bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity
Authors: Teixeira Antonio R. L. , Hecht Mariana M. , Guimaro Maria C. , Sousa Alessandro O. , Nitz Nadjar
Published: July 2011

AcuteTrypanosoma cruziinfections can be asymptomatic, but chronically infected individuals can die of Chagas' disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas' disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas' disease is achieved with the cross-kingdom chicken model system, which is refractory toT. cruziinfections. The inoculation ofT. cruziinto embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8+γδ, and CD8α+T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas' disease is a genetically driven autoimmune disease.
Laboratory Adaptation of Bordetella pertussis Is Associated with the Loss of Type Three Secretion System Functionality
Authors: Gaillard M. E. , Bottero D. , Castuma C. E. , Basile L. A. , Hozbor D.
Published: July 2011

Although
Bordetella pertussis
contains and transcribes loci encoding type III secretion system (TTSS) homologues, expression of TTSS-associated proteins has been reported only for non-laboratory-adapted Irish clinical isolates. Here we confirm such a result for clinical isolates obtained from patients treated in Argentinean hospitals. Moreover, we demonstrate that the expression of TTSS-associated proteins is independent both of the year in which the isolate was obtained and of the types of polymorphic alleles for other virulence factors but is dependent on environmental growth conditions. Interestingly, we observed that TTSS-associated protein expression is lost after successive
in vitro
passages but becomes operative again when bacteria come into contact with the host. This
in vivo
activation of TTSS expression was observed not only for clinical isolates previously adapted to the laboratory after successive
in vitro
passages but also for vaccine strains that did not express the system
in vitro
. The reversibility of TTSS expression, demonstrated by its switching off-on when the bacterium comes into contact with the host, appears to be an adaptive response of this pathogen.
Prevalence, course and associations of desire for hastened death in a UK palliative population: a cross-sectional study
Authors: Price Annabel , Lee William , Goodwin Laura , Rayner Lauren , Humphreys Rosemary , Hansford Penny , Sykes Nigel , Monroe Barbara , Higginson Irene , Hotopf Matthew
Published: July 2011

Objectives

To determine the prevalence, severity and remission of desire for hastened death (DHD) in a UK representative sample of patients with advanced disease receiving palliative care and to examine the associations of desire for death.

Design

A cross-sectional survey with 4-week follow-up.

Setting

St Christopher's Hospice, Sydenham, South London, which is a large hospice with homecare, outpatient and inpatient facilities serving five London boroughs.

Participants

300 patients newly referred to the hospice for palliative care.

Main outcome measures

The Desire for Death Rating Scale (DDRS).

Results

At T1 33/300 (11%) reported DHD and 11/300 (3.7%) had more serious or pervasive DHD. Of those who expressed DHD at T1 and were interviewed at both time points, 35% no longer reported these thoughts. Of those who reported no DHD at T1, 8% reported DHD at T2. The majority of those who had more severe DHD at T1 had a reduced DHD score by T2. Factors associated with T1 DHD included presence of non-malignant disease, depression, more severe physical symptoms, hopelessness and perceived loss of dignity.

Conclusions

The prevalence of DHD was at the lower end of that seen in previous studies using similar samples. More severe DHD was uncommon and for most part remitted to some extent during the study. The provision of symptom control and timely detection and intervention for depression coupled with a focus on optimising function, instilling hope and preserving dignity are likely to contribute to alleviation of DHD in patients with advanced illness.
Oxalate nephropathy in a laboratory colony of common marmoset monkeys (Callithrix jacchus) following the ingestion of Eucalyptus viminalis
Authors: Vanselow B. A. , Pines M. K. , Bruhl J. J. , Rogers L. J.
Published: July 2011

Seven common marmoset monkeys (Callithrix jacchus) from a laboratory colony of 17 died over a period of eight months. Death of six of these monkeys was attributed to kidney failure from an oxalate‐induced nephropathy. The epidemiology of this outbreak suggested an exogenous source and there was strong evidence that the source was bark and leaves from an Eucalyptus viminalis tree. Branches of this tree were introduced one month before the first death. The branches were removed one month after deaths commenced, but deaths continued for another five months. Urinalysis of all surviving marmosets at 80 and 122 days after initial contact with the E viminalis branches suggested that these monkeys had renal impairment. In the cases described here, the eating behaviour of common marmosets apparently exposed the animals to toxic levels of oxalate in the bark and leaves of an E viminalis tree.
GAUGE INVARIANCE AND THE GOLDSTONE THEOREM
Authors: GURALNIK GERALD S.
Published: July 2011

This paper was originally created for and printed in the "Proceedings of seminar on unified theories of elementary particles" held in Feldafing, Germany from July 5 to 16, 1965 under the auspices of the Max-Planck-Institute for Physics and Astrophysics in Munich. It details and expands upon the 1964 Guralnik, Hagen, and Kibble paper demonstrating that the Goldstone theorem does not require physical zero mass particles in gauge theories.
ASSESSMENT OF OSTEOARTHRITIS INITIATIVE–KELLGREN AND LAWRENCE SCORING PROJECTS QUALITY USING COMPUTER ANALYSIS
Authors: Shamir Lior , Felson David T. , Ferrucci Luigi , Goldberg Ilya G.
Published: July 2011

The detection of knee osteoarthritis (OA) is a subjective task, and even two highly experienced and well-trained readers might not always agree on a specific case. This problem is noticeable in OA population studies, in which different scoring projects provide significantly different scores for the same knee X-rays. Here we propose a method for quantitative assessment and comparison of knee X-ray scoring projects in OA population studies. The method works by applying an image analysis method that automatically detects OA in knee X-ray images, and comparing the consistency of the scores when using each of the scoring projects as "gold standard." The method was applied to compare the osteoarthritis initiative (OAI) clinic reading derived Kellgren and Lawrence (K&L) scores to central reading, and showed that when using the derived K&L scores the automatic image analysis method was able to accurately differentiate between healthy joints and moderate OA joints in ~70% of the cases. When the OAI central reading scores were used as gold standard, the detection accuracy was elevated to ~77%. These results show that the OAI central readings scores are more consistent with the X-rays, indicating that the central reading better reflects the radiographic features associated with OA, compared to the OAI K&L scores derived from clinic readings.
Evidence on Stock Reaction to Market-Wide Information
Authors: Du Ding , Denning Karen , Zhao Xiaobing
Published: July 2011

The main purpose of this paper is to show that the lack of misreaction to common information in previous research may be due to methodological weakness. As of now, there is no evidence which suggests that stocks under-react to common information at short horizons and over-react at longer horizons. Even if stocks under- and/or over-react to common information at the security level, the reaction pattern may not be evident at the market level if only some stocks have such a pattern and their capitalization is small. We show in this manuscript that the lack of misreaction to common information in previous research may be due to methodological weakness. By focusing on the stock level reaction, we find a statistically and economically significant reaction pattern to common information as the behavioral models suggest. This finding thus complements the findings of stock misreaction to firm-specific information, and may benefit researchers attempting to understand investor behavior.
A MIXED INTEGER PROGRAMMING MODEL FOR MULTIPLE-CLASS DISCRIMINANT ANALYSIS
Authors: SUN MINGHE
Published: July 2011

A mixed integer programming model is proposed for multiple-class discriminant and classification analysis. When multiple discriminant functions, one for each class, are constructed with the mixed integer programming model, the number of misclassified observations in the sample is minimized. This model is an extension of the linear programming models for multiple-class discriminant analysis but may be considered as a generalization of mixed integer programming formulations for two-class classification analysis. Properties of the model are studied. The model is immune from any difficulties of many mathematical programming formulations for two-class classification analysis, such as nonexistence of optimal solutions, improper solutions, and instability under linear data transformation. In addition, meaningful discriminant functions can be generated under conditions where other techniques fail. Examples are provided. Results on publically accessible datasets show that this model is very effective in generating powerful discriminant functions.
STRUCTURAL AND INTERACTION PROPERTIES OF ENCAPSULATED MnO2 NANOWIRES FILLED MWCNTs
Authors: ABD RAZAK SAIFUL IZWAN , SHARIF ZEIN SHARIF HUSSEIN
Published: July 2011

Uniform encapsulated MnO2 nanowires were achieved within the cavity of multiwalled carbon nanotubes (MWCNTs). The Raman spectra revealed a charge-transfer shifts between the MnO2 particles and the inner tube of MWCNTs. Thin, uniform and continuous MnO2 was observed with a diameter of 9 nm.
ISOMETRIES OF POLYHEDRAL HILBERT GEOMETRIES
Authors: LEMMENS BAS , WALSH CORMAC
Published: July 2011

We show that the isometry group of a polyhedral Hilbert geometry coincides with its group of collineations (projectivities) if and only if the polyhedron is not an n-simplex with n ≥ 2. Moreover, we determine the isometry group of the Hilbert geometry on the n-simplex for all n ≥ 2, and find that it has the collineation group as an index-two subgroup. The results confirm several conjectures of P. de la Harpe for the class of polyhedral Hilbert geometries.
APPROXIMATING THE FIRST L2-BETTI NUMBER OF RESIDUALLY FINITE GROUPS
Authors: LÜCK W. , OSIN D.
Published: July 2011

We show that the first L2-betti number of a finitely generated residually finite group can be estimated from below by using ordinary first betti numbers of finite index normal subgroups. As an application, we construct a finitely generated infinite residually finite torsion group with positive first L2-betti number.
Study on the Effects of Zr-Incorporated InZnO Thin-Film Transistors Using a Solution Process
Authors: Jeong Tae Hoon , Kim Si Joon , Yoon Doo Hyun , Jeong Woong Hee , Kim Dong Lim , Lim Hyun Soo , Kim Hyun Jae
Published: July 2011

The effects of adding Zr into solution-processed InZnO (IZO) thin-film transistors (TFTs) were investigated with varying Zr content. ZrInZnO (ZIZO) TFTs showed a lower off-current and a sharper subthreshold swing than IZO TFTs. The addition of Zr plays a role in reducing the oxygen vacancies, and thus effectively decreases the carrier concentrations of the ZIZO active layer. The characteristics of various DC bias stresses are provided and discussed to evaluate the reliability of ZIZO TFTs. After 1000 s of various DC bias stresses, although the threshold voltage may shift dramatically, variations in subthreshold swing are negligible.
Enhancing Photovoltaic Characteristics of Iron Doped Amphous Carbon/Al2O3/Si Solar Cell by Al2O3 Interface Passivation
Authors: Tan Xinyu , Zhang Xiaozhong , Wan Caihua , Gao Xili , Lin Hong , Zhang Jing
Published: July 2011

This letter reports the enhanced photovoltaic (PV) performance of Fe doped amorphous carbon (a-C) film/n-Si heterojunctions by depositing a thin Al2O3 layer at the interface of a-C:Fe and Si substrate. We demonstrate that a thin Al2O3 film at the interface of Fe-doped a-C/Si heterojunction allows significantly improving the devices' PV performances up to one order of magnitude under AM1.5 illumination. The enhancement of the PV effect on a-C:Fe/Al2O3/Si solar cells can be ascribed to the inserted Al2O3 layer which increases the built-in electric field barrier and realizes interface passivation by use of suppressing the charge recombination, reducing the interface states.
Influence of Ion Bombardment onto Phosphor Layer on Temporal Image Sticking in Alternating-Current Plasma Display Panel
Authors: Park Choon-Sang , Kim Sang-Yup , Jung Eun-Young , Tae Heung-Sik
Published: July 2011

We found that ion bombardment onto a phosphor layer during a sustained discharge was a key factor in inducing temporal image sticking of alternating-current (AC) plasma display panels (PDPs) through facilitated absorption of H2O onto the phosphor layer. We also found that ion bombardment onto the phosphor layer during the sustain discharge strongly depended on the bias conditions of the address electrode on which the phosphor layers were deposited. As a result, the positive-biased or floated address electrode condition could minimize the ion bombardment onto the phosphor layer during the sustain discharge, thus suppressing the absorption of H2O onto the phosphor layer, and ultimately preventing temporal image sticking.
Phase Change Line Memory Cell Based on Ge2Sb2Te5Fabricated Using Focused Ion Beam
Authors: Du Xiaofeng , Zhang Ting , Song Zhitang , Liu Weili , Liu Xuyan , Gu Yifeng , Lv Shilong , Xue Weijia , Xi Wei
Published: July 2011

Using focused-ion-beam-deposited SiO2as a hard mask, a new phase change line memory cell fabrication method was developed in this work. A phase change line memory cell with a length of 150 nm and width of 100 nm was fabricated and electrical characterization was performed. Reversible phase transition between amorphous (RESET) and polycrystalline (SET) states was realized. Threshold current of the device is only 0.5 µA, which is considerably low owning to the line structure. The reset operation was achieved by applying a voltage pulse with a magnitude of 3.5 V and duration of 50 ns, and the set operation was achieved by applying 1.6 V for 1000 ns. The dynamic resistance switching ratio (off/on ratio) was nearly 104. The device fabrication method enables simplified scaling to ultrasmall phase change device dimensions.
DNA Electromagnetophoresis under the Condition of Magnetic Fields Perpendicular to Electric Fields
Authors: Ozawa Shun , Kurosaka Daiki , Yamamoto Isao , Takamasu Tadashi
Published: July 2011

The effects of magnetic fields on DNA electrophoresis have been studied under the condition of horizontal electric fields and vertical homogeneous magnetic fields. The migration course of DNA bends to the cross-product direction of the electric field and the magnetic field. The electrophoretic distance of the DNA differs between magnetic fields of 0 and 13 T. The decreases in the electrophoretic velocity are discovered under the condition of magnetic fields perpendicular to electric fields. The results are discussed concerning the Lorentz force, and a new separation method for DNAs is suggested.
Quasi-In vivo Heart Electrocardiogram Measurement of ST Period Using Convolution of Cell Network Extracellular Field Potential Propagation in Lined-Up Cardiomyocyte Cell-Network Circuit
Authors: Kaneko Tomoyuki , Nomura Fumimasa , Yasuda Kenji
Published: July 2011

A model for the quasi-in vivo heart electrocardiogram (ECG) measurement of the ST period has been developed. As the part of ECG data at the ST period is the convolution of the extracellular field potentials (FPs) of cardiomyocytes in a ventricle, we have fabricated a lined-up cardiomyocyte cell-network on a lined-up microelectrode array and a circular microelectrode in an agarose microchamber, and measured the convoluted FPs. When the ventricular tachyarrhythmias of beating occurred in the cardiomyocyte network, the convoluted FP profile showed similar arrhythmia ECG-like profiles, indicating the convoluted FPs of the in vitro cell network include both the depolarization data and the propagation manner of beating in the heart.
Characterization of three IGFBP mRNAs in Atlantic croaker and their regulation during hypoxic stress: potential mechanisms of their upregulation by hypoxia
Authors: Rahman Md. Saydur , Thomas Peter
Published: July 2011

Insulin-like growth factor-binding proteins (IGFBPs) play important roles in downregulating IGF activity and growth and development in vertebrates under hypoxic stress. However, the mechanisms of hypoxia regulation of IGFBPs in teleost fishes are unknown. The involvement of reactive oxygen species (ROS) and hypoxia-inducible factors (HIFs) in hypoxia upregulation of IGFBPs in Atlantic croaker were investigated. Three croaker IGFBPs, IGFBP-1, IGFBP-2, and IGFBP-5, were cloned and characterized. Chronic hypoxia exposure [dissolved oxygen (DO): 1.7 mg/l for 2–4 wk] caused significant increases in hepatic and neural IGFBP-1 mRNA expression compared with tissue mRNA levels in fish held under normoxic conditions (6.5 mg DO/l). Moreover, longer-term chronic hypoxia exposure (2–2.7 mg DO/l for 15–20 wk) caused significant increases in mRNA levels of all three IGFBPs in both liver and brain tissues. Hypoxia exposure also markedly increased superoxide radical (O2·−, an index of ROS) production and HIF-1α mRNA and HIF-2α protein expression in croaker livers. Pharmacological treatment with an antioxidant attenuated the hypoxia-induced increases in O2·− production and HIFα mRNA and protein expression as well as the elevation of IGFBP-1 mRNA levels. These results suggest that the upregulation of IGFBP expression under hypoxia stress is due, in part, to alterations in the antioxidant status, which may involve ROS and HIFs.
Ludwig's Angina—A Controversial Surgical Emergency: How We Do It
Authors: Hasan Wael , Leonard David , Russell John
Published: July 2011

Objectives. To review the current protocols used for management of Ludwig's angina and to assess the efficacy of conservative measures in these cases.Methods. A retrospective review of patients who were admitted to our institution for management of Ludwig's angina between 2003 and 2010.Results. Two patients were identified. Both were managed successfully with conservative measures and close airway observation. None needed an emergency intubation or surgical tracheostomy. There were no mortalities, and both had a short hospital stay.Conclusion. Recently, management of Ludwig's angina has evolved from aggressive airway management into a more conservative one. This is based on close airway observation on a specialised airway unit and a serial clinical airway assessment. Improved imaging modalities, antibiotic therapy, surgical skills, and clinical experience are the key factors behind this change in practice.
Antinociceptive Activity of the Chloroform Fraction of Dioclea virgata (Rich.) Amshoff (Fabaceae) in Mice
Authors: Mota Vanine Gomes , de Carvalho Fabíola Lélis , de Morais Liana Clébia Soares Lima , Bhattacharyya Jnanabrata , de Almeida Reinaldo Nóbrega , de Alencar Jacicarlos Lima
Published: July 2011

Acute treatment with the chloroform fraction of Dioclea virgata (Rich.) Amshoff (CFDv) in mice produced decreased ambulation and sedation in the behavioral pharmacological screening. Doses of 125 and 250 mg/kg CFDv decreased latency of sleep onset in the test of sleeping time potentiation. In the open field, animals treated with CFDv reduced ambulation and rearing (250 mg/kg), as well as defecation (125; 250 mg/kg). Regarding the antinociceptive activity, CFDv (125, 250, 500 mg/kg) increased latency to first writhing and decreased the number of writhings induced by acetic acid. In the formalin test, CFDv (250 mg/kg) decreased paw licking time in the first and second phases indicating antinociceptive activity that can be mediated both peripherally and at the central level. CFDv did not affect motor coordination until 120 minutes after treatment. CFDv shows psychopharmacological effects suggestive of CNS‐depressant drugs with promising antinociceptive activity.
Rimonabant: From RIO to Ban
Authors: Sam Amir H. , Salem Victoria , Ghatei Mohammad A.
Published: July 2011

Endocannabinoid antagonism as a treatment for obesity and the metabolic syndrome became a hugely anticipated area of pharmacology at the start of the century. The CB1 receptor antagonist Rimonabant entered the European mass market on the back of several trials showing weight loss benefits alongside improvements in numerous other elements of the metabolic syndrome. However, the drug was quickly withdrawn due to the emergence of significant side effects—notably severe mood disorders. This paper provides a brief overview of the Rimonabant story and places the recent spate of FDA rejections of other centrally acting weight loss drugs entering Phase 3 trials in this context.
LDL-C/HDL-C Ratio Predicts Carotid Intima-Media Thickness Progression Better Than HDL-C or LDL-C Alone
Authors: Enomoto Mika , Adachi Hisashi , Hirai Yuji , Fukami Ako , Satoh Akira , Otsuka Maki , Kumagae Shun-Ichi , Nanjo Yasuki , Yoshikawa Kuniko , Esaki Eishi , Kumagai Eita , Ogata Kinuka , Kasahara Akiko , Tsukagawa Eri , Yokoi Kanako , Ohbu-Murayama Kyoko , Imaizumi Tsutomu
Published: July 2011

High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are strong predictors of atherosclerosis. Statin-induced changes in the ratio of LDL-C to HDL-C (LDL-C/HDL-C) predicted atherosclerosis progression better than LDL-C or HDL-C alone. However, the best predictor of subclinical atherosclerosis remains unknown. Our objective was to investigate this issue by measuring changes in carotid intima-media thickness (IMT). A total of 1,920 subjects received health examinations in 1999, and were followed up in 2007. Changes in IMT (follow-up IMT/baselineIMT×100) were measured by ultrasonography. Our results showed that changes in IMT after eight years were significantly related to HDL-C (inversely,P<0.05) and to LDL-C/HDL-C ratio (P<0.05). When the LDL-C/HDL-C ratios were divided into quartiles, analysis of covariance showed that increases in the ratio were related to IMT progression (P<0.05). This prospective study demonstrated the LDL-C/HDL-C ratio is a better predictor of IMT progression than HDL-C or LDL-C alone.
Modelling Inverse Gaussian Data with Censored Response Values: EM versus MCMC
Authors: Sparks R. S. , Sutton G. , Toscas P. , Ormerod J. T.
Published: July 2011

Low detection limits are common in measure environmental variables. Building models using data containing low or high detection limits without adjusting for the censoring produces biased models. This paper offers approaches to estimate an inverse Gaussian distribution when some of the data used are censored because of low or high detection limits. Adjustments for the censoring can be made if there is between 2% and 20% censoring using either the EM algorithm or MCMC. This paper compares these approaches.
Data Fusion for Electromagnetic and Electrical Resistive Tomography Based on Maximum Likelihood
Authors: Nordebo Sven , Gustafsson Mats , Sjöden Therese , Soldovieri Francesco
Published: July 2011

This paper presents a maximum likelihood based approach to data fusion for electromagnetic (EM) and electrical resistive (ER) tomography. The statistical maximum likelihood criterion is closely linked to the additive Fisher information measure, and it facilitates an appropriate weighting of the measurement data which can be useful with multiphysics inverse problems. The Fisher information is particularly useful for inverse problems which can be linearized similar to the Born approximation. In this paper, a proper scalar product is defined for the measurements and a truncated Singular Value Decomposition (SVD) based algorithm is devised which combines the measurement data of the two imaging modalities in a way that is optimal in the sense of maximum likelihood. As a multiphysics problem formulation with applications in geophysics, the problem of tunnel detection based on EM and ER tomography is studied in this paper. To illustrate the connection between the Green's functions, the gradients and the Fisher information, two simple and generic forward models are described in detail regarding two-dimensional EM and ER tomography, respectively.
Elderly at Greater Risk for Root Caries: A Look at the Multifactorial Risks with Emphasis on Genetics Susceptibility
Authors: Gati Daniel , Vieira Alexandre R.
Published: July 2011

Root caries is one of the most significant dental problems among older adults today. Many studies have demonstrated that older adults are at greater risk for developing root caries. Here we examine what risk factors older adults are prone to and explain how they contribute to higher rates of oral disease, in particular root caries. The elderly are at risk for root caries due to dentures, lack of dexterity, a shift from complex to simple sugars, and poor oral hygiene. Decreased salivary flow and its manifestations with other social/behavioral and medical factors may provide a more comprehensive explanation to a higher frequency of root caries in older adults.
HCV Virus and Lymphoid Neoplasms
Authors: Tsutsumi Yutaka , Ito Shinichi , Ogasawara Reiki , Kudo Kazuhiro , Tanaka Junji , Asaka Masahiro , Imamura Masahiro
Published: July 2011

Hepatitis C virus (HCV) is one of the viruses known to cause hepatic cancer. HCV is also believed to be involved in malignant lymphoma. In this paper, we investigated characteristics of malignant lymphoma cases that were anti-HCV antibody (HCV-Ab) positive. We were able to perform pathological examinations on 13 out of 14 HCV-positive cases. Of these, lymphoid tissues of 10 stained positive for HCV-Ab. There was no significant correlation between the degree of HCV staining and the rate of recurrence or resistance to treatment. However, there did appear to be a consistent decrease in the amount of HCV-RNA between pre- and posttreatment among HCV-Ab-positive cases; that is, treatment-resistant cases that exhibited resistance from the first treatment and recurrent cases more frequently had a higher HCV level at treatment termination compared to the pretreatment level. This suggests that the HCV virus either accelerates oncogenesis by direct interaction with B cells or indirectly affects lymphoma prognosis.
Individual Physician versus Team-Based Medical Encounters: Maximizing the Efficiency of a Medical Relief Service in Rural Honduras
Authors: Whitney Rachel , Stevens Michael , Bearman Gonzalo
Published: July 2011

Background. For several years, the Virginia Commonwealth University (VCU) Department of Internal Medicine has traveled to the towns of La Hicaca and Coyoles in rural Honduras. In 2010, a new encounter method was employed during the brigade in Coyoles. Objectives. To examine the differences in clinical encounters and adherence with chronic diseases and public health screening between the traditional and team-based encounter methods. Methods. Chi-square analysis was used to determine statistical significance between encounter methods over several variables used in the standard interview form. Results. 314 patients were interviewed using the team-based approach, and 153 patients were interviewed with the traditional model. Statistically significant increases in compliance using the team-based method were observed with diabetes screening and selecting candidacy for antihelminthic therapy. Other variables with significantly increased compliance using the team-based method were compliance with checking a blood glucose value, diagnosing GERD, and prescribing medication such as analgesics and multivitamins. Conclusion. Our results show a statistically significant increase in compliance with data collection and clinical screening using the new team-based encounter method. This design provides a more goal-oriented approach to the patient interview. These data will help guide more effective delivery of health care on future medical relief trips to Honduras.
Does Acupuncture Needling Induce Analgesic Effects Comparable to Diffuse Noxious Inhibitory Controls?
Authors: Schliessbach Juerg , van der Klift Eveline , Siegenthaler Andreas , Arendt-Nielsen Lars , Curatolo Michele , Streitberger Konrad
Published: July 2011

Diffuse noxious inhibitory control (DNIC) is described as one possible mechanism of acupuncture analgesia. This study investigated the analgesic effect of acupuncture without stimulation compared to nonpenetrating sham acupuncture (NPSA) and cold-pressor-induced DNIC. Forty-five subjects received each of the three interventions in a randomized order. The analgesic effect was measured using pressure algometry at the second toe before and after each of the interventions. Pressure pain detection threshold (PPDT) rose from 299 kPa (SD 112 kPa) to 364 kPa (SD 144), 353 kPa (SD 135), and 467 kPa (SD 168) after acupuncture, NPSA, and DNIC test, respectively. There was no statistically significant difference between acupuncture and NPSA at any time, but a significantly higher increase of PPDT in the DNIC test compared to acupuncture and NPSA. PPDT decreased after the DNIC test, whereas it remained stable after acupuncture and NPSA. Acupuncture needling at low pain stimulus intensity showed a small analgesic effect which did not significantly differ from placebo response and was significantly less than a DNIC-like effect of a painful noninvasive stimulus.
Attempted Replication of 50 Reported Asthma Risk Genes Identifies a SNP in RAD50 as Associated with Childhood Atopic Asthma
Authors: Murk William , Walsh Kyle , Hsu Ling-I , Zhao Linlu , Bracken Michael B. , DeWan Andrew T.
Published: July 2011

Objectives: Asthma is a childhood disease that is strongly influenced by genetic factors. We sought to replicate an association between single nucleotide polymorphisms (SNPs) of the top-ranked candidate genes and childhood atopic asthma in Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM) study subjects. Methods: Using data from a systematic literature search and an exploratory genome-wide association study conducted in a subset of the PRAM cohort, we followed a strict procedure to generate a ranked list of candidate genes. SNPs in the top 50 genes were genotyped in the full PRAM cohort (n = 103 cases with doc- tor-diagnosed atopic asthma at age 6, and n = 499 controls). Results: The literature search identified 251 prior risk genes from 469 publications. RAD50 (rs2706347) and PTPRE (rs10830196) revealed crude associations with asthma at a Bonferroni-corrected level of significance (p < 0.0011). IL4R (rs1801275), CCL5 (rs2280788), and TBXA2R (rs4523) revealed nominal significance (p < 0.05). When adjusted for race and gender, only rs2706347 in RAD50 remained significantly associated with asthma. SNPs in frequently replicated asthma risk genes, including TNF, IL13, ADAM33, TGFB1, and MS4A2, revealed no association. Conclusion:RAD50 may be a promising candidate asthma risk gene. Lack of evidence of highly reported polymorphisms in the present study highlights the genetic heterogeneity of asthma and emphasizes the need for robust replication of candidate genes.
Interaction between Susceptibility and Environment: Examples from the Digestive Tract
Authors: Rogler Gerhard
Published: July 2011

During the last few years a significant advance has been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). From twin studies it was evident that there is more that 50% concordance of Crohn’s disease (CD) in monozygotic twin pairs, however it is only 3.6% among dizygotic twins. These data indicate that the genetic background may be responsible for 50% of the risk or ‘susceptibility’ to develop CD. Obviously it is not a sufficient condition as otherwise there would be 100% concordance of disease in monozygotic twin pairs. Environmental factors as well must play an important role. This is further supported by the fact that there is only low development in genetic risk factors over ten thousands of years. In contrast, the incidence of CD and ulcerative colitis (UC) has dramatically increased in Western countries in the last 100 years. This further supports the concept of a ‘Western lifestyle factor(s)’ that triggers chronic intestinal inflammation in a genetically susceptible host. The proof of the concept of a genetic susceptibility was achieved in 2001 with the discovery that NOD2 is the most important susceptibility gene for CD. The function of NOD2 has been investigated in detail. NOD2 is an intracellular ‘alarm button’, a receptor recognizing invading bacteria that entered the mucosal wall. NOD2 mutants associated with susceptibility to CD seem to be deficient in their recognition of bacterial wall products. In a genome-wide association study a disease association was found in the autophagy-related 16-like 1 gene (ATG16L1). The ATG16L1 gene encodes a protein in the autophagosome pathway that processes intracellular bacteria. Based on these findings, CD is now discussed as an impaired and inadequate immune reaction to the gut bacteria which are a part of our environment (or perhaps ‘in-vironment’). In addition to NOD2 and ATG16L1, there are more ‘innate’ pathways by which commensal and pathogenic bacteria can directly interact with cells of the intestinal mucosa. The ‘environment concept’ and the ‘genetic concept’ of IBD pathophysiology are converging. With the finding that most susceptibility genes for CD and UC are involved in innate immune mechanisms and the primary defense against bacteria entering the mucosa, for the first time a unifying concept of the ‘genetic pathophysiology hypothesis’ and the ‘environment pathophysiology hypothesis’ of IBD was possible. Bacteria are the link between the environment and mucosal defense system.
Hygiene and Other Early Childhood Influences on the Subsequent Function of the Immune System
Authors: Rook Graham A.W.
Published: July 2011

The current ‘Darwinian’ synthesis of the hygiene (or ‘Old Friends’) hypothesis suggests that the increase in chronic inflammatory disorders that started in Europe in the mid-19th century and progressed until the late 20th century is at least partly attributable to immunodysregulation resulting from lack of exposure to microorganisms that were tasked by co-evolutionary processes with establishing the ‘normal’ background levels of immunoregulation, a role that they perform in concert with the normal microbiota. This is an example of ‘evolved dependence’. The relevant organisms co-evolved with mammals, already accompanied early hominids in the Paleolithic era and are associated with animals, mud and faeces. These organisms often establish stable carrier states, or are encountered continuously in primitive environments as ‘pseudocommensals’ from mud and water. These organisms were not lost during the first epidemiological transition, which might even have resulted in increased exposure to them. However, the crucial organisms are lost progressively as populations undergo the second epidemiological transition (modern urban environment). Recently evolved sporadic ‘childhood infections’ are not likely to have evolved immunoregulatory roles, and epidemiology supports this contention. The consequences of the loss of the Old Friends and distortion of the microbiota are aggravated by other modern environmental changes that also lead to enhanced inflammatory responses (obesity, vitamin D deficiency, pollution (dioxins), etc.). The range of chronic inflammatory disorders affected may be larger than had been assumed (allergies, autoimmunity, inflammatory bowel disease, but also coeliac disease, food allergy, vascular disease, some cancers, and depression/anxiety when accompanied by raised inflammatory cytokines).
Nutritional Influences in Selected Gastrointestinal Diseases
Authors: Lakatos Peter Laszlo , Kiss Lajos S. , Miheller Pal
Published: July 2011

Nutritional factors, as sources of luminal antigens, have been thought to be important factors in the immunopathogenesis of numerous gastrointestinal diseases. In some diseases, the role of the nutritional component is causal in the susceptible host. Such diseases include celiac disease, a common heritable chronic inflammatory condition of the small intestine induced by dietary wheat, rye and barley, in susceptible individuals. Specific HLA-DQ2 and HLA-DQ8 risk alleles are necessary, but not sufficient, for disease development. The well-defined role of HLA-DQ heterodimers encoded by these alleles is to present cereal peptides to CD4+ T cells, activating an inflammatory immune response in the intestine. Genome-wide association studies have been performed which identified the IL2-IL21 risk locus and other genes with immune functions and key roles in thymic T-cell selection. Another example for this group is Wilson’s disease, an autosomal recessive disorder of copper metabolism caused by mutation of the ATP7B gene, resulting in a defect of biliary copper excretion and toxic accumulation in the body, especially in the liver, brain and cornea, resulting in hepatic and/or neurological symptoms. In other diseases, however, the association is less well established. In such endeavor, epidemiological observations may become a valuable part of the overall investigations aimed at identifying dietary factors, which are involved in the initiation and perpetuation of the specific disease. As an example, relationships between nutrition and colorectal cancer have been hypothesized early on (e.g. folate, calcium, vitamin D, red meat). Similarly, intake of certain diet constituents like fat, refined sugar, fruits, vegetables and fiber was reported to be associated with the expression of inflammatory bowel diseases. In addition, in children with active Crohn’s disease, enteral nutrition was found to be equally effective as corticosteroids in induction of remission, with mucosal healing induced by downregulation of mucosal pro-inflammatory cytokine profiles in both the ileum and the colon after enteral nutrition. However, the particular effect of the consumption of each type of food remains questionable in most cases, at least in part because of insufficient data and serious methodological limitations (e.g. recall bias, heterogeneity between collected data, lack of correction for covariates, difficulties in double blinding).
Bacteria as Trigger for Chronic Gastrointestinal Disorders
Authors: Marteau Philippe , Chaput Ulriikka
Published: July 2011

Apart from acute infections, microorganisms may also induce or perpetuate chronic inflammatory diseases and reversible or irreversible proliferation of various cells in the gastrointestinal tract (the extreme being adenocarcinoma and lymphoma). Helicobacter pylori is not only involved in the pathogenesis of lymphoma and gastric adenocarcinoma. The steps and mechanisms of the carcinogenic process involve host predisposition, environmental factors, and strain virulence. The steps of lymphoma genesis include chronic inflammation, acquisition of mucosa-associated lymphoid tissue in the stomach, proliferation of the B lymphocytes in an inflammatory context, acquisition of genetic anomalies and dysregulation of the NF-ĸB pathway. The role of Campylobacter jejuni in immunoproliferative small bowel disease has also been shown and eradication of this bacterium can cure the lymphoma at its early stage. The evidence for the role of some bacteria in colon cancer development is discussed. Opportunistic pathogens are detected in the stools or mucosa of a proportion of subjects with Crohn’s disease. They include Mycobacterium avium paratuberculosis, adherent invasive Escherichia coli, and Clostridium difficile. A dysbiosis has been repeatedly observed in patients with inflammatory bowel disease. Instability of the dominant microbiota and decreased biodiversity (especially in the firmicutes phylum) are major characteristics. The decrease of Faecalibacterium prausnitzii seems to have a prognostic value to predict relapse of Crohn’s disease after surgery. Finally, important perspectives are opened by new tools such as metagenomics and metabolomics of the gastrointestinal ecosystems. Major tracks concern irritable bowel syndrome, colon cancer and obesity.
Mechanisms of Drug Toxicity or Intolerance
Authors: Egan Laurence J.
Published: July 2011

Classically, adverse drug reactions had been considered as type A reactions which are related to the main pharmacological action of the drug and therefore are predictable. Such reactions are predictable, reversible, and usually can be managed by lowering the dose of the offending drug. However, other adverse effects of drugs can occur which are unrelated to the main pharmacological action of the drug – type B reactions. Such adverse effects are termed idiosyncratic and are often initiated by metabolites of the parent drug or by other indirect mechanisms. The detailed understanding of adverse drug events has become a major focus of the regulatory agencies throughout the world. The pharmacotherapy of gastrointestinal and liver disorders is becoming increasingly complex. In recent years, with the advent of novel therapeutic agents to treat a host of disorders, including viral hepatitis, gastrointestinal motility disorders, inflammatory bowel disease and others, the potential for serious clinically relevant drug reactions has increased. In the pharmacotherapy of gastrointestinal and liver diseases, a significant number of adverse events that occur can be explained by drug interactions. Some pharmacokinetic drug interactions are based on the competitive inhibition of the rate of drug metabolism of one of the drugs, leading to an increased concentration of the drug which was not intended. In other examples, the interaction can be mechanistic in which one or more drugs when co-administered potentiate each other’s actions without any change in drug levels, termed pharmacodynamic interactions.
Infections and the Liver
Authors: Eksteen Bertus
Published: July 2011

Background: Hepatitis B (HBV) and hepatitis C virus (HCV) have infected nearly half a billion individuals worldwide and are major indications for liver transplantation. Key requirements to successful outcomes with modern antiviral drugs are favourable host factors. Results: Single nucleotide polymorphisms near the IL28B gene location which encode for interferon (IFN)-λ3 have a large effect in determining the likelihood of patients obtaining a cure from pegylated IFN-α and ribavirin combination therapy or spontaneous clearance of the HCV. 80% of patients who carry two copies of this advantageous variant cleared the virus during IFN therapy and remained virus-free with a sustained viral response. This mutation is more common in Caucasian and Asian populations, whereas it is only found in the 40–50% of sub-Saharan Africans who are known to be more resistant to combination therapy. Similarly, host factors control tolerance to chronic HBV infection and can fluctuate over time with increased risk of progression to cirrhosis and particularly liver cancer. Loss of viral tolerance with reactivation and hepatitis is increasingly seen with the widespread use of biological treatments for diseases such as inflammatory bowel disease or rheumatoid arthritis. Natural disasters and conflicts in some parts of the world have also seen an increase in cases of hepatitis A and E virus infection and highlighted the global public health burden from viral-induced hepatitis. Conclusions: Increased appreciation of the interaction between host factors and the viral life cycles is likely to significantly alter the way we target these infections in the future.
From Aphthous Ulcer to Full-Blown Crohn’s Disease
Authors: Rutgeerts Paul J.
Published: July 2011

At onset, Crohn’s disease (CD) is characterized by transmural inflammation with mucosal ulcerations. In its earliest phase the lesions are mainly aphthous ulcers. The ulcers then become larger, a nodular pattern develops and penetration of the deep ulcers leads to fistulas and collagen deposition to fibrotic strictures. The best model to study the earliest lesions in CD is the postoperative recurrence situation where these early lesions recur within weeks to months after surgery. CD recurrence is triggered by the fecal contents of the gut since temporary diversion prevents the recurrence of bowel inflammation. With the development of newer techniques, such as microarray analysis of total mucosal gene expression and molecular analysis of gut content and mucosal microbiome, this model will allow to shed light on the earliest pathogenic features of CD.
Colon Cancer: A Civilization Disorder
Authors: Watson Alastair J.M. , Collins Paul D.
Published: July 2011

Colorectal cancer arises in individuals with acquired or inherited genetic predisposition who are exposed to a range of risk factors. Many of these risk factors are associated with affluent Western societies. More than 95% of colorectal cancers are sporadic, arising in individuals without a significant hereditary risk. Geographic variation in the incidence of colorectal cancer is considerable with a higher incidence observed in the West. Environmental factors contribute substantially to this variation. A number of these risk factors are associated with a Western lifestyle and could be considered a product of ‘civilization’. Recently, smoking has been recognized as a risk factor. Energy consumption also influences colorectal cancer risk, with obesity increasing risk and exercise reducing risk. However, the strongest contribution to environmental risk for colorectal cancer is dietary. Consumption of fat, alcohol and red meat is associated with an increased risk. Fresh fruit and vegetables and dietary fibre may be protective. Much has been learnt recently about the molecular pathogenesis of colorectal cancer. Colorectal cancer always arises in the context of genomic instability. There is inactivation of the tumour suppressor genes adenomatous polyposis coli, p53, transforming growth factor-β, activation of oncogene pathways including K-ras, and activation of the cyclooxygenase-2, epidermal growth factor receptor and vascular endothelial growth factor pathways. The mechanisms by which some environmental factors modify the mutation risk in these pathways have been described.
Pathophysiology of Non-Alcoholic Steatohepatitis and Basis for Treatment
Authors: Pinzani Massimo
Published: July 2011

Non-alcoholic fatty liver disease (NAFLD) is likely the most common cause of liver disease in adults as well as in children and adolescents. Its occurrence is closely associated with obesity and insulin resistance. NAFLD may lead to non-alcoholic steatohepatitis (NASH) with possible evolution towards cirrhosis and hepatocellular carcinoma. In addition to steatosis, NASH is characterized by necroinflammation and fibrosis. While the presence of simple steatosis can be assessed by imaging studies, the occurrence of NASH and its staging requires a liver biopsy. Along these lines, major efforts are directed at identifying non-invasive methodologies able to discriminate simple NAFLD from NASH and to predict the stage of fibrotic evolution. Current treatment relies on weight loss and exercise, although various insulin-sensitizing agents, antioxidants and anti-inflammatory and antifibrogenic agents are under evaluation.