bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the Contribution of Hemocytes and Autophagy to Drosophila Antiviral Immunity
Authors: Lamiable Olivier , Arnold Johan , de Faria Isaque Joao da Silva , Olmo Roenick Proveti , Bergami Francesco , Meignin Carine , Hoffmann Jules A. , Marques Joao Trindade , Imler Jean-Luc
Published: March 2016

Antiviral immunity in the model organism
Drosophila melanogaster
involves the broadly active intrinsic mechanism of RNA interference (RNAi) and virus-specific inducible responses. Here, using a panel of six viruses, we investigated the role of hemocytes and autophagy in the control of viral infections. Injection of latex beads to saturate phagocytosis, or genetic depletion of hemocytes, resulted in decreased survival and increased viral titers following infection with Cricket paralysis virus (CrPV), Flock House virus (FHV), and vesicular stomatitis virus (VSV) but had no impact on Drosophila C virus (DCV), Sindbis virus (SINV), and Invertebrate iridescent virus 6 (IIV6) infection. In the cases of CrPV and FHV, apoptosis was induced in infected cells, which were phagocytosed by hemocytes. In contrast, VSV did not trigger any significant apoptosis but we confirmed that the autophagy gene
Atg7
was required for full virus resistance, suggesting that hemocytes use autophagy to recognize the virus. However, this recognition does not depend on the Toll-7 receptor. Autophagy had no impact on DCV, CrPV, SINV, or IIV6 infection and was required for replication of the sixth virus, FHV. Even in the case of VSV, the increases in titers were modest in
Atg7
mutant flies, suggesting that autophagy does not play a major role in antiviral immunity in
Drosophila
. Altogether, our results indicate that, while autophagy plays a minor role, phagocytosis contributes to virus-specific immune responses in insects.

IMPORTANCE
Phagocytosis and autophagy are two cellular processes that involve lysosomal degradation and participate in
Drosophila
immunity. Using a panel of RNA and DNA viruses, we have addressed the contribution of phagocytosis and autophagy in the control of viral infections in this model organism. We show that, while autophagy plays a minor role, phagocytosis contributes to virus-specific immune responses in
Drosophila
. This work brings to the front a novel facet of antiviral host defense in insects, which may have relevance in the control of virus transmission by vector insects or in the resistance of beneficial insects to viral pathogens.
HCF1 and OCT2 Cooperate with EBNA1 To Enhance OriP-Dependent Transcription and Episome Maintenance of Latent Epstein-Barr Virus
Authors: Dheekollu Jayaraju , Wiedmer Andreas , Sentana-Lledo Daniel , Cassel Joel , Messick Troy , Lieberman Paul M.
Published: March 2016

Epstein-Barr virus (EBV) establishes latent infections as multicopy episomes with complex patterns of viral gene transcription and chromatin structure. The EBV origin of plasmid replication (OriP) has been implicated as a critical control element for viral transcription, as well as viral DNA replication and episome maintenance. Here, we examine cellular factors that bind OriP and regulate histone modification, transcription regulation, and episome maintenance. We found that OriP is enriched for histone H3 lysine 4 (H3K4) methylation in multiple cell types and latency types. Host cell factor 1 (HCF1), a component of the mixed-lineage leukemia (MLL) histone methyltransferase complex, and transcription factor OCT2 (octamer-binding transcription factor 2) bound cooperatively with EBNA1 (Epstein-Barr virus nuclear antigen 1) at OriP. Depletion of OCT2 or HCF1 deregulated latency transcription and histone modifications at OriP, as well as the OriP-regulated latency type-dependent C promoter (Cp) and Q promoter (Qp). HCF1 depletion led to a loss of histone H3K4me3 (trimethylation of histone H3 at lysine 4) and H3 acetylation at Cp in type III latency and Qp in type I latency, as well as an increase in heterochromatic H3K9me3 at these sites. HCF1 depletion resulted in the loss of EBV episomes from Burkitt's lymphoma cells with type I latency and reactivation from lymphoblastoid cells (LCLs) with type III latency. These findings indicate that HCF1 and OCT2 function at OriP to regulate viral transcription, histone modifications, and episome maintenance. As HCF1 is best known for its function in herpes simplex virus 1 (HSV-1) immediate early gene transcription, our findings suggest that EBV latency transcription shares unexpected features with HSV gene regulation.

IMPORTANCE
EBV latency is associated with several human cancers. Viral latent cycle gene expression is regulated by the epigenetic control of the OriP enhancer region. Here, we show that cellular factors OCT2 and HCF1 bind OriP in association with EBNA1 to maintain elevated histone H3K4me3 and transcriptional enhancer function. HCF1 is known as a transcriptional coactivator of herpes simplex virus (HSV) immediate early (IE) transcription, suggesting that OriP enhancer shares aspects of HSV IE transcription control.
Defensins at the Mucosal Surface: Latest Insights into Defensin-Virus Interactions
Authors: Wilson Sarah S. , Wiens Mayim E. , Holly Mayumi K. , Smith Jason G.
Published: March 2016

Defensins are innate immune effector peptides expressed at mucosal surfaces throughout the human body and are potently antiviral
in vitro
. The role of defensins in viral pathogenesis
in vivo
is poorly understood; however, recent studies have revealed that defensin-virus interactions
in vivo
are complicated and distinct from their proposed antiviral mechanisms
in vitro
. These findings highlight the need for additional research that connects defensin neutralization of viruses in cell culture to
in vivo
antiviral mechanisms.
The Rotavirus Interferon Antagonist NSP1: Many Targets, Many Questions
Authors: Arnold Michelle M.
Published: March 2016

Rotavirus is a leading cause of death due to diarrhea among young children across the globe. Despite the limited coding capacity that is characteristic of RNA viruses, rotavirus dedicates substantial resources to avoiding the host innate immune response. Among these strategies is use of the interferon antagonist protein NSP1, which targets cellular proteins required for interferon production to be degraded by the proteasome. Although numerous cellular targets have been described, there remain many questions about the mechanism of NSP1 activity and its role in promoting replication in specific host species.
Protocol for a feasibility study to inform the development of a multicentre randomised controlled trial of asthma-tailored pulmonary rehabilitation versus usual care for individuals with severe asthma
Authors: Majd Sally , Apps Lindsay D , Hudson Nicky , Hewitt Stacey , Eglinton Elizabeth , Murphy Anna , Bradding Peter , Singh Sally , Green Ruth , Evans Rachael
Published: March 2016

Introduction

Pulmonary rehabilitation with core components of exercise training and multiprofessional education is an integral part of the management of patients with chronic lung disease. International guidelines for individuals with asthma recommend exercise as exercise improves symptoms, indices of cardiopulmonary efficiency, health status and psychosocial outcome. However, there is little published evidence evaluating safety and acceptability of exercise training for individuals with severe asthma and there are concerns regarding exercise-induced asthma. We propose a feasibility study for a multicentre randomised controlled trial (RCT) of asthma-tailored pulmonary rehabilitation (asthma-tailored PR) versus usual care in individuals with severe asthma.

Methods and analysis

The study will be conducted in three stages. Adults with severe asthma will be included if they have persistent symptoms despite being at step 4 or 5 of the British Thoracic Society guidelines. Stage 1: semistructured interviews will be used in a sample of 20–30 individuals with severe asthma to understand the experience and attitudes of this population towards exercise. Stage 2: eight focus groups of at least six healthcare professionals involved in the care of patients with severe asthma will be conducted to understand their attitudes towards exercise for this population. Stage 3: a small-scale RCT of the proposed multicentre RCT of asthma-tailored PR versus usual care for individuals with severe asthma will be conducted. The primary outcome measures will be recruitment, retention and adverse event rates. Semistructured interviews with participants of stage 3 will be used to identify further barriers or facilitators to participation in PR and the trial. Thematic analysis will be used for the interpretation of all interviews.

Ethics and dissemination

The study results will inform the design of a larger multicentre RCT. The National Research Ethics Service Committee East Midland approved the study protocol.

Trial registration number

ISRCTN96143888.
Variations by state in physician disciplinary actions by US medical licensure boards
Authors: Harris John Alexander , Byhoff Elena
Published: March 2016

Objective

To investigate the variation in the rate of state medical board physician disciplinary actions between US states.

Methods

Longitudinal study of state medical board physician disciplinary action rates using the US National Practitioner Data Bank and American Medical Association estimates of physician demographics across all 50 states and the District of Columbia from 2010 to 2014. Results were reliability adjusted using a multilevel logistic model controlling for year of disciplinary action, physicians per capita in each state and the rate of malpractice claims per physician in each state.

Results

From 2010 to 2014, there were a total of 5046 506 physician licensure years present. Medical boards reported a total of 21 647 disciplinary actions, of which 5137 (23.7%) were major disciplinary actions involving revocation, suspension or surrender of licence. The mean, reliability-adjusted rate of all disciplinary actions was 3.76 (95% CI 3.21 to 4.42) with a significant variation between states. State rates ranged from 2.13 (95% CI 1.86 to 2.45) to 7.93 (95% CI 6.33 to 9.93) actions per 1000 physicians. The mean rate of major disciplinary actions was 2.71 (95% CI 1.93 to 3.82), ranging from 0.64 (95% CI 0.53 to 0.76) to 2.71 (95% CI 1.93 to 3.82) actions per 1000 physicians. The correlation between the rate of major disciplinary action and minor disciplinary actions was 0.34.

Conclusions

There is a significant, fourfold variation in the annual rate of medical board physician disciplinary action by state in the USA. When indicated, state medical boards should consider policies aimed at improving standardisation and coordination to provide consistent supervision to physicians and ensure public safety.
Anaemia secondary to erythropoietin resistance: important predictor of adverse outcomes in chronic obstructive pulmonary disease
Authors: Sharma Rahul Kumar , Chakrabarti Shibdas
Published: March 2016

Purpose

Anaemia is increasingly being linked to chronic obstructive pulmonary disease (COPD) as comorbidity with erythropoietin resistance secondary to chronic inflammation is hypothesised to have some role. This study purported to evaluate the occurrence of anaemia in COPD and its association with inflammatory markers, erythropoietin levels, severity and exacerbations of COPD.

Methods

Two hundred patients with COPD (90% men, mean age 62.4±8.33 years) were enrolled and subjected to detailed clinical and laboratory evaluation, including complete blood count, erythropoietin levels, C-reactive protein (CRP), pulmonary function test, blood gas analysis and chest X-ray. Severity of COPD was defined on the basis of forced expiratory volume in 1 s according to GOLD guidelines.

Results

Anaemia was diagnosed in 14% of patients (n=28, predominantly normocytic normochromic type (92.8%)) and polycythmia in 5% of patients (n=10). The prevalence of anaemia increased with increasing severity of COPD (stage 2: 8%, stage 3: 14.4% and stage 4: 17.2%; p=0.46). Serum erythropoietin was significantly higher in more advanced COPD, with mean levels being 30.2±6.5, 31.78±8.09 and 39.33±7.68 mIU/mL in stage 2, 3 and 4 respectively. Moreover erythropoietin levels inversely correlated with mean haemoglobin levels(r=−0.25), indicating erythropoietin resistance. CRP reactivity increased with increasing stage of disease in patients with anaemia (p=0.026). On follow-up, significant inverse correlation was observed between haemoglobin and COPD exacerbations (p<0.001).

Conclusions

Anaemia is a significant comorbidity of COPD with a negative prognostic impact on lung health. It can be ascribed to a state of systemic inflammation resulting in blunting of erythropoietin response with increasing severity of disease, leading to greater morbidity and hospitalisation.
Prediction of maintenance cost for road construction equipment: a case study
Authors: Bayzid Sharif Mohammad , Mohamed Yasser , Al-Hussein Maria
Published: March 2016

Equipment maintenance cost is significant in construction operations budgets. This study proposes a systematic approach to predict maintenance cost of road construction equipment. First, maintenance cost data over more than 10 years was collected from a partner company’s equipment management information system. Data was cleaned and analyzed to obtain a general understanding of maintenance costs trends. Next, traditional cumulative cost models and alternative data mining models were generated to predict maintenance cost based on available equipment and operation attributes. Data mining models were evaluated and validated using portions of the collected data that have not been used in model development. Data collection, analyses, modeling, and validation steps are discussed. The paper also presents the performance of different model types. Based on the case study data, regression model trees performed better than other model types with equipment work hours being the most significant parameter for predicting maintenance cost.
Evaluation of rheological behavior and performance to permanent deformation of nanomodified asphalt mixtures with carbon nanotubes
Authors: de Melo João Victor Staub , Trichês Glicério
Published: March 2016

Rutting is one of the most important issues associated with asphalt pavements. This defect leads to the accelerated degradation of the pavement and considerably reduces the level of road safety. This paper reports on the results obtained in the optimization of nanocomposite asphalt containing carbon nanotubes (CNTs) with regard to the resistance to permanent deformation. Nanocomposite asphalts were prepared with the addition of different proportions of CNTs. Based on a study on the empirical and rheological properties of the nanocomposites developed, optimization of the CNT content incorporated into the conventional asphalt binder was carried out. Then two asphalt mixtures were investigated, a reference mixture and a nanomodified mixture with CNTs (optimal content). The rheological evaluations were carried out on four-point fatigue equipment and the resistance to permanent deformation was tested in a traffic simulator (wheel tracking test). The results demonstrate the efficient contribution of the nanocomposite to the resistance to permanent deformation.
Analysis of the traditional vehicle’s running cost and the electric vehicle’s running cost under car-following model
Authors: Tang Tie-Qiao , Xu Ke-Wei , Yang Shi-Chun , Shang Hua-Yan
Published: March 2016

In this paper, we use car-following theory to study the traditional vehicle’s running cost and the electric vehicle’s running cost. The numerical results illustrate that the traditional vehicle’s running cost is larger than that of the electric vehicle and that the system’s total running cost drops with the increase of the electric vehicle’s proportion, which shows that the electric vehicle is better than the traditional vehicle from the perspective of the running cost.
The vasodilatory effect of sulfur dioxide via SGC/cGMP/PKG pathway in association with sulfhydryl-dependent dimerization
Authors: Yao Qiuyu , Huang Yaqian , Liu Angie Dong , Zhu Mingzhu , Liu Jia , Yan Hui , Zhang Qingyou , Geng Bin , Gao Yuansheng , Du Shuxu , Huang Pan , Tang Chaoshu , Du Junbao , Jin Hongfang
Published: March 2016

The present study was designed to explore the role of soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/PKG pathway in sulfur dioxide (SO2)-induced vasodilation. We showed that SO2induced a concentration-dependent relaxation of phenylephrine (PE)-precontracted rat aortic rings in association with an increase in cGMP concentration, whereas l-aspartic acid β-hydroxamate (HDX), an inhibitor of SO2synthase, contracted rings in a dose-dependent manner. Pretreatment of aortic rings with the sGC inhibitor ODQ (30 μM) attenuated the vasodilatory effects of SO2, suggesting the involvement of cGMP pathway in SO2-induced vasodilation. Mechanistically, SO2upregulated the protein levels of sGC and PKG dimers, while HDX inhibited it, indicating SO2could promote cGMP synthesis through sGC activation. Furthermore, the dimerization of sGC and PKG and vasodilation induced by SO2in precontracted rings were significantly prevented by thiol reductants dithiothreitol (DTT). In addition, SO2reduced the activity of phosphodiesterase type 5 (PDE5), a cGMP-specific hydrolytic enzyme, implying that SO2elevated cGMP concentration by inhibiting its hydrolysis. Hence, SO2exerted its vasodilatory effects at least partly by promoting disulfide-dependent dimerization of sGC and PKG, resulting in an activated sGC/cGMP/PKG pathway in blood vessels. These findings revealed a new mode of action and mechanisms by which SO2regulated the vascular tone.
Dual inhibition of renin-angiotensin-aldosterone system and endothelin-1 in treatment of chronic kidney disease
Authors: Komers Radko , Plotkin Horacio
Published: March 2016

Inhibition of the renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in treatment of chronic kidney diseases (CKD). However, reversal of the course of CKD or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. New treatments are needed to enhance protective actions of RAAS inhibitors (RAASis), such as angiotensin-converting enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and improve prognosis in CKD patients. Inhibition of endothelin (ET) system in combination with established RAASis may represent such an approach. There are complex interactions between both systems and similarities in their renal physiological and pathophysiological actions that provide theoretical rationale for combined inhibition. This view is supported by some experimental studies in models of both diabetic and nondiabetic CKD showing that a combination of RAASis with ET receptor antagonists (ERAs) ameliorate proteinuria, renal structural changes, and molecular markers of glomerulosclerosis, renal fibrosis, or inflammation more effectively than RAASis or ERAs alone. Practically all clinical studies exploring the effects of RAASis and ERAs combination in nephroprotection have thus far applied add-on designs, in which an ERA is added to baseline treatment with ACEIs or ARBs. These studies, conducted mostly in patients with diabetic nephropathy, have shown that ERAs effectively reduce residual proteinuria in patients with baseline RAASis treatment. Long-term studies are currently being conducted to determine whether promising antiproteinuric effects of the dual blockade will be translated in long-term nephroprotection with acceptable safety profile.
Calibrated variability of muscle sympathetic nerve activity during graded head-up tilt in humans and its link with noradrenaline data and cardiovascular rhythms
Authors: Marchi Andrea , Bari Vlasta , De Maria Beatrice , Esler Murray , Lambert Elisabeth , Baumert Mathias , Porta Alberto
Published: March 2016

Muscle sympathetic nerve activity (MSNA) variability is traditionally computed through a low-pass filtering procedure that requires normalization. We proposed a new beat-to-beat MSNA variability computation that preserves dimensionality typical of an integrated neural discharge (i.e., bursts per unit of time). The calibrated MSNA (cMSNA) variability technique is contrasted with the traditional uncalibrated MSNA (ucMSNA) version. The powers of cMSNA and ucMSNA variabilities in the low-frequency (LF, from 0.04 to 0.15 Hz) band were computed with those of the heart period (HP) of systolic and diastolic arterial pressure (SAP and DAP, respectively) in seven healthy subjects (age, 20–28 years; median, 22 years; 5 women) during a graded head-up tilt. Subjects were sequentially tilted at 0°, 20°, 30°, 40°, and 60° table inclinations. The LF powers of ucMSNA and HP variabilities were expressed in normalized units (LFnu), whereas all remaining spectral markers were expressed in absolute units. We found that 1) the LF power of cMSNA variability was positively correlated with tilt angle, whereas the LFnu power of the ucMSNA series was uncorrelated; 2) the LF power of cMSNA variability was correlated with LF powers of SAP and DAP, LFnu power of HP and noradrenaline concentration, whereas the relationship of the LFnu power of ucMSNA variability to LF powers of SAP and DAP was weaker and that to LFnu power of HP was absent; and 3) the stronger relationship of cMSNA variability to SAP and DAP spectral markers compared with the ucMSNA series was confirmed individually. The cMSNA variability appears to be more suitable in describing sympathetic control in humans than traditional ucMSNA variability.
Peritoneal dialysis: from bench to bedside and bedside to bench
Authors: Perl Jeffrey , Bargman Joanne M.
Published: March 2016

For patients with end-stage kidney disease unable to receive a kidney transplant, replacement of kidney function with dialysis is necessary to extend life. Peritoneal dialysis (PD) and hemodialysis (HD) are the two major forms of dialysis therapy. HD involves the passage of blood via an extracorporeal circuit whereby removal of small solutes, toxins, and water is achieved across a synthetic, semipermeable dialysis membrane. In contrast, in PD, the dialysis membrane is the highly vascularized internal lining of the peritoneal cavity. Intraperitoneal installation of hypertonic high glucose PD solution creates a transmembrane osmotic and diffusive gradient that facilitates water removal [ultrafiltration (UF)], convection, and diffusion of uremic toxins. Insight into the physiology of solute and water transport across the peritoneal membrane has been enhanced by the proposal of the ′'three-pore model'' of peritoneal membrane transport. Transport characteristics and UF capacity of the peritoneal membrane vary among individuals, and deleterious changes in the membrane may ensue over time. The degree to which these changes are a direct consequence of the type and composition of currently available PD solutions, recurrent infectious episodes, genetic differences among individuals, or a combination thereof is the subject of intense study. Adverse consequences resulting from the systemic and local metabolic effects of intraperitoneal glucose exposure, infection of the PD fluid, PD catheter dysfunction, and patient burnout from self-care often limit the long-term success of the therapy. Research aimed at addressing these challenges will examine the use of more biocompatible PD solutions and strategies aimed at attenuating progressive peritoneal membrane injury.
Ways of calcium reabsorption in the kidney
Authors: Moor Matthias B. , Bonny Olivier
Published: March 2016

The role of the kidney in calcium homeostasis has been reshaped from a classic view in which the kidney was regulated by systemic calcitropic hormones such as vitamin D3 or parathyroid hormone to an organ actively taking part in the regulation of calcium handling. With the identification of the intrinsic renal calcium-sensing receptor feedback system, the regulation of paracellular calcium transport involving claudins, and new paracrine regulators such as klotho, the kidney has emerged as a crucial modulator not only of calciuria but also of calcium homeostasis. This review summarizes recent molecular and endocrine contributors to renal calcium handling and highlights the tight link between calcium and sodium reabsorption in the kidney.
Spontaneous Peritonitis from Perforation of the Colon in Collagenous Colitis
Authors: Freeman HJ , James D , Mahoney CJ
Published: March 2016

A 37-year-old woman presented with an acute abdomen following the onset of watery diarrhea. Spontaneous peritonitis was detected, along with evidence of a focal sigmoid colon perforation. Subsequent postoperative colonoscopic studies revealed collagenous colitis with a focal, deep, nongranulomatous ulcer in the sigmoid colon. Although the literature suggests that collagenous colitis tends to have a relatively 'benign' clinical course characterized by chronic or episodic watery diarrhea. Potentially serious and life- threatening complications may occur in this microscopic form of inflammatory bowel disease.
Acute Lower Gastrointestinal Bleeding: Part I
Authors: Enns Robert
Published: March 2016

Acute lower gastrointestinal (LGI) bleeding is typically caused by vascular malformations, diverticuli and neoplasia. Although endoscopic evaluation of the colon is relatively standard in stable patients with LGI bleeding, those with significant ongoing hemorrhage are often more difficult to evaluate endoscopically. Other investigative techniques such as nuclear scintigraphy, angiography and surgical exploration have been commonly used in unstable patients with LGI bleeding when the exact site is unknown. These investigative techniques have had variable measures of success. This two‐part review evaluates the literature in an attempt to review the optimal investigative approach in patients with LGI hemorrhage, in particular patients who have had significant and ongoing bleeding. Part 1 of this article concentrates on the etiology of LGI hemorrhage, followed in a subsequent article by diagnostic and management strategies. Following the review, a consensus update will be included with guidelines for clinical use.
Treatment of Sclerosing Mesenteritis with Corticosteroids and Azathioprine
Authors: Bala Anand , Coderre Sylvain P , Johnson Douglas RE , Nayak V
Published: March 2016

Sclerosing (idiopathic) mesenteritis is a rare disease that may present with abdominal pain or bowel obstruction. A 21‐year‐old man was diagnosed with sclerosing mesenteritis, and treated with a partial ileal resection and defunctioning ileostomy. He was subsequently started on corticosteroids and azathioprine. Five months later, at the time of ileostomy reversal, he was disease‐free. The diagnosis and management of this disease are discussed.
Characteristics of Colorectal Cancer that Produce Positive Immunochemical Occult Blood Test Results on Stool Obtained by Digital Rectal Examination
Authors: Nakama Hidenori , Zhang Bing , Abdul Fattah ASM , Kamijo Noboru , Zhang Xing
Published: March 2016

OBEJCTIVE: To clarify the clinicopathological features of colorectal cancer that show positive results on an immunochemical fecal occult blood test of stool obtained by digital rectal examination.

METHODS: In a cross-sectional study, 9952 subjects received both an immunochemical fecal occult blood test of stool obtained by digital rectal examination and colonoscopy annually over a nine-year period of medical checkups; 64 patients with colorectal cancer were identified. The study subjects comprised 39 patients with colorectal cancer who had positive results (positive group) and 25 patients with colorectal cancer who had negative results (negative group) on an immunochemical fecal occult blood test of stool obtained by digital rectal examination. The positive and negative groups were compared in terms of their individual factors, such as site, size, Dukes classification and histological type of the cancer lesions.

RESULTS: The prevalence of rectal cancers was higher in the positive group than in the negative group (P<0.05), but there were no differences between the two groups with respect to any other factors.

CONCLUSIONS: These findings indicate that stool obtained during the digital rectal examination is unsuitable for detecting fecal occult blood, especially for the detection of proximal colon neoplasms.
Clinical Perspectives - Biologics in IBD: What's All the Fuss?
Authors: Steinhart Hillary
Published: March 2016

Up until the present time, agents with relatively nonspecific anti-inflammatory or immunomodulatory effects such as 5-acetylsalicylic acid, corticosteroids and azathioprine have been the mainstay of inflammatory bowel disease medical therapy. These drugs have been quite useful in one or more clinical settings, but they have been hampered by modest efficacy, significant toxicity or both. With greater understanding of the specific pathways of the gut mucosal immune response, it is hoped that newer biologic response modifiers will provide better efficacy, with an improved adverse event profile compared with older existing therapies. This article examines the evidence behind the use of biologic therapies such as anti-tumour necrosis factor-alpha, interleukin-10, interleukin-11, anti-integrin antibody and antisense intercellular adhesion molecule-1 oligonucleotide.
Liver Failure with Marked Hyperferritinemia: ‘Ironing Out’ the Diagnosis
Authors: Natsheh Susan E , Roberts Eve A , Ngan Bo , Chait Peter , Ng Vicky Lee
Published: March 2016

Hemophagocytic lymphohistiocytosis (HLH) may manifest as neonatal liver failure characterized by hepatosplenomegaly, profound coagulopathy, ascites and hyperbilirubinemia. Marked hyperferritinemia may be present in these patients, mimicking perinatal hemochromatosis. Tissue specimens are critical in distinguishing these two diseases and in directing management. Clinical recognition and diagnosis of HLH can be difficult but are crucial for appropriate therapy and genetic counselling. Liver transplantation is absolutely contraindicated for patients with HLH but may be the only life‐saving treatment modality for patients with perinatal hemochromatosis.
Liver Enzymes as Surrogate Markers of Hepatitis C Histopathology – Avoiding the Liver Biopsy Needle?
Authors: Wong Stephen GM , Yoshida Eric M
Published: March 2016

A retrospective cohort study of 79 patients with chronic hepatitis C was performed to assess the predictive nature of various variables (age, sex, route of transmission, extent of steatosis, alcohol consumption and serum aminotransferase values), with the underlying hepatic histopathology. The newly modified Knodell histological activity index by Desmet et al (1), which separately scores the inflammation from the fibrosis on the liver biopsy, was used. Using stepwise multivariate logistic regression, it was discovered that serum aspartate aminotransferase (AST) values had a predictive relationship with overall histological activity (r=0.62), portal inflammation (r=0.58), piecemeal necrosis (r=0.61) and extent of hepatic fibrosis (r=0.64). Serum AST values correctly predicted the inflammatory grade in 63 of 79 (80%) patients, and the fibrosis stage in 50 of 79 (63%) patients - higher than the predictive values of ALT. Serum alanine aminotransferase (ALT) values did not correlate with the degree of histological inflammation (r=0.39) but did correlate mildly with the extent of hepatic fibrosis (r=0.51). There were no significant correlations of the other variables with histological inflammation or fibrosis.
A Case ofHistoplasma capsulatumCausing Granulomatous Liver Disease and Addisonian Crisis
Authors: Wong P , Houston S , Power B , Lalor E , Bain VG
Published: March 2016

A 56-year-old man with persistently elevated liver enzyme levels, fatigue, lethargy and a 9.0 kg weight loss over six months underwent a percutaneous liver biopsy that demonstrated multiple granulomas. Screening serologies were positive for histoplasmosis, and he was started on itraconazole treatment. He returned to hospital the same night with coffee-ground emesis and in Addisonian crisis requiring parenteral steroids and intensive care unit support. An abdominal computed tomography scan revealed bilaterally enlarged, nonenhancing adrenal glands suggestive of infarcts, presumed secondary to histoplasmosis. Treatment was initiated with amphotericin B, andHistoplasma capsulatumwas cultured from his urine and cerebrospinal fluid. A serum immunodiffusion test was also positive for both H and M bands, indicating active infection withHistoplasmosisspecies. His serum and urine samples were also weakly positive for the antigen. Despite complications of renal failure, pneumonia and congestive heart failure, he recovered with medical therapy and was discharged home to complete a prolonged course of itraconazole therapy. While hepatic granulomas often reflect an occult disease process, the cause may remain undiscovered in 30% to 50% of patients despite exhaustive investigations.H capsulatumis an uncommon cause of granulomatous liver disease, and with its protean clinical presentation, a high index of suspicion is needed to make the diagnosis and avoid the potentially high fatality rate associated with disseminated infection.
Gastric Cancer: Past, Present and Future
Authors: Chan Annie On-On , Wong Benjamin Chun-Yu , Lam Shiu-Kum
Published: March 2016

Gastric cancer remains a major cause of cancer mortality in the world. However, in the past 10 decades, the view of gastric cancer has been changing. This includes the unexplained decline in the incidence of the cancer, the proximal shift of the cancer in the stomach, the identification ofHelicobacter pylorias an etiological agent, rapid development in molecular tumour biology, new treatment modalities and the adoption of mass screening for prevention. This article reviews the changing views of gastric cancer and the latest developments.
Repair of Postoperative Abdominal Hernia in a Child with Congenital Omphalocele Using Porcine Dermal Matrix
Authors: Lambropoulos V. , Mylona E. , Mouravas V. , Tsakalidis C. , Spyridakis I. , Mitsiakos G. , Karagianni P.
Published: March 2016

Introduction.Incisional hernias are a common complication appearing after abdominal wall defects reconstruction, with omphalocele and gastroschisis being the most common etiologies in children. Abdominal closure of these defects represents a real challenge for pediatric surgeons with many surgical techniques and various prosthetic materials being used for this purpose.Case Report.We present a case of repair of a postoperative ventral hernia occurring after congenital omphalocele reconstruction in a three-and-a-half-year-old child using an acellular, sterile, porcine dermal mesh.Conclusion.Non-cross-linked acellular porcine dermal matrix is an appropriate mesh used for the reconstruction of abdominal wall defects and their postoperative complications like large ventral hernias with success and preventing their recurrence.
IncF Plasmids Are Commonly Carried by Antibiotic ResistantEscherichia coliIsolated from Drinking Water Sources in Northern Tanzania
Authors: Lyimo Beatus , Buza Joram , Subbiah Murugan , Temba Sylivester , Kipasika Honest , Smith Woutrina , Call Douglas R.
Published: March 2016

The aim of this study was to identify the replicon types of plasmids, conjugation efficiencies, and the complement of antibiotic resistance genes for a panel of multidrug resistantE. coliisolates from surface waters in northern Tanzania. Standard membrane filtration was used to isolate anduidAPCR was used to confirm the identity of strains asE. coli. Antibiotic susceptibility was determined by breakpoint assay and plasmid conjugation was determined by filter-mating experiments. PCR and sequencing were used to identify resistance genes and PCR-based replicon typing was used to determine plasmid types. Filter mating experiments indicated conjugation efficiencies ranged from 10−1to 10−7. Over 80% of the donor cells successfully passed their resistance traits and eleven different replicon types were detected (IncI1, FIC, P, FIIA, A/C, FIB, FIA, H12, K/B B/O, and N). IncF plasmids were most commonly detected (49% of isolates), followed by types IncI1 and IncA/C. Detection of these public health-relevant conjugative plasmids and antibiotic resistant traits in Tanzanian water suggests the possible pollution of these water sources from human, livestock, and wild animal wastes and also shows the potential of these water sources in the maintenance and transmission of these resistance traits between environments, animals, and people.
TheNLRP3 rs10754558Polymorphism Is Associated with the Occurrence and Prognosis of Coronary Artery Disease in the Chinese Han Population
Authors: Zhou Dong , Wang Xinhong , Chen Tao , Wen Wen , Liu Yang , Wu Yue , Yuan Zuyi
Published: March 2016

The objective of this study is to investigate the potential association of theNLRP3 rs10754558andCARD8 rs2043211polymorphisms with the occurrence and prognosis of CAD. Gene polymorphisms were analyzed using the ABI PRISM-Snapshot multiplex method in 515 CAD patients and 401 control subjects. The serum level of IL-1βwas investigated by ELISA assays. The clinical endpoints were evaluated during a median follow-up period of 32 months. TheNLRP3 rs10754558gene polymorphism was significantly associated with the occurrence of CAD, while theCARD8 rs2043211gene polymorphism was not involved. Patients carrying G allele ofNLRP3 rs10754558had more severe coronary artery stenosis. Multivariable analysis revealed a significant association of the G allele with major adverse cardiac event. The serum IL-1βconcentrations in patients with GG genotype were significantly increased compared with those in the patients with CC genotype. Our findings for the first time show that theNLRP3rs10754558 polymorphism is involved in the occurrence of CAD in the Chinese Han population; and G allele can effectively predict clinical outcome of CAD. The G allele susceptibility to CAD is maybe associated with the increased level of serum IL-1β.
Investigations of Electron Properties of Carbon Nanotubes Decorated with Platinum Nanoparticles with Their Varying Fraction
Authors: Dobrzańska-Danikiewicz Anna , Łukowiec Dariusz , Kubacki Jerzy
Published: March 2016

The paper presents the outcomes of investigations into electron properties and a qualitative and quantitative analysis of the chemical composition of unmodified carbon nanotubes with comparison to nanotubes decorated with platinum nanoparticles. The fabricated nanocomposite materials of the CNT-Pt type differed in a varying mass concentration of platinum nanoparticles (5, 10, and 20% of Pt). X-ray photoelectron spectroscopy (XPS) was employed to examine the structure and to analyse chemical composition. Survey spectra measurements within a wide range of the binding energy of 0–1400 eV were performed in the first phase of the investigations. The core lines of C1s carbon, Pt4f platinum, and O1s oxygen and a valence band were then measured. The chemical composition of the studied materials was determined based on the measured spectra of the core lines. The purpose of the investigations is to determine the effect of platinum nanoparticles on the structure and electron properties of the fabricated CNT-Pt nanocomposites.
Influence of Cultural and Pest Management Practices on Performance of Runner, Spanish, and Virginia Market Types in North Carolina
Authors: Lassiter Bridget R. , Jordan David L. , Wilkerson Gail G. , Shew Barbara B. , Brandenburg Rick L.
Published: March 2016

Virginia market type peanut (Arachis hypogaeaL.) cultivars are grown primarily in North Carolina, South Carolina, and Virginia in the US, although growers in these states often plant other market types if marketing opportunities are available. Information on yield potential and management strategies comparing these market types is limited in North Carolina. In separate experiments, research was conducted to determine response of runner, Spanish, and Virginia market types to calcium sulfate and inoculation withBradyrhizobiumat planting, planting and digging dates, planting patterns, and seeding rates. In other experiments, control of thrips (Frankliniellaspp.) using aldicarb, southern corn rootworm (Diabrotica undecimpunctataHowardi) using chlorpyrifos, eclipta (Eclipta prostrataL.) using threshold-based postemergence herbicides, and leaf spot disease (caused by the fungiCercospora arachidicolaandCercosporidium personatum) fungicide programs was compared in these market types. Results showed that management practice and market types interacted for peanut pod yield in only the planting date experiment. Yield of runner and Virginia market types was similar and exceeded yield of the Spanish market type in most experiments.
Near-Exact Distributions for Likelihood Ratio Statistics Used in the Simultaneous Test of Conditions on Mean Vectors and Patterns of Covariance Matrices
Authors: Coelho Carlos A. , Marques Filipe J. , Oliveira Sandra
Published: March 2016

The authors address likelihood ratio statistics used to test simultaneously conditions on mean vectors and patterns on covariance matrices. Tests for conditions on mean vectors, assuming or not a given structure for the covariance matrix, are quite common, since they may be easily implemented. But, on the other hand, the practical use of simultaneous tests for conditions on the mean vectors and a given pattern for the covariance matrix is usually hindered by the nonmanageability of the expressions for their exact distribution functions. The authors show the importance of being able to adequately factorize the c.f. of the logarithm of likelihood ratio statistics in order to obtain sharp and highly manageable near-exact distributions, or even the exact distribution in a highly manageable form. The tests considered are the simultaneous tests of equality or nullity of means and circularity, compound symmetry, or sphericity of the covariance matrix. Numerical studies show the high accuracy of the near-exact distributions and their adequacy for cases with very small samples and/or large number of variables. The exact and near-exact quantiles computed show how the common chi-square asymptotic approximation is highly inadequate for situations with small samples or large number of variables.
The Identification and Synthesis of Lead Apatite Minerals Formed in Lead Water Pipes
Authors: Hopwood Jeremy D. , Derrick Glyn R. , Brown David R. , Newman Christopher D. , Haley John , Kershaw Richard , Collinge Mike
Published: March 2016

Phosphate is added to drinking water in the UK to minimise the release of lead from lead water pipes. The phosphate encourages the formation of insoluble lead apatites on the walls of the pipe. Hydroxylpyromorphite Pb5(PO4)3OH is the lead apatite that is most often used to model lead levels in tap water; however, its presence has not been confirmed. Our aims were to identify the lead pipe apatite and synthesise it. The synthetic mineral would then be used in future solubility studies to produce better predictions of lead levels in tap water. XRD and FTIR were used to characterise the minerals on a range of lead pipes. Pyromorphite and hydroxylpyromorphite were absent and instead a range of mixed calcium lead apatites were present. For every five lead ions in the general formula Pb5(PO4)3X between one and two ions were replaced with calcium and there was evidence of substitution ofPO43-by eitherCO32-orHPO42-. Calcium lead apatites with similar unit cell dimensions to those found on lead water pipes were then synthesised. The calcium : lead ratio in these reaction mixtures was in excess of 500 : 1 and the resulting crystals were shown by TEM to be nanosized rods and flakes. The synthetic apatites that most closely resembled the unit cell dimensions of the apatites on lead water pipes were shown to be Pb3.4Ca1.3(PO4)3Cl0.03OH0.97, Pb3.6Ca1.2(PO4)3Cl0.07OH0.93, and Pb3.6Ca1.2(PO4)3Cl0.27OH0.73.
A Wearable Wireless Energy Link for Thin-Film Batteries Charging
Authors: Monti Giuseppina , Corchia Laura , De Benedetto Egidio , Tarricone Luciano
Published: March 2016

A wireless charger for low capacity thin-film batteries is presented. The proposed device consists of a nonradiative wireless resonant energy link and a power management unit. Experimental data referring to a prototype operating in the ISM band centered at 434 MHz are presented and discussed. In more detail, in order to facilitate the integration into wearable accessories (such as handbags or suitcases), the prototype of the wireless energy link was implemented by exploiting a magnetic coupling between two planar resonators fabricated by using a conductive fabric on a layer of leather. From experimental data, it is demonstrated that, at 434 MHz, the RF-to-RF power transfer efficiency of the link is approximately 69.3%. As for the performance of the system as a whole, when an RF power of 7.5 dBm is provided at the input port, a total efficiency of about 29.7% is obtained. Finally, experiments performed for calculating the charging time for a low capacity thin-film battery demonstrated that, for RF input power higher than 6 dBm, the time necessary for recharging the battery is lower than 50 minutes.
MET Exon 14 Alterations in Lung Cancer: Exon Skipping Extends Half-Life
Authors: Drilon Alexander
Published: March 2016

MET exon 14 alterations are a diverse group of mutations, many of which disrupt splice acceptor or donor sites leading to exon 14 skipping, impaired receptor degradation, and oncogenic transformation. These alterations are clinically targetable with MET-directed therapy. Clin Cancer Res; 22(12); 2832–4. ©2016 AACR.

See related article by Tong et al., p. 3048
Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma
Authors: Lescarbeau Rebecca S. , Lei Liang , Bakken Katrina K. , Sims Peter A. , Sarkaria Jann N. , Canoll Peter , White Forest M.
Published: March 2016

Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine-mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors. To assess the role of this checkpoint as a potential therapeutic target, syngeneic primary cell lines derived from these tumors were treated with MK-1775, an inhibitor of Wee1, the kinase responsible for CDK1 Y15 phosphorylation. MK-1775 treatment led to mitotic catastrophe, as defined by increased DNA damage and cell death by apoptosis. To assess the extensibility of targeting Wee1/CDK1 in GBM, patient-derived xenograft (PDX) cell lines were also treated with MK-1775. Although the response was more heterogeneous, on-target Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line. These results were also validated in vivo, where single-agent MK-1775 demonstrated an antitumor effect on a flank PDX tumor model, increasing mouse survival by 1.74-fold. This study highlights the ability of unbiased quantitative phosphoproteomics to reveal therapeutic targets in tumor models, and the potential for Wee1 inhibition as a treatment approach in preclinical models of GBM. Mol Cancer Ther; 15(6); 1332–43. ©2016 AACR.