bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α
Authors: Kim Kang Ho , Moore David D.
Published: March 2017

Background: The liver undergoes major changes in substrate utilization and metabolic output over the daily feeding and fasting cycle. These changes occur acutely in response to hormones such as insulin and glucagon, with rapid changes in signaling pathways mediated by protein phosphorylation and other post-translational modifications. They are also reflected in chronic alterations in gene expression in response to nutrient-sensitive transcription factors. Among these, the nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator activated receptor α (PPARα) provide an intriguing, coordinated response to maintain energy balance in the liver. FXR is activated in the fed state by bile acids returning to the liver, while PPARα is activated in the fasted state in response to the free fatty acids produced by adipocyte lipolysis or possibly other signals. Key Messages: Previous studies indicate that FXR and PPARα have opposing effects on each other's primary targets in key metabolic pathways including gluconeogenesis. Our more recent work shows that these 2 nuclear receptors coordinately regulate autophagy: FXR suppresses this pathway of nutrient and energy recovery, while PPARα activates it. Another recent study indicates that FXR activates the complement and coagulation pathway, while earlier studies identify this as a negative target of PPARα. Since secretion is a very energy- and nutrient-intensive process for hepatocytes, it is possible that FXR licenses it in the nutrient-rich fed state, while PPARα represses it to spare resources in the fasted state. Energy balance is a potential connection linking FXR and PPARα regulation of autophagy and secretion, 2 seemingly unrelated aspects of hepatocyte function. Conclusions: FXR and PPARα act coordinately to promote energy balance and homeostasis in the liver by regulating autophagy and potentially protein secretion. It is quite likely that their impact extends to additional pathways relevant to hepatic energy balance, and that these pathways will in turn interface with other well-known nutrient-responsive mechanisms of energy control.
The Emerging Role of Soluble Adenylyl Cyclase in Primary Biliary Cholangitis
Authors: Chang Jung-Chin , Beuers Ulrich , Oude Elferink Ronald P.J.
Published: March 2017

Background: Primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) is a chronic fibrosing cholangiopathy with the signature of an autoimmune disease and features of intrahepatic cholestasis. Immunosuppressing treatments are largely unsuccessful. Responsiveness to ursodeoxycholic acid and reduced expression of anion exchanger 2 (AE2) on canalicular membranes and small bile ducts underline the importance of bicarbonate transportation in its disease mechanism. Soluble adenylyl cyclase (sAC; ADCY10) is an evolutionarily conserved bicarbonate sensor that regulates apoptosis, barrier function and TNF signaling. Key Messages: The biliary epithelium defends against the toxic bile by bicarbonate secretion and by maintaining a tight barrier. Passive diffusion of weak acid conjugates (e.g. bile salts and other toxins) across plasma membrane is pH-dependent. Reduced AE2 expression results in both reduced bicarbonate secretion and accumulation of bicarbonate in the cells. Increased intracellular bicarbonate leads to increased sAC activity, which regulates bile salt-induced apoptosis. Reduced bicarbonate secretion causes more bile salts to enter cells, which further increase sAC activity by releasing intracellular Ca2+ store. In vitro studies demonstrate that inhibition of sAC not only corrects sensitization to bile salt-induced apoptosis as a result of AE2 down-regulation but also prevents bile salt-induced apoptosis altogether. Targeting sAC is also likely to slow down disease progression by strengthening the barrier function of biliary epithelia and by reducing oxidative stress as a result of chronic inflammation. Conclusions: sAC is a potential therapeutic target for PBC. More in vitro and in vivo studies are needed to understand how sAC regulates bile salt-induced apoptosis and to establish its therapeutic value in PBC and other cholestatic cholangiopathies.
Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage
Authors: Reich Maria , Klindt Caroline , Deutschmann Kathleen , Spomer Lina , Häussinger Dieter , Keitel Verena
Published: March 2017

Background: TGR5 (G protein-coupled bile acid receptor 1, M-Bar) is a G protein-coupled cell surface receptor responsive to bile acids (BA) and different steroid hormones. TGR5 mRNA is detected almost ubiquitious in human and rodent tissues with a very high expression in gallbladder, liver and intestine. In liver, TGR5 is found in sinusoidal endothelial cells, Kupffer cells and cholangiocytes. Activation of TGR5 triggers an elevation of intracellular cyclic AMP and further downstream signalling. Key Messages: TGR5 exerts anti-inflammatory effects, protects cholangiocytes from BA-induced toxicity, promotes cholangiocyte secretion and proliferation and reduces portal perfusion pressure. Furthermore, TGR5 mediates gallbladder filling. TGR5 knockout mice have a smaller BA pool size with altered composition and develop more severe liver injury after BA feeding, common bile duct ligation or injection of lipopolysaccharide. The absence of TGR5 also reduces the proliferative and regenerative capacity after partial hepatectomy or liver damage. Stimulation of TGR5 signalling can improve steatohepatitis, portal hypertension and hepatic inflammation in rodent models of liver damage. However, TGR5 activation also promotes the proliferation of cystic and malignant-transformed cholangiocytes. Conclusions: TGR5 plays an important role in the protection of the liver from BA toxicity under cholestatic conditions. Stimulation of the receptor prevents excessive liver damage in rodent models of cholestasis, steatohepatitis, liver fibrosis and inflammation and also promotes liver regeneration. However, the activation of TGR5-dependent signalling may also trigger proliferation and apoptosis resistance of cystic cholangiocytes and malignantly transformed cholangiocytes, thus promoting cyst growth in polycystic liver disease or progression of cholangiocarcinoma. Depending on the type of liver disease stimulation as well as inhibition of TGR5, signalling may present a useful therapeutic approach.
Bile Acid Uptake Transporters as Targets for Therapy
Authors: Slijepcevic Davor , van de Graaf Stan F.J.
Published: March 2017

Background: Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP) and the apical sodium dependent bile acid transporter (ASBT) ensure an effective circulation of (conjugated) bile acids. The modulation of these transport proteins affects bile acid localization, dynamics and signaling. The NTCP-specific pharmacological inhibitor myrcludex B inhibits hepatic uptake of conjugated bile acids. Multiple ASBT-inhibitors are already in clinical trials to inhibit intestinal bile acid uptake. Here, we discuss current insights into the consequences of targeting bile acid uptake transporters on systemic and intestinal bile acid dynamics and discuss the possible therapeutic applications that evolve as a result.
Extended Abstract: Deficiency of Sodium Taurocholate Cotransporting Polypeptide (SLC10A1): A New Inborn Error of Metabolism with an Attenuated Phenotype
Authors: Vaz Frédéric M. , Huidekoper Hidde H. , Paulusma Coen C.
Published: March 2017

We present the first patient with a defect in the Na+-taurocholate cotransporting polypeptide SLC10A1 (NTCP), which plays a key role in the enterohepatic circulation of bile salts. The clinical presentation of the child was mild and the child showed no signs of liver dysfunction or pruritus despite extremely elevated plasma bile salt levels (>100-fold upper-limit of normal). A homozygous point mutation was found in the SLC10A1 gene (resulting in amino acid change R252H) and functional studies confirmed the pathogenicity of the mutation. This confirms the role of NTCP as the major transporter of conjugated bile salts into the liver as part of the enterohepatic circulation and shows that other transporters partly can take over its function, resulting in a relatively mild phenotype. This work was published previously in [Vaz et al.: Hepatology 2015;61:260-267] and supplemented with some follow-up information of the patient.
Apical Sodium-Dependent Transporter Inhibitors in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis
Authors: Hegade Vinod S. , Jones David E.J. , Hirschfield Gideon M.
Published: March 2017

Bile acids (BAs) have gained mainstream attention since the discovery of their key role as signalling molecules in health and disease. The apical sodium-dependent transporter (ASBT) protein located in the terminal ileum plays an important physiological role in the enterohepatic circulation of BAs and therefore essential for the BA homeostasis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the 2 most common cholestatic liver diseases are characterised by altered BA flow and BA composition, which contribute to disease progression and symptom (pruritus) development. Therefore, changing the circulating BA pool in patients with PBC and PSC may have therapeutic implications. To this end, pharmacological inhibition of ASBT is fast emerging as an interesting target. In this review, we discuss the recent evidence for potential therapeutic use of ASBT inhibitors to treat PBC and PSC patients.
Rethinking Vygotskian Cultural-Historical Theory in Light of Pepperian Root Metaphor Theory: Dynamic Interplay of Organicism and Contextualism
Authors: Karimi-Aghdam Saeed
Published: March 2017

This article examines Vygotskian cultural-historical theory by putting it into dialogue with Stephen Pepper's root metaphor theory. I focus on Vygotsky's insistence on the dialectical unity of the phylogenetic and ontogenetic domains in ontogenesis, which he articulated in his account of how the natural-psychological and cultural-psychological lines of development merge with the emergence of speeching in ontogenesis. I compare Vygotsky's two genetic domains and Pepper's world hypotheses of organicism and contextualism. I argue that Vygotsky transcended what is often thought of as a fundamental dichotomy between organicism and contextualism. In accomplishing this effective reconciliation, Vygotsky demonstrated that it is possible both to traverse the ontological schism between subjective psychology and objective psychology, and to foreground the integrative, complex, dynamic, emergent, and mediated nature of human consciousness.
Evaluation of the Impact of a New Synthetic Vitamin E-Bonded Membrane on the Hypo-Responsiveness to the Erythropoietin Therapy in Hemodialysis Patients: A Multicenter Study
Authors: Locatelli Francesco , Andrulli Simeone , Viganò Sara Maria , Concetti Massimo , Urbini Sauro , Giacchino Franca , Broccoli Roberto , Aucella Filippo , Cossu Maria , Conti Paolo , Fattori Laura , Punzo Giorgio , Angelini Daniela , Peruzzini Marco , Di Giulio Salvatore , Piroddi Marta , Galli Francesco , Del Vecchio Lucia
Published: March 2017

Background: Oxidative stress has been related to hypo-response to erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. The aim of this study was to verify whether vitamin E (ViE) on a synthetic polysulfone dialyzer can improve ESA responsiveness. Methods: This controlled, multicenter study involved 93 HD patients on stable ESA therapy, who were randomized to either ViE-coated polysulfone dialyzer or to a low-flux synthetic dialyzer. The primary outcome measure was the change in ESA resistance index (ERI) from baseline. Results: Mean ERI decreased in the ViE group by 1.45 IU/kg*g/dl and increased in the control group by 0.53 IU/kg*g/dl, with a mean difference of 1.98 IU/kg*g/dl (p = 0.001 after adjusting for baseline ERI, as foreseen by the study protocol). Baseline ERI was inversely related to its changes during follow-up only in the control group (R2 = 0.29). Conclusions: The ViE dialyzer can improve ESA response in HD patients. Changes in ERI during follow-up are independent from baseline ERI only in the ViE group. Video Journal Club ‘Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=453442.
Therapeutic Mechanisms of Bile Acids and Nor-Ursodeoxycholic Acid in Non-Alcoholic Fatty Liver Disease
Authors: Steinacher Daniel , Claudel Thierry , Trauner Michael
Published: March 2017

Non-alcoholic fatty liver disease is one of the most rapidly rising clinical problems in the 21st century. So far no effective drug treatment has been established to cure this disease. Bile acids (BAs) have a variety of signaling properties, which can be used therapeutically for modulating hepatic metabolism and inflammation. A side-chain shorted derivative of ursodeoxycholic acid (UDCA) is 24 nor-ursodeoxycholic acid (NorUDCA) and it represents a new class of drugs for treatment of liver diseases. NorUDCA has unique biochemical and therapeutic properties, since it is relatively resistant to conjugation with glycine or taurine compared to UDCA. NorUDCA undergoes cholehepatic shunting, resulting in ductular targeting, bicarbonate-rich hypercholeresis, and cholangiocyte protection. Furthermore, it showed anti-fibrotic, anti-inflammatory, and anti-lipotoxic properties in several animal models. As such, NorUDCA is a promising new approach in the treatment of cholestatic and metabolic liver diseases. This review is a summary of current BA-based therapeutic approaches in the treatment of the fatty liver disease.
Midbrain Gliofibroma Presenting in Adulthood following “Cure” of a Childhood Intraventricular Pilocytic Astrocytoma
Authors: Ahmad Mohammad U. , Barborie Atik , Pizer Barry , Husband David , Mallucci Conor , Jenkinson Michael D.
Published: March 2017

Introduction: Gliofibromas are rare biphasic tumours with a good prognosis that usually occur in childhood. Rare adult spinal cases have been treated with radiotherapy. This report describes the case of a gliofibroma occurring in a young adult 10 years after treatment for a childhood pilocytic astrocytoma. Case: A 14-year-old female underwent complete resection of a right lateral ventricle pilocytic astrocytoma confirmed on postoperative magnetic resonance imaging (MRI). At the age of 17, the tumour recurred, and a second complete resection was performed. Due to the early recurrence, she was placed on long-term MRI surveillance. At the age of 23, an enhancing left midbrain tumour was identified that was suspected to be a recurrent pilocytic astrocytoma. Following surgical resection the histopathology revealed a gliofibroma. Due to the growth of further tumour nodules she was treated with fractionated radiotherapy. There is no disease recurrence after 36 months of follow-up, and the patient remains well. Discussion: Gliofibromas are tumours which usually occur in childhood; this case report identifies a rare occurrence in an adult. The childhood intraventricular pilocytic astrocytoma was in an anatomically distinct location to the midbrain gliofibroma. Radiotherapy can control these tumours, and follow-up is required to understand the long-term outcome and prognosis.
Risk Factors for Skin Infections in Mycosis Fungoides
Authors: Lebas Eve , Arrese Jorge E. , Nikkels Arjen F.
Published: March 2017

Background: Mycosis fungoides (MF) is the most frequent type of primary cutaneous natural killer and T-cell lymphoma. MF-required immunosuppressive therapies and MF-related immunosuppressive characteristics render patients with MF more prone to infections. Aim: To describe the clinical features of cutaneous infections observed in MF patients. Materials and Methods: A series of 56 MF patients were followed prospectively over 3 years and screened for cutaneous infections. Type of Study: Prospective observational study. Results: Four herpes simplex virus type-I (HSV-I), 2 staphylococcal (S. aureus) impetiginizations and 2 Malassezia infections were detected in single isolated plaque/patch stage MF as well as 1 varicella zoster virus infection (herpes zoster, HZ) and 2 cases of cellulitis in 10 patients. All patients presented advanced MF. All the diagnoses were delayed due to atypical clinical presentations. Conclusions: Patients with advanced MF should be particularly monitored for skin infections, especially by HSV and S. aureus. Unexplained exacerbation or the sudden appearance of oozing or ulcerations in MF lesions should initiate a search for viral or bacterial agents. Cellulitis and HZ can be severer and prolonged in MF patients.
Cutaneous Neoplasms in Myotonic Dystrophy Type 1
Authors: Marcoval Joaquim , Olivé Montserrat , Bonfill-Ortí Montserrat , Martínez-Molina Laura , Talavera-Belmonte Ana
Published: March 2017

Background: The most frequent skin features associated with myotonic dystrophy type 1 (DM1) are frontal alopecia and pilomatrixomas. Several reports suggest that the incidence of basal cell carcinoma is increased in DM1. However, two recently published studies examining this topic have contradictory results. Objective: To retrospectively study the incidence of cutaneous tumours in patients with DM1. Methods: The clinical features of 102 Caucasian patients diagnosed with DM1 at Bellvitge Hospital in Barcelona, Spain, were retrospectively analysed. Clinical charts of the patients were reviewed, and cutaneous tumours diagnosed in our hospital were recorded. A group of 103 Caucasian patients matched for age and sex were used as the control group. Results: A total of 56 male and 46 female patients with DM1 were included in the study (mean age 49.07 years, SD 13.02). At least 1 basal cell carcinoma was diagnosed in 6 patients in the DM1 group versus 3 patients in the control group (p = 0.332). The mean age at diagnosis of the first basal cell carcinoma was 51 years compared with 66 years in the control group (p = 0.035). Five patients with DM1 presented pilomatrixomas versus none in the control group (p = 0.029). We did not detect any melanoma in our DM1 patients. Conclusion: Basal cell carcinomas appeared at a significantly younger age in our DM1 patients than in the general population, and this suggests that, at least in some patients, DM1 may predispose to the development of basal cell carcinomas.
Potential Utility of Diffusion-Weighted Magnetic Resonance Imaging in Diagnosis of Residual Bladder Cancer before Second Transurethral Resection
Authors: Nakamura Yuki , Yoshida Soichiro , Tanaka Hiroshi , Inoue Masaharu , Ito Masaya , Kijima Toshiki , Yokoyama Minato , Ishioka Junichiro , Matsuoka Yoh , Saito Kazutaka , Fujii Yasuhisa , Kihara Kazunori
Published: March 2017

Introduction: The study aimed to investigate the diagnostic utility of diffusion-weighted MRI (DW-MRI) in differentiating residual bladder cancer from benign postoperative changes before a second transurethral resection of the bladder (TURB). Materials and Methods: Of the 75 bladder cancer patients who underwent a second TURB from 2013 to 2015, 23 patients who underwent multi-sequence bladder MRI after their initial TURB were retrospectively evaluated. Thirty lesions were histologically examined at the second TURB and the results of them were compared with the findings obtained through T2-weighted MRI, dynamic contrast-enhanced MRI (DCE-MRI), and DW-MRI. Results: Positive findings of 27, 28, and 15 lesions showed up on T2W-, DCE-, and DW-MRI, respectively. Thirteen lesions were confirmed histologically to constitute residual cancer. The sensitivity/specificity/accuracy of T2W-, DCE-, and DW-MRI were 100/18/53, 100/12/50, and 92/82/87%, respectively. DW-MRI was significantly superior in specificity and accuracy to T2W- (p < 0.01 for both) and DCE-MRI (p < 0.01 for both). Conclusions: This study first showed the superiority of DW-MRI to T2W- and DCE-MRI in differentiating residual cancer before a second TURB.
Conjunctival Chemosis Caused by Exposure of the Lacrimal Caruncle: A Case Report
Authors: Baba Akinori , Matsuda Hiromichi , Shiba Takuya , Takahashi Yasuhiro , Tsuneoka Hiroshi
Published: March 2017

An 84-year-old woman presented with a 3-month history of conjunctival chemosis in the left eye. At the first examination, the chemosis neighbored the lacrimal caruncle and was localized in the inferomedial region of the conjunctiva. During eyelid closure, only the left lacrimal caruncle was exposed. One month later, the chemosis further extended to the inferolateral region. We debulked the lacrimal caruncle to prevent the exposure of the caruncle. One month after the surgery, conjunctival chemosis had resolved completely. At the postoperative 6-month follow-up, the patient showed no recurrence of chemosis.
Retinal Nerve Fiber Loss in Anti-VEGF Therapy for Age-Related Macular Degeneration Can Be Decreased by Anterior Chamber Paracentesis
Authors: Enders Philip , Sitnilska Vasilena , Altay Lebriz , Schaub Friederike , Muether Philipp S. , Fauser Sascha
Published: March 2017

Purpose: To analyze peripapillary retinal nerve fiber layer thickness (RNFLT) change after long-term intravitreal anti-VEGF therapy. Patients with regular anterior chamber paracentesis (ACP) prior to intravitreal injections (IVIs) were compared to those without ACP. Methods: Neovascular age-related macular degeneration (nAMD) was treated in a pro re nata regimen with a minimum of 9 IVIs. RNFLT change was determined in spectral domain optical coherence tomography. Results: In 32 patients without ACP, mean RNFLT loss (-2.16 ± 3.60 µm) was significantly higher than in 44 patients with regular ACP (0.16 ± 3.60; p = 0.029). Both groups were comparable in age (75.0 vs. 76.8 years; p = 0.35), number of IVIs (16.2 vs. 16.6; p = 0.98), and observational time (30.0 vs. 32.3 months; p = 0.32). In patients without ACP, RNFLT loss was higher compared to IVI-naive fellow eyes (p = 0.005), whereas in ACP patients, no difference was detected (p = 0.5). Conclusions: A moderate RNFLT loss is found in nonglaucomatous patients after injection therapy for nAMD. As it is decreased with regular ACP, tight management of intraocular pressure seems advisable.
Human Papillomavirus and the Development of Different Cancers
Authors: Gao Ge , Smith David I.
Published: March 2017

Human papillomaviruses (HPV) are responsible for the development of almost all cervical cancers. HPV is also found in 85% of anal cancer and in 50% of penile, vulvar, and vaginal cancers, and they are increasingly found in a subset of head and neck cancers, i.e., oropharyngeal squamous cell carcinomas (OPSCC). The model for how HPV causes cancer is derived from several decades of study on cervical cancer, and it is just presumed that this model is not only completely valid for cervical cancer but for all other HPV-driven cancers as well. Next-generation sequencing (NGS) has now provided the necessary tools to characterize genomic alterations in cancer cells and can precisely determine the physical status of HPV in those cells as well. We discuss recent discoveries from different applications of NGS in both cervical cancer and OPSCCs, including whole-genome sequencing and mate-pair NGS. We also discuss what NGS studies have revealed about the different ways that HPV can be involved in cancer formation, specifically comparing cervical cancer and OPSCC.
Coexpression of NUP98/TOP1 and TOP1/NUP98 in de novo Acute Myeloid Leukemia with t(11;20)(p15;q12) and t(2;5)(q33;q31)
Authors: Yamamoto Katsuya , Minami Yosuke , Yakushijin Kimikazu , Mizutani Yu , Inui Yumiko , Kawamoto Shinichiro , Matsui Keiji , Nakamachi Yuji , Kawano Seiji , Matsuoka Hiroshi , Minami Hironobu
Published: March 2017

The t(11;20)(p15;q11∼12) translocation is a very rare but recurrent cytogenetic aberration that occurs in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). This translocation was shown to form a fusion gene between NUP98 at 11p15 and TOP1 at 20q12. Here, we describe a new case of de novo AML M2 with t(11;20) which was associated with another balanced translocation. An 81-year-old man was admitted to undergo salvage therapy for relapsed AML. G-banding and spectral karyotyping showed 46,XY,t(2;5)(q33;q31),t(11;20)(p15;q12)[20]. Expression of the NUP98/TOP1 fusion transcript was confirmed: NUP98 exon 13 was in-frame fused with TOP1 exon 8. The reciprocal TOP1/NUP98 fusion transcript was also detected: TOP1 exon 7 was fused with NUP98 exon 14. After achieving hematological complete remission, the karyotype converted to 46,XY,t(2;5)(q33;q31)[19]/46,sl,t(11;20)(p15;q12)[1]. FISH analysis demonstrated that the 5q31 breakpoint of t(2;5) was centromeric to EGR1. In all 10 cases described in the literature, the NUP98 exon 13/TOP1 exon 8 fusion transcript was expressed, indicating that it may be responsible for the pathogenesis of MDS/AML with t(11;20). On the other hand, the TOP1/NUP98 transcript was coexpressed in 4 cases of de novo AML, but not in 3 cases of therapy-related MDS. Thus, this reciprocal fusion may be associated with progression to AML.
Radiologic Differences between Human Papillomavirus-Related and Human Papillomavirus-Unrelated Oropharyngeal Carcinoma on Diffusion-Weighted Imaging
Authors: Chan Michael W. , Higgins Kevin , Enepekides Danny , Poon Ian , Symons Sean P. , Moineddin Rahim , Weinreb Ilan , Shearkhani Omid , Chen Amy , Beelen Jocelyne , Chan Aimee , Maralani Pejman Jabehdar
Published: March 2017

Background and Purpose: Human papilloma virus-related oropharyngeal carcinoma (HPV+ OPC) is a unique entity compared to HPV-unrelated (HPV-) OPC. Previous studies were inconclusive regarding the differences between HPV+ and HPV- OPCs on diffusion-weighted imaging (DWI). This study sought to determine if there is an association between HPV status and apparent diffusion coefficient (ADC) values as an imaging biomarker in OPCs. Materials and Methods: OPC patients with pretreatment MRI including DWI were retrospectively reviewed and analyzed as a blinded, controlled cohort. HPV status was biopsy-ascertained with p16 staining. ADC values were determined by placing the largest possible circular region of interest in solid portions of primary tumors and/or metastatic lymph nodes. Necrotic and cystic portions were excluded. Results: Twenty-eight HPV+ and 12 HPV- patients were included. Adjusted for age and sex, ADC values were significantly lower in HPV+ OPC primary tumors (p = 0.013) and lymph node metastases (p = 0.013). The area under the curve (AUC) was 0.85 and 0.90, respectively. A model with a linear combination of the 2 variables yielded an AUC of 0.92. Conclusion: ADC values were significantly lower in both the primary tumors and lymph node metastases in HPV+ OPCs compared to HPV- OPCs. These results confirm the results of prior studies.
Obesity and Kidney Disease: Hidden Consequences of the Epidemic
Authors: Kovesdy Csaba P. , Furth Susan L. , Zoccali Carmine ,   on behalf of the World Kidney Day Steering Committee
Published: March 2017

Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease, and also for chronic kidney disease. A high body mass index is one of the strongest risk factors for new-onset chronic kidney disease. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing chronic kidney disease in the long-term. The incidence of obesity-related glomerulopathy has increased 10-fold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year, the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that make preventive behaviors an affordable option. Video Journal Club ‘Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=458481.
Impact of Hepatitis C Virus Eradication on the Clinical Outcome of Patients with Hepatitis C Virus-Related Advanced Hepatocellular Carcinoma Treated with Sorafenib
Authors: Kawaoka Tomokazu , Aikata Hiroshi , Teraoka Yuji , Inagaki Yuki , Honda Fumi , Hatooka Masahiro , Morio Kei , Morio Reona , Kobayashi Tomoki , Nagaoki Yuko , Nakahara Takashi , Hiramatsu Akira , Tsuge Masataka , Imamura Michio , Kawakami Yoshiiku , Chayama Kazuaki
Published: March 2017

Objective: To evaluate the impact of hepatitis C virus (HCV) eradication on the clinical outcome of patients with HCV-related advanced hepatocellular carcinoma (HCC) treated with sorafenib. Methods: A total of 58 HCV-related advanced HCC patients with Child-Pugh grade A disease who were treated with sorafenib were enrolled in this retrospective cohort study. Of these, 27 patients were HCV RNA negative as a result of previous antiviral therapy (sustained viral response [SVR] group), while the remaining 31 were HCV RNA positive (non-SVR group). Results: The response rate, disease control rate and median time to progression in the SVR group (6, 46.0%, and 3.8 months, respectively) were similar to those in the non-SVR group (3, 51.5%, and 2.7 months, respectively). On the other hand, the median time to treatment failure (TTTF), post-progression survival (PPS), and overall survival (OS) were significantly longer in the SVR group than in the non-SVR group (9.7, 8.5, and 15 months vs. 5.9, 5.2, and 9.3 months; p = 0.023, 0.02, and 0.014, respectively). On multivariate analysis, SVR was identified as a significant and independent determinant of PPS (p = 0.009), TTTF (p = 0.028), and OS (p = 0.01). Conclusion: HCV eradication before sorafenib treatment for HCV-related advanced HCC could prolong PPS and TTTF and improve OS.
Responsiveness of Coronary Arteries to Nitroglycerin under Hypoxia: The Importance of the Endothelium
Authors: Tawa Masashi , Shimosato Takashi , Sakonjo Hiroshi , Okamura Tomio
Published: March 2017

Background/Aims: Nitroglycerin is widely used as a coronary vasodilator in the treatment of ischemic heart diseases. This study investigated the influence of hypoxia on nitroglycerin-induced relaxation in endothelium-intact and -denuded rabbit, monkey, and porcine coronary arteries. Methods: Helically cut strips of coronary arteries were suspended in organ chambers, and isometric tension was recorded. Results: Nitroglycerin concentration dependently relaxed endothelium-intact rabbit coronary arteries, which were not different under normoxic and hypoxic conditions. On the other hand, nitroglycerin-induced relaxation of endothelium-denuded arteries was significantly attenuated by hypoxia. Similarly, the relaxant response of endothelium-intact monkey coronary arteries to nitroglycerin was not affected by hypoxia, whereas that of endothelium-denuded arteries was impaired. As is the case with rabbit and monkey coronary arteries, exposure to hypoxia resulted in impaired relaxation by nitroglycerin in endothelium-denuded but not endothelium-intact porcine coronary arteries. Conclusion: These findings suggest that coronary endothelium plays a pivotal role in preventing the hypoxia-induced impairment of nitroglycerin responsiveness, regardless of the animal species.
Protective Effects of Glucagon-Like Peptide-1 Analog on Renal Tubular Injury in Mice on High-Fat Diet
Authors: Guo Honglei , Li Hongmei , Wang Bin , Ding Wei , Ling Lilu , Yang Min , Gu Yong , Niu Jianying
Published: March 2017

Aims: The study aimed to investigate the renoprotective effect of glucagon-like peptide-1 (GLP-1) against renal tubular injury in C57BL/6 mice induced by a high-fat diet (HFD). Methods: Twenty C57BL/6 mice were fed HFD for 12 weeks. Ten of these mice were treated with GLP-1 at 200 µg/kg subcutaneously twice daily for 4 weeks (HFDG group), and the other ten mice received vehicle only (HFD group). Ten mice fed standard rodent chow served as controls (Con group). Body weight, kidney weight, food intake, and systolic blood pressure were measured. The expression of endoplasmic reticulum stress (ERS) markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis in the kidney were examined utilizing western blotting, immunohistochemistry and TUNEL, respectively. Angiotensin II and angiotensin II type 1 receptor (AT1R) were examined by ELISA. Human proximal tubule epithelial cells (HK2) were treated with GLP-1(150 nM) followed by treatment with palmitic acid (500 nM [PA]) for 24 h. HK2 cells treated with BSA were used as controls. The protein levels of ERS markers, apoptosis-associated protein, and AT1R were measured by western blotting. Results: Increase of body weight, food intake, and systolic blood pressure was less pronounced in GLP-1 treated HFDG mice compared to HFD mice. The levels of ERS markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis decreased following GLP-1 treatment in vivo and in vitro (p<0.05). Increased AT1R induced by HFD and PA were blocked with GLP-1 treatment. In contrast, the level of angiotensin II after GLP-1 treatment was not significantly different between the HFD and HFDG mice. Conclusion: The study indicated that saturated fatty acids induced ERS and apoptosis in the kidney and increased AT1R expression. GLP-1 treatment exerted renoprotective effects against saturated fatty acid-induced kidney tubular cell ERS and apoptosis together with inhibition of AT1R expression in vivo and in vitro.
Raf Kinase Inhibitor Protein Attenuates Ischemic-Induced Microglia Cell Apoptosis and Activation Through NF-κB Pathway
Authors: Su Li , Zhang Rongrong , Chen Yuanyuan , Zhu Zhenyu , Ma Chao
Published: March 2017

Background: Acute ischemic stroke is one of the most important factors leading to disability and death with the characterization of accumulated neuron death and injured supportive neurovascular structures. Raf-1 kinase inhibitory protein (RKIP) is a key molecule in cell response to survival or death stimuli. However, the role of RKIP in stroke is worthy to be further studied. Methods: We used lentivirus mediated RKIP knockdown and overexpression to investigate the effect of RKIP on animal models of focal cerebral ischemia. Cell Counting Kit-8 assay, lactate dehydrogenase release analysis, and Annexin V-APC apoptosis assay were used to detect the effect RKIP on microglial cell apoptosis and survival. Transwell migration assay was carried out to evaluate the migration of microglia cells. The releases of inflammatory cytokines were determined by ELISA. The activation of NF-kappaB signaling pathway was determined by western blot. Results: Overexpression of RKIP reduced focal cerebral ischemia injury. RKIP knockdown and overexpression regulated survival, activation, and motility via the NF-κB pathway. NF-κB inhibitor BAY 11-7082 blocked the changes caused by RKIP down-regulation after oxygen-glucose deprivation (OGD). RKIP overexpression inhibited the upregulation of phosphorylation of NF-κB induced by OGD and cerebral ischemia. Conclusions: The present study showed that RKIP protects against ischemic stroke through inhibition of microglial excessive activation, inhibits its motility, and promotes neuronal survival partly though IKKβ-IκBα-NF-κB signaling axis and indicate that RKIP is a new target for the treatment of ischemic stroke.
Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits
Authors: Braeckman Bart P. , Dhondt Ineke
Published: March 2017

The insulin/IGF-1 signalling (IIS) pathway connects nutrient levels to metabolism, growth and lifespan in eukaryotes ranging from yeasts to humans, including nematodes such as the genetic model organismCaenorhabditis elegans. The link between ageing and the IIS pathway has been thoroughly studied inC. elegans; upon reduced IIS signalling, a genetic survival program is activated resulting in a drastic lifespan extension. One of the components of this program is the upregulation of antioxidant activity but experiments failed to show a clear causal relation to longevity. However, oxidative damage, such as protein carbonyls, accumulates at a slower pace in long-livedC. elegansmutants with reduced IIS. This is probably not achieved by increased macroautophagy, a process that sequesters cellular components to be eliminated as protein turnover rates are slowed down in IIS mutants. The IIS mutantdaf-2, bearing a mutation in the insulin/IGF-1 receptor, recapitulates the dauer survival program, including accumulation of fat and glycogen. Fat can be converted into glucose and glycogenviathe glyoxylate shunt, a pathway absent in vertebrates. These carbohydrates can be used as substrates for trehalose synthesis, also absent in mammals. Trehalose, a non-reducing homodimer of glucose, stabilises intracellular components and is responsible for almost half of the lifespan extension in IIS mutants. Hence, the molecular mechanisms by which lifespan is extended under reduced IIS may differ substantially between phyla that have an active glyoxylate cycle and trehalose synthesis, such as ecdysozoans and fungi, and vertebrate species such as mammals.
Contested Foreignness: Indian Migrants and the Politics of Exclusion in Early Colonial Zimbabwe, 1890 to 1923
Authors: Musoni Francis
Published: March 2017

The British South Africa Company’s conquest of Zimbabwe in the 1890s opened the country to settlement by immigrants from Europe, South Africa, India and other regions. Using their position as benefactors of the emerging colony, the British-born settlers deployed various notions of foreignness to marginalize the indigenous populations and other groups. Focusing on thirty-three years of company rule in Zimbabwe, this article examines how Indian immigrants contested the British attempts to foreignize them in the emerging colony. Rather than presenting Indian migrants as passive victims of discrimination and marginalization, the study emphasizes their creativity and determination to establish their own destiny, against all odds. It also shows that foreignness in colonial Zimbabwe was a key factor in the politics of power, identity formation and nation-state building. In that respect, the article explores the constructed-ness as well as the malleability of foreignness in processes of nation-state formation in Africa.
Geographical variation in limb muscle mass of the Andrew’s toad (Bufo andrewsi)
Authors: Yang Sheng Nan , Huang Xiao Fu , Zhong Mao Jun , Liao Wen Bo
Published: March 2017

Muscles are vital for the process of movement, mating and escape of predators in amphibians. During evolution, the morphological and genetic characteristics as well as the size of muscles in species will change to adapt different environments. Theory predicts that low male-male competition in high-altitude/latitude selects for small limb muscles. Here, we used the Andrew’s toad (Bufo andrewsi) as a model animal to test this prediction by analyzing geographical variation in the mass of limb muscles across nine populations from the Hengduan Mountains in China. Inconsistent with the prediction, we found that latitude and altitude did not affect the relative mass of total combined limb muscles and mass of combined hindlimb muscles among populations. Meanwhile, the relative mass of combined forelimb muscles, the two forelimb muscles (flexor carpi radialis and extensor carpi radialis) and the four hindlimb muscles (e.g. biceps femoris, semimebranous, semitendinosus and peroneus) was lowest in middle latitude and largest in low latitude whereas gracilis minor was largest in high latitudes. However, we did not find any correlations between the two forelimb muscles and the four hindlimb muscles and altitude. Our findings suggest that combined forelimb muscles, flexor carpi radialis, extensor carpi radialis, biceps femoris, semimebranous, semitendinosus and peroneus are largest in low latitudes due to pressures of mate competition.
Lectotypification of Artemisia mongolica (= A. vulgaris var. mongolica, Asteraceae)
Authors: MOSYAKIN SERGEI L. , BOIKO GANNA V. , VERLOOVE FILIP
Published: March 2017

Artemisia mongolica, initially described as A. vulgaris var. mongolica, is lectotypified by a specimen annotated by Besser (the author of the basionym) that originated from Fischer’s herbarium and is deposited in the Besser Memorial Collection at KW, with three isolectotypes in LE. An earlier neotypification by Filatova (2003) is therefore unnecessary. Further nomenclatural and historical notes are provided on the original material and publication of the name.
Peucetia casseli Simon, 1900 has priority over P. longipes Pocock, 1900 (Araneae, Oxyopidae)
Authors: BLICK THEO , GLOOR DANIEL
Published: March 2017

The World Spider Catalog (WSC 2016) currently lists Peucetia longipes Pocock, 1899 as a senior synonym of P. casseli Simon, 1899; according to Niekerk & Dippenaar-Schoeman (1994: 16). The synonymy decision per se is not to be doubted but, regarding the senior name choice, it was stated that “As both P. [Peucetia] longipes and P. casseli were described in 1899, we decided to give P. longipes priority over P. casseli as the former species was more often referred to in the literature.” So Niekerk & Dippenaar-Schoeman (1994) did not check the month or even the day of the two relevant publications.
Changes in North American Atmospheric Circulation and Extreme Weather: Influence of Arctic Amplification and Northern Hemisphere Snow Cover
Authors: Vavrus Stephen J. , Wang Fuyao , Martin Jonathan E. , Francis Jennifer A. , Peings Yannick , Cattiaux Julien
Published: March 2017

This study tests the hypothesis that Arctic amplification (AA) of global warming remotely affects midlatitudes by promoting a weaker, wavier atmospheric circulation conducive to extreme weather. The investigation is based on the late twenty-first century over greater North America (20°–90°N, 50°–160°W) using 40 simulations from the Community Earth System Model Large Ensemble, spanning 1920–2100. AA is found to promote regionally varying ridging aloft (500 hPa) with strong seasonal differences reflecting the location of the strongest surface thermal forcing. During winter, maximum increases in future geopotential heights are centered over the Arctic Ocean, in conjunction with sea ice loss, but minimum height increases (troughing) occur to the south, over the continental United States. During summer the location of maximum height inflation shifts equatorward, forming an annular band across mid-to-high latitudes of the entire Northern Hemisphere. This band spans the continents, whose enhanced surface heating is aided by antecedent snow-cover loss and reduced terrestrial heat capacity. Through the thermal wind relationship, midtropospheric winds weaken on the equatorward flank of both seasonal ridging anomalies—mainly over Canada during winter and even more over the continental United States during summer—but strengthen elsewhere to form a dipole anomaly pattern in each season. Changes in circulation waviness, expressed as sinuosity, are inversely correlated with changes in zonal wind speed at nearly all latitudes, both in the projections and as observed during recent decades. Over the central United States during summer, the weaker and wavier flow promotes drying and enhanced heating, thus favoring more intense summer weather.
Evaluation Criteria on the Design for Assimilating Remote Sensing Data Using Variational Approaches
Authors: Lu Sha , Heemink Arnold , Lin Hai Xiang , Segers Arjo , Fu Guangliang
Published: March 2017

Remote sensing, as a powerful tool for monitoring atmospheric phenomena, has been playing an increasingly important role in inverse modeling. Remote sensing instruments measure quantities that often combine several state variables as one. This creates very strong correlations between the state variables that share the same observation variable. This may cause numerical problems resulting in a low convergence rate or inaccurate estimates in gradient-based variational assimilation if improper error statistics are used. In this paper, two criteria or scoring rules are proposed to quantify the numerical robustness of assimilating a specific set of remote sensing observations and to quantify the reliability of the estimates of the parameters. The criteria are derived by analyzing how the correlations are created via shared observation data and how they may influence the process of variational data assimilation. Experimental tests are conducted and show a good level of agreement with theory. The results illustrate the capability of the criteria to indicate the reliability of the assimilation process. Both criteria can be used with observing system simulation experiments (OSSEs) and in combination with other verification scores.
Managing Content in Cross-Cultural Public Relations Campaigns: A Case Study of the Paris Terrorist Attacks
Authors: Ginesta Xavier , Ordeix Enric , Rom Josep
Published: March 2017

This article studies how traditional media functions have changed due the new media growth in terms of consumption and influence and how this has affected the public relations (PR) campaigns in terms of storytelling and managing content. The starting point of this article is the media coverage of the Paris attacks on the 13th November, as well as the institutional ceremonies that the French government organized as a tribute to 120 victims. The methodology of this article is based in a sample of the mainstream media in French and English language published in Europe. The analysis indicators are the following: (a) the “message,” as the story based on organizational essentials, values and identity; (b) the publics in a media relations campaign: opinion leaders and opinion makers; (c) the social dimension and the agenda setting; (d) effectiveness versus excellence and vice versa; (e) role of the media: traditional media (or mainstream media) and new media; (f) trends and challenges for professionals. As we will see, new trends of communication are redirecting the media strategy in PR campaigns in terms of influencing other key publics that generates major engagement in institutional reputation. Hence, traditional media functions (setting agenda, transmitting values, and creating opinion) operate in a new digital context of mashup journalism where cross-cultural PR seeks to better align media agenda’s with public and political agenda’s in order to set frames of sociability and community engagement.
Is a Plea Really a Bargain? An Analysis of Plea and Trial Dispositions in New York City
Authors: Kutateladze Besiki L. , Lawson Victoria Z.
Published: March 2017

The study challenges the common notion that plea bargaining is necessarily beneficial to defendants. It examines the factors influencing the likelihood of taking a misdemeanor case to trial, and the probability of acquittal upon reaching trial. Defendants charged with more serious crimes, persons crimes, crimes with victims, and represented by private attorneys were more likely to go to trial than to be pleaded out. By contrast, very few factors influenced trial outcomes, and the effect of race was fairly weak. Perhaps most important is the finding that two in five cases going to trial resulted in acquittal, showing that guilt is not a foregone conclusion which may provide leverage to defendants in the plea-bargaining process.