), IL-12RB2, IL-23p40, IL-23p19, IL-17, and IL-23R using liver from PBC (n = 51) and non-PBC (n = 80) control liver disease patients. Multiple portal tracts in each patient were blindly evaluated and individually scored. We report herein that although IL-12/Th1 and IL-23/Th17 staining was detected in all of the liver sections, they were primarily localized around the damaged interlobular bile ducts in PBC. Most important, Th17 skewing was prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around IL-23R, IL-12RB2, and IFN-γ expressing degenerated cholangiocytes. Our novel finding on the direct association of Th17 skewing and disease severity illustrates the significance of the IL-23/Th17 pathway in the perpetuation of IL-12/Th1-mediated immunopathology in PBC. Furthermore, localized IL-23p19 production by hepatocytes may enhance profibrotic Th17 signaling and proinflammatory IFN-γ production that contribute to PBC pathology.

Conclusion :

Our data emphasize the pathogenic relevance of IL-12/Th1 and IL-23/Th17 in the evolution of PBC. Of significance, however, the shift from a Th1 to a Th17 imbalance at advanced stages of the disease suggests the necessity to consider modulation of the IL-23/Th17 pathway as a potential target for therapeutic intervention. (Hepatology 2014;59:1944–1953)
Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury
Authors: Belcher Justin M. , Sanyal Arun J. , Peixoto Aldo J. , Perazella Mark A. , Lim Joseph , Thiessen-Philbrook Heather , Ansari Naheed , Coca Steven G. , Garcia-Tsao Guadalupe , Parikh Chirag R.
Published: December 2013

Acute kidney injury (AKI) is common in patients with cirrhosis and associated with significant mortality. The most common etiologies of AKI in this setting are prerenal azotemia (PRA), acute tubular necrosis (ATN), and hepatorenal syndrome (HRS). Accurately distinguishing the etiology of AKI is critical, as treatments differ markedly. However, establishing an accurate differential diagnosis is extremely challenging. Urinary biomarkers of kidney injury distinguish structural from functional causes of AKI and may facilitate more accurate and rapid diagnoses. We conducted a multicenter, prospective cohort study of patients with cirrhosis and AKI assessing multiple biomarkers for differential diagnosis of clinically adjudicated AKI. Patients (n = 36) whose creatinine returned to within 25% of their baseline within 48 hours were diagnosed with PRA. In addition, 76 patients with progressive AKI were diagnosed by way of blinded retrospective adjudication. Of these progressors, 39 (53%) patients were diagnosed with ATN, 19 (26%) with PRA, and 16 (22%) with HRS. Median values for neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), and albumin differed between etiologies and were significantly higher in patients adjudicated with ATN. The fractional excretion of sodium (FENa) was lowest in patients with HRS, 0.10%, but did not differ between those with PRA, 0.27%, or ATN, 0.31%, P = 0.54. The likelihood of being diagnosed with ATN increased step-wise with the number of biomarkers above optimal diagnostic cutoffs. Conclusion: Urinary biomarkers of kidney injury are elevated in patients with cirrhosis and AKI due to ATN. Incorporating biomarkers into clinical decision making has the potential to more accurately guide treatment by establishing which patients have structural injury underlying their AKI. Further research is required to document biomarkers specific to HRS. (Hepatology 2014;60:622–632)
Toll-Like Receptor 7-Mediated Type I Interferon Signaling Prevents Cholestasis- and Hepatotoxin-Induced Liver Fibrosis
Authors: Roh Yoon Seok , Park Surim , Kim Jong Won , Lim Chae Woong , Seki Ekihiro , Kim Bumseok
Published: December 2013

Toll-like receptor 7 (TLR7) signaling predominantly regulates production of type I interferons (IFNs), which has been suggested in clinical studies to be antifibrotic. However, the mechanistic role of the TLR7-type I IFN axis in liver fibrosis has not been elucidated. In the present study, liver fibrosis was induced in wild-type (WT), TLR7-deficient, and IFN-α/β receptor-1 (IFNAR1)-deficient mice and TLR7-mediated signaling was assessed in liver cells isolated from these mice. TLR7-deficient and IFNAR1-deficient mice were more susceptible to liver fibrosis than WT mice, indicating that TLR7-type I IFN signaling exerts a protective effect against liver fibrosis. Notably, the hepatic expression of interleukin-1 receptor antagonist (IL-1ra) was suppressed in TLR7- or IFNAR1-deficient mice compared with respective WT mice, and treatment with recombinant IL-1ra reduced liver fibrosis.

In vivo

activation of TLR7 significantly increased IFNa4 and IL-1ra expression in the liver. Interestingly, each cytokine had a different cellular source, showing that dendritic cells (DCs) are the responsible cell type for production of type I IFN, while Kupffer cells (KCs) mainly produce IL-1ra in response to type I IFN. Furthermore, TLR7 activation by R848 injection suppressed liver fibrosis and production of proinflammatory cytokines, and these effects were dependent on type I IFN signaling. Consistent with

in vivo

data, IFN-α significantly induced IL-1ra production in primary KCs.

Conclusion :

TLR7 signaling activates DCs to produce type I IFN, which in turn induces antifibrogenic IL-1ra production in KCs. Thus, manipulation of the TLR7-type I IFN-IL-1ra axis may be a new therapeutic strategy for the treatment of liver fibrosis. (Hepatology 2014;60:237–249)
Cyclosporin A and Its Analogs Inhibit Hepatitis B Virus Entry Into Cultured Hepatocytes Through Targeting a Membrane Transporter, Sodium Taurocholate Cotransporting Polypeptide (NTCP)
Authors: Watashi Koichi , Sluder Ann , Daito Takuji , Matsunaga Satoko , Ryo Akihide , Nagamori Shushi , Iwamoto Masashi , Nakajima Syo , Tsukuda Senko , Borroto-Esoda Katyna , Sugiyama Masaya , Tanaka Yasuhito , Kanai Yoshikatsu , Kusuhara Hiroyuki , Mizokami Masashi , Wakita Takaji
Published: December 2013

Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. Although nucleos(t)ide analogs inhibiting viral reverse transcriptase are clinically available as anti-HBV agents, emergence of drug-resistant viruses highlights the need for new anti-HBV agents interfering with other targets. Here we report that cyclosporin A (CsA) can inhibit HBV entry into cultured hepatocytes. The anti-HBV effect of CsA was independent of binding to cyclophilin and calcineurin. Rather, blockade of HBV infection correlated with the ability to inhibit the transporter activity of sodium taurocholate cotransporting polypeptide (NTCP). We also found that HBV infection-susceptible cells, differentiated HepaRG cells and primary human hepatocytes expressed NTCP, while nonsusceptible cell lines did not. A series of compounds targeting NTCP could inhibit HBV infection. CsA inhibited the binding between NTCP and large envelope protein

in vitro

. Evaluation of CsA analogs identified a compound with higher anti-HBV potency, having a median inhibitory concentration <0.2 μM.

Conclusion :

This study provides a proof of concept for the novel strategy to identify anti-HBV agents by targeting the candidate HBV receptor, NTCP, using CsA as a structural platform. (Hepatology 2014;59:1726–1737)
Love and Sexuality in the Therapeutic Relationship
Authors: Gelso Charles J. , Pérez Rojas Andres E. , Marmarosh Cheri
Published: December 2013

We examine sexual and loving feelings, on the part of both the therapist and patient, as they relate to their real relationship, patient transference, and therapist countertransference. Loving feelings (agape) often are part of a strong real relationship and they tend to have a positive effect. Sexual feelings, too, may be part of the real relationship, but they are also often more conflict‐based, residing in the transference and countertransference experience. It is deeply important for the therapist to seek understanding of his or her own and the patient's loving and sexual feelings, and to tease apart, as much as possible, the extent to which they are real relationship versus transference‐countertransference‐based. The patient's loving and sexual feelings toward the therapist need to be explored and understood just as other feelings. Although it is crucial that the therapist seek understanding of his or her own loving and sexual feelings toward the patient, we express serious reservations about the therapeutic value of sharing these with the patient.
Telomere Length Maintenance, Shortening, and Lengthening
Authors: Zhao Zhenrong , Pan Xinghua , Liu Lin , Liu Na
Published: December 2013

Telomeres maintain chromosome stability and cell replicative capacity. Telomere shortening occurs concomitant with aging. Short telomeres are associated with some diseases, such as dyskeratosis congenita, idiopathic pulmonary fibrosis, and aplastic anemia. Telomeres are longer in pluripotent stem cells than in somatic cells and lengthen significantly during preimplantation development. Furthermore, telomere elongation during somatic cell reprogramming is of great importance in the acquisition of authentic pluripotency. This review focuses primarily on regulatory mechanisms of telomere length maintenance in pluripotent cells, telomere length extension in early embryo development, and also telomere rejuvenation in somatic cell reprogramming. Telomere related diseases are also discussed in this review. J. Cell. Physiol. 229: 1323–1329, 2014. © 2014 Wiley Periodicals, Inc.
Epithelial Immune Response in Drosophila Malpighian Tubules: Interplay Between Diap2 and Ion Channels
Authors: Verma Puja , Tapadia Madhu G.
Published: December 2013

Systemic immune response via the Immune deficiency pathway requires Drosophila inhibitor of apoptosis protein 2 to activate the NF‐κB transcription factor Relish. Malpighian tubules (MTs), simple epithelial tissue, are the primary excretory organs, performing additional role in providing protection to Drosophila against pathogenic infections. MTs hold a strategic position in Drosophila as one of the larval tissues that are carried over to adults, unlike other larval tissues that are histolysed during pupation. In this paper we show that Diap2 is an important regulator of local epithelial immune response in MTs and depletion of Diap2 from MTs, increases susceptibility of flies to infection. In the absence of Diap2, activation and translocation of Relish to the nucleus is abolished and as a consequence the production of IMD pathway dependent AMPs are reduced. Ion channels, (Na+/K+)‐ATPase and V‐ATPase, are important for the immune response of MTs and expression of AMPs and the IMD pathway genes are impaired on inhibition of transporters, and they restrict the translocation of Relish into the nucleus. We show that Diap2 could be regulating ion channels, as loss of Diap2 consequently reduces the expression of ion channels and affects the balance of ion concentrations which results in reduced uric acid deposition. Thus Diap2 seems to be a key regulator of epithelial immune response in MTs, perhaps by modulating ion channels. J. Cell. Physiol. 229: 1078–1095, 2014. © 2013 Wiley Periodicals, Inc.
Fast pediatric 3D free‐breathing abdominal dynamic contrast enhanced MRI with high spatiotemporal resolution
Authors: Zhang Tao , Cheng Joseph Y. , Potnick Aaron G. , Barth Richard A. , Alley Marcus T. , Uecker Martin , Lustig Michael , Pauly John M. , Vasanawala Shreyas S.
Published: December 2013

Purpose

To develop a method for fast pediatric 3D free‐breathing abdominal dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) and investigate its clinical feasibility.

Materials and Methods

A combined locally low rank parallel imaging method with soft gating is proposed for free‐breathing DCE MRI acquisition. With Institutional Review Board (IRB) approval and informed consent/assent, 23 consecutive pediatric patients were recruited for this study. Free‐breathing DCE MRI with ∼1 mm3 spatial resolution and a 6.5‐sec frame rate was acquired on a 3T scanner. Undersampled data were reconstructed with a compressed sensing method without motion correction (FB‐CS) and the proposed method (FB‐LR). A follow‐up respiratory‐triggered acquisition (RT‐CS) was performed as a reference standard. The reconstructed images were evaluated independently by two radiologists. Wilcoxon tests were performed to test the hypothesis that there was no significant difference between different reconstructions. Quantitative evaluation of contrast dynamics was also performed.

Results

The mean score of overall image quality of FB‐LR was 4.0 on a 5‐point scale, significantly better (P < 0.05) than FB‐CS reconstruction (mean score 2.9), and similar to RT‐CS (mean score 4.1). FB‐LR also matched the temporal fidelity of contrast dynamics with a root mean square error less than 5%.

Conclusion

Fast 3D free‐breathing DCE MRI with high scan efficiency and image quality similar to respiratory‐triggered acquisition is feasible in a pediatric clinical setting. J. Magn. Reson. Imaging 2015;41:460–473.© 2013 Wiley Periodicals, Inc.
Neurovascular protection of cilostazol in stroke‐prone spontaneous hypertensive rats associated with angiogenesis and pericyte proliferation
Authors: Omote Yoshio , Deguchi Kentaro , Kono Syoichiro , Liu Ning , Liu Wentao , Kurata Tomoko , Yamashita Toru , Ikeda Yoshio , Abe Koji
Published: December 2013

Stroke is the major cause of death and decrease in the activities of daily living. This study sought to evaluate the effects of commonly used antiplatelet drugs on spontaneous cerebral infarction in relation to neurovascular protection associated with angiogenesis and pericyte proliferation. Stroke‐prone spontaneously hypertensive rats (SHR‐SP) were treated with vehicle, aspirin, clopidogrel, or cilostazol from 8 to 10 weeks of age. The interaction of neurovascular components among endothelial cells, pericytes, and astrocytic endfeet were immunohistochemically examined in brain sections. Angiogenesis associated with vascular endothelial growth factor receptor 2 (VEGFR2) and pericyte proliferation were also examined immunohistochemically. The expression and activity of matrix metalloproteinase 9 (MMP‐9) were assessed immunohistochemically and by gelatin zymography. Among the antiplatelet drugs, cilostazol preserved the neurovascular unit (NVU) by preventing astrocytic endfeet or pericytes from pathological detachment found in the vehicle and aspirin treatment. Cilostazol also inhibited the expression and activity of MMP‐9, which led to protection of the NVU. Furthermore, in the periinfarct area, cilostazol increased VEGFR2 expression, promoting angiogenesis through proliferation of pericytes. The present study showed a strong protection of NVU integrity by cilostazol and the promotion of angiogenesis by stimulating both endothelial VEGFR2 expression and pericyte proliferation. In addition to the antioxidative effect, these pleiotropic effects of cilostazol contribute to reduce spontaneous infarct volume and preserve motor and cognitive function in SHR‐SP. © 2013 Wiley Periodicals, Inc.
Isocitrate supplementation promotes breathing generation, gasping, and autoresuscitation in neonatal mice
Authors: Rivera‐Angulo Ana‐Julia , Peña‐Ortega Fernando
Published: December 2013

Breathing is a vital function generated and controlled by a brainstem neural network, which is able to adjust its function to fit different metabolic demands. For instance, the pre‐Bötzinger complex (preBötC) can respond to low oxygen availability (hypoxia) by an initial increase in rhythm frequency followed by a decrease in respiratory efforts that leads to gasping generation. Gasping is essential for autoresuscitation, which has motivated studies of the cellular mechanisms involved in these processes. Hypoxia has different effects on enzymes that participate in the Krebs cycle. In particular, aconitase is downregulated, whereas isocitrate dehydrogenase is unaffected or upregulated under hypoxic conditions. We hypothesized that the application of isocitrate, the product of aconitase and the substrate of isocitrate dehydrogenase as well as an alternative metabolic substrate, might enhance breathing and render it more resistant to hypoxic insult. We tested the effects of isocitrate applied on brainstem slices containing the preBötC as well as its central effects in vivo using plethysmography. Our results show that isocitrate increases the frequency of fictive eupnea and fictive gasping produced by the preBötC in vitro. Moreover, isocitrate increases the amplitude of ventilation in vivo in normoxia, increases ventilation during gasping, and favors autoresuscitation when animals were subjected to asphyxiation. In conclusion, we have found that isocitrate improves ventilation under both normoxic and hypoxic conditions through a mechanism that involves the preBötC and possibly other respiratory neural networks. Thus, isocitrate would be useful to avoid the failure of gasping generation and autoresuscitation in pathological conditions. © 2013 Wiley Periodicals, Inc.
Characterization of thoracic motor and sensory neurons and spinal nerve roots in canine degenerative myelopathy, a potential disease model of amyotrophic lateral sclerosis
Authors: Morgan Brandie R. , Coates Joan R. , Johnson Gayle C. , Shelton G. Diane , Katz Martin L.
Published: December 2013

Canine degenerative myelopathy (DM) is a progressive, adult‐onset, multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced‐stage DM. To determine whether other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MNs) and dorsal root ganglia (DRG) and in motor and sensory nerve root axons from DM‐affected boxers and Pembroke Welsh corgis (PWCs). No alterations in MNs or motor root axons were observed in either breed. However, advanced‐stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, nor of their axons. Axonal loss in thoracic sensory roots and sensory neuron death suggest that sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS. © 2013 Wiley Periodicals, Inc.
Critical point defect detection for small‐pixel thin‐film transistor array applied to medical display
Authors: Wang Yao‐Chin , Lin Bor‐Shyh
Published: December 2013

Thin‐film transistor (TFT) array testing technique has been used, which provides defect detection capability to control the yield of the TFT process. In the past, several defect inspection technologies have been developed and applied for the TFT array testing. When the TFT array pixel size is getting smaller and the resolution is higher, they also encounter the performance limitation on detecting the critical defect in this small‐pixel TFT array and facing a limited testing requirement. For medical display applications, the display pixels on an array panel are getting smaller and smaller; therefore, defect detection is getting more important and critical for managing yield with quality. In this study, a novel approach for defect detection was proposed. Here, the proposed voltage imaging technique is used for the TFT array test, and it provides better small‐pixel TFT array defect detection capability. The experimental results show that by using the voltage imaging technique, detecting critical point defect of TFT array can be effectively improved. And the detected small‐pixel size of TFT array panels can be smaller than 55 µm of an advanced medical display.
Assessment of multimodality therapy use for extremity sarcoma in the United States
Authors: Sherman Karen L. , Wayne Jeffrey D. , Chung Jeanette , Agulnik Mark , Attar Samer , Hayes John P. , Laskin William B. , Peabody Terrance D. , Bentrem David J. , Pollock Raphael E. , Bilimoria Karl Y.
Published: December 2013

Background

Extremity sarcoma national guidelines offer several stage‐specific treatment options; therefore, treatment approaches are not standardized. Our objectives were to examine multimodality treatment trends, practice patterns, and factors associated with neoadjuvant or postoperative adjuvant therapy utilization.

Methods

Using the National Cancer Data Base (2000–2009), treatment of non‐metastatic extremity sarcoma was examined. Regression models were developed to identify factors associated with neoadjuvant or postoperative adjuvant therapy receipt and treatment sequence.

Results

Twenty‐two thousand fifty‐one patients underwent resection (stage I: 45.2%, stage II: 27.7%, stage III: 27.1%). Over 10 years, neoadjuvant radiation (6.4–11.6%, P < 0.001) and chemotherapy utilization (1.4–1.8%, P = 0.037) increased, while postoperative radiation (34.3–29.2%, P = 0.023) and trimodality therapy decreased (10.5–9.6%, P = 0.002). After adjusting for age, comorbidities, and histology, patients with large high‐grade tumors treated at high‐volume academic centers were more likely to receive neoadjuvant therapy (all P < 0.001). Postoperative chemotherapy utilization was associated with younger age, synovial histology, high grade, and surgical margins (all P < 0.001).

Conclusions

Utilization of neoadjuvant therapy for extremity sarcoma has increased over time. Practice patterns are not only related to tumor size, grade, histology, and margins but also hospital type. Opportunities remain to better define the most effective multimodality treatment for extremity sarcoma. J. Surg. Oncol. 2014 109:395–404. © 2013 Wiley Periodicals, Inc.
Influence of pre‐existing oxides layer and interface condition with carbonated concrete on active reinforcing steel corrosion
Authors: Castel A. , Nasser A.
Published: December 2013

This work focuses on carbonation‐induced corrosion in concrete. This paper presents specific experiments which were developed in order to assess the influence of both pre‐existing oxides layer at the surface of the steel bars and steel–concrete interface condition on active corrosion. Two types of active corrosion are studied: Microcell corrosion and galvanic corrosion. Results show that pre‐existing oxide layer contributes to reduce both galvanic and microcell corrosion. Steel–concrete interface defect leads to a strong increase in galvanic corrosion but does not affect significantly microcell corrosion in carbonated concrete. The quantity of pre‐existing oxides is highly scattered and these scatters can be superior to the mass of new oxides formed during relatively short‐term corrosion tests in natural condition which makes mass loss analysis very difficult.
The influence mechanism of Fe3+ on corrosion behavior of Ti6Al4V in sulfuric acid solutions
Authors: Wang L. , Cheng X. Q. , Gao S. J. , Li X. G. , Zou S. W.
Published: December 2013

The corrosion behavior of titanium alloy Ti6Al4V in 44.6 wt% sulfuric acid solutions, was studied via potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), Mott–Schottky and X‐ray photoelectron spectroscopy (XPS) techniques. The results indicated that the Fe3+ played an important role in the passivation and stability of the passive film formed on Ti6Al4V. When the concentration of Fe3+ reached to 0.001 M, the hydrogen evolution reaction (cathodic process) was remarkably influenced, the anode process of the corrosion reaction changed from active state to passivation state, and it showed an enormous increase of the impedance values (Rc) with the capacitive arc varying from two to one. XPS results showed that as the concentration of Fe3+ increased, there were less intermediate valence oxides Ti2O3 and more stable valence oxides TiO2. Fe3+ made more intermediate valence titanium ions or instability titanium oxides transformed into stable valence oxides, which enhanced the stability of the passive film.
Selective corrosion of duplex stainless steel bars in acid
Authors: Bautista A. , Alvarez S. M. , Velasco F.
Published: December 2013

The selective corrosion of the phases comprised in four duplex stainless steels (DSS) is studied in acid media (H2SO4 + HCl solutions). The work considers traditional UNS S32205 grade as well as other economical‐advantageous grades (UNS S32001 and UNS S32304). The samples of the lean DSS come from bars formed by hot working (HW), while those of the S32205 come both from HW bars and bars obtained by cold working. The amount of strain‐induced martensite in the austenitic phase of DSS that the processing has induced is highly dependent on the DSS composition. The change in the relative corrosion resistance of the different phases comprised in the microstructure with the potential is considered. The influence of the composition of the DSS is discussed. It has been checked that, at potentials close to the corrosion potential (Ecorr), the corrosion of the ferritic phase is more favored than that of the austenite. Increasing potentials in the anodic activation region tends to favor the selective corrosion of the austenite. The trend to selective dissolution is less marked for the least alloyed DSS. The strain‐induced martensite in the austenitic phase exhibits a corrosion resistance clearly higher than that of the ferrite at Ecorr or potentials close to Ecorr. The possible influence of TiN precipitates in the corrosion development is also analyzed.
Polymer–Clay Nanocomposite Microspheres and their Thermosensitive Characteristics
Authors: Haraguchi Kazutoshi , Takada Tetsuo
Published: December 2013

Polymer–clay nanocomposite (P‐NC) microspheres are synthesized through in situ free‐radical polymerization in aqueous media without the use of surfactants. Uniform aqueous dispersions of P‐NC microspheres without flocculation/precipitation are obtained for five types of (co)polymers with different hydrophilic/hydrophobic natures, in which the exfoliated clay platelets play an important role as crosslinkers and stabilizers in water. The sol–gel boundary, transparency of the aqueous dispersion, microsphere particle size, etc. vary depending on the compositions and polymerization methods. Aqueous dispersions of P‐NC microspheres with a well‐defined lower critical solution temperature (LCST)‐type thermosensitive transition are obtained by using N‐isopropylacrylamide (NIPA), 2‐methoxyethylacrylate (MEA), and N,N‐dimethylacrylamide (DMAA) as the (co)monomers. In the case of P‐NC microspheres consisting of inorganic clay and NIPA‐DMAA or MEA‐DMAA copolymers, the LCST is controlled over a wide range, particularly depending on the DMAA content. The P‐NC microspheres applied within double‐layer glass plates are examined as reversible and efficient thermosensitive optical shutters.

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Onset latency of segmental dystonia after deep brain stimulation cessation: A randomized, double‐blind crossover trial
Authors: Levin Johannes , Singh Arun , Feddersen Berend , Mehrkens Jan‐Hinnerk , Bötzel Kai
Published: December 2013

Background

Deep brain stimulation (DBS) of the globus pallidus internus is an effective treatment for cervical dystonia (CD). Interestingly, the onset of initial DBS effects is significantly prolonged compared with that in other diseases, such as Parkinson's disease. The return of symptoms after cessation of DBS could be delayed as well, but this has not been studied systematically.

Methods

In patients who were treated for CD using DBS and had a good treatment effect, we compared interruption of DBS with sham‐OFF in a randomized, double‐blind crossover trial.

Results

We observed that dystonic features appeared within a few minutes at almost full intensity in all patients after the cessation of DBS.

Conclusions

The almost immediate onset of dystonic features in our sample seems to exclude mechanisms with long time constants from the pathophysiology of dystonia. Thus, it is likely that, in these patients, an aberrant pattern of neural activity representing an inappropriate set point value for the position of the head is responsible for dystonia. © 2013 International Parkinson and Movement Disorder Society
Exercise increases utrophin protein expression in the mdx mouse model of Duchenne muscular dystrophy
Authors: Gordon Bradley S. , Lowe Dawn A. , Kostek Matthew C.
Published: December 2013

Introduction: Duchenne muscular dystrophy (DMD) is a lethal genetic disease caused by mutations in the dystrophin gene resulting in chronic muscle damage, muscle wasting, and premature death. Utrophin is a dystrophin protein homologue that increases dystrophic muscle function and reduces pathology. Currently, no treatments that increase utrophin protein expression exist. However, exercise increases utrophin mRNA expression in healthy humans. Therefore, the purpose was to determine whether exercise increases utrophin protein expression in dystrophic muscle. Methods: Utrophin protein was measured in the quadriceps and soleus muscles of mdx mice after 12 weeks of voluntary wheel running exercise or sedentary controls. Muscle pathology was measured in the quadriceps. Results: Exercise increased utrophin protein expression 334 ± 63% in the quadriceps relative to sedentary controls. Exercise increased central nuclei 4 ± 1% but not other measures of pathology. Conclusions: Exercise may be an intervention that increases utrophin expression in patients with DMD. Muscle Nerve 49: 915–918, 2014
Simulating the effects of induced anisotropy on liquefaction potential using a new constitutive model
Authors: Than Trong Tran H. , Wong H. , Dubujet Ph. , Doanh T.
Published: December 2013

The effects of induced anisotropy on the undrained behaviour of very loose and saturated sands have been a subject of intensive investigation, both experimentally and theoretically, by several authors in the past few years. This paper proposes an original constitutive model well‐adapted to simulate the behaviour of sands subject to complex stress histories, in particular, the preloading cycle along the classical drained stress path in compression. The developed model belongs to the family of critical state models. Its construction is based on a few theoretical concepts taken from the theory of ‘Bounding Surface Plasticity’ developed among others by Y. Dafalias and Popov (1975), the ‘Clay And Sand Model’ (CASM) of H. Yu (2006), the CJS model (B. Cambou and K. Jafari (1988)) and the hyperelastic isotropic model of P. Lade (1987). To accurately simulate volume changes, which represent a key element in soil behaviour, a state‐dependent dilatancy rule is proposed, which can account for the influences of stress and void ratio. The current void ratio depends implicitly on the irreversible strains already accumulated hence the strain history. A kinematic hardening is combined with an isotropic hardening, involving rotation and distortion of the bounding surface, in order to capture correctly the experimental observations. Comparisons of experimental results to numerical simulations show that the model is able to simulate with a good precision the major trends of undrained responses of loose and presheared sands. It predicts correctly rapid static liquefaction at small or null drained preloading, as well as the progressive transition to a completely stable behaviour typical of dense sands, while the sample is loose in reality. At intermediate to large amplitudes of preloadings, the model also predicts correctly the temporary stage of instability when the deviatoric stress decreases slightly before rising up again. Copyright © 2013 John Wiley & Sons, Ltd.
Anisotropic damage of rock joints during cyclic loading: constitutive framework and numerical integration
Authors: White Joshua A.
Published: December 2013

This work describes a constitutive framework for modeling the behavior of rough joints under cyclic loading. Particular attention is paid to the intrinsic links between dilatancy, surface degradation, and mobilized shear strength. The framework also accounts for the important effect of shear‐induced anisotropy. The resulting approach is fully three‐dimensional and is not restricted to plane‐displacement kinematics. Both the governing formulation and an algorithm for implicit numerical integration are presented. While the proposed methods are general, we also postulate a specific model that is compared with experimental data. It employs relatively few free parameters but shows good agreement with laboratory tests. Copyright © 2013 John Wiley & Sons, Ltd.
Do Nonprofits Treat Their Employees Differently? Incentive Pay and Health Benefits
Authors: Chen Xinxiang , Ren Ting , Knoke David
Published: December 2013

We examine how nonprofit, public, and for‐profit establishments vary in the provision of health benefits and insurance and performance‐based incentives using the 2002 National Organization Survey of establishments in the United States. We found that in comparison to for‐profit firms, both nonprofit and public organizations are less likely to use performance‐based incentives, although they provide their employees with better health benefits and insurance. Sectoral differences in the provision of health benefits and insurance and use of performance‐based incentives persist after controlling for correlates of sector that predict these outcomes, including establishment size, independence of establishment, market competition, establishment age, and unionization. We also found trade‐offs between the provision of health benefits and insurance and use of performance‐based incentives. Our results are generally consistent with the prediction from agency theory and also consistent with a view that public and nonprofit organizations are more concerned with the well‐being of their employees.
Evaluating a Product Donation Program: Challenges for Charitable Capacity
Authors: Gazley Beth , Abner Gordon
Published: December 2013

This article offers one of the first efforts at describing the impact of a national product donation program. Despite the importance of in‐kind giving to the corporate and charitable sectors, little research has explained how in‐kind gifts are used effectively once they leave the donor's hands. In this study we examine outcomes and impacts associated with a product donation program, including numbers served, a faith‐based mission, the ability to process product donations effectively, the extent of performance measurement, and the effect of program experience on continued participation. Data come from Good360's Framing Hope program, a partnership between The Home Depot stores and local charities across the United States. Our findings support the organizational capacity literature in suggesting that experience with this program only partly mitigates the challenges of participation and that success may be due to how central the program is to organizational objectives.
Democratic Values and Civic Engagement of Local Voluntary Associations
Authors: Lundåsen Susanne Wallman
Published: December 2013

In this study I investigate whether and to what extent local voluntary associations in Sweden maintain values of democratic governance. The study is based upon a survey of about 400 local voluntary associations within four local communities. The results show that a vast majority of these associations are supportive of member influence and governance through internal democracy. These values can also explain civic engagement of these local voluntary associations. The results indicate that if these values would change radically it would probably have an impact on civic engagement of these organizations, but at present the support remains solid.