bluuebunny/crossref_metadata_2025 huggingface dataset:
Generation of Nitric Oxide from Organic Nitrovasodilators during Passage through the Coronary Vascular Bed and Its Role in Coronary Vasodilation and Nitrate Tolerance
Authors: Schrör Karsten , Woditsch Isabelle , Förster Stefan
Published: April 2017

This study investigated the release of nitric oxide (NO) from glyceryl trinitrate (GTN) and SIN-1 in Langendorff rabbit hearts. Infusion of either GTN (10–40µM) or SIN-1 (0.45–4.5 µM) into the coronary inflow tract resulted in a decrease in coronary perfusion pressure and NO release (oxyhemoglobin technique) into the coronary effluent. NO release fom SIN-1 occurred spontaneously whereas passage through the coronary circulation, i.e. active metabolism, was required for NO release from GTN. Removal of the coronary endothelium and blockade of endothelial NO formation did not affect NO release from GTN and SIN-1. In GTN-tolerant hearts, there was a considerable inhibition of GTN- but not SIN-1-induced NO formation and coronary vasodilation. These data suggest (1) that metabolic NO release from GTN occurs during passage of the coronary circulation and is independent of the presence of endothelium, and (2) reduced NO release is a major cause of nitrate tolerance.
Heme-Dependent Activation of Guanylate Cyclase by Nitric Oxide: A Novel Signal Transduction Mechanism
Authors: Ignarro Louis J.
Published: April 2017

The interaction between nitric oxide (NO) synthesized in one cell and cytosolic guanylate-cyclase-bound heme located in adjacent target cells to generate the NO-heme adduct of guanylate cyclase represents a novel and widespread signal transduction mechanism that links extracellular stimuli to the biosynthesis of cyclic GMP in target cells. A variety of chemical factors interact with selective extracellular receptors and trigger the biosynthesis of NO from L-arginine. The unique chemistry of NO endows this molecule with the capacity to diffuse rapidly into nearby cells and stimulate cyclic GMP formation. Cyclic GMP acts as a messenger in each cell type to trigger different but complementary cellular responses within a localized environment. This transcellular signaling is a form of rapid intercellular communication allowing the simultaneous local initiation of increased blood flow, inhibition of platelet-induced thrombosis and other cellular functions.
Molecular Biology of Adrenergic Receptors: Model Systems for the Study of G-Protein-Mediated Signal Transduction
Authors: Fraser Claire M.
Published: April 2017

Elucidation of the gene structure of several receptors known to mediate the signal of hormone or transmitter binding to intracellular effector systems through guanine-nucleotide-binding proteins (G proteins) has revealed that these receptors comprise a super-family of related proteins. The hallmark of all G-protein-linked receptors is a presumed topography of 7 membrane-spanning loops, analogous to the structure of bacteriorhodopsin. Members of this gene superfamily contain regions, particularly with the hydrophobic domains, of homologous sequence. The expression of G-protein-linked receptors in heterologous cell systems has allowed for the study of the pharmacological and biochemical properties of individual receptor subtypes in a manner not previously possible with intact tissues containing multiple receptors. Site-directed mutagenesis experiments have identified many conserved amino acids which are involved in ligand binding, receptor activation by agonists and receptor-G protein coupling, and suggest that the conservation of receptor structure throughout this gene family may reflect a conservation of important functional domains within these proteins.
Interaction of Vascular Alpha-1 Adrenoceptors with Multiple Signal Transduction Pathways
Authors: Ruffolo, Jr. Robert R. , Nichols Andrew J. , Oriowo Mabayoje A.
Published: April 2017

In the rat vasculature, a single α1-adrenoceptor may be coupled to two distinct G proteins, one of which regulates phospholipase C activity and is insensitive to pertussis toxin, and another which regulates calcium channel function and is highly sensitive to inhibition by pertussis toxin. α1-Adrenoceptor agonists may in theory activate both pathways, but the efficiency of α1-adrenoceptor coupling to the pertussis toxin-insensitive pathway is low relative to the other pathway that couples the α1-adrenoceptor to calcium channels. As such, only full agonists with high intrinsic efficacy can activate both pathways, whereas partial agonists, by virtue of their lower intrinsic efficacies, are less able to activate the pertussis-toxin-insensitive pathway, thereby rendering partial α1-adrenoceptor agonists more sensitive than full α1-adrenoceptor agonists to inhibition by calcium channel blockers and pertussis toxin.
Towards an Understanding of the Mechanism of Action of Cyclic AMP and Cyclic GMP in Smooth Muscle Relaxation
Authors: Lincoln Thomas M. , Cornwell Trudy L.
Published: April 2017

Cyclic GMP (cGMP) mediates the relaxing action of a variety of vasodilator drugs and endogenous vasodilator substances. Cyclic AMP (cAMP) mediates relaxation by β-adrenergic agonists as well as other activators of adenylate cyclase. Both second messengers appear to reduce the concentration of intracellular Ca2+ in vascular smooth muscle cells, thus affecting relaxation. The presence of cGMP-dependent protein kinase in vascular smooth muscle cells is required for the reduction of Ca2+ by cAMP and cGMP, suggesting that this enzyme mediates the relaxing effects of both cyclic nucleotides. Although the specific substrate proteins for cGMP-dependent protein kinase are not well characterized in vascular smooth muscle, new evidence indicates that Ca2+-ATPase activation by phosphorylation of phospholamban by the kinase may underlie the mechanism of action of cyclic-nucleotide-dependent relaxation.
Contractile Protein Interactions in Smooth Muscle
Authors: Rüegg J.C. , Pfitzer G.
Published: April 2017

Smooth muscle tone and ‘holding economy’ depend on the rate constants governing the cross-bridge cycle. Thus, calcium activation via calmodulin-dependent myosin light chain phosphorylation may determine the apparent rate constant (‘f’) at which cross-bridges enter the force-generating state, forming actin-attached, strongly bound cross-bridges. This phosphorylation of the light chain may be inhibited in skinned fibers by a peptide mimic of the calmodulin recognition site of the myosin light chain kinase (RS 20) that relaxes smooth muscle. In smooth muscle, the apparent cross-bridge detachment rate constant (‘g’) also seems to be variable, a low constant allowing for a high holding economy and low shortening velocity in the ‘latch state’. It may also account for force maintenance at low levels of myosin phosphorylation. Additionally, cross-bridge attachment may, however, be also controlled by other regulatory proteins such as calponin and caldesmon.
Heterogeneity of Capillary Perfusion
Authors: Gaehtgens P.
Published: April 2017

Heterogeneity represents a general feature of capillary networks. All of the parameters which describe hemodynamic, geometric or functional aspects of such networks exhibit considerable spatial dispersion. This is to some extent the result of the morphological and topological design of the network, reinforced by the nonhomogeneous nature of the flowing blood. Temporal dispersions are introduced by smooth muscle activity, which may be rhythmic or just oscillatory, but also by the passage of white cells causing transient perturbations. The functional relevance of perfusion heterogeneity follows from its effect on exchange efficiency. While evidence for the existence of physiological control mechanisms of heterogeneity is uncertain, intranetwork communication between upstream and downstream vessel segments appears to support the adaptation of supply to demand under physiological conditions.
In vitro Methodology for Resistance Arteries
Authors: Halpern W. , Kelley M.
Published: April 2017

Two commonly used methods for examining the physiological and pharmacological properties of isolated resistance arteries are the ring-mounted preparation and the cannulated, pressurized vessel. Each technique is discussed and consideration given to limitations and advantages. Also presented are examples of comparative differences between them, and practical experimental schemes for calibrating cannulae and for perfusing resistance arteries. Although both methods are valuable, the cannulated approach may better reflect the in vivo properties of the arteries.
Catecholamine and Neuropeptide Y Levels in Tissues from Young Dahl Rats following 5 Days Low- or High-Salt Diet
Authors: Kong J.Q. , Curto K.A. , Fleming W.W. , Kotchen T.A. , Taylor D.A.
Published: April 2017

The mesenteric vasculature of Dahl salt-sensitive (DS) rats on high-salt diet is supersensitive to nerve stimulation and to norepinephrine. The current experiments were undertaken to examine whether the enhanced sensitivity to nerve stimulation is due solely to the postsynaptic supersensitivity to norepinephrine, to increased sympathetic innervation, to altered transmitter release or to the presence of another transmitter acting as a potentiator. Catecholamine content and neuropeptide Y (NPY) presence were determined in tissues from young (approximately 5 weeks old) male Dahl rats exposed to 5 days of high (7%) or low (0.45%) salt diet. Catecholamine content from mesenteric artery, renal artery, caudal artery, right atrium, aorta, vas deferens and adrenal gland was quantified by high-pressure liquid chromatography with an electrochemical detector. A strain difference, independent of diet, between young DS and Dahl salt-resistant (DR) rats was seen only in adrenal epinephrine content. DS high-salt (+) rats displayed reduced norepinephrine content relative to DR+ in the mesenteric artery and right atrium. The release of norepinephrine from isolated mesenteric vasculature into the perfusate in response to transmural stimulation showed no significant differences between DS+ and DR+ preparations under basal, or deoxycorticosterone acetate (DOCA; 30 µM) perfusion conditions. The addition of 5 µM cocaine to the DOCA perfusion, while increasing total norepinephrine outflow in all preparations, failed to differentiate between DS+ and DR+. NPY immunofluorescence along mesenteric artery sections of DS+ and DR+ rats was not significantly different. Thus, in the tissues examined, enhanced responsiveness of vascular smooth muscle may not be explained by hypernoradrenergic innervation, elevated NPY innervation or altered release of transmitter.
SKF-525A Does Not Inhibit Release of Endothelium-Derived Relaxing Factor from Rat Thoracic Aorta and Dog Mesenteric and Femoral Artery
Authors: Xie Jianming , Wang Ye , Greenberg Stanley S.
Published: April 2017

SKF-525A (proadifen) inhibits endothelium-dependent relaxations induced by acetylcholine, arachidonic acid and the calcium ionophore A23187. This suggests that SKF-525A is an inhibitor of endothelium-derived relaxing factor (EDRF) and that EDRF may be a product of arachidonic acid metabolism formed via a cytochrome P-450-dependent pathway or that EDRF release is dependent on cytochrome P-450. We tested this postulate using both isolated rings of rat thoracic aorta and dog mesenteric and femoral artery and the perfusion-superfusion bioassay. Rings of rat thoracic aorta and dog mesenteric and femoral artery with intact endothelium were precontracted with an EC50 concentration of norepinephrine (0.1 nmol/l) or U46619 (0.05 µmol/l) and the relaxation to acetylcholine (ACh), bradykinin, adenosine triphosphate (ATP) or nitroglycerin (GTN) were obtained before, 30 min after addition of, and 30 min after washout of SKF-525A (50 µmol/l). SKF-525A inhibited ACh-induced endothelium-dependent relaxation of rat aortic rings and endothelium-dependent relaxation of the dog mesenteric and femoral artery produced by ACh and ATP, but did not affect relaxation to bradykinin or GTN. The inhibitory effect on SKF-525A on ACh and ATP-induced relaxation was partially reversed upon its washout from the muscle chamber. Pretreatment of the blood vessels with ibuprofen (1 µmol/l) did not attenuate SKF-525A-mediated inhibition of the relaxations to any agonist. Selective exposure of dog femoral artery (donor) to SKF-525A (50 µmol/l) for 60 min did not affect the relaxation responses of endothelium-rubbed coronary artery (bioassay tissue) to basal EDRF nor to the effluent from donor tissues stimulated with ACh (10–1,000 pmol), ATP (1–100 nmol) or bradykinin (3–100 pmol). The results show that SKF-525A exhibited a reversible inhibition of endothelium-dependent relaxation by a smooth muscle mechanism unrelated to the generation of EDRF from endothelium.
Comparison between Human Umbilical Artery and Rabbit Abdominal Aorta as Substrata for Platelet Adhesion and Platelet Thrombus Formation under Flow Conditions
Authors: Escolar Ginés , Garrido Marta , Aznar-Salatti José , Ordinas Antonio , Bastida Eva
Published: April 2017

Rabbit abdominal aortas and human umbilical arteries are currently used as substrata for the study of platelet adhesion and aggregate formation under flow conditions. Using immunohistochemical and ultrastructural methods, we have analyzed both vessel surfaces. The reactivity towards platelets of the subendothelium (SE) exposed on these vessels after mechanical or enzymatic digestion (α-chymotrypsin) was morphometrically quantified and the nature of the interaction studied in the electron microscope. After mechanical damage, the ultrastructural study of rabbit aortas showed a clearly defined internal elastic lamina (IEL). In contrast, umbilical vessels lacked a consistent IEL and masses of amorphous material often located deeper in the media were the main constitutents of the SE. Immunohistochemical labeling of the von Willebrand factor bound to both types of vessel differed considerably. Quantification of platelet interactions after perfusion of citrated blood showed qualitative differences between mechanically damaged rabbit or human vessels. Enzymatic digestion produced a more thrombogenic surface on rabbit aortas (p < 0.01 vs. nondigested), but decreased their reactivity towards platelets on umbilical arteries (p < 0.01 vs. nondigested). The ultrastructural study of the interacting platelets revealed that aggregates, when present, were found on the extracellular matrix underlying endothelial cells of rabbit aortas, but interacting with fibrillar structures probably derived from cell elements of the media in the case of umbilical arteries. These findings indicate that rabbit aortas and umbilical arteries possess structural characteristics that result in different thrombogenic properties with respect to circulating platelets.
Hemorheological Effects of Buflomedil: Action on Shape and Functions of the Human Neutrophils
Authors: Boisseau Michel R. , Freyburger Geneviève , Belloc Francis , Seigneur Martine
Published: April 2017

In vitro studies on the action of buflomedil (BFL) and its derivative CRL 41034 on the polymorphonuclear cells (PMN) has been performed using functional tests and scanning electron microscopy. The two drugs exhibited the same effects. BFL does not change the in vitro chemotaxis of PMN, but exhibits a regulatory effect on ZMS-induced aggregation of these cells. BFL also appeared to decrease superoxide production of PMN, in a dose- and time-dependent way. The cytoskeleton F-actin polymerization, analyzed through the binding of rhodamin-phalloidin, was increased when the total F-actin of the cells was unchanged. When cell extensions were studied morphologically a change in the shape of the pseudopods as well as the general aspect of the PMN (cottonous aspect) was observed as compared to controls. These drug-induced modifications in the shape change may be efficient in adhesion processes. Finally this latter effect and the influence on oxygen metabolite production could be another means of BFL to protect the microvessels during ischemia, in addition to its vasomotion promoting properties.
Norepinephrine, Phentolamine and Buflomedil Influence on Arteriolar Vasomotion in the Hamster Skinfold Preparation
Authors: Carpentier P.H.
Published: April 2017

Vasomotion is a potential target for drugs in vascular diseases. In this work, the effects on arteriolar vasomotion of norepinephrine, phentolamine and the vasoactive drug buflomedil were assessed in the hamster skinfold preparation. Results show the strong vaso-kinetic properties of alpha-sympathetic receptor activation by norepinephrine and an expected depressive effect of the alpha-blocker phentolamine. Buflomedil 10–4M enhances vasomotion and arteriolar reactivity and does not interfere with norepinephrine. The mechanism of these properties of buflomedil remains to be investigated.
Dying in Yoghurt: The Number of Living Bacteria in Probiotic Yoghurt Decreases under Exposure to Room Temperature
Authors: Scharl Michael , Geisel Steffen , Vavricka Stephan R. , Rogler Gerhard
Published: April 2017

Background/Aims: While probiotic bacteria are successfully used in the treatment of ulcerative colitis, the effect of commercially available probiotic products is still controversial. Here, we study whether the number of living probiotic bacteria in yoghurts is altered by an interruption of the cold chain. Methods: Three commonly available probiotic yoghurts were kept at 4°C or put at room temperature (RT) for 6 h or 24 h. An aliquot of each yoghurt was applied on Man-Rogosa-Sharpe agar and incubated at 37°C for 48 h. Colony forming units (CFU) were counted by microscopy. Results: The first yoghurt, containing Lactobacillus johnsonii, showed a significant decrease in CFU after 6 h of storage at RT, which was further pronounced after 24 h. The number of CFU of the second yoghurt, containing Lactobacillus GG, was also decreased after 6 h and further diminished after 24 h at RT. From the third yoghurt, containing Lactobacillus acidophilus, only 53.8% of the CFU remained after 6 h at RT; after 24 h, only about one fourth of the CFU were found. Conclusions: Our data demonstrate that the number of living probiotic bacteria in yoghurt products decreases dramatically after exposure to RT. This represents an important information for consumers of such products.
Disadvantage of Operation Cost in Laparoscopy-Assisted Distal Gastrectomy under the National Health Insurance System in Japan
Authors: Hoya Yoshiyuki , Taki Tetsuya , Tanaka Yujirou , Yano Humiaki , Hirabayashi Tsuyoshi , Okamoto Tomoyoshi , Kashiwagi Hideyuki , Yanaga Katsuhiko
Published: April 2017

Background: The utility and problems including the socioeconomic aspect of laparoscopy-assisted distal gastrectomy for gastric cancer have not been fully evaluated. Subjects and Methods: We compared open distal gastrectomy and laparoscopy-assisted distal gastrectomy for the clinical benefit, quality of life, and problems of operation cost by the reference documents in which the difference between open distal gastrectomy and laparoscopy-assisted distal gastrectomy was examined in detail. The reference documents retrieved by the key words ‘gastric, cancer, laparoscopic, surgery’ were 22 in PubMed with the following limits activated: Humans, Clinical Trial, Meta-Analysis, Randomized Controlled Trial, Review, English, Core clinical journals, published in the last 10 years. Results: The operation time of laparoscopy-assisted distal gastrectomy is longer than that of open distal gastrectomy. However, if skilled, the blood loss of laparoscopy-assisted distal gastrectomy is less, the hospitalization days and the duration of fasting after laparoscopy-assisted distal gastrectomy are shorter than those after open distal gastrectomy. The number of excised lymph nodes and the incidence of postoperative complications were similar between laparoscopy-assisted distal gastrectomy and open distal gastrectomy. On the other hand, in the national health insurance system, the operation fee of open distal gastrectomy was USD 6,637 as compared to USD 7,586 for laparoscopy-assisted distal gastrectomy. In spite of the USD 949 difference in the operation fee, the use of disposable instruments for laparoscopy-assisted distal gastrectomy results in a deficit of USD 1,500 over open distal gastrectomy. Conclusion: In spite of the medical superiority of laparoscopy-assisted distal gastrectomy over open distal gastrectomy (if a skilled surgeon operates) as less invasive surgery, laparoscopy-assisted distal gastrectomy is associated with less financial benefit to the hospital as compared to open distal gastrectomy in the current Japanese health insurance system.
An Illustrative Case of Neurofibromatosis Type 1 and NF1 Microdeletion
Authors: Praxedes L.A. , Pereira F.M. , Mazzeu J.F. , Costa S.S. , Bertola D.R. , Kim C.A. , Vianna-Morgante A.M. , Otto P.A.
Published: April 2017

We report on a patient with NF1 microdeletion and clinical manifestations that fulfill the diagnostic criteria for neurofibromatosis type 1 but also presenting features reminiscent of Proteus syndrome.
A Novel LMNA Mutation Causes Altered Nuclear Morphology and Symptoms of Familial Partial Lipodystrophy (Dunnigan Variety) with Progeroid Features
Authors: Saha B. , Lessel D. , Hisama F.M. , Leistritz D.F. , Friedrich K. , Martin G.M. , Kubisch C. , Oshima J.
Published: April 2017

Dunnigan-type partial lipodystrophy (familial partial lipodystrophy, Dunnigan variety, FPLD2) can be caused by LMNA mutations. We identified a novel heterozygous LMNA mutation, P485R, in a patient referred to the International Registry of Werner Syndrome because of features consistent with that of progeroid disorder but who was wild type at the WRN locus. The novel mutation is located 2 amino acids away from the canonical FPLD mutations in exon 8 of the LMNA gene. Immunocytochemical analysis revealed abnormal nuclear morphology characteristic of laminopathies within primary fibroblast cultures, but not in a lymphoblastoid cell line, in keeping with previous observations. Our findings indicate that FPLD2 should be considered in the differential diagnosis of the Werner syndrome.
Longitudinal Associations between Blood Pressure and Dementia in the Very Old
Authors: Molander Lena , Gustafson Yngve , Lövheim Hugo
Published: April 2017

Background/Aims: Midlife hypertension is associated with an increased risk for dementia, but the association between blood pressure and dementia in very old age is unclear. Methods: In a population-based cohort study, a total of 102 individuals aged 85, 90 or ≧95 years participated in 2 examinations with a 5-year interval. The investigations consisted of a structured interview, blood pressure measurement, rating scales such as the Mini-Mental State Examination (MMSE) and an investigation of medical charts. Results: The majority of participants exhibited a decline in blood pressure. Baseline systolic blood pressure (SBP), diastolic blood pressure or pulse pressure (PP) were not associated with incident dementia or with decline in MMSE scores in multiple regression analyses adjusted for age and sex. However, incident dementia cases exhibited a greater decline in SBP (p = 0.02) and PP (p = 0.04), and decline in SBP was associated with a decline in MMSE score (p = 0.008). Conclusion: In this small longitudinal study on the very old, no association between baseline blood pressure and incident dementia was found, but individuals who developed dementia exhibited a greater blood pressure decline. Low blood pressure could be an effect of dementia in the very old.
Low Incidence of Asymptomatic Contrast-Enhancing Brain Lesions in Japanese Patients with Multiple Sclerosis
Authors: Tanaka Masami , Matsui Masaru , Tahara Masayuki , Tanaka Keiko
Published: April 2017

Background: The number of contrast-enhancing brain lesions is used as an endpoint in multiple sclerosis (MS) clinical trials. However, the incidence of asymptomatic contrast-enhancing brain lesions (AEBLs) in Japanese patients with MS has not been determined. Objective: To describe the number of AEBLs per scan in Japanese patients with relapsing-remitting MS (RRMS). Methods: We reviewed the medical records of 23 Japanese patients with RRMS who showed (1) a stable or improving condition for at least 30 days before a magnetic resonance imaging (MRI) examination and (2) at least one relapse in the preceding year or two relapses in the preceding 2 years. Results: The percentage of patients with AEBLs was 39.1% (9/23 patients) and the number of AEBLs per scan was 0.37. Conclusions: The results suggest that the disease activity shown by brain MRI was lower in Japanese patients with MS compared with that in Caucasian patients.
Prediction of Implantable Pulse Generator Longevity in Deep Brain Stimulation: Limitations and Possible Solutions in Clinical Practice
Authors: Stewart Colin D.M. , Eljamel Sam
Published: April 2017

Background: Deep brain stimulation (DBS) is used in the treatment of movement disorders, chronic pain and certain neuropsychiatric conditions. Its effect is achieved through local stimulation of specific targets of the brain. Electrical pulses are delivered at settings that can be tailored to provide optimum symptom control. DBS is powered by an implantable pulse generator (IPG). These IPGs do not have an indefinite lifespan and will eventually become depleted. Therefore, regular checks are carried out to monitor the IPG’s power status. Objective: To evaluate the utility of computer-based prediction of IPG longevity in patients with DBS devices by imputing the device’s settings. Patients: Eighty-two IPGs in 47 consecutive patients were studied comparing the actual longevity of the IPGs with their predicted longevity using a computer-based calculator. Results: Our study showed that the predicted longevities were too different from actual longevities to have a role in clinical practice. The time difference varied by more than 12 months in some cases, with a correlation coefficient of <0.68. There were multiple reasons for this. Conclusion: The longevities of IPGs could not be predicted accurately enough for the computer-based calculator to have a role in clinical practice or the proactive scheduling of IPG replacement. However, rechargeable IPGs may help avoid premature replacements and battery depletions.
Obesity and Fatty Liver Are ‘Grease’ for the Machinery of Hepatic Fibrosis
Authors: Bosserhoff Anja , Hellerbrand Claus
Published: April 2017

Nonalcoholic fatty liver disease (NAFLD) starts with hepatic steatosis, which can progress with inflammation to nonalcoholic steatohepatitis, and a subset of patients develop progressive fibrosis and ultimately cirrhosis. In the majority of cases, NAFLD is associated with (components of) the metabolic syndrome. Obesity, diabetes and hepatic steatosis are also independent risk factors for hepatic fibrosis in different chronic liver diseases. However, the question is whether it is actually nonalcoholic steatohepatitis and not ‘simple’ steatosis that promotes fibrosis progression based on hepatocellular injury. In this review, the concept will be put forward that (1) hepatic steatosis per se is profibrogenic, and (2) that in NAFLD development and progression of hepatic fibrosis is not simply determined by (the degree of) hepatic inflammation. In addition to the liver, this view is expanded to other organs affected by the metabolic syndrome, which affects hepatic injury and fibrosis also via extrahepatic pathophysiological alterations. In conclusion, fatty liver and the metabolic syndrome, respectively, have to be recognized as significant lubricants of hepatic fibrosis, and simple hepatic steatosis cannot be considered as benign.
Role of the Hepatic Parenchyma in Liver Transplant Tolerance: A Paradigm Revisited
Authors: Benseler Volker , Tay Szun Szun , Bowen David G. , Bertolino Patrick
Published: April 2017

Unlike other solid organs, liver transplants are spontaneously accepted in a wide range of animal models. In the clinic, transplanted livers also display privileged immunological properties allowing weaning of immunosuppression therapy in up to 20% of selected patients. To explain this phenomenon, many studies have focused on the role of donor-derived ‘passenger’ leukocytes that are thought to induce antigen-specific tolerance by migrating from the graft into recipient secondary lymphoid tissues. Although convincing evidence exists that these cells are able to elicit antiallograft T cell hyporesponsiveness, several studies argue against an exclusive role for this cell population and even question whether it is critical in conferring donor MHC-specific tolerance. Instead, these studies suggest that the hepatic parenchyma plays a more critical role in this phenomenon. In this review we will reinterpret the results of old and more recent literature in light of recent advances in the field of liver immunology to explain the contribution of both passenger leukocytes and liver tissue in the liver tolerance effect.
Immune Control of Hepatitis B Virus
Authors: Bauer Tanja , Sprinzl Martin , Protzer Ulrike
Published: April 2017

Human hepatitis B virus (HBV) infects the liver of humans or humanoid primates. In humans, HBV infection often causes an inflammatory liver disease – hepatitis B. The virus is transmitted by perinatal, percutaneous and sexual exposure, as well as by close person-to-person contact. The latter occurs especially among young children, presumably by open cuts or sores. Vertical transmission from mothers to their neonates, or infection during the first year of life, results in persistent often lifelong infection in >90% of cases. In contrast, infection during adulthood is cleared in >95% of cases, and results in lifelong protective immunity. While a correlation between the strength of HBV-specific T cell responses and virus clearance has been established, factors determining the strength of a T cell response as well as factors shifting the balance from immune tolerance to immune clearance are hardly understood. The innate immune response, early adaptive B and T cell responses, regulatory T cells, the liver microenvironment, and the peculiar properties of hepatocytes and nonparenchymal liver cells to present antigen seem to play a role. Understanding this complex interplay requires systematic immune monitoring of well characterized human cohorts, but also experimental approaches using primary human cells and genetically modified mouse models. Using these models, we begin to understand the immune recognition of HBV and how it influences the outcome of HBV infection. In this paper we review the current knowledge about virus-host interactions and how it influences the outcome of HBV infection and describe the immune signatures associated with clinical recovery and/or persistent infection.
High Glycated Hemoglobin Levels and Intracranial Artery Stenosis Are Predictive Factors for Early Motor Worsening Events in Patients with Penetrating Artery Infarction
Authors: Isa Katsunori , Sakima Hirokuni , Nakachi Koh , Kokuba Kazuhito , Ishihara Satoshi , Tokashiki Takashi , Ohya Yusuke
Published: April 2017

Background: The purpose of this study was to identify typical clinical characteristics to predict early motor worsening (EMW) of patients with penetrating artery infarction. Methods: We reviewed 65 consecutive patients with pure motor hemiparesis, sensorimotor stroke, and ataxic hemiparesis. EMW was defined as deterioration by ≥1 point on the National Institutes of Health Stroke Scale for motor function within 5 days of admission. Results: EMW was observed in 22 patients (34%). HbA1c levels were higher in patients with EMW than in those without EMW (7.9 ± 2.6 vs. 6.3 ± 1.6%; p < 0.01). The percentage of EMW patients with intracranial artery stenosis (ICAS) was greater than that of non-EMW patients with ICAS (13/22 patients, 59% vs. 8/43 patients, 19%; p < 0.01). Multivariate logistic regression analysis indicated that HbA1c levels ≥7.0% (OR 3.0, 95% CI 1.5–6.8; p < 0.005) or ICAS (OR 2.3, 95% CI 1.2–4.8; p < 0.05) increased the risk of EMW, and the combination of these factors increased the risk in an additive manner (OR 7.6, 95% CI 2.5–40; p < 0.005). Conclusion: HbA1c levels ≥7.0% and/or ICAS in patients with penetrating artery infarction are associated with EMW.
Airway Hyperresponsiveness Is Negatively Associated with Obesity or Overweight Status in Patients with Asthma
Authors: Kwon Jae-Woo , Kim Sae-Hoon , Kim Tae-Bum , Kim Sang-Heon , Park Heung-Woo , Chang Yoon-Seok , Jang An-Soo , Cho You Sook , Nahm Dong-Ho , Park Jung-Won , Yoon Ho Joo , Cho Young-Joo , Choi Byoung Whui , Moon Hee-Bom , Cho Sang-Heon
Published: April 2017

Background: Obesity is a risk factor for asthma in the general population, but the effect of obesity on airway hyperresponsiveness (AFHR) or airway inflammation in asthma is not clear. This study evaluated the relationship between obesity and asthma, assessing aspects of symptoms, AHR, and severity. Methods: In total, 852 patients with asthma diagnosed by asthma specialists based on AHR as confirmed by a methacholine bronchial provocation test, were enrolled from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) adult asthma cohort. The intensity of AHR was assessed by the concentration of methacholine needed to cause a 20% decrease in FEV1 (PC20). Patients were classified into four categories based on body mass index (BMI): underweight (<18.5), normal weight (18.5–24.9), overweight (25.0–29.9), and obese (≥30). Results: BMI was negatively correlated with FEV1 (l), FVC (l), and FEV1/FVC (%) in lung function tests. The prevalence of wheezing increased with higher BMI after adjustment for age, sex, smoking, medication history, and PC20 (p < 0.0001). logPC20 was lower in the normal weight group compared with the overweight group (p = 0.003). The risk of moderate or severe AHR (PC20 ≤ 4 mg/ml) decreased with increased BMI after adjustment for age, sex, smoking, and medication history (p = 0.035). Conclusions: Obesity is a risk factor for asthma in the general population, but obesity in asthmatic patients is negatively correlated with the intensity of AHR and is not related to asthma severity. Obesity is positively related with the prevalence of wheezing but negatively related to AHR in asthmatic patients.
Acral Peeling Skin Syndrome Resembling Epidermolysis Bullosa Simplex in a 10-Month-Old Boy
Authors: Kavaklieva S. , Yordanova I. , Bruckner-Tuderman L. , Has C.
Published: April 2017

The acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder clinically characterized by asymptomatic desquamation of the skin limited to the hands and feet and histologically by cleavage at the stratum granulosum and stratum corneum level [Kiritsi et al.: J Invest Dermatol 2010;130:1741-1746]. We report on a 10-month-old boy with a history of skin peeling limited to the hands and feet since 2 months of age. Clinical examination revealed erythematous erosions with peripheral desquamation and flaccid blisters. DNA mutation analysis detected two heterozygous TGM5 mutations: c.2T>C, p.M1T in exon 1 and c.337G>T, p.G113C in exon 3 in keeping with the diagnosis of APSS. The clinical presentation of APSS alone might be confusing and strongly resemble epidermolysis bullosa simplex making the differential diagnosis difficult.
Performance of Repetitive Alternating Elbow Movements in Parkinson's Disease
Authors: Spiegel Jörg , Uhrig Igna , Krick Christoph , Behnke Stefanie , Faßbender Klaus , Dillmann Ulrich
Published: April 2017

Background: Bradydiadochokinesia is one main clinical symptom in idiopathic Parkinson's disease (IPD). The pathogenesis of bradydiadochokinesia is not completely clear. Methods: Fifteen patients with IPD and 15 age-matched healthy volunteers had to perform rhythmic alternating flexion and extension movements in the elbow joint. The rhythm was provided auditorily by a click tone stimulator. Six maneuvers (spatial extents of 48 and 83° at frequencies of 0.45, 0.75 and 1.25 Hz) had to be absolved. The potentiometer converted the horizontal forearm movements into a variable voltage. Results: The duration of single movements varied more significantly in patients than in controls (p < 0.05; Mann-Whitney U test). Patients executed all conditions more slowly than controls, but this difference was only significant at the most difficult condition (83° at 1.25 Hz; p < 0.01). The movement amplitudes or their variability were not significantly different at any condition. No parameter correlated significantly with the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) or with the duration of disease. Conclusion: An insufficient temporal coordination contributes to bradydiadochokinesia in IPD. This deficit occurs independently of other parkinsonian cardinal motor symptoms.
Smoking Status and Severity of Ischemic Stroke. A Population-Based Study
Authors: Béjot Yannick , Jacquin Agnès , Daubail Benoit , Lainay Claire , Janoura Samer , Aboa-Eboulé Corine , Durier Jérôme , Giroud Maurice
Published: April 2017

We aimed to investigate the impact of smoking status on clinical severity in patients with ischemic stroke event (IS). Patients were prospectively identified among residents of the city of Dijon, France (ca. 151,000 inhabitants), using a population-based registry, between 2006 and 2011. Demographic and clinical data were recorded. The initial clinical severity was quantified by the means of the National Institutes of Health Stroke Scale (NIHSS). Multivariable ordinal logistic regression was used to assess the effect of smoking status on severity. Among the 1,056 recorded patients with IS, data about smoking status were available for 973 (92.1%), of whom 658 (67.3%) were non-smokers, 187 (19.2%) were current smokers, and 128 (13.2%) were former smokers. Compared with non-smoking, former smoking was associated with less severe IS (OR 0.55; 95% CI 0.38-0.82, p = 0.003), whereas this association was not found for current smokers (OR 0.97; 95% CI 0.69-1.36, p = 0.856). Further work is needed to understand the underlying mechanisms of this finding.
Hodgkin Lymphoma and Hypothermia: Case Report and Review of the Literature
Authors: Shepshelovich Daniel , Shpilberg Ofer , Lahav Meir , Itchaki Gilad , Yakimov Maxim , Raanani Pia , Cohen Amos
Published: April 2017

We report the development of hypothermia in a patient with Hodgkin lymphoma which resolved with chemotherapy administration. A review of the literature revealed 16 previous reports of hypothermia in patients with Hodgkin lymphoma. Overall prognosis seems to be unfavorable. To the best of our knowledge this is the first report of hypothermia in a patient with Hodgkin lymphoma transforming from chronic lymphocytic leukemia (Richter's syndrome). A possible pathophysiology could be paraneoplastic autonomic neuropathy. Physicians should be aware that Hodgkin lymphoma can present with hypothermia and should carefully monitor newly diagnosed patients with advanced disease for this complication. Likewise, patients with Hodgkin lymphoma who develop hypothermia should be screened for signs of autonomic neuropathy.
Safety Profile Comparison between Extemporaneous and a Licensed Preparation of Caffeine Citrate in Preterm Infants with Apnea of Prematurity
Authors: Vatlach Scarlet , Arand Joerg , Engel Corinna , Poets Christian F.
Published: April 2017

Background: Given the lack of a licensed product (LP), extemporaneous caffeine citrate (ECC) has been used by many hospital pharmacies. Objectives: Since July 2011, an LP has been available in Germany. We prospectively compared the safety profile of ECC and LP in preterm infants with apnea of prematurity. Methods: Between April 2010 and April 2013, selected side effects occurring with ECC or LP were documented in 6 German NICUs for infants ≤34 weeks' gestation using a longitudinal study design. The software developed for daily prescriptions in NICU residents requires entries if any of the following symptoms occurred during the last 24 h: tachycardia (resting heart rate >200/min), clinical or encephalographic seizures, gastric residuals, vomiting, or necrotizing enterocolitis (NEC). ECC and LP were administered at identical doses (20 mg/kg/day loading, 5-10 mg/kg/day maintenance) and in similar formulations either orally or intravenously. Results: 562 infants with 14,590 treatment days on ECC and 538 infants with 12,813 treatment days on LP were evaluated. The mean gestational age was similar (29.20 weeks for ECC vs. 29.14 weeks for LP). No relevant differences were seen concerning tachycardia, gastric residuals, or vomiting, but ECC was associated with a higher risk of NEC (risk ratio: 2.68, 95% CI: 1.01-7.23, p = 0.047) and, albeit not significantly so, seizures (risk ratio: 1.91, 95% CI: 0.53-6.96, p = 0.35). Conclusion: This survey demonstrates a similar safety profile for both forms of caffeine citrate. The lower NEC and seizure rate seen with the LP is intriguing, but requires confirmation in a controlled study design.
Anxiety in Children and Adolescents with Chronic Kidney Disease - Multicenter National Study Results
Authors: Kiliś-Pstrusińska Katarzyna , Medyńska Anna , Adamczak Piotr , Bałasz- Chmielewska Irena , Grenda Ryszard , Kluska-Jóźwiak Agnieszka , Leszczyńska Beata , Olszak-Szot Ilona , Miklaszewska Monika , Szczepańska Maria , Tkaczyk Marcin , Wasilewska Anna , Zachwieja Katarzyna , Zajączkowska Maria , Ziółkowska Helena , Zagożdżon Ilona , Zwolińska Danuta
Published: April 2017

Background/Aims: Chronic medical illness is a significant risk factor for the development of psychiatric disorders. The aims of the study were: to investigate the level of anxiety in children with chronic kidney disease (CKD) and to identify factors associated with the presence of that emotional problem. Methods: CKD children on hemodialysis (HD, n=22), peritoneal dialysis (PD, n=20,) and on conservative treatment (CT, n=95) were enrolled in the study. We used State-Trait Anxiety Inventory (STAI) for adolescents and STAI-C for children. Socio-demographic and physical factors were assessed. Results: There was a significantly higher level of anxiety-state among HD children (8-12 years) compared with other groups of participants of the same age and Polish population norms. The level of anxiety among adolescents (13-18 years), both anxiety-state and anxiety-trait, was significantly higher in the HD group compared with other groups, which did not differ among themselves. In the HD adolescents, there was a correlation between the anxiety-state and the duration of the disease as well as with the number of hospitalizations. PD adolescents in the mainstream education had higher levels of anxiety-state and anxiety-trait compared with home schooled patients. Conclusions: Even though children and adolescents with CKD are at risk of developing a variety of emotional disorders, the level of anxiety among the researched group, with the exception of HD patients, was not significantly different than the level of anxiety among healthy subjects. Adolescents on HD who present a high level of anxiety should undergo long-term psychological treatment.
Epinephrine Evokes Renalase Secretion via a-Adrenoceptor/NF-κB Pathways in Renal Proximal Tubular Epithelial Cells
Authors: Wang Feng , Cai Hongyan , Zhao Qing , Xing Tao , Li Junhui , Wang Niansong
Published: April 2017

Background/Aims: Renalase is a recently discovered, kidney-specific monoamine oxidase that metabolizes circulating catecholamines. These findings present new insights into hypertension and chronic kidney diseases. Previous data demonstrated that renalase was mainly secreted from proximal tubules which could be evoked by catecholamines. The purpose of this study is to investigate whether renalase expression is induced by epinephrine via a-adrenoceptor/NFκB pathways. Methods: HK2 cells were utilized to explore renalase expression in response to epinephrine in vitro. Phentolamine, an a-adrenoceptor antagonist, and Tosyl Phenylalanyl Chloromethyl Ketone (TPCK) were used to block a-adrenoceptor and to knock down the transcription factor NFκB, respectively. Renalase expression was analyzed using Western blot and quantitative PCR. Results: Both protein and mRNA levels of renalase in HK2 cells increased in response to epinephrine (P<0.05). Epinephrine-evoked renalase expression was attenuated by phentolamine and TPCK separately (P<0.05). Conclusion: Epinephrine evokes renalase secretion via a-adrenoceptor/NF-κB pathways in renal proximal tubular epithelial cells.
Recent Advances on Hepatitis C Virus in Dialysis Population
Authors: Fabrizi Fabrizio , Messa Piergiorgio , Martin Paul
Published: April 2017

Hepatitis C virus (HCV) infection remains common among patients undergoing regular dialysis and good evidence supports the detrimental role of HCV on survival in patients undergoing maintenance dialysis. According to an updated meta-analysis of clinical studies (n=15; 195,370 unique patients on maintenance dialysis), the summary estimate for adjusted relative risk (all-cause mortality) with anti-HCV across the published studies was 1.32 with a 95% Confidence Intervals of 1.24; 1.42, homogeneity assumption was not rejected. Various mechanisms support the excess death risk of HCV-infected patients on regular dialysis, in addition to liver disease-related mortality. The adjusted relative risk for cardiovascular mortality among HCV-infected patients on regular dialysis was 1.26 (95% Confidence Intervals, 1.10; 1.45); the increased cardiovascular mortality in anti-HCV positive patients has been associated in part to malnutrition and chronic inflammation. The current standard of care for HCV in dialysis population is combined antiviral therapy (pegylated interferon plus ribavirin) with a rate of viral response of around 60%. Triple therapy with telaprevir proved to be effective and safe in dialysis patients with HCV but only anecdotal evidence exists. Antiviral treatment of HCV-infected patients on maintenance dialysis could lead to cure the liver damage and the extrahepatic complications. The future availability of all-oral interferon/ribavirin free regimens for antiviral treatment of HCV will help nephrologists to improve survival in this high-risk group.
Performance of the Rockall Scoring System in Predicting the Need for Intervention and Outcomes in Patients with Nonvariceal Upper Gastrointestinal Bleeding in a Brazilian Setting: A Prospective Study
Authors: Custódio Lima Juliana , Garcia Montes Ciro , Kibune Nagasako Cristiane , Soares Ruppert Reis Glaucia Fernanda , Meirelles dos Santos José Olympio , Guerrazzi Fabio , Mesquita Maria Aparecida
Published: April 2017

Background/Aims: This prospective study investigated the performance of pre-endoscopy and the complete Rockall scores in predicting the occurrence of adverse outcomes and the need for endoscopic or surgical intervention in patients with nonvariceal upper gastrointestinal bleeding. Methods: All 656 consecutive patients who underwent endoscopy due to nonvariceal upper gastrointestinal bleeding between 2007 and 2011 were included. Receiver operating characteristic (ROC) curves were plotted for the outcomes of therapeutic intervention, rebleeding and death. The discriminative accuracy of the risk scores was assessed by the area under the ROC curve. Results: Endoscopic treatment was performed in 55.2% of the patients. Rebleeding and mortality rates were 7.6 and 3.8%, respectively. The pre-endoscopy Rockall scores showed unsatisfactory accuracy in predicting the need for intervention, rebleeding or death, as shown by the respective area under the ROC curve values of 0.52, 0.52 and 0.65. The accuracy of the complete Rockall score in predicting rebleeding was poor (area under ROC: 0.52), but it was higher for mortality (area under ROC: 0.69). Conclusions: The pre-endoscopy Rockall score was not useful for predicting the need for therapeutic intervention or adverse outcomes. The complete Rockall score showed an acceptable performance in predicting mortality, but was unable to predict rebleeding.