bluuebunny/crossref_metadata_2025_split huggingface dataset:
Negative Hemodynamic Effects of Pantoprazole at High Infusion Rates in Mice
Authors: Unsöld Bernhard , Teucher Nils , Didié Michael , Sossalla Samuel , Jacobshagen Claudius , Seidler Tim , Schillinger Wolfgang , Hasenfuß Gerd 
Published: December 2014

SummaryBackgroundPantoprazole has been shown to exert a negative inotropic effect in isolated myocardium. The purpose of this study was to evaluate the hemodynamic effects of pantoprazole in vivo in healthy myocardium and in the setting of heart failure.Methods and ResultsHealthy mice and mice with heart failure 4 weeks after myocardial infarction induced by permanent LAD ligation were instrumented with a Millar Mikrotip conductance catheter to record pressure–volume loops. Pantoprazole was infused at rates of 3 and 10 mg/kg/min intravenously, and hemodynamic parameters were recorded. Infusion of pantoprazole at increasing rates lead to a significant decline of end systolic LV pressure by decreasing heart rate, myocardial contractility and arterial elastance. These effects were quick, beginning immediately with the infusion and usually reaching a plateau after 2 or 3 min of infusion. The effects on blood pressure and heart rate were of comparable size in healthy mice and mice with MI. However, in sham‐operated mice, there was a compensatory increase in stroke volume that sufficed to maintain cardiac output at a constant level, which was missing in mice with MI. In 4 of 13 mice with MI infusion of 10 mg/kg/min pantoprazole lead to pump failure, which was lethal in 2 of these animals.ConclusionAt higher infusion rates, pantoprazole is able to induce negative hemodynamic responses. In particular, in the setting of heart failure, these effects can lead to significant impairment of cardiac function. Therefore, high infusion rates of pantoprazole should be avoided especially in heart failure patients.
Hepatitis C seroconversion in methadone maintenance treatment programs in Wuhan, China
Authors: Zhou Wang , Wang Xia , Zhou Sheng , Xie Nianhua , Liu Pulin , Luo Li , Peng Jinsong , Liu Manqing , Desrosiers Alethea , Schottenfeld Richard , Chawarski Marek C. 
Published: December 2014

AbstractBackground and aimsTo decrease infectious disease transmission, China is expanding methadone maintenance treatment (MMT). This study evaluated the prevalence of hepatitis C virus (HCV) infection at MMT entry, seroconversion rates after admission and potential risk factors for HCV seroconversion during MMT in Wuhan, China.DesignCross‐sectional survey of all patients entering MMT and prospective follow‐up of patients HCV seronegative at admission.SettingAll MMT clinics in Wuhan, China.ParticipantsA total of 12 755 opiate‐dependent individuals entering MMT between May 2006 and June 2011; 1200 participants HCV seronegative at admission were followed.MeasurementsSerological tests for HCV and self‐report data on risk behaviors at MMT admission; urine toxicology results and repeated assessments of serological status and risk behaviors during treatment on patients HCV seronegative at admission.FindingsHCV seroprevalence at admission was 72.1% [95% confidence interval (CI) = 71.3–72.9%] and 555/1200 (46.3%, 95% CI = 43.5–49.1%) patients seroconverted to HCV during MMT. The mean time to HCV seroconversion was 3 (95% CI = 2.84–3.07) years with a cumulative seroconversion rate of 34.5 (95% CI = 31.5–36.9) per 100 person‐years. Significant predictors of HCV conversion included injection drug use in the past 30 days [relative hazard (RH) 2.0, 95% CI: 1.6 – 2.4, P=0.002] and the rate of opiate‐positive urine tests during MMT (RH 2.0, 95% CI = 1.3–3.1, P<0.001).ConclusionsMethadone maintenance treatment patients in Wuhan, China show a high prevalence of hepatitis C virus at admission (72.1%) and a high rate of seroconversion during treatment (46.3%). Seroconversion is associated with continuing injection drug use.
A Novel Homozygous Nonsense Mutation in the PVRL4 Gene and Expansion of Clinical Spectrum of EDSS1
Authors: Raza Syed Irfan , Nasser Dar Rashid , Shah Anwar Ali , Ahmad Wasim 
Published: December 2014

SummaryEctodermal dysplasias (EDs) belong to a group of genetic diseases which result from alterations in ectoderm‐derived appendages including hair, nail, teeth and sweat glands. Ectodermal dysplasia syndactyly syndrome (EDSS1) is one of the rare forms of ED caused by mutations in nectin‐4, encoded by the PVRL4 gene. The present study described clinical investigation of the EDSS1 identified in a large consanguineous family. Furthermore, DNA sequence analysis revealed a novel homozygous nonsense mutation (181C>T, p.Asp61*) in the PVRL4 gene.
Choroidal thickness and high myopia: a case–control study of young Chinese men in Singapore
Authors: Gupta Preeti , Saw Seang‐Mei , Cheung Carol Y. , Girard Michael J. A. , Mari Jean Martial , Bhargava Mayuri , Tan Colin , Tan Mellisa , Yang Adeline , Tey Frederick , Nah Gerard , Zhao Paul , Wong Tien Yin , Cheng Ching‐Yu 
Published: December 2014

AbstractPurposeTo determine the distribution of choroidal thickness (CT) and ocular factors associated with CT in high myopic eyes in comparison with emmetropic eyes of young healthy adults.MethodsA case–control study of 648 young, male subjects, including 520 high myopes and 128 emmetropes. Choroidal imaging was performed using enhanced depth imaging spectral domain optical coherence tomography. Images were postprocessed using adaptive compensation for quality enhancement. CT was measured at nine locations, including subfovea and 1.5 and 3 mm nasal, temporal, superior and inferior to fovea.ResultsThe CT at the subfovea was significantly thinner (mean ± standard error: 225.87 ± 5.51 μm) for high myopes compared to emmetropes (375.15 ± 6.58 μm, p < 0.001). Likewise, CT in high myopic group was significantly thinner than emmetropic control group at all locations (p for trend <0.001 for all locations). Distribution of CT showed a markedly different pattern in high myopic eyes (thickest superiorly at 3 mm, 265.97 ± 5.97 μm) and emmetropic eyes (thickest subfoveally, 375.15 ± 6.58 μm). Choroid was thinnest at nasal 3 mm location in both the myopic (108.85 ± 3.97 μm) and emmetropic (238.25 ± 6.72 μm) groups. Among the ocular factors studied, axial length, posterior staphyloma and chorio‐retinal atrophy were the significant predictors of CT.ConclusionsHighly myopic eyes have significantly thinner choroid and showed different distribution pattern, compared to emmetropes. Axial length, posterior staphyloma and chorio‐retinal atrophy are the strongest determinants of CT.
Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health
Authors: Bhandage A. K. , Hellgren C. , Jin Z. , Olafsson E. B. , Sundström‐Poromaa I. , Birnir B. 
Published: December 2014

AbstractAimThe concept of nerve‐driven immunity recognizes a link between the nervous and the immune system. γ‐aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, and receptors activated by GABA can be expressed by immune cells. Here, we examined whether the expression of GABA receptors and chloride transporters in human peripheral blood mononuclear cells (PBMCs) was influenced by gender, pregnancy or mental health.MethodsWe used RT‐qPCR to determine the mRNA expression level in PBMCs from men (n = 16), non‐pregnant women (n = 19), healthy pregnant women (n = 27) and depressed pregnant women (n = 15).ResultsThe ρ2 subunit had the most prominent expression level of the GABA‐A receptor subunits in all samples. The δ and ρ2 subunits were up‐regulated by pregnancy, whereas the ε subunit was more frequently expressed in healthy pregnant women than non‐pregnant women who, in turn, commonly expressed the α6 and the γ2 subunits. The β1 and ε subunits expression was altered by depression in pregnant women. The GABA‐B1 receptor was up‐regulated by depression in pregnant women, while the transporters NKCC1 and KCC4 were down‐regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs.ConclusionThe results demonstrate the impact gender, pregnancy and mental health have on the expression of GABA receptors and chloride transporters expressed in human PBMCs.
Lipid Signalling Dynamics at the β‐cell Plasma Membrane
Authors: Wuttke Anne 
Published: December 2014

AbstractPancreatic β‐cells are clustered in islets of Langerhans and secrete insulin in response to increased concentrations of circulating glucose. Insulin in turn acts on liver, muscle and fat tissue to store energy and normalize the blood glucose level. Inappropriate insulin release may lead to impaired glucose tolerance and diabetes. In addition to glucose, other nutrients, neural stimuli and hormonal stimuli control insulin secretion. Many of these signals are perceived at the plasma membrane, which is also the site where insulin granules undergo exocytosis. Therefore, it is not surprising that membrane lipids play an important role in the regulation of insulin secretion. β‐cells release insulin in a pulsatile fashion. Signalling lipids integrate the nutrient and neurohormonal inputs to fine‐tune, shape and co‐ordinate the pulsatility. An important group of signalling lipids are phosphoinositides and their downstream messengers. This MiniReview will discuss new insights into lipid signalling dynamics in β‐cells obtained from live‐cell imaging experiments with fluorescent translocation biosensors. The plasma membrane concentration of several phosphoinositides and of their downstream messengers changes rapidly upon nutrient or neurohormonal stimulation. Glucose induces the most complex spatio‐temporal patterns, typically involving oscillations of messenger concentrations, which sometimes are locally restricted. The tightly controlled levels of lipid messengers can mediate specific binding of downstream effectors to the plasma membrane, contributing to the appropriate regulation of insulin secretion.
Cerebral Amyloid Angiopathy, Subcortical White Matter Disease and Dementia: Literature Review and Study in OPTIMA
Authors: Esiri Margaret , Chance Steven , Joachim Catharine , Warden Donald , Smallwood Aidan , Sloan Carolyn , Christie Sharon , Wilcock Gordon , Smith A. David 
Published: December 2014

AbstractCerebral amyloid angiopathy (CAA) is of increasing clinical and research interest as the ability to detect it and its consequences by neuroimaging in living subjects has advanced. There is also increasing interest in understanding its possible role in the development of intracerebral hemorrhage, Alzheimer's disease (AD) and vascular dementia. In this article, the literature on this subject is reviewed and novel findings relating CAA to subcortical white matter damage in 224 subjects in the Oxford project to Investigate Memory and Ageing (OPTIMA) are reported. The relationship between CAA and subcortical tissue damage in the OPTIMA subjects was found to be critically dependent on ApoE genotype, there being a positive relationship between measures of CAA and subcortical small vessel disease in ApoEε4 carriers and a significant negative relationship in ApoEε2 carriers. These findings draw attention, as have many other studies, to the importance of ApoE genotype as a major risk factor not only for dementia but also for damage to blood vessels in the aging brain.
Endothelial Cells and Human Cerebral Small Vessel Disease
Authors: Hainsworth Atticus H. , Oommen Asho T. , Bridges Leslie R. 
Published: December 2014

AbstractBrain endothelial cells have unique properties in terms of barrier function, local molecular signaling, regulation of local cerebral blood flow (CBF) and interactions with other members of the neurovascular unit. In cerebral small vessel disease (arteriolosclerosis;SVD), the endothelial cells in small arteries survive, even when mural pathology is advanced and myocytes are severely depleted. Here, we review aspects of altered endothelial functions that have been implicated inSVD: localCBFdysregulation, endothelial activation and blood–brain barrier (BBB) dysfunction. ReducedCBFis reported in the diffuse white matter lesions that are a neuroradiological signature ofSVD. This may reflect an underlying deficit in localCBFregulation (possibly via the nitric oxide/cGMPsignaling pathway). While many laboratories have observed an association of symptomaticSVDwith serum markers of endothelial activation, it is apparent that the origin of these circulating markers need not be brain endothelium. Our own neuropathology studies did not confirm local endothelial activation in small vessels exhibitingSVD. LocalBBBfailure has been proposed as a cause ofSVDand associated parenchymal lesions. Some groups find that computational analyses of magnetic resonance imaging (MRI) scans, following systemic injection of a gadolinium‐based contrast agent, suggest that extravasation into brain parenchyma is heightened in people withSVD. Our recent histochemical studies of donated brain tissue, using immunolabeling for large plasma proteins [fibrinogen, immunoglobulinG(IgG)], do not support an association ofSVDwith recent plasma protein extravasation. It is possible that a trigger leakage episode, or a size‐selective loosening of theBBB, participates inSVDpathology.
Making sense of ‘lower’ and ‘upper’ stem‐group Euarthropoda, with comments on the strict use of the name Arthropoda von Siebold, 1848
Authors: Ortega‐Hernández Javier 
Published: December 2014

ABSTRACTThe ever‐increasing number of studies that address the origin and evolution of Euarthropoda – whose extant representatives include chelicerates, myriapods, crustaceans and hexapods – are gradually reaching a consensus with regard to the overall phylogenetic relationships of some of the earliest representatives of this phylum. The stem‐lineage of Euarthropoda includes numerous forms that reflect the major morphological transition from a lobopodian‐type to a completely arthrodized body organization. Several methods of classification that aim to reflect such a complex evolutionary history have been proposed as a consequence of this taxonomic diversity. Unfortunately, this has also led to a saturation of nomenclatural schemes, often in conflict with each other, some of which are incompatible with cladistic‐based methodologies. Here, I review the convoluted terminology associated with the classification of stem‐group Euarthropoda, and propose a synapomorphy‐based distinction that allows ‘lower stem‐Euarthropoda’ (e.g. lobopodians, radiodontans) to be separated from ‘upper stem‐Euarthropoda’ (e.g. fuxianhuiids, Cambrian bivalved forms) in terms of the structural organization of the head region and other aspects of overall body architecture. The step‐wise acquisition of morphological features associated with the origins of the crown‐group indicate that the node defining upper stem‐Euarthropoda is phylogenetically stable, and supported by numerous synapomorphic characters; these include the presence of a deutocerebral first appendage pair, multisegmented head region with one or more pairs of post‐ocular differentiated limbs, complete body arthrodization, posterior‐facing mouth associated with the hypostome/labrum complex, and post‐oral biramous arthropodized appendages. The name ‘Deuteropoda’ nov. is proposed for the scion (monophyletic group including the crown‐group and an extension of the stem‐group) that comprises upper stem‐Euarthropoda and Euarthropoda. A brief account of common terminological inaccuracies in recent palaeontological studies evinces the utility of Deuteropoda nov. as a reference point for discussing aspects of early euarthropod phylogeny.
Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1‐deficient mice
Authors: Morioka Takamitsu , Miyoshi‐Imamura Tomoko , Blyth Benjamin J. , Kaminishi Mutsumi , Kokubo Toshiaki , Nishimura Mayumi , Kito Seiji , Tokairin Yutaka , Tani Shusuke , Murakami‐Murofushi Kimiko , Yoshimi Naoki , Shimada Yoshiya , Kakinuma Shizuko 
Published: December 2014

Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long‐term chronic inflammation is also a key risk factor, responsible for colitis‐associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation‐induced colon carcinogenesis in DNA mismatch repair‐proficient and repair‐deficient mice. Male and female Mlh1−/− and Mlh1+/+ mice were irradiated with 2 Gy X‐rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X‐rays and/or DSS treatment in Mlh1+/+ mice. Colon tumors developed after DSS treatment alone in Mlh1−/− mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well‐to‐moderately differentiated adenocarcinomas with tumor‐infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β‐catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis‐associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency.
Synthesis and therapeutic effect of styrene–maleic acid copolymer‐conjugated pirarubicin
Authors: Tsukigawa Kenji , Liao Long , Nakamura Hideaki , Fang Jun , Greish Khaled , Otagiri Masaki , Maeda Hiroshi 
Published: December 2014

Previously, we prepared a pirarubicin (THP)‐encapsulated micellar drug using styrene–maleic acid copolymer (SMA) as the drug carrier, in which active THP was non‐covalently encapsulated. We have now developed covalently conjugated SMA‐THP (SMA‐THP conjugate) for further investigation toward clinical development, because covalently linked polymer–drug conjugates are known to be more stable in circulation than drug‐encapsulated micelles. The SMA‐THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation. Consequently, SMA‐THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor‐targeting efficiency by the enhanced permeability and retention (EPR) effect. As a result, remarkable antitumor effect was achieved against two types of tumors in mice without apparent adverse effects. Significantly, metastatic lung tumor also showed the EPR effect, and this conjugate reduced metastatic tumor in the lung almost completely at 30 mg/kg once i.v. (less than one‐fifth of the maximum tolerable dose). Although SMA‐THP conjugate per se has little cytotoxicity in vitro (1/100 of free drug THP), tumor‐targeted accumulation by the EPR effect ensures sufficient drug concentrations in tumor to produce an antitumor effect, whereas toxicity to normal tissues is much less. These findings suggest the potential of SMA‐THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor‐targeting properties in vivo.
Molecular targeted therapy against B cells in multiple sclerosis
Authors: Miyazaki Yusei , Niino Masaaki 
Published: December 2014

AbstractB cells have been implicated in the pathology of multiple sclerosis (MS) since the initial observation in the 1940s and 50s of increased immunoglobulin concentrations in the cerebrospinal fluid of MS patients. Until recently, B cells have been considered to participate in MS pathology through the secretion of antibodies specific to central nervous system antigens. However, the successful targeting of B cells with anti‐CD20 monoclonal antibodies without affecting immunoglobulin levels suggests that B cells have antibody‐independent functions in immune regulation in MS. Furthermore, the recent identification of B cell‐rich follicle‐like structures in the meninges of patients with secondary progressive MS indicates that B cells also have pathogenic roles within the central nervous system, where they contribute to disease progression by inducing cortical injury. These observations suggest that B cells are key players in the pathogenesis of MS, and are therefore attractive targets for therapeutic intervention. In addition to CD20, several other molecules and pathways related to B cell function are being evaluated as therapeutic targets in other autoimmune diseases. Furthermore, based on the increased understanding of the molecular mechanisms underlying B cell effector function, particularly those involved in MS, therapeutic strategies for specifically inhibiting the pro‐inflammatory activity of B cells while preserving or even enhancing their role in protective immune response are under active investigation. Here, we review recent advances in molecular targeted therapies against B cells for MS, and discuss perspectives for future therapies targeting B cells and related molecules.
Molecular targeted therapy against the blood–brain barrier in multiple sclerosis
Authors: Kanda Takashi 
Published: December 2014

AbstractPrevious therapeutic strategies for multiple sclerosis (MS) include the non‐selective suppression of systemic immunity (immunosuppressive agents, such as glucocorticoids, mitoxantrone and azathioprine) and immunomodulation (type I interferons or intravenous immunoglobulin). The recent development of two pivotal drugs, fingolimod and natalizumab, has resulted in a third category of MS treatment, namely the sequestration of pathogenic T cells. Natalizumab, a humanized monoclonal antibody that binds to the α4‐integrin molecule on the surface of circulating lymphocytes and thus blocks very late antigen‐4/vascular cell adhesion molecule‐1 interactions at the blood–brain barrier (BBB), is now widely accepted as a potent tool for treating relapsing–remitting MS. This drug is epoch‐making, as it is the first agent to confirm the efficacy of merely inhibiting the transfer of T cells across the BBB in the treatment of MS; however, the risk of a potentially fatal central nervous system opportunistic infection, progressive multifocal leukoencephalopathy, should always be kept in mind. Because the onset of progressive multifocal leukoencephalopathy might be partly due to the almost total blockage of T cells, including those participating in immune surveillance, the development of novel therapies that selectively inhibit only the entrance of pathogenic T cells is now eagerly awaited. In addition to the blockade of mononuclear cell intrusion, restoring the integrity of the BBB might quickly terminate the process of local inflammation. In addition, manipulating the BBB to enhance the transfer of useful molecules, including a variety of growth factors, could facilitate axonal regeneration. Therefore, the BBB is a promising target of future therapeutic strategies in MS.