bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced age influences the dynamic changes in circulating C-reactive protein following injury
Authors: Pinato David J , Bains Jasmeen , Irkulla Sashidhar , Pomroy Josh , Ujam Bedri , Gaze David , Mendall Michael A
Published: March 2013

Background

The concentration of C-reactive protein (CRP), a biomarker of systemic inflammation, is determined by genetic, clinical and demographic factors including gender, smoking and body mass index (BMI). The influence of age on CRP dynamic changes following insult has, however, been poorly characterised.

Methods

We used unilateral hernia repair as a model of standardised insult to investigate the influence of baseline demographic and clinico-pathological factors affecting the dynamic changes in CRP, interleukin (IL) 6 and tumour necrosis factor-α over a time course of 48 h following injury.

Results

We derived CRP negativisation kinetics on 100 prospectively enrolled male subjects with mean age of 60.6 years (range 24–90 years) and mean BMI of 25.7 kg/m2(range 17.9–37 kg/m2). Patients who failed to normalise CRP to<10 mg/l at 48 h (n=74) were significantly older (p<0.001), had longer surgical times (p=0.05), higher waist/hip ratio (p=0.02). Multiple regression analysis confirmed age as the only independent predictor of delayed CRP normalisation (p=0.03). Persistent CRP elevation was associated with higher peak CRP values (p<0.001), higher IL-6 concentrations at 24 (p=0.01) and 48 h (p=0.03).

Conclusions

CRP decline following insult is delayed in elderly patients as a result of unopposed IL-6 release. Age should be routinely incorporated in the assessment of CRP response to avoid misinterpretation of age-related delay in CRP clearance with ongoing systemic inflammation.
Developing a cumulative anatomic scoring system for military perineal and pelvic blast injuries
Authors: Mossadegh Somayyeh , Midwinter M , Parker P
Published: March 2013

Background

Improvised explosive device (IED) yields in Afghanistan have increased resulting in more proximal injuries. The injury severity score (ISS) is an anatomic aggregate score of the three most severely injured anatomical areas but does not accurately predict severity in IED related pelvi-perineal trauma patients. A scoring system based on abbreviated injury score (AIS) was developed to reflect the severity of these injuries in order to better understand risk factors, develop a tool for future audit and improve performance.

Method

Using standard AIS descriptors, injury scales were constructed for the pelvis (1, minor to 6, maximal). The perineum was divided into anterior and posterior zones as relevant to injury patterns and blast direction with each soft tissue structure being allocated a score from its own severity scale. A cumulative score, from 1 to 36 for soft tissue, or a maximum of 42 if a pelvic fracture was involved, was created for all structures injured in the anterior and posterior zones.

Results

Using this new scoring system, 77% of patients survived with a pelvi-perineal trauma score (PPTS) below 5. There was a significant increase in mortality, number of pelvic fractures and amputations with increase in score when comparing the first group (score 1–5) to the second group (score 6–10). For scores between 6 and 16 survival was 42% and 22% for scores between 17 and 21. In our cohort of 62 survivors, 1 patient with an IED related pelvi-perineal injury had a ‘theoretically un-survivable’ maximal ISS of 75 and survived, whereas there were no survivors with a PPTS greater than 22 but this group had no-one with an ISS of 75 suggesting ISS is not an accurate reflection of the true severity of pelvi-perineal blast injury.

Conclusions

This scoring system is the initial part of a more complex logistic regression model that will contribute towards a unique trauma scoring system to aid surgical teams in predicting fluid requirements and operative timelines. In austere environments, it may also help to prevent futile resuscitations. Better correlation between measurement of severity and outcome would aid performance improvement monitoring. In the longer term it will also allow benchmarking of current survival rates and comparisons in the future.
Managing endocrine dysfunction following blast injury to the male external genitalia
Authors: Woods David R , Phillip R , Quinton R
Published: March 2013

Blast injury to the external genitalia is associated with considerable morbidity, including the risk of primary hypogonadism due to insufficient testosterone. It is of the utmost importance that, prior to any testosterone replacement being commenced, serious consideration is given to sperm retrieval. The clinical and biochemical picture of hypogonadism allows a relatively straightforward diagnosis in most cases although it is important to be alert to the possibility of hypogonadism in the context of partial testicular tissue preservation. It is also prudent to consider the possibility of secondary hypogonadism especially in patients with chronic pain or those on opiate medication. Therapeutic options for testosterone replacement are diverse but relatively simple. This article aims to give guidance to the non-specialist in the consideration, diagnosis, and treatment of hypogonadism, with particular reference to blast injury of the external genitalia.
Immediate surgical management of combat-related injury to the external genitalia
Authors: Sharma Davendra M , Bowley D M
Published: March 2013

Patterns of survivable injury after combat injury have changed during recent years as wounding mechanisms have altered, ballistic protection has improved and the military chain of trauma care has evolved. Combat casualties now survive injuries that would have been fatal in previous wars and service personnel can be left with injuries that have significantly detrimental effects on their quality of life. Severe, destructive injuries to the external genitalia are rarely life-threatening, but can be profoundly life altering and the immediate management of these injuries deserves special scrutiny. The general principles of haemorrhage control, wound debridement, urinary diversion, and organ preservation should be observed. An up-to-date review of the management of these relative rare injuries is based on recent, albeit scanty literature and the experiences of managing casualties in the medical evacuation chain of the United Kingdom Defence Medical Services. The rationale behind the current emphasis on post-injury fertility preservation is also discussed.
Anorectal injury in pelvic blast
Authors: Brogden Tom G , Garner JP
Published: March 2013

The signature injury of the Afghanistan campaign has, amongst other things, included an increased incidence of destructive anorectal injury. There is no significant body of evidence about this type of injury on which to base management strategies. This review examines the historical military data, later civilian reports, many of which have challenged the military dogmas of Vietnam, and the spartan contemporaneous military data which does not particularly address pelviperineal blast injury. There is no evidence to support a move away from the doctrine of the four D's (diversion, distal washout, drainage and direct repair), but sound surgical judgement remains the mainstay of managing these challenging and highly morbid injuries.
Complex lower genitourinary reconstruction following combat-related injury
Authors: Uppal L , Anderson P , Evriviades Demetrius
Published: March 2013

There is little data in the literature on the reconstruction of combat related lower genitourinary trauma. Published reports document patterns of injury, which is useful for epidemiological analysis of military trauma, but very few describe the reconstructive management. We aim to describe a systematic multidisciplinary approach to planning the challenging reconstruction of the severely injured male perineum.
Dermatological manifestations and relationship to outcomes of patients admitted to a medical intensive care unit: a study from a tertiary care hospital in India
Authors: Agrawal Poonam , Peter John Victor , George Renu
Published: March 2013

Aim

To determine the prevalence of dermatological manifestations in intensive care unit (ICU) patients and assess its impact on outcomes.

Methods

This was a prospective cohort study of 1013 ICU patients admitted between December 2009 and April 2011. Patients were categorised following an initial screening (within 48 h) and subsequent daily review as those with dermatological manifestations in association with multisystem disorder (category 1), occurring due to treatment or critical illness (category 2), coincidental lesions (category 3) or primary dermatological conditions needing intensive care (category 4). Outcomes included mortality, duration of ventilation and hospitalisation. Factors associated with mortality were explored using univariate and multivariate analyses.

Results

Dermatological manifestations were observed in 427 (42.2%) patients, predominantly of categories 1 (n=159) and 2 (n=160). Common aetiologies were infections (39.3%) and mechanical, thermal or physical injuries (32.8%). Primary dermatological conditions (n=33) included 21 patients with cutaneous infections, 3 with angioedema, 2 each with pemphigus, toxic epidermal necrolysis and psoriasis, and 1 each with Stevens–Johnson syndrome, drug hypersensitivity syndrome and crusted scabies. The presence of cutaneous lesions increased mortality risk (OR 1.56, 95% CI 1.20 to 2.03) and significantly (p<0.001) prolonged ventilation and hospitalisation. Mortality was higher (p<0.001) in patients in categories 4 (65.6%) and 2 (57.5%) compared to those without manifestations (35.5%). After adjusting for age, Acute Physiology And Chronic Health Evaluation II (APACHE-II) score, ventilation and dialysis, the association between dermatological manifestations and mortality was insignificant (OR 1.37, 95% CI 0.97 to 1.95).

Conclusions

Dermatological manifestations are common in ICU patients. Their presence may impact mortality and duration of ventilation and hospitalisation.
Mechanics of Dynamin-Mediated Membrane Fission
Authors: Morlot Sandrine , Roux Aurélien
Published: March 2013

In eukaryotic cells, membrane compartments are split into two by membrane fission. This ensures discontinuity of membrane containers and thus proper compartmentalization. The first proteic machinery implicated in catalyzing membrane fission was dynamin. Dynamin forms helical collars at the neck of endocytic buds. This structural feature suggested that the helix of dynamin could constrict in order to promote fission of the enclosed membrane. However, verifying this hypothesis revealed itself to be a challenge, which inspired many in vitro and in vivo studies. The primary goal of this review is to discuss recent structural and physical data from biophysical studies that have refined our understanding of the dynamin mechanism. In addition to the constriction hypothesis, other models have been proposed to explain how dynamin induces membrane fission. We present experimental data supporting these various models and assess which model is the most probable.
Torque Measurement at the Single-Molecule Level
Authors: Forth Scott , Sheinin Maxim Y. , Inman James , Wang Michelle D.
Published: March 2013

Methods for exerting and measuring forces on single molecules have revolutionized the study of the physics of biology. However, it is often the case that biological processes involve rotation or torque generation, and these parameters have been more difficult to access experimentally. Recent advances in the single-molecule field have led to the development of techniques that add the capability of torque measurement. By combining force, displacement, torque, and rotational data, a more comprehensive description of the mechanics of a biomolecule can be achieved. In this review, we highlight a number of biological processes for which torque plays a key mechanical role. We describe the various techniques that have been developed to directly probe the torque experienced by a single molecule, and detail a variety of measurements made to date using these new technologies. We conclude by discussing a number of open questions and propose systems of study that would be well suited for analysis with torsional measurement techniques.
Solid-State NMR of Nanomachines Involved in Photosynthetic Energy Conversion
Authors: Alia A. , Buda Francesco , de Groot Huub J.M. , Matysik Jörg
Published: March 2013

Magic-angle spinning NMR, often in combination with photo-CIDNP, is applied to determine how photosynthetic antennae and reaction centers are activated in the ground state to perform their biological function upon excitation by light. Molecular modeling resolves molecular mechanisms by way of computational integration of NMR data with other structure-function analyses. By taking evolutionary historical contingency into account, a better biophysical understanding is achieved. Chlorophyll cofactors and proteins go through self-assembly trajectories that are engineered during evolution and lead to highly homogeneous protein complexes optimized for exciton or charge transfer. Histidine-cofactor interactions allow biological nanomachines to lower energy barriers for light harvesting and charge separation in photosynthetic energy conversion. In contrast, in primordial chlorophyll antenna aggregates, excessive heterogeneity is paired with much less specific characteristics, and both exciton and charge-transfer character are encoded in the ground state.
Metabolic Engineering with Plants for a Sustainable Biobased Economy
Authors: Yoon Jong Moon , Zhao Le , Shanks Jacqueline V.
Published: March 2013

Plants are bona fide sustainable organisms because they accumulate carbon and synthesize beneficial metabolites from photosynthesis. To meet the challenges to food security and health threatened by increasing population growth and depletion of nonrenewable natural resources, recent metabolic engineering efforts have shifted from single pathways to holistic approaches with multiple genes owing to integration of omics technologies. Successful engineering of plants results in the high yield of biomass components for primary food sources and biofuel feedstocks, pharmaceuticals, and platform chemicals through synthetic biology and systems biology strategies. Further discovery of undefined biosynthesis pathways in plants, integrative analysis of discrete omics data, and diversified process developments for production of platform chemicals are essential to overcome the hurdles for sustainable production of value-added biomolecules from plants.
Thin-Film Growth and Patterning Techniques for Small Molecular Organic Compounds Used in Optoelectronic Device Applications
Authors: Biswas Shaurjo , Shalev Olga , Shtein Max
Published: March 2013

Rapid advances in research and development in organic electronics have resulted in many exciting discoveries and applications, including organic light-emitting devices for information display and illumination, solar cells, photodetectors, chemosensors, and logic. Organic optoelectronic materials are broadly classified as polymeric or small molecular. For the latter category, solvent-free deposition techniques are generally preferred to form well-defined interfaces and improve device performance. This article reviews several deposition and patterning methods for small molecular thin films and devices, including organic molecular beam deposition, vacuum thermal evaporation, organic vapor phase deposition, and organic vapor jet printing, and compares them to several other methods that have been proposed recently. We hope this review provides a compact but informative summary of the state of the art in organic device processing and addresses the various techniques' governing physical principles.
Composition and State of the Core
Authors: Hirose Kei , Labrosse Stéphane , Hernlund John
Published: March 2013

The composition and state of Earth's core, located deeper than 2,900 km from the surface, remain largely uncertain. Recent static experiments on iron and alloys performed up to inner core pressure and temperature conditions have revealed phase relations and properties of core materials. These mineral physics constraints, combined with theoretical calculations, continue to improve our understanding of the core, in particular the crystal structure of the inner core and the chemical composition, thermal structure and evolution, and possible stratification of the outer core.
Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-α on tight junction proteins and signaling pathways in intestinal epithelial cells
Authors: Fischer Andreas , Gluth Markus , Pape Ulrich-Frank , Wiedenmann Bertram , Theuring Franz , Baumgart Daniel C.
Published: March 2013

Intestinal barrier dysfunction is pivotal in the etiology of inflammatory bowel diseases. Combined clinical and endoscopic remission (“mucosal healing”) in patients who received anti-TNF-α therapies suggests restitution of the intestinal barrier, but the mechanisms involved are largely unknown. We therefore investigated the impact of the anti-TNF-α antibody adalimumab on barrier function in two in vitro models. Combined stimulation of Caco-2 and T-84 cells with interferon-γ and TNF-α resulted in a significant decrease of transepithelial electrical resistance (TEER) within 6 h that was prevented by adalimumab in concentrations down to 100 ng/ml. Adalimumab furthermore antagonized the appearance of irregular membrane undulations and prevented internalization of tight junction proteins upon cytokine exposure. In addition, TNF-α induced a downregulation of claudin-1, claudin-2, claudin-4, and occludin as well as activation of phosphatidylinositol 3-kinase signaling in T-84 but not Caco-2 cells, which was reversed by adalimumab. At the signaling level, adalimumab prevented increased phosphorylation of myosin light chain as well as activation of p38 MAPK and NF-κB accompanying the decline in TEER in both model systems. Pharmacological inhibition of NF-κB signaling partially prevented the TNF-α-induced TEER loss, whereas inhibition of p38 worsened barrier dysfunction in Caco-2 but not T-84 cells. Taken together, these data demonstrate that adalimumab prevents barrier dysfunction induced by TNF-α both functionally and structurally as well as at the level of signal transduction. Barrier protection might therefore constitute a novel mechanism how anti-TNF-α therapy contributes to epithelial restitution and tissue repair in inflammatory bowel diseases.
Emerging neuropeptide targets in inflammation: NPY and VIP
Authors: Chandrasekharan Bindu , Nezami Behtash Ghazi , Srinivasan Shanthi
Published: March 2013

The enteric nervous system (ENS), referred to as the “second brain,” comprises a vast number of neurons that form an elegant network throughout the gastrointestinal tract. Neuropeptides produced by the ENS play a crucial role in the regulation of inflammatory processes via cross talk with the enteric immune system. In addition, neuropeptides have paracrine effects on epithelial secretion, thus regulating epithelial barrier functions and thereby susceptibility to inflammation. Ultimately the inflammatory response damages the enteric neurons themselves, resulting in deregulations in circuitry and gut motility. In this review, we have emphasized the concept of neurogenic inflammation and the interaction between the enteric immune system and enteric nervous system, focusing on neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). The alterations in the expression of NPY and VIP in inflammation and their significant roles in immunomodulation are discussed. We highlight the mechanism of action of these neuropeptides on immune cells, focusing on the key receptors as well as the intracellular signaling pathways that are activated to regulate the release of cytokines. In addition, we also examine the direct and indirect mechanisms of neuropeptide regulation of epithelial tight junctions and permeability, which are a crucial determinant of susceptibility to inflammation. Finally, we also discuss the potential of emerging neuropeptide-based therapies that utilize peptide agonists, antagonists, siRNA, oligonucleotides, and lentiviral vectors.
Large-conductance Ca2+-activated potassium channel in mitochondria of endothelial EA.hy926 cells
Authors: Bednarczyk Piotr , Koziel Agnieszka , Jarmuszkiewicz Wieslawa , Szewczyk Adam
Published: March 2013

In the present study, we describe the existence of a large-conductance Ca2+-activated potassium (BKCa) channel in the mitochondria of the human endothelial cell line EA.hy926. A single-channel current was recorded from endothelial mitoplasts (i.e., inner mitochondrial membrane) using the patch-clamp technique in the mitoplast-attached mode. A potassium-selective current was recorded with a mean conductance equal to 270 ± 10 pS in a symmetrical 150/150 mM KCl isotonic solution. The channel activity, which was determined as the open probability, increased with the addition of calcium ions and the potassium channel opener NS1619. Conversely, the activity of the channel was irreversibly blocked by paxilline and iberiotoxin, BKCa channel inhibitors. The open-state probability was found to be voltage dependent. The substances known to modulate BKCa channel activity influenced the bioenergetics of mitochondria isolated from human endothelial EA.hy926 cells. In isolated mitochondria, 100 μM Ca2+, 10 μM NS1619, and 0.5 μM NS11021 depolarized the mitochondrial membrane potential and stimulated nonphosphorylating respiration. These effects were blocked by iberiotoxin and paxilline in a potassium-dependent manner. Under phosphorylating conditions, NS1619-induced, iberiotoxin-sensitive uncoupling diverted energy from ATP synthesis during the phosphorylating respiration of the endothelial mitochondria. Immunological analysis with antibodies raised against proteins of the plasma membrane BKCa channel identified a pore-forming α-subunit and an auxiliary β2-subunit of the channel in the endothelial mitochondrial inner membrane. In conclusion, we show for the first time that the inner mitochondrial membrane in human endothelial EA.hy926 cells contains a large-conductance calcium-dependent potassium channel with properties similar to those of the surface membrane BKCa channel.
Characterization of the inflammatory and metabolic profile of adipose tissue in a mouse model of chronic hypoxia
Authors: van den Borst Bram , Schols Annemie M. W. J. , de Theije Chiel , Boots Agnes W. , Köhler S. Eleonore , Goossens Gijs H. , Gosker Harry R.
Published: March 2013

In both obesity and chronic obstructive pulmonary disease (COPD), altered oxygen tension in adipose tissue (AT) has been suggested to evoke AT dysfunction, subsequently contributing to metabolic complications. Studying the effects of chronic hypoxia on AT function will add to our understanding of the complex pathophysiology of alterations in AT inflammation, metabolism, and mass observed in both obesity and COPD. This study investigated the inflammatory and metabolic profile of AT after chronic hypoxia. Fifty-two-week-old C57Bl/6J mice were exposed to chronic hypoxia (8% O2) or normoxia for 21 days, after which AT and plasma were collected. Adipocyte size, AT gene expression of inflammatory and metabolic genes, AT macrophage density, and circulating adipokine concentrations were measured. Food intake and body weight decreased upon initiation of hypoxia. However, whereas food intake normalized after 10 days, lower body weight persisted. Chronic hypoxia markedly reduced AT mass and adipocyte size. AT macrophage density and expression of Emr1, Ccl2, Lep, and Tnf were decreased, whereas Serpine1 and Adipoq expression levels were increased after chronic hypoxia. Concomitantly, chronic hypoxia increased AT expression of regulators of oxidative metabolism and markers of mitochondrial function and lipolysis. Circulating IL-6 and PAI-1 concentrations were increased, and leptin concentration was decreased after chronic hypoxia. Chronic hypoxia is associated with decreased rather than increased AT inflammation, and markedly decreased fat mass and adipocyte size. Furthermore, our data indicate that chronic hypoxia is accompanied by significant alterations in AT metabolic gene expression, pointing toward an enhanced AT metabolic rate.
Endothelial Cell Protein C Receptor Opposes Mesothelioma Growth Driven by Tissue Factor
Authors: Keshava Shiva , Sahoo Sanghamitra , Tucker Torry A. , Idell Steven , Rao L. Vijaya Mohan , Pendurthi Usha R.
Published: March 2013

The procoagulant protein tissue factor (F3) is a powerful growth promoter in many tumors, but its mechanism of action is not well understood. More generally, it is unknown whether hemostatic factors expressed on tumor cells influence tissue factor-mediated effects on cancer progression. In this study, we investigated the influence of tissue factor, endothelial cell protein C receptor (EPCR, PROCR), and protease activated receptor-1 (PAR1, F2R) on the growth of malignant pleural mesothelioma (MPM), using human MPM cells that lack or express tissue factor, EPCR or PAR1, and an orthotopic nude mouse model of MPM. Intrapleural administration of MPM cells expressing tissue factor and PAR1 but lacking EPCR and PAR2 (F2RL1) generated large tumors in the pleural cavity. Suppression of tissue factor or PAR1 expression in these cells markedly reduced tumor growth. In contrast, tissue factor overexpression in nonaggressive MPM cells that expressed EPCR and PAR1 with minimal levels of tissue factor did not increase their limited tumorigenicity. More importantly, ectopic expression of EPCR in aggressive MPM cells attenuated their growth potential, whereas EPCR silencing in nonaggressive MPM cells engineered to overexpress tissue factor increased their tumorigenicity. Immunohistochemical analyses revealed that EPCR expression in tumor cells reduced tumor cell proliferation and enhanced apoptosis. Overall, our results enlighten the mechanism by which tissue factor promotes tumor growth through PAR1, and they show how EPCR can attenuate the growth of tissue factor-expressing tumor cells. Cancer Res; 73(13); 3963–73. ©2013 AACR.
RETRACTED: Collagen Prolyl Hydroxylases Are Essential for Breast Cancer Metastasis
Authors: Gilkes Daniele M. , Chaturvedi Pallavi , Bajpai Saumendra , Wong Carmen C. , Wei Hong , Pitcairn Stephen , Hubbi Maimon E. , Wirtz Denis , Semenza Gregg L.
Published: March 2013

The presence of hypoxia and fibrosis within the primary tumor are two major risk factors for metastasis of human breast cancer. In this study, we demonstrate that hypoxia-inducible factor 1 activates the transcription of genes encoding collagen prolyl hydroxylases that are critical for collagen deposition by breast cancer cells. We show that expression of collagen prolyl hydroxylases promotes cancer cell alignment along collagen fibers, resulting in enhanced invasion and metastasis to lymph nodes and lungs. Finally, we establish the prognostic significance of collagen prolyl hydroxylase mRNA expression in human breast cancer biopsies and show that ethyl 3,4-dihydroxybenzoate, a prolyl hydroxylase inhibitor, decreases tumor fibrosis and metastasis in a mouse model of breast cancer. Cancer Res; 73(11); 3285–96. ©2013 AACR.
Elevated 4-Aminobiphenyl and 2,6-Dimethylaniline Hemoglobin Adducts and Increased Risk of Bladder Cancer among Lifelong Nonsmokers—The Shanghai Bladder Cancer Study
Authors: Tao Li , Day Billy W. , Hu Bibin , Xiang Yong-Bing , Wang Renwei , Stern Mariana C. , Gago-Dominguez Manuela , Cortessis Victoria K. , Conti David V. , Van Den Berg David , Pike Malcolm C. , Gao Yu-Tang , Yu Mimi C. , Yuan Jian-Min
Published: March 2013

Background: 4-Aminobiphenyl (ABP) is an established human bladder carcinogen, with tobacco smoke being a major source of human exposure. Other arylamine compounds, including 2,6-dimethylaniline (2,6-DMA), have been implicated as possible human bladder carcinogens. Hemoglobin adducts of 4-ABP and 2,6-DMA are validated biomarkers of exposure to those compounds in humans.

Methods: The Shanghai Bladder Cancer Study enrolled 581 incident bladder cancer cases and 604 population controls. Each participant was solicited for his/her history of tobacco use and other lifestyle factors and donation of blood and urine specimens. Red blood cell lysates were used to quantify both hemoglobin adducts of 4-ABP and 2,6-DMA. Urine samples were used to quantify total cotinine. ORs and 95% confidence intervals (CI) for bladder cancer were estimated using unconditional logistic regression methods.

Results: Among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for low (below median of positive values) and high versus undetectable levels of 2,6-DMA hemoglobin adducts were 3.87 (1.39–10.75) and 6.90 (3.17–15.02), respectively (Ptrend < 0.001). Similarly, among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for third and fourth versus first/second quartiles of 4-ABP hemoglobin adducts was 1.30 (0.76–2.22) and 2.29 (1.23–4.24), respectively (Ptrend = 0.009). The two associations were independent of each other.

Conclusion: Hemoglobin adducts of 4-ABP and 2,6-DMA were significantly and independently associated with increased bladder cancer risk among lifelong nonsmokers in Shanghai, China.

Impact: The findings of the present study in China with previous data in Los Angeles, California strongly implicate arylamines as potential causal agents of human bladder cancer. Cancer Epidemiol Biomarkers Prev; 22(5); 937–45. ©2013 AACR.
A Systems Biology Framework Identifies Molecular Underpinnings of Coronary Heart Disease
Authors: Huan Tianxiao , Zhang Bin , Wang Zhi , Joehanes Roby , Zhu Jun , Johnson Andrew D. , Ying Saixia , Munson Peter J. , Raghavachari Nalini , Wang Richard , Liu Poching , Courchesne Paul , Hwang Shih-Jen , Assimes Themistocles L. , McPherson Ruth , Samani Nilesh J. , Schunkert Heribert ,   Coronary ARteryDIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium, International Consortium for Blood Pressure GWAS (ICBP), Meng Qingying , Suver Christine , O’Donnell Christopher J. , Derry Jonathan , Yang Xia , Levy Daniel
Published: March 2013

Objective—

Genetic approaches have identified numerous loci associated with coronary heart disease (CHD). The molecular mechanisms underlying CHD gene–disease associations, however, remain unclear. We hypothesized that genetic variants with both strong and subtle effects drive gene subnetworks that in turn affect CHD.

Approach and Results—

We surveyed CHD-associated molecular interactions by constructing coexpression networks using whole blood gene expression profiles from 188 CHD cases and 188 age- and sex-matched controls. Twenty-four coexpression modules were identified, including 1 case-specific and 1 control-specific differential module (DM). The DMs were enriched for genes involved in B-cell activation, immune response, and ion transport. By integrating the DMs with gene expression–associated single-nucleotide polymorphisms and with results of genome-wide association studies of CHD and its risk factors, the control-specific DM was implicated as CHD causal based on its significant enrichment for both CHD and lipid expression–associated single-nucleotide polymorphisms. This causal DM was further integrated with tissue-specific Bayesian networks and protein–protein interaction networks to identify regulatory key driver genes. Multitissue key drivers (
SPIB
and
TNFRSF13C
) and tissue-specific key drivers (eg,
EBF1
) were identified.

Conclusions—

Our network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk.
Gene Expression Signatures of Coronary Heart Disease
Authors: Joehanes Roby , Ying Saixia , Huan Tianxiao , Johnson Andrew D. , Raghavachari Nalini , Wang Richard , Liu Poching , Woodhouse Kimberly A. , Sen Shurjo K. , Tanriverdi Kahraman , Courchesne Paul , Freedman Jane E. , O’Donnell Christopher J. , Levy Daniel , Munson Peter J.
Published: March 2013

Objective—

To identify transcriptomic biomarkers of coronary heart disease (CHD) in 188 cases with CHD and 188 age- and sex-matched controls who were participants in the Framingham Heart Study.

Approach and Results—

A total of 35 genes were differentially expressed in cases with CHD versus controls at false discovery rate<0.5, including
GZMB
,
TMEM56
, and
GUK1
. Cluster analysis revealed 3 gene clusters associated with CHD, 2 linked to increased erythrocyte production and a third to reduced natural killer and T cell activity in cases with CHD. Exon-level results corroborated and extended the gene-level results. Alternative splicing analysis suggested that
GUK1
and 38 other genes were differentially spliced in cases with CHD versus controls. Gene Ontology analysis linked ubiquitination and T-cell–related pathways with CHD.

Conclusions—

Two bioinformatically defined groups of genes show consistent associations with CHD. Our findings are consistent with the hypotheses that hematopoesis is upregulated in CHD, possibly reflecting a compensatory mechanism, and that innate immune activity is disrupted in CHD or altered by its treatment. Transcriptomic signatures may be useful in identifying pathways associated with CHD and point toward novel therapeutic targets for its treatment and prevention.
Tissue Characterization After Drug-Eluting Stent Implantation Using Optical Coherence Tomography
Authors: Malle Caroline , Tada Tomohisa , Steigerwald Kristin , Ughi Giovanni J. , Schuster Tibor , Nakano Masataka , Massberg Steffen , Jehle Johannes , Guagliumi Giulio , Kastrati Adnan , Virmani Renu , Byrne Robert A. , Joner Michael
Published: March 2013

Objective—

To validate optical coherence tomography (OCT) imaging for assessment of vascular healing in a preclinical animal model and human autopsy cases and to translate the findings to the assessment of vascular healing after drug-eluting stent implantation in clinical practice.

Approach and Results—

Drug-eluting and bare metal stents were imaged 28 and 42 days after implantation in atherosclerotic rabbits using OCT and simultaneously evaluated by histology. After coregistration with histology, gray-scale signal intensity (GSI) was measured for identified mature or immature neointimal tissue. Autopsy specimens were imaged with OCT and GSI values correlated with histology. Finally, prospective OCT imaging and GSI measurements were acquired in 10 patients undergoing follow-up 6 months after stenting with drug-eluting stents. Histopathologic and OCT morphometric analysis of implanted stents showed excellent correlation. Neointimal growth and vessel healing at 28 days in the animal model best correlated with human stented arteries at 6 months. In animal and human autopsy specimens, mature neointimal tissue consistently showed higher GSI values. Receiver operating characteristic curve analysis displayed high sensitivity and specificity for detection of mature neointima in animal (96% and 79%, respectively) and human autopsy (89% and 71%, respectively) data. In patients undergoing OCT follow-up 6 months after drug-eluting stent implantation, prospective GSI analysis revealed that a minimum of 27.7% of areas above stent struts represented mature neointima.

Conclusions—

Novel GSI analysis of OCT imaging data allows distinction between mature and immature neointimal tissue in animal models, autopsy specimens, and patients undergoing invasive surveillance in simple atherosclerotic lesions.
Long-Term Safety and Effectiveness of Mechanical Versus Biologic Aortic Valve Prostheses in Older Patients
Authors: Brennan J. Matthew , Edwards Fred H. , Zhao Yue , O’Brien Sean , Booth Michael E. , Dokholyan Rachel S. , Douglas Pamela S. , Peterson Eric D.
Published: March 2013

Background—

There is a paucity of long-term data comparing biological versus mechanical aortic valve prostheses in older individuals.

Methods and Results—

We performed follow-up of patients aged 65 to 80 years undergoing aortic valve replacement with a biological (n=24 410) or mechanical (n=14 789) prosthesis from 1991 to 1999 at 605 centers within the Society of Thoracic Surgeons Adult Cardiac Surgery Database using Medicare inpatient claims (mean, 12.6 years; maximum, 17 years; minimum, 8 years), and outcomes were compared by propensity methods. Among Medicare-linked patients undergoing aortic valve replacement (mean age, 73 years), both reoperation (4.0%) and endocarditis (1.9%) were uncommon to 12 years; however, the risk for other adverse outcomes was high, including death (66.5%), stroke (14.1%), and bleeding (17.9%). Compared with those receiving a mechanical valve, patients given a bioprosthesis had a similar adjusted risk for death (hazard ratio, 1.04; 95% confidence interval, 1.01–1.07), higher risks for reoperation (hazard ratio, 2.55; 95% confidence interval, 2.14–3.03) and endocarditis (hazard ratio, 1.60; 95% confidence interval, 1.31–1.94), and lower risks for stroke (hazard ratio, 0.87; 95% confidence interval, 0.82–0.93) and bleeding (hazard ratio, 0.66; 95% confidence interval, 0.62–0.70). Although these results were generally consistent among patient subgroups, bioprosthesis patients aged 65 to 69 years had a substantially elevated 12-year absolute risk of reoperation (10.5%).

Conclusions—

Among patients undergoing aortic valve replacement, long-term mortality rates were similar for those who received bioprosthetic versus mechanical valves. Bioprostheses were associated with a higher long-term risk of reoperation and endocarditis but a lower risk of stroke and hemorrhage. These risks varied as a function of a patient’s age and comorbidities.
Dietary Fiber Intake and Risk of First Stroke
Authors: Threapleton Diane E. , Greenwood Darren C. , Evans Charlotte E.L. , Cleghorn Cristine L. , Nykjaer Camilla , Woodhead Charlotte , Cade Janet E. , Gale Chris P. , Burley Victoria J.
Published: March 2013

Background and Purpose—

Fiber intake is associated with reduced stroke risk in prospective studies, but no meta-analysis has been published to date.

Methods—

Multiple electronic databases were searched for healthy participant studies reporting fiber intake and incidence of first hemorrhagic or ischemic stroke, published between January 1990 and May 2012.

Results—

Eight cohort studies from the United States, northern Europe, Australia, and Japan met inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke, with some evidence of heterogeneity between studies (I
2
; relative risk per 7 g/day, 0.93; 95% confidence interval, 0.88–0.98; I
2
=59%). Soluble fiber intake, per 4 g/day, was not associated with stroke risk reduction with evidence of low heterogeneity between studies, relative risk 0.94 (95% confidence interval, 0.88–1.01; I
2
=21%). There were few studies reporting stroke risk in relation to insoluble fiber or fiber from cereals, fruit, or vegetables.

Conclusions—

Greater dietary fiber intake is significantly associated with lower risk of first stroke. Overall, findings support dietary recommendations to increase intake of total dietary fiber. However, a paucity of data on fiber from different foods precludes conclusions regarding the association between fiber type and stroke. There is a need for future studies to focus on fiber type and to examine risk for ischemic and hemorrhagic strokes separately.
Mesenchymal Stem Cell Transplantation Attenuates Brain Injury After Neonatal Stroke
Authors: van Velthoven Cindy T.J. , Sheldon R. Ann , Kavelaars Annemieke , Derugin Nikita , Vexler Zinaida S. , Willemen Hanneke L.D.M. , Maas Mirjam , Heijnen Cobi J. , Ferriero Donna M.
Published: March 2013

Background and Purpose—

Brain injury caused by stroke is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. Mesenchymal stem cells (MSC) have been shown to improve outcome after neonatal hypoxic-ischemic brain injury mainly by secretion of growth factors stimulating repair processes. We investigated whether MSC treatment improves recovery after neonatal stroke and whether MSC overexpressing brain-derived neurotrophic factor (MSC-BDNF) further enhances recovery.

Methods—

We performed 1.5-hour transient middle cerebral artery occlusion in 10-day-old rats. Three days after reperfusion, pups with evidence of injury by diffusion-weighted MRI were treated intranasally with MSC, MSC-BDNF, or vehicle. To determine the effect of MSC treatment, brain damage, sensorimotor function, and cerebral cell proliferation were analyzed.

Results—

Intranasal delivery of MSC- and MSC-BDNF significantly reduced infarct size and gray matter loss in comparison with vehicle-treated rats without any significant difference between MSC- and MSC-BDNF–treatment. Treatment with MSC-BDNF significantly reduced white matter loss with no significant difference between MSC- and MSC-BDNF–treatment. Motor deficits were also improved by MSC treatment when compared with vehicle-treated rats. MSC-BDNF–treatment resulted in an additional significant improvement of motor deficits 14 days after middle cerebral artery occlusion, but there was no significant difference between MSC or MSC-BDNF 28 days after middle cerebral artery occlusion. Furthermore, treatment with either MSC or MSC-BDNF induced long-lasting cell proliferation in the ischemic hemisphere.

Conclusions—

Intranasal administration of MSC after neonatal stroke is a promising therapy for treatment of neonatal stroke. In this experimental paradigm, MSC- and BNDF-hypersecreting MSC are equally effective in reducing ischemic brain damage.
Al Fārūqī between the History of Religions and Islamic Theology
Authors: Tayob Abdulkader
Published: March 2013

Abstract

Ismāʿīl Rājī al Fārūqī (1921–1986) played a considerable role in the academic study of Islam as it was developing in North America in the 1960s and 1970s. This paper is a critical examination of how he employed the categories of religion and religious studies in his scholarly, dialogical, and Islamist work. The paper follows his ideas of religious traditions, their truth claims, and ethical engagement in the world. For Al Fārūqī, these constituted the main foundations of all religions, and provided a distinctive approach to the study of religions. Al Fārūqī was critical of the then prevailing approaches, asserting that they were either too subjective or too reductionist. He offered an approach to the study of religions based on a Kantian approach to values. Al Fārūqī’s method and theory, however, could not escape the bias and prejudice that he tried to avoid. Following his arguments, I show that his reflections on religion and its systematic study in academia charted an approach to religions, but also provided a language for a particular Islamic theology that delegitimized other approaches, particularly experiential ones, in modern Islam.
Abraham Abulafĳia’s “Mystical” Reading of the Guide for the Perplexed
Authors: Hofer Nathan
Published: March 2013

Abstract

The Spanish kabbalist Abraham Abulafia (d. 1291) wrote three Hebrew commentaries on the Guide for the Perplexed of Moses Maimonides (d. 1204). Abulafia’s third and final commentary, Sitrey Torah (The Mysteries of the Torah), is an uncovering and extended treatment of 36 “secrets” that he believed to be hidden within the text of the Guide. In this article I investigate the specificities of Abulafia’s mystical hermeneutic as he applies it to the Guide and how this mystical system is made to fit with Maimonides’ neoplatonic philosophy. I argue that Abulafia’s commentary is not actually a mystical text in and of itself. Rather, he intends the mystical text to be generated within the mind of the reader, who is meant to join experientially the text of the Guide with Abulafia’s commentary. The result is a paradoxical disclosure of secrets in which the linguistic mysteries must be disclosed discursively before they can become experiential mysteries to be disclosed mystically. Such a conception might offer scholars a new way of thinking about what constitutes a mystical text as well as problematizing the ways in which we categorize and analyze the “mystical.”
‘Before Pharaoh seized Gaza’. A Reappraisal of the Date, Function, and Purpose of the Superscription of Jeremiah 47
Authors: Peels Eric
Published: March 2013

Abstract

In this article it is argued that the phrase ‘before Pharaoh seized Gaza’ in Jer 47:1 is not a mere chronological precision, pointing at the (ultimate) fulfilment of the prophecy against Philistia, but a heading with its own proper function and purpose. The superscription of Jer. 47:1 refers to Pharaoh Neco’s capture of that city in 601/0 BCE, whereas the oracle of 47:2-7 itself is to be dated ca. 604. Neco was able to take Gaza after he had beaten the Babylonian army at the Egyptian border, so that the Babylonians had to withdraw to their homeland. In this time of political upheaval, the heading was added to the oracle of Jer 47 in order to warn the people of Judah that YHWH’s judgment through the sword of Babylon was still to be expected, notwithstanding Pharaoh’s recent success.
Tenure and Grant in Ezekiel’s Paradise (47:13-48:29)
Authors: Warren Nathanael
Published: March 2013

Abstract

The temple building program described in Ezekiel chapters 40-48 culminates in a description of paradisiacal national borders and internal tribal allotments in 47:13-48:29. David H. Engelhard was the first to tentatively identify the form of this pericope to be Ezekiel’s prophetic adaptation of the classical ancient Near Eastern royal grant. While this identification is a step in the right direction, I argue that 47:13-48:29 more closely follows the form of grants concerned with the tenure of temple lands, offerings, and sinecures surrounding the establishment or reinstitution of a temple cult. Unlike the classical grants of land in which the focus was on the gift of land, in 47:13-48:29 the focus is on the proper tenure of the temple. Thus Ezekiel’s particular description of land in these chapters serves to establish in a concrete manner the interrelationship between people, priests, prince, land, and temple in paradise.
Female acoustic reply to variation in the male call in a duetting katydid, Scudderia pistillata
Authors: Villarreal S.M. , Gilbert C.
Published: March 2013

Female phaneropterinae katydids (Orthoptera: Tettigoniidae) commonly reply to conspecific male attraction calls with a brief, broadband acoustic tick. In this paper we describe the complex interaction of the katydid Scudderia pistillata female tick response with the variation in male call, which comprises a bout of increasing length multisyllabic phrases. The female responds to each phrase in the bout with a variable number of ticks. She adjusts her tick response, ranging from 1 to 8, with the number of syllables the male presents, responding maximally to 7–9 syllables per phrase. Females reduce their number of ticks in response to later phrases when presented with to various manipulations of a male bout. By adjusting her ticks in response to variability in the male call, the female potentially provides information to the calling male on her preference for certain call characteristics. The temporal latency for the female to reply is not fixed, but is highly correlated with both the number of syllables she hears, as well as the number of ticks she produces.