bluuebunny/crossref_metadata_2025 huggingface dataset:
The Pre-S2 Domain of the Hepatitis B Virus Is Dispensable for Infectivity but Serves a Spacer Function for L-Protein-Connected Virus Assembly
Authors: Ni Yi , Sonnabend Jessika , Seitz Stefan , Urban Stephan
Published: February 2010

The envelope of the human hepatitis B virus (HBV) contains three membrane proteins (L, M, and S). They accomplish different functions in HBV infectivity and nucleocapsid envelopment. Infectivity determinants have been assigned to the N-terminal part of the pre-S1 domain of the L protein and the antigenic loop of the S domain in the L and/or S protein. Nucleocapsid envelopment requires a C-terminal sequence within pre-S1, including the five N-terminal amino acids of pre-S2 as part of the L protein. However, the role of the M protein and the pre-S2 domain of the L protein are not entirely understood. We addressed this question and analyzed assembly competence and infectivity of viruses that lack the M protein and, at the same time, carry alterations in the pre-S2 domain of L. These include deletions, in part frameshift mutations and a randomization of virtually the entire pre-S2 sequence. We found that the M protein is dispensable for HBV
in vitro
infectivity. Viruses that lack the M protein and contain a mostly randomized pre-S2 sequence assemble properly and are infectious in HepaRG cells and primary human hepatocytes. While deletions of 20 amino acids in the pre-S2 domain of L protein allowed the production of infectious virions, more extended deletions interfered with assembly. This indicates that the pre-S2 domain of the L protein serves an important role for virus assembly, presumably as a spacer that supports conformational changes of L protein but does not participate as part of the M protein or as a subdomain of the L protein in virus entry.
Species-Specific Inhibition of Foamy Viruses from South American Monkeys by New World Monkey TRIM5α Proteins
Authors: Pacheco Beatriz , Finzi Andrés , McGee-Estrada Kathleen , Sodroski Joseph
Published: February 2010

Foamy virus evolution closely parallels that of the host species, indicating virus-host coadaptation. We studied simian foamy viruses (SFVs) from common marmosets, spider monkeys, and squirrel monkeys, New World monkey (NWM) species that share geographic ranges. The TRIM5α protein from each of these NWM species inhibited the replication of at least one of the SFVs associated with the other two species but did not affect the replication of its own SFV. Thus, TRIM5α has potentially shaped the evolution of SFVs in NWM hosts. Conversely, SFVs may have influenced the evolution of TRIM5 variants in New World primates.
Anodic stripping voltammetry using graphite composite solid electrode
Authors: Navrátil Tomáš , Barek Jiří , Kopanica Miloslav
Published: February 2010

A graphite (carbon) composite solid electrode, prepared from graphite powder and epoxy resin, was used as a working electrode for anodic stripping voltammetry. The underpotential deposition effect, which appears at metallic electrodes, was clearly observed on this type of electrode as well. In the case of a simultaneous deposition of two metals on the surface of the composite solid electrode, the anodic dissolution of the metal, which is anodically dissolved at more negative potentials, is substantially influenced by the presence of the other deposited metal. This effect was exploited for the determination of lead in the presence of other metals by differential pulse anodic stripping voltammetry. The article presents possible applicability of such a type of very simple composite electrode to studies of the underpotential deposition effect as well as for analytical purposes.
Polarographic and voltammetric study of genotoxic 2,7-dinitrofluoren-9-one and its determination using mercury electrodes
Authors: Vyskočil Vlastimil , Barek Jiří
Published: February 2010

Electrochemical behavior of genotoxic 2,7-dinitrofluoren-9-one was investigated by DC polarography and DC tast polarography, both at a dropping mercury electrode, and by cyclic voltammetry at a hanging mercury drop electrode, in buffered aqueous-methanolic solutions. The number of exchanged electrons was determined by constant-potential coulometry at a mercury pool electrode. A possible mechanism of the electrochemical reduction has been proposed. Optimal conditions were found for the determination of 2,7-dinitrofluoren-9-one by DC tast polarography in the concentration range from 2 × 10–6to 1 × 10–5mol l–1and by differential pulse polarography (from 2 × 10–7to 1 × 10–5mol l–1), both at dropping mercury electrode, by differential pulse voltammetry (from 2 × 10–8to 1 × 10–5mol l–1) and by adsorptive stripping voltammetry (from 2 × 10–9to 1 × 10–7mol l–1), both at hanging mercury drop electrode. Practical applicability of the developed methods was verified on the direct determination of 2,7-dinitrofluoren-9-one in drinking water in 10–8mol l–1concentration range, and in drinking and river water (both in 10–9mol l–1concentration range) using preliminary separation and preconcentration by solid-phase extraction.
Skeletal age determination in adolescents involved in judicial procedures: from evidence-based principles to medical practice
Authors: Pruvost Marie-Odile , Boraud Cyril , Chariot Patrick
Published: February 2010

Background

The ideal basis of age estimation is considered to be a combination of clinical, skeletal and dental examinations. It is not easy to determine how forensic physicians take account of evidence-based data obtained from medical journals in their medical decision-making. The question of what is an ethically acceptable probability that adolescents are incorrectly considered to be over 18 has not been answered.

Methods

In a retrospective study over 1 year (2007), 498 files (for 141 female subjects and 357 male subjects) regarding age assessment requested by the public prosecutor's office for purposes of criminal or asylum proceedings were reviewed. Chronological age was estimated from a combination of physical examination, radiographic examination of the left hand and determination of dental status.

Results

Estimates of chronological age in 498 subjects claiming to be 9–14 years old were incompatible with the alleged age in 356 (71%) when made by the forensic physician but in only 17 (3%) when based on data from published studies on age estimation in adolescents.

Conclusions

The present study suggests that in most cases the forensic physician ignores the adolescent's word. Medical mission and ethics imply a need to listen to the claims of persons in custody, whatever the risk of false claims. This situation should prompt forensic physicians to keep up with published data on estimating the age of adolescents.
Are physicians obligated always to act in the patient's best interests?
Authors: Wendler David
Published: February 2010

The principle that physicians should always act in the best interests of the present patient is widely endorsed. At the same time, and often within the same document, it is recognised that there are appropriate exceptions to this principle. Unfortunately, little, if any, guidance is provided regarding which exceptions are appropriate and how they should be handled. These circumstances might be tenable if the appropriate exceptions were rare. Yet, evaluation of the literature reveals that there are numerous exceptions, several of which pervade clinical medicine. This situation leaves physicians without adequate guidance on when to allow exceptions and how to address them, increasing the chances for unfairness in practice. The present article considers the range of exceptions, illustrates how the lack of guidance poses ethical concern and describes an alternative account of physician obligations to address this concern.
The forearm and finger rolling tests
Authors: Anderson Neil E
Published: February 2010

A variety of clinical tests are used to detect a subtle upper motor neuron lesion but only a few studies have measured their sensitivity and specificity. The forearm rolling test and its variant, the finger rolling test, is one such. These tests are simple and only take 5–10 s to perform. Their sensitivity has varied in different studies but in general both are more likely to be abnormal in a patient with a focal brain lesion than abnormal power, tone and reflexes. The finger rolling test is more sensitive than forearm rolling. Furthermore, an abnormal response on testing forearm and finger rolling has a high specificity for the presence of a focal brain lesion.
COMPUTATION OF MEAN FIELD EQUILIBRIA IN ECONOMICS
Authors: LACHAPELLE AIME , SALOMON JULIEN , TURINICI GABRIEL
Published: February 2010

Motivated by a mean field games stylized model for the choice of technologies (with externalities and economy of scale), we consider the associated optimization problem and prove an existence result. To complement the theoretical result, we introduce a monotonic algorithm to find the mean field equilibria. We close with some numerical results, including the multiplicity of equilibria describing the possibility of a technological transition.
Excitation-contraction coupling alterations in mdx and utrophin/dystrophin double knockout mice: a comparative study
Authors: Capote Joana , DiFranco Marino , Vergara Julio L.
Published: February 2010

The double knockout mouse for utrophin and dystrophin ( utr−/− /mdx) has been proposed to be a better model of Duchenne Muscular Dystrophy (DMD) than the mdx mouse because the former displays more similar muscle pathology to that of the DMD patients. In this paper the properties of action potentials (APs) and Ca2+ transients elicited by single and repetitive stimulation were studied to understand the excitation-contraction (EC) coupling alterations observed in muscle fibers from mdx and utr−/− /mdx mice. Based on the comparison of the AP durations with those of fibers from wild-type (WT) mice, fibers from both mdx and utr−/− /mdx mice could be divided in two groups: fibers with WT-like APs ( group 1) and fibers with significantly longer APs ( group 2). Although the proportion of fibers in group 2 was larger in utr−/− /mdx (36%) than in mdx mice (27%), the Ca2+ release elicited by single stimulation was found to be similarly depressed (32–38%) in utr−/− /mdx and mdx fibers compared with WT counterparts regardless of the fiber's group. Stimulation at 100 Hz revealed that, with the exception of those from utr−/− /mdx mice, group 1 fibers were able to sustain Ca2+ release for longer than group 2 fibers, which displayed an abrupt limitation even at the onset of the train. The differences in behavior between fibers in groups 1 and 2 became almost unnoticeable at 50 Hz stimulation. In general, fibers from utr−/− /mdx mice seem to display more persistent alterations in the EC coupling than those observed in the mdx model.
Cardiac response to startle stimuli in larval zebrafish: sympathetic and parasympathetic components
Authors: Mann Kara D. , Hoyt Carlton , Feldman Shaina , Blunt LaChelle , Raymond Aaron , Page-McCaw Patrick S.
Published: February 2010

Central regulation of cardiac output via the sympathetic and parasympathetic branches of the autonomic nervous system allows the organism to respond to environmental changes. Sudden onset stimuli, startle stimuli, are useful probes to study central regulatory responses to the environment. In mammals, startle stimuli induce a transient bradycardia that habituates with repeated stimulation. Repeated presentation of the stimulus results in tachycardia. In this study, we investigate the behavioral regulation of heart rate in response to sudden stimuli in the zebrafish. Larval zebrafish show a stereotyped heart rate response to mild electrical shock. Naïve fish show a significant increase in interbeat interval that resolves in the 2 s following stimulation. This transient bradycardia decreases on repeated exposure to the stimulus. Following repeated stimulation, the fish become tachycardic within 1 min of stimulation. Both the transient bradycardia and following tachycardia responses are blocked with administration of the ganglionic blocker hexamethonium, demonstrating that these responses are mediated centrally. The transient bradycardia is blocked by the muscarinic antagonist atropine, suggesting that this response is mediated by the parasympathetic system, while the following tachycardia is specifically blocked by the beta-adrenergic antagonist propranolol, suggesting that this response is mediated by the sympathetic nervous system. Together, these results demonstrate that at the larval stage, zebrafish actively regulate cardiac output to changes in their environment using both the parasympathetic and sympathetic branches of the autonomic nervous system, a behavioral response that is markedly similar to that observed in mammals to similar sudden onset stimuli.
Modulation of ureteric Ca signaling and contractility in humans and rats by uropathogenic E. coli
Authors: Floyd Rachel V. , Winstanley Craig , Bakran Ali , Wray Susan , Burdyga Theodor V.
Published: February 2010

Ascending urinary tract infections, a significant cause of kidney damage, are predominantly caused by uropathogenic Escherichia coli (UPEC). However, the role and mechanism of changes in ureteric function during infection are poorly understood. We therefore investigated the effects of UPEC on Ca signaling and contractions in rat ( n = 17) and human ( n = 6) ureters. Ca transients and force were measured and effects of UPEC on the urothelium were monitored in live tissues. In both species, luminal exposure of ureters to UPEC strains J96 and 536 caused significant time-dependent decreases in phasic and high K depolarization-induced contractility, associated with decreases in the amplitude and duration of the Ca transients. These changes were significant after 3–5 h and irreversible over the next 5 h. The infection causes increased activity of K channels, causing inhibition of voltage-gated Ca entry, and K channel blockers could reverse the effects of UPEC on ureteric function. A smaller direct effect on Ca entry also occurs. Nonpathogenic E. coli (TG2) or abluminal application of UPEC did not produce changes in Ca signaling or contractility. UPEC exposure also caused significant impairment of urothelial barrier function; luminal application of the Ca channel blocker nifedipine caused a reduction in contractions as it entered the tissue, an effect not observed in untreated ureters. Thus, UPEC impairs ureteric contractility in a Ca-dependent manner, largely caused by stimulation of potassium channels and this mechanism is dependent on host-urothelium interaction.
Quality, Stability, and Safety Data of Packed Red Cells and Plasma Processed by Gravity Separation Using a New Fully Integrated Hollow-Fibre Filter Device
Authors: Brune T. , Hannemann-Pohl K. , Nißle K. , Ecker N. , Garritsen H.
Published: February 2010

Background. We developed a completely closed system based on gravity separation without centrifugation steps for separation of whole blood. With this new system we compared quality and stability of the processed blood components (PRC and plasma) with respect to classical preparation. Furthermore the cost-effectiveness of this hollow fibre system was evaluated.Study Design and Methods. Whole blood collections of 15 regular blood donors were used for component preparation using the U shaped hollow fibre filter device. Results were compared to 15 whole blood preparations using centrifugation. The following parameters were evaluated: total hemoglobin, leukocyte counts, the serum concentration of total protein, lactate dehydrogenase (LDH) and potassium. Furthermore ATIII, vWF and F VIII were analyzed at different timepoints.Results. packed red cells: the data directly after separation and after 42 days of storage are in line with the guidelines of the council of Europe.Plasma. all plasma quality data are in line with the guidelines of the council of Europe for quality assurance of plasma, except for a low protein amount (factor 0.75).Conclusion. Separation of whole blood on a clinical scale in this new closed system is feasible, however the plasma protein content must be optimized.
An Overview of the Importance of Conformational Flexibility in Gene Regulation by the Transcription Factors
Authors: Khan Shagufta H. , Kumar Raj
Published: February 2010

A number of proteins with intrinsically disordered (ID) regions/domains are reported to be found disproportionately higher in transcription factors. Available evidences suggest that presence of ID region/domain within a transcription factor plays an important role in its biological functions. These ID sequences provide large flexible surfaces that can allow them to make more efficient physical and functional interactions with their target partners. Since transcription factors regulate expression of target genes by interacting with specific coregulatory proteins, these ID regions/domains can be used as a platform for such large macromolecular interactions, and may represent a mechanism for regulation of cellular processes. The precise structural basis for the function of these ID regions/domains of the transcription factors remains to be determined. In the recent years there has been growing evidence suggesting that an induced fit-like process leads to imposition of folded functional structure in these ID domains on which large multiprotein complexes are built. These multiprotein complexes may eventually dictate the final outcome of the gene regulation by the transcription factors.
Spin‐Stabilized Spacecrafts: Analytical Attitude Propagation Using Magnetic Torques
Authors: Garcia Roberta Veloso , Zanardi Maria Cecília F. P. S. , Kuga Hélio Koiti
Published: February 2010

An analytical approach for spin‐stabilized satellites attitude propagation is presented, considering the influence of the residual magnetic torque and eddy currents torque. It is assumed two approaches to examine the influence of external torques acting during the motion of the satellite, with the Earth′s magnetic field described by the quadripole model. In the first approach is included only the residual magnetic torque in the motion equations, with the satellites in circular or elliptical orbit. In the second approach only the eddy currents torque is analyzed, with the satellite in circular orbit. The inclusion of these torques on the dynamic equations of spin stabilized satellites yields the conditions to derive an analytical solution. The solutions show that residual torque does not affect the spin velocity magnitude, contributing only for the precession and the drift of the spacecraft′s spin axis and the eddy currents torque causes an exponential decay of the angular velocity magnitude. Numerical simulations performed with data of the Brazilian Satellites (SCD1 and SCD2) show the period that analytical solution can be used to the attitude propagation, within the dispersion range of the attitude determination system performance of Satellite Control Center of Brazil National Research Institute.
Anterior Hip Dislocation in a Football Player: A Case Report
Authors: Schuh Alexander , Doleschal Sylvia , Schmickal Thomas
Published: February 2010

Hip dislocations during sporting activities represent only 2%–5% of all hip dislocations. Most hip dislocations in sports can be categorised as “less complicated traumatic hip dislocations” by the Stewart-Milford classification due to the fact that minimal force is involved. The incidence of avascular necrosis of the femoral head greatly increases if the time to reduction is more than six hours. We report the case of a 38-year-old football player who suffered hip dislocation while kicking the ball with the medial aspect of the right foot in an external rotated manner of the right hip. Closed reduction was performed within 2 hours; postoperative follow-up was uneventful. Six months later the patient is out of any complaints; there is no sign of AVN of the femoral head.
Software Test Automation in Practice: Empirical Observations
Authors: Kasurinen Jussi , Taipale Ossi , Smolander Kari
Published: February 2010

The objective of this industry study is to shed light on the current situation and improvement needs in software test automation. To this end, 55 industry specialists from 31 organizational units were interviewed. In parallel with the survey, a qualitative study was conducted in 12 selected software development organizations. The results indicated that the software testing processes usually follow systematic methods to a large degree, and have only little immediate or critical requirements for resources. Based on the results, the testing processes have approximately three fourths of the resources they need, and have access to a limited, but usually sufficient, group of testing tools. As for the test automation, the situation is not as straightforward: based on our study, the applicability of test automation is still limited and its adaptation to testing contains practical difficulties in usability. In this study, we analyze and discuss these limitations and difficulties.
Analyzing Adherence to Prenatal Supplement: Does Pill Count Measure Up?
Authors: Appelgren Kristie E. , Nietert Paul J. , Hulsey Thomas C. , Hollis Bruce W. , Wagner Carol L.
Published: February 2010

Objective. To determine if adherence as measured by pill count would show a significant association with serum-based measures of adherence.Methods. Data were obtained from a prenatal vitamin D supplementation trial where subjects were stratified by race and randomized into three dosing groups: 400 (control), 2000, or 4000 IU vitaminD3/day. One measurement of adherence was obtained via pill counts remaining compared to a novel definition for adherence using serum 25-hydroxy-vitamin D (25-OH-D) levels (absolute change in 25(OH)D over the study period and the subject's steady-state variation in their 25(OH)D levels). A multivariate logistic regression model examined whether mean percent adherence by pill count was significantly associated with the adherence measure by serum metabolite levels.Results. Subjects' mean percentage of adherence by pill count was not a significant predictor of adherence by serum metabolite levels. This finding was robust across a series of sensitivity analyses.Conclusions. Based on our novel definition of adherence, pill count was not a reliable predictor of adherence to protocol, and calls into question how adherence is measured in clinical research. Our findings have implications regarding the determination of efficacy of medications under study and offer an alternative approach to measuring adherence of long half-life supplements/medications.
Diagnostic Strategies for Postmenopausal Bleeding
Authors: Breijer M. C. , Timmermans A. , van Doorn H. C. , Mol B. W. J. , Opmeer B. C.
Published: February 2010

Postmenopausal bleeding (PMB) is a common clinical problem. Patients with PMB have 10%–15% chance of having endometrial carcinoma and therefore the diagnostic workup is aimed at excluding malignancy. Patient characteristics can alter the probability of having endometrial carcinoma in patients with PMB; in certain groups of patients the incidence has been reported to be as high as 29%. Transvaginal sonography (TVS) is used as a first step in the diagnostic workup, but different authors have come to different conclusions assessing the accuracy of TVS for excluding endometrial carcinoma. Diagnostic procedures obtaining material for histological assessment (e.g., dilatation and curettage, hysteroscopy, and endometrial biopsy) can be more accurate but are also more invasive. The best diagnostic strategy for diagnosing endometrial carcinoma in patients with PMB still remains controversial. Future research should be focussed on achieving a higher accuracy of different diagnostic strategies.
A Clinical Correlate of the Dysregulated Immunoendocrine Response in Human Tuberculosis
Authors: Santucci Natalia , D’Attilio Luciano , Besedovsky Hugo , del Rey Adriana , Bay María Luisa , Bottasso Oscar
Published: February 2010

Wasting is a prominent feature in tuberculosis (TB), but its underlying mechanisms are incompletely understood. Immunoendocrine disturbances may be linked to the consumption state of TB patients, since hormones and cytokines can affect energy expenditure and metabolism. To approach this possibility, we have determined leptin, IL-18, and adrenal steroid plasma levels and body mass index (BMI) in newly diagnosed patients with mild, moderate and severe pulmonary TB, household contacts (HHC), and healthy controls (HCO). HHC displayed higher levels of leptin than HCO and TB patients. TB patients showed a gradual decrease in BMI and leptin concentrations with increasing disease severity, whereas a positive correlation between this hormone and BMI was found in the HCO group. Cortisol concentrations tended to be higher in TB patients. DHEA levels were decreased in TB patients and to a lesser extent in HHC, whereas IL-18 concentration was significantly increased in patients with severe disease. Since HHC are known to cause a latent subclinical infection, it seems clear that controlled tuberculous infection and manifested TB disease are accompanied by a dissimilar profile of immunoendocrine markers.
Immune Neuroendocrine Interactions during a Fungal Infection in Immunocompetent or Immunosuppressed Hosts
Authors: Rodríguez-Galán María Cecilia , Sotomayor Claudia E. , Cano Roxana , Porporatto Carina , Renna María Sol , Paraje María Gabriela , Cejas Hugo , Correa Silvia G.
Published: February 2010

The yeast Candida albicans belongs to the microflora of healthy individuals, although it can infect a variety of tissues ensuing changes in the host’s immune status. To evaluate the effect of neuroendocrine input on the early immune response during the fungal infection, we use a 3-day paradigm of chronic varied stress in Wistar rats infected with C. albicans. We find that stress mediators contribute to the spread of the fungus and downregulate critical functions of phagocytic cells at the infection site. Phenotypic and functional alterations of effector cells account for the decreased resistance to candidiasis and condition the development of the adaptive response. Stressed hosts exhibit a higher fungal burden in kidneys and livers associated with hyphal forms. The hepatic inflammatory reaction is compromised with severe steatosis, increment of functional enzymes, marked lipid peroxidation and hepatocyte apoptosis. Moreover, infection-related sickness symptoms are significantly increased by exposure to stress with anorexia, weight loss, lack of leptin and depletion of glycogen depots. Food deprivation exacerbates the liver injury. Stress mediators perturb the complex immune and metabolic program that operates early during fungal spread and promotes severe tissue damage.
Evaluation of Stress Systems by Applying Noninvasive Methodologies: Measurements of Neuroimmune Biomarkers in the Sweat, Heart Rate Variability and Salivary Cortisol
Authors: Marques Andrea H. , Silverman Marni N. , Sternberg Esther M.
Published: February 2010

The two main arms of the stress system include the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. These two neural stress systems coordinate the response of many other physiological systems to a stressor, including the immune and cardiovascular systems, bringing the body back to homeostasis. The nervous and immune systems communicate with each other in a bidirectional manner. In this review, we will discuss the use of noninvasive methods to evaluate the immune system, ANS and HPA axis. Collection of sweat and saliva, and measurement of heart rate variability are noninvasive methods that can be applied to evaluate neuroimmune interactions. Recently, we validated a new methodology to simultaneously evaluate a large array of neural and immune biomarkers in sweat, collected through cutaneous sweat patches and measured by recycling immunoaffinity chromatography. Noninvasive and ambulatory methodologies of biomarker collection can overcome several limitations intrinsic to invasive methods, such as reducing the stress triggered by collection itself and allowing a wider application to field and community-based settings. Ultimately, simultaneous evaluation of neural and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems and their role in disease susceptibility and progression of stress-related disorders.
Malignancy in Crohn’s Disease: Incidence and Clinical Characteristics in Japan
Authors: Mizushima Tsunekazu , Ohno Yuko , Nakajima Kiyokazu , Kai Yasuyuki , Iijima Hideki , Sekimoto Mitsugu , Nishida Toshirou , Nezu Riichiro , Ito Toshinori , Doki Yuichiro , Mori Masaki
Published: February 2010

Background/Aims: This study investigated the occurrence of malignancies in Japanese patients with Crohn’s disease (CD) and compared the incidence with that in the general population. Methods: The medical records of 294 CD patients, treated between 1989 and 2009, were reviewed and the prevalence of malignancies was assessed. Registration of person-years at risk was calculated individually, from the year of CD diagnosis until the year of cancer diagnosis, death or end of follow-up. The observed number of cancer cases was compared with the expected number, calculated on the basis of the individually computed person-years at risk and the corresponding age- and sex-specific incidence rates in the background population. Results: Thirteen cancers developed in 12 patients among a total of 4,248 person-years available for analysis. There were six CRCs, two gastric cancers, two uterine cancers, one small bowel cancer, one biliary cancer, and one cancer of unknown primary site. The risk of cancer (all sites) was significantly increased from that of the background population; SIR 2.24 (95% CI 1.19–3.83). In particular, the risk of CRC significantly increased in comparison to that of the background population; SIR 5.80 (95% CI 2.13–12.68). Conclusions: Japanese patients with CD are at increased risk of cancer, particularly CRC.
HES1 and HES5 Are Dispensable for Cartilage and Endochondral Bone Formation
Authors: Karlsson C. , Brantsing C. , Kageyama R. , Lindahl A.
Published: February 2010

Notch signalling, via its downstream mediators HES1 and HES5, regulates development of several different tissues. In vitro studies suggest that these genes are also involved in chondrogenesis and endochondral bone formation. In order to investigate the importance of HES1 and HES5 for these developmental processes, mice lacking chondrogenic expression of HES1 and HES5 were constructed by interbreeding HES5–/– mice homozygous for the floxed HES1 allele (HES1flox/flox) with COL2A1-Cre transgenic mice, creating conditional HES1;HES5 double mutant mice. The formation of cartilage and endochondral bone was studied in these mice using histological and immunohistochemical stainings, including Alcian Blue van Gieson, Safranin-O, modified Mallory Aniline Blue, tartrate-resistant acid phosphatase and collagen type II stainings. The mice were also studied using several different morphometrical analyses and the differentiation potential of the chondrocytes was evaluated in vitro. Unexpectedly, the conditional HES1;HES5 double mutant mice did not display impaired development of cartilage or endochondral bone. Lack of altered phenotype in the conditional HES1;HES5 double mutant mice can be explained either by the HES1 and HES5 genes not being involved in cartilage and endochondral bone development or by functional redundancy between the genes belonging to the family of HES genes: that is, disruption of one gene could be compensated for by the activity of another. Our results further shed light on the compensatory reserves available during the developing cartilage and bone.
Heparin-Induced Thrombocytopenia in Patients with Philadelphia-Negative Myeloproliferative Disorders and Unusual Splanchnic or Cerebral Vein Thrombosis
Authors: Randi Maria L. , Tezza Fabiana , Scapin Margherita , Duner Elena , Scarparo Pamela , Scandellari Raffaella , Fabris Fabrizio
Published: February 2010

Background: Philadelphia-negative myeloproliferative disorders (Ph-MPD) are common causes of unusual splanchnic or cerebral vein thrombosis, which is treated with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Heparin-induced thrombocytopenia (HIT) is a dangerous potential complication of this therapy, but it has rarely been reported in Ph-MPD. Patients and Methods: We retrospectively reviewed clinical records of 29 patients with Ph-MPD who have been treated with UFH or LMWH for unusual splanchnic or cerebral vein thrombosis (3 cerebral sinus, 6 portal and 20 hepatic vein). The goal of the study was to determine the occurrence of new thrombotic events during heparin therapy secondary to HIT (HITT). Results: During heparin therapy, 5 out of the 29 patients (17%) developed a new thrombotic episode (pulmonary embolism) with a high clinical probability of HIT based on the 4 T’s score even though not all the patients developed ‘true’ thrombocytopenia. A diagnosis of HIT was established in 2 patients (6.8%) through the presence of heparin-related antibodies. Conclusions: Ph-MPD patients on heparin warrant careful monitoring and HIT has to be suspected whenever platelet counts drop or a new thrombosis is detectable.
Malnutrition-Inflammation Score Independently Determined Cardiovascular and Infection Risk in Peritoneal Dialysis Patients
Authors: Ho Li-Chun , Wang Hsi-Hao , Chiang Chih-Kang , Hung Kuan-Yu , Wu Kwan-Dun
Published: February 2010

Background: The malnutrition-inflammation score (MIS) is an indicator of malnutrition-inflammation complex syndrome and an outcome predictor in maintenance hemodialysis patients. However, its utility in peritoneal dialysis (PD) patients and its association with the Charlson comorbidity index (CCI) have not yet been examined. Methods: All chronic stable PD outpatients in the PD center of the National Taiwan University Hospital in January 2006 were studied and followed for up to 18 months. The baseline MIS and CCI at the beginning of the study and the dates and causes of mortality or hospitalization during the study period were obtained. Results: A total of 141 PD patients were enrolled. During the study period, 8 patients died and 40 patients had at least one fatal or nonfatal major cardiovascular or infection event. The CCI correlated positively and significantly with the MIS (r = +0.344, p < 0.001). The MIS and CCI were both independent predictors of cardiovascular and infection events in the multivariate Cox proportional hazard model. For every unit increase in the MIS, the adjusted hazard ratio for mortality was 1.177 (95% confidence interval, CI, 1.050–1.320, p = 0.005). For every unit increase in the CCI, the adjusted hazard ratio for mortality was 1.180 (95% CI, 1.046–1.330, p = 0.007). Conclusions: MIS can predict fatal and nonfatal cardiovascular and infection events in chronic stable PD patients. The CCI, which is closely associated with the MIS, is an independent determinant of cardiovascular and infection events as well. Interventional studies are indicated to confirm the utility of the MIS in PD populations who undergo nutritional or anti-inflammatory treatments.
Takotsubo Cardiomyopathy as an Underlying Mediator of Myocardial Infarction with Normal Coronary Arteries
Authors: Chen Cheng-Kang , Chang Rei-Yeuh , Chen Cheng-Yun , Chen Yung-Ping , Chu I-Tseng , Liang Hsin-Li , Hsu Chen-Tung
Published: February 2010

Objective: The purpose of the present study was to describe our experience with myocardial infarction with normal coronary arteries (MINCA) with regards to the prevalence, clinical characteristics, possible underlying etiologies (including Takotsubo cardiomyopathy, TCM) and the short- and long-term outcomes associated with this condition. Methods: We retrospectively analyzed the records of 596 consecutive patients presenting with acute myocardial infarction over a 4-year period and identified 24 patients (14 female, 10 male) with angiographically normal coronary arteries. Demographic and clinical variables and outcomes were reviewed. Results: Mean patient age was 59 ± 20 years. The presumed MINCA mechanism was TCM in 10 patients (41.7%), probable myocarditis in 5 (20.8%), coronary spasm in 4 (16.7%), coronary thrombus in 3 (12.5%) and aortic dissection in 2 patients (8.3%). After a mean follow-up of 19 ± 14 months, 2 patients with probable myocarditis had died of cardiovascular causes, 1 patient with aortic dissection had died due to sepsis after surgery and 1 patient with TCM had died of noncardiovascular causes 2 years after discharge. Conclusion: In this study, we found that MINCA occurred in 4% of patients with acute myocardial infarction undergoing emergent coronary angiography, with the most frequent underlying mechanism being TCM.
Prevalence of Comorbidities in Patients with Chronic Obstructive Pulmonary Disease
Authors: Cazzola Mario , Bettoncelli Germano , Sessa Emiliano , Cricelli Claudio , Biscione Gianluca
Published: February 2010

Background: Chronic obstructive pulmonary disease (COPD) is associated with many comorbidities, but the percentage of COPD patients who develop comorbidities has not been clearly defined. Objectives: We aimed to examine the relationship between COPD and comorbidities using information obtained from the Health Search Database (HSD) owned by the Italian College of General Practitioners (SIMG), which stores information on about 1.5% of the total Italian population served by general practitioners. Methods: We conducted a population-based retrospective study using information obtained from the HSD. The software system used codes all the diagnostic records using the 9th Revision of the International Classification of Diseases. Results: Compared to the non-COPD people, COPD patients were at increased risk for cardiovascular events [ischemic heart disease (6.9% in the general population vs. 13.6% in COPD patients), cardiac arrhythmia (6.6% in the general population vs. 15.9% in COPD patients), heart failure (2.0% in the general population vs. 7.9% in COPD patients), and other forms of heart disease (10.7% in the general population vs. 23.1% in COPD patients); with a higher impact of COPD in the elderly]; non-psychotic mental disorders, including depressive disorders (29.1% in the general population vs. 41.6% in COPD patients; with a higher impact of COPD on women aged <75 years); diabetes mellitus (10.5% in the general population vs. 18.7% in COPD patients); osteoporosis (10.8% in the general population vs. 14.8% in COPD patients), with a higher impact of COPD on women aged <75 years, and malignant pulmonary neoplasms (0.4% in the general population vs. 1.9% in COPD patients). Conclusions: Our results indicate that COPD is a risk factor for these comorbid conditions.
Nuclear and Chromatin Reorganization during Cell Senescence and Aging – A Mini-Review
Authors: Shin Dong-Myung , Kucia Magda , Ratajczak Mariusz Z.
Published: February 2010

Genetic material in the nucleus governs mechanisms related to cell proliferation, differentiation, and function. Thus, senescence and aging are directly tied to the change of nuclear function and structure. The most important mechanisms that affect cell senescence are: (i) telomere shortening; (ii) environmental stress-mediated accumulation of DNA mutations, and (iii) the intrinsically encoded biological clock that dictates lifespan events of any particular cell type. Overall, these changes lead to modification of the expression of genes that are responsible for: (i) organization of the nuclear structure; (ii) integrity of transcriptionally inactive heterochromatin, and (iii) epigenetic modification of chromosomes due to DNA methylation and/or histone modifications. These aging-related nuclear alterations do not only affect somatic cells. More importantly, they affect stem cells, which are responsible for proper tissue rejuvenation. In this review, we focus on epigenetic changes in the chromatin structure and their impact on the biology and function of adult cells as they age. We will also address aging-related changes in a compartment of the most primitive pluripotent stem cells that were recently identified by our team and named ‘very small embryonic/epiblast-like stem cells’.
Clopidogrel non-responsiveness and risk of cardiovascular morbidity
Authors: Marcucci Rossella , Gori Anna Maria , Giusti Betti , Abbate Rosanna , Gensini Gian Franco , Sofi Francesco
Published: February 2010

We performed this meta-analysis to update the clinical evidences on the relation between clopidogrel non-responsiveness and clinical outcomes in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention. An electronic literature search through MEDLINE, EMBASE, Web of Science, and the Cochrane Library and bibliographies of retrieved articles up to January, 2009 was conducted. Studies were included if they had a cohort prospective design, if they analysed clopidogrel responsiveness in CAD patients in relation to death and/or occurrence of adverse coronary events during follow-up, and if they reported an adequate statistical analysis. Fourteen studies, totalling 4,564 CAD patients followed for a time ranging from 14 days to one year, were included. The cumulative analysis reported that residual platelet reactivity despite clopidogrel treatment was significantly associated with an increased risk of death and/or thrombotic recurrences (odds ratio [OR] 5.67, 95% confidence interval [CI] 2.97 to 10.84; p<0.00001). However, four studies contributed to a consistent heterogeneity of the model and evidenced a significant risk of publication bias, so were excluded from the analysis. This exclusion, however, did not influence the overall result, by confirming the increased risk of cardiovascular recurrences for patients with a poor response to clopidogrel treatment (OR 3.58, 95%CI 2.54 to 5.05; p<0.00001). The present updated meta-analysis documents a significant association between residual platelet reactivity under clopidogrel treatment and recurrent cardiovascular events, so suggesting the relevance of ongoing interventional studies aimed at tailoring the antithrombotic therapy in CAD patients.
Neuroserpin, a thrombolytic serine protease inhibitor (serpin), blocks transplant vasculopathy with associated modification of T-helper cell subsets
Authors: Munuswamy-Ramanujam Ganesh , Dai Erbin , Liu Liying , Shnabel Mira , Sun Yun Ming , Bartee Mee , Lomas David , Lucas Alexandra
Published: February 2010

Thrombolytic serine proteases not only initiate fibrinolysis, but also are up-regulated in vascular disease and acute inflammatory responses. Although the serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is considered a main regulator of thrombolysis, PAI-1 is also associated with vascular inflammation. The role of other serpins that target thrombolytic proteases, PAI-2, PAI-3, and neuroserpin (NSP), in vascular inflammation is, however, less well defined. NSP is a mammalian serpin that, similar to PAI-1, inhibits urokinase- and tissue-type plasminogen activators (uPA and tPA, respectively) and has been most closely associated with the nervous system, with a demonstrated protective role after cerebral infarction in mouse models. However, the role of NSP in systemic arterial inflammation and plaque growth is not known. Serp-1 is a myxoma viral serpin that also inhibits tPA and uPA, as well as additionally inhibiting plasmin and factor Xa (fXa). Serp-1 has proven highly potent anti-inflammatory and anti-atherogenic activity. Here we assess the effects of NSP treatment on plaque growth and T-helper (Th) lymphocyte activity in a mouse aortic allograft transplant model, with comparison to Serp-1. NSP and Serp-1 both significantly reduced plaque growth and T-cell invasion. T-bet (a Th1 differentiation marker) was significantly reduced in transplanted aorta with associated reductions in Th1 and Th17, but not Th2, in splenocytes. NSP had additional Th modifying activity in non-transplanted mice. In summary, this is the first report that NSP possesses anti-inflammatory activity in systemic arteries, modifying Th cell responses and significantly reducing plaque growth in mouse aortic allografts.
Prognostic value of plasma von Willebrand factor-cleaving protease (ADAMTS13) antigen levels in patients with coronary artery disease
Authors: Kaikita Koichi , Matsukawa Masakazu , Soejima Kenji , Fuchigami Shunichiro , Miyazaki Yuji , Ono Takamichi , Uemura Takashi , Tsujita Kenichi , Hokimoto Seiji , Sumida Hitoshi , Matsui Kunihiko , Yamabe Hiroshige , Ogawa Hisao , Miura Mitsutoshi
Published: February 2010

High plasma level of von Willebrand factor (VWF) is a marker of future cardiovascular events in patients at high risk of coronary artery disease (CAD). The purpose of this study was to examine the changes and the prognostic value of plasma VWF-cleaving protease (ADAMTS13) levels in patients with CAD. Plasma VWF and ADAMTS13 levels were measured in 225 patients with CAD (152 men and 73 women, age, 70.3 ± 8.9 years, mean ± SD) and 100 patients without CAD who were ageand gender-matched to the CAD patients (60 men and 40 women, age, 68.6 ± 8.9 years). The CAD patients had higher VWF and lower ADAMTS13 antigen levels compared to patients without CAD. During 22.3 ± 10.4 months follow-up period, 20 major adverse cardiac and cerebrovascular events (MACCE) occurred in 222 patients with CAD who could be followed up. Kaplan-Meier analysis demonstrated that CAD patients with high plasma VWF antigen levels were significantly more likely to develop MACCE. Furthermore, eight cardiac and cerebrovascular thrombotic events [acute coronary syndrome (n=4) and cerebral infarction (n=4)] occurred in CAD patients with both high plasma VWF and low ADAMTS13 antigen levels. Multivariate Cox hazards regression analysis identified high plasma VWF and low ADAMTS13 antigen levels as significant and independent predictors of future MACCE and thrombotic events during the follow-up period in CAD patients. Our findings suggest that low plasma ADAMTS13 as well as high VWF level is a useful predictor of cardiac and cerebrovascular events in CAD patients.
Protein
S
-Nitrosylation and Cardioprotection
Authors: Sun Junhui , Murphy Elizabeth
Published: February 2010

Abstract
:

Nitric oxide (NO) plays an important role in the regulation of cardiovascular function. In addition to the classic NO activation of the cGMP-dependent pathway, NO can also regulate cell function through protein
S
-nitrosylation, a redox dependent, thiol-based, reversible posttranslational protein modification that involves attachment of an NO moiety to a nucleophilic protein sulfhydryl group. There are emerging data suggesting that
S
-nitrosylation of proteins plays an important role in cardioprotection. Protein
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-nitrosylation not only leads to changes in protein structure and function but also prevents these thiol(s) from further irreversible oxidative/nitrosative modification. A better understanding of the mechanism regulating protein
S
-nitrosylation and its role in cardioprotection will provide us new therapeutic opportunities and targets for interventions in cardiovascular diseases.
Managing Death in the Burning Grounds of Varanasi, India: A Terror Management Investigation
Authors: Fernandez Silvia , Castano Emanuele , Singh Indramani
Published: February 2010

Is it possible to reach a subconscious acceptance of death? Building on Terror Management Theory, the authors investigated in-group identification and cultural worldview among two groups of Hindus with naturally occurring high ( N = 120) versus low ( N = 120) death exposure. In each group, half were reminded about death and the other half of a control topic. Results indicated that making mortality salient increased identification with India and cultural worldview defense in the low-exposure but not in the high-exposure sample, the latter showing consistently higher levels on these variables across experimental conditions. Chronic death exposure may lead to chronic cultural worldview defense rather than a deeper acceptance of the inevitability of death.