bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution
Authors: de Bruin Elza C. , McGranahan Nicholas , Mitter Richard , Salm Max , Wedge David C. , Yates Lucy , Jamal-Hanjani Mariam , Shafi Seema , Murugaesu Nirupa , Rowan Andrew J. , Grönroos Eva , Muhammad Madiha A. , Horswell Stuart , Gerlinger Marco , Varela Ignacio , Jones David , Marshall John , Voet Thierry , Van Loo Peter , Rassl Doris M. , Rintoul Robert C. , Janes Sam M. , Lee Siow-Ming , Forster Martin , Ahmad Tanya , Lawrence David , Falzon Mary , Capitanio Arrigo , Harkins Timothy T. , Lee Clarence C. , Tom Warren , Teefe Enock , Chen Shann-Ching , Begum Sharmin , Rabinowitz Adam , Phillimore Benjamin , Spencer-Dene Bradley , Stamp Gordon , Szallasi Zoltan , Matthews Nik , Stewart Aengus , Campbell Peter , Swanton Charles
Published: October 2014

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non–small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.
A local clue to the reionization of the universe
Authors: Borthakur Sanchayeeta , Heckman Timothy M. , Leitherer Claus , Overzier Roderik A.
Published: October 2014

Identifying the population of galaxies that was responsible for the reionization of the universe is a long-standing quest in astronomy. We present a possible local analog that has an escape fraction of ionizing flux of 21%. Our detection confirms the existence of gaps in the neutral gas enveloping the starburst region. The candidate contains a massive yet highly compact star-forming region. The gaps are most likely created by the unusually strong winds and intense ionizing radiation produced by this extreme object. Our study also validates the indirect technique of using the residual flux in saturated low-ionization interstellar absorption lines for identifying such leaky galaxies. Because direct detection of ionizing flux is impossible at the epoch of reionization, this represents a highly valuable technique for future studies.
Biorobotics: Using robots to emulate and investigate agile locomotion
Authors: Ijspeert Auke J.
Published: October 2014

The graceful and agile movements of animals are difficult to analyze and emulate because locomotion is the result of a complex interplay of many components: the central and peripheral nervous systems, the musculoskeletal system, and the environment. The goals of biorobotics are to take inspiration from biological principles to design robots that match the agility of animals, and to use robots as scientific tools to investigate animal adaptive behavior. Used as physical models, biorobots contribute to hypothesis testing in fields such as hydrodynamics, biomechanics, neuroscience, and prosthetics. Their use may contribute to the design of prosthetic devices that more closely take human locomotion principles into account.
Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence
Authors: Ma Zhiqiang , Wang Xiaolei , Wang Xiao , Rodriguez Rodrigo A. , Moore Curtis E. , Gao Shuanhu , Tan Xianghui , Ma Yuyong , Rheingold Arnold L. , Baran Phil S. , Chen Chuo
Published: October 2014

Cycloaddition is an essential tool in chemical synthesis. Instead of using light or heat as a driving force, marine sponges promote cycloaddition with a more versatile but poorly understood mechanism in producing pyrrole–imidazole alkaloids sceptrin, massadine, and ageliferin. Through de novo synthesis of sceptrin and massadine, we show that sponges may use single-electron oxidation as a central mechanism to promote three different types of cycloaddition. Additionally, we provide surprising evidence that, in contrast to previous reports, sceptrin, massadine, and ageliferin have mismatched chirality. Therefore, massadine cannot be an oxidative rearrangement product of sceptrin or ageliferin, as is commonly believed. Taken together, our results demonstrate unconventional chemical approaches to achieving cycloaddition reactions in synthesis and uncover enantiodivergence as a new biosynthetic paradigm for natural products.
Of snakes and robots
Authors: Socha John J.
Published: October 2014

How can snakes and robots move up sandy slopes?

[Also see Report by

Marvi
et al.

]
Five years of translation
Authors: Kelner Katrina L. , McNutt Marcia
Published: October 2014

In October 2009, the Nobel committee awarded prizes for basic research on ribosomes and telomeres. In the same month, AAAS launched a new journal with a different focus—
Science Translational Medicine
(
SciTM
)—staking out a clear role for the organization in advancing clinical medicine. One year later, awards at the pinnacle of science also recognized more translational achievements.
*
Racing the thaw
Authors: Curry Andrew
Published: October 2014

Archaeologists scramble to recover artifacts emerging from alpine ice.
Getting a feel for the world
Authors: DuRant Hassan , You Jia
Published: October 2014

Robots fumble to make sense of their surroundings.
In our own image
Authors: Normile Dennis
Published: October 2014

Will humans be more comfortable living with robots that look less like machines and more like pets—or ourselves?
Impaired Haemophilus influenzae Type b Transplacental Antibody Transmission and Declining Antibody Avidity through the First Year of Life Represent Potential Vulnerabilities for HIV-Exposed but -Uninfected Infants
Authors: Gaensbauer James T. , Rakhola Jeremy T. , Onyango-Makumbi Carolyne , Mubiru Michael , Westcott Jamie E. , Krebs Nancy F. , Asturias Edwin J. , Fowler Mary Glenn , McFarland Elizabeth , Janoff Edward N.
Published: October 2014

To determine whether immune function is impaired among HIV-exposed but -uninfected (HEU) infants born to HIV-infected mothers and to identify potential vulnerabilities to vaccine-preventable infection, we characterized the mother-to-infant placental transfer ofHaemophilus influenzaetype b-specific IgG (Hib-IgG) and its levels and avidity after vaccination in Ugandan HEU infants and in HIV-unexposed U.S. infants. Hib-IgG was measured by enzyme-linked immunosorbent assay in 57 Ugandan HIV-infected mothers prenatally and in their vaccinated HEU infants and 14 HIV-unexposed U.S. infants at birth and 12, 24, and 48 weeks of age. Antibody avidity at birth and 48 weeks of age was determined with 1 M ammonium thiocyanate. A median of 43% of maternal Hib-IgG was transferred to HEU infants. Although its level was lower in HEU infants than in U.S. infants at birth (P< 0.001), Hib-IgG was present at protective levels (>1.0 μg/ml) at birth in 90% of HEU infants and all U.S. infants. HEU infants had robust Hib-IgG responses to a primary vaccination. Although Hib-IgG levels declined from 24 to 48 weeks of age in HEU infants, they were higher than those in U.S. infants (P= 0.002). Antibody avidity, comparable at birth, declined by 48 weeks of age in both populations. Early vaccination of HEU infants may limit an initial vulnerability to Hib disease resulting from impaired transplacental antibody transfer. While initial Hib vaccine responses appeared adequate, the confluence of lower antibody avidity and declining Hib-IgG levels in HEU infants by 12 months support Hib booster vaccination at 1 year. Potential immunologic impairments of HEU infants should be considered in the development of vaccine platforms for populations with high maternal HIV prevalence.
Development of a New Molecular Subtyping Tool for Salmonella enterica Serovar Enteritidis Based on Single Nucleotide Polymorphism Genotyping Using PCR
Authors: Ogunremi Dele , Kelly Hilary , Dupras Andrée Ann , Belanger Sebastien , Devenish John
Published: October 2014

The lack of a sufficiently discriminatory molecular subtyping tool for
Salmonella enterica
serovar Enteritidis has hindered source attribution efforts and impeded regulatory actions required to disrupt its food-borne transmission. The underlying biological reason for the ineffectiveness of current molecular subtyping tools such as pulsed-field gel electrophoresis (PFGE) and phage typing appears to be related to the high degree of clonality of
S
. Enteritidis. By interrogating the organism's genome, we previously identified single nucleotide polymorphisms (SNP) distributed throughout the chromosome and have designed a highly discriminatory PCR-based SNP typing test based on 60 polymorphic loci. The application of the SNP-PCR method to DNA samples from
S
. Enteritidis strains (
n
= 55) obtained from a variety of sources has led to the differentiation and clustering of the
S
. Enteritidis isolates into 12 clades made up of 2 to 9 isolates per clade. Significantly, the SNP-PCR assay was able to further differentiate predominant PFGE types (e.g., XAI.0003) and phage types (e.g., phage type 8) into smaller subsets. The SNP-PCR subtyping test proved to be an accurate, precise, and quantitative tool for evaluating the relationships among the
S
. Enteritidis isolates tested in this study and should prove useful for clustering related
S
. Enteritidis isolates involved in outbreaks.
First Case Reports of Ignatzschineria (Schineria) indica Associated with Myiasis
Authors: Barker Heather S. , Snyder James W. , Hicks Adam B. , Yanoviak Stephen P. , Southern Paul , Dhakal Bijaya K. , Ghimire Giri R. , Couturier Marc R.
Published: October 2014

We report three cases of infection due to the Gram-negative rodIgnatzschineria(Schineria)indicainvolving bacteremia and the urinary tract. Two cases were clearly associated with maggot infestation, and the third could conceivably have had unrecognized maggot infestation of the urinary tract. We believe these cases to be the firstI. indicainfections reported in association with maggot infestation and myiasis.
Clinical Validation of the Cervista HPV HR Test According to the International Guidelines for Human Papillomavirus Test Requirements for Cervical Cancer Screening
Authors: Boers Aniek , Wang Rong , Slagter-Menkema Lorian , van Hemel Bettien M. , Ghyssaert Hilde , van der Zee Ate G. J. , Wisman G. Bea A. , Schuuring Ed
Published: October 2014

This study demonstrates that both the clinical sensitivity and specificity of the Cervista HPV HR test for high-risk human papillomavirus (HPV) detection are not inferior to those of the Hybrid Capture 2 (HC2) test. The intra- and interlaboratory reproducibilities of Cervista were 92.0% (kappa, 0.83) and 90.4% (kappa, 0.80), respectively. The Cervista HPV HR test fulfills all the international HPV test requirements for cervical primary screening purposes.
A Novel Pseudomonas aeruginosa Strain with an
oprD
Mutation in Relation to a Nosocomial Respiratory Infection Outbreak in an Intensive Care Unit
Authors: Yan Yingjun , Yao Xiangyu , Li Haijing , Zhou Zhonghua , Huang Wenfang , Stratton Charles W. , Lu Chung-Dar , Tang Yi-Wei
Published: October 2014

Seven imipenem-resistant
Pseudomonas aeruginosa
isolates were recovered from the sputum samples of pneumonia patients in southwestern China. They had identical antibiotic resistance patterns and indistinguishable pulsed-field gel electrophoresis profiles. Nucleotide sequence analysis revealed a 4-bp (AGTC) insertion in the
oprD
gene, resulting in a frameshift in the cognate open reading frame. These isolates became imipenem susceptible when the chromosomal
oprD
lesion was complemented, indicating that the 4-bp insertion in the
oprD
gene resulted in imipenem resistance.
Recombinant Modified Vaccinia Virus Ankara Generating Excess Early Double-Stranded RNA Transiently Activates Protein Kinase R and Triggers Enhanced Innate Immune Responses
Authors: Wolferstätter Michael , Schweneker Marc , Späth Michaela , Lukassen Susanne , Klingenberg Marieken , Brinkmann Kay , Wielert Ursula , Lauterbach Henning , Hochrein Hubertus , Chaplin Paul , Suter Mark , Hausmann Jürgen
Published: October 2014

Double-stranded RNA (dsRNA) is an important molecular pattern associated with viral infection and is detected by various extra- and intracellular recognition molecules. Poxviruses have evolved to avoid producing dsRNA early in infection but generate significant amounts of dsRNA late in infection due to convergent transcription of late genes. Protein kinase R (PKR) is activated by dsRNA and triggers major cellular defenses against viral infection, including protein synthesis shutdown, apoptosis, and type I interferon (IFN-I) production. The poxviral E3 protein binds and sequesters viral dsRNA and is a major antagonist of the PKR pathway. We found that the highly replication-restricted modified vaccinia virus Ankara (MVA) engineered to produce excess amounts of dsRNA early in infection showed enhanced induction of IFN-β in murine and human cells in the presence of an intact E3L gene. IFN-β induction required a minimum overlap length of 300 bp between early complementary transcripts and was strongly PKR dependent. Excess early dsRNA produced by MVA activated PKR early but transiently in murine cells and induced enhanced systemic levels of IFN-α, IFN-γ, and other cytokines and chemokines in mice in a largely PKR-dependent manner. Replication-competent chorioallantois vaccinia virus Ankara (CVA) generating excess early dsRNA also enhanced IFN-I production and was apathogenic in mice even at very high doses but showed no
in vitro
host range defect. Thus, genetically adjuvanting MVA and CVA to generate excess early dsRNA is an effective method to enhance innate immune stimulation by orthopoxvirus vectors and to attenuate replicating vaccinia virus
in vivo
.

IMPORTANCE
Efficient cellular sensing of pathogen-specific components, including double-stranded RNA (dsRNA), is an important prerequisite of an effective antiviral immune response. The prototype poxvirus vaccinia virus (VACV) and its derivative modified vaccinia virus Ankara (MVA) produce dsRNA as a by-product of viral transcription. We found that inhibition of cellular dsRNA recognition established by the virus-encoded proteins E3 and K3 can be overcome by directing viral overexpression of dsRNA early in infection without compromising replication of MVA in permissive cells. Early dsRNA induced transient activation of the cellular dsRNA sensor protein kinase R (PKR), resulting in enhanced production of interferons and cytokines in cells and mice. Enhancing the capacity of MVA to activate the innate immune system is an important approach to further improve the immunogenicity of this promising vaccine vector.
Complex Expression of the UL136 Gene of Human Cytomegalovirus Results in Multiple Protein Isoforms with Unique Roles in Replication
Authors: Caviness Katie , Cicchini Louis , Rak Michael , Umashankar Mahadevaiah , Goodrum Felicia
Published: October 2014

Human cytomegalovirus (HCMV) is a complex DNA virus with a 230-kb genome encoding 170 and up to 750 proteins. The upper limit of this coding capacity suggests the evolution of complex mechanisms to substantially increase the coding potential from the 230-kb genome. Our work examines the complexity of one gene, UL136, encoded within the UL
b
′ region of the genome that is lost during serial passage of HCMV in cultured fibroblasts. UL136 is expressed as five protein isoforms. We mapped these isoforms and demonstrate that they originate from both a complex transcriptional profile and, possibly, the usage of multiple translation initiation sites. Intriguingly, the pUL136 isoforms exhibited distinct subcellular distributions with varying association with the Golgi apparatus. The subcellular localization of membrane-bound isoforms of UL136 differed between when they were expressed exogenously and when they were expressed in the context of viral infection, suggesting that the trafficking of these isoforms is mediated by infection-specific factors. While UL136, like most UL
b
′ genes, was dispensable for replication in fibroblasts, the soluble 23- and 19-kDa isoforms suppressed virus replication. In CD34
+
hematopoietic progenitor cells (HPCs) infected
in vitro
, disruption of the 23- and 19-kDa isoforms resulted in increased replication and a loss of the latency phenotype, similar to the effects of the UL138 latency determinant encoded within the same genetic locus. Our work suggests a complex interplay between the UL136 isoforms which balances viral replication in multiple cell types and likely contributes to the cell type-dependent phenotypes of the UL133/8 locus and the outcome of HCMV infection.

IMPORTANCE
HCMV is a significant cause of morbidity in immunocompromised individuals, including transplant patients. The lifelong persistence of the virus results in a high seroprevalence worldwide and may contribute to age-related pathologies, such as atherosclerosis. The mechanisms of viral persistence are poorly understood; however, understanding the molecular basis of persistence is imperative for the development of new treatments. In this work, we characterize a complex HCMV gene, UL136, which is expressed as five protein isoforms. These isoforms arise predominantly from complex transcriptional mechanisms, which contribute to an increased coding capacity of the virus. Further, the UL136 isoforms oppose the activity of one another to balance HCMV replication in multiple cell types. We identify soluble isoforms of UL136 that function to suppress virus replication in fibroblasts and in CD34
+
HPCs for latency.
Blocking ESCRT-Mediated Envelopment Inhibits Microtubule-Dependent Trafficking of Alphaherpesviruses
In Vitro
Authors: Kharkwal Himanshu , Smith Caitlin G. , Wilson Duncan W.
Published: October 2014

Herpes simplex virus (HSV) and, as reported here, pseudorabies virus (PRV) utilize the ESCRT apparatus to drive cytoplasmic envelopment of their capsids. Here, we demonstrate that blocking ESCRT-mediated envelopment using the dominant-negative inhibitor Vps4A-EQ (Vps4A in which glutamate [E] at position 228 in the ATPase active site is replaced by a glutamine [Q]) reduced the ability of HSV and PRV particles to subsequently traffic along microtubules
in vitro
. HSV and PRV capsid-associated particles with bound green fluorescent protein (GFP)-labeled Vps4A-EQ were readily detected by fluorescence microscopy in cytoplasmic extracts of infected cells. These Vps4A-EQ-associated capsid-containing particles bound to microtubules
in vitro
but were unable to traffic along them. Using a PRV strain expressing a fluorescent capsid and a fluorescently tagged form of the envelope protein gD, we found that similar numbers of gD-positive and gD-negative capsid-associated particles accumulated in cytoplasmic extracts under our conditions. Both classes of PRV particle bound to microtubules
in vitro
with comparable efficiency, and similar results were obtained for HSV using anti-gD immunostaining. The gD-positive and gD-negative PRV capsids were both capable of trafficking along microtubules
in vitro
; however, motile gD-positive particles were less numerous and their trafficking was more sensitive to the inhibitory effects of Vps4A-EQ. We discuss our data in the context of microtubule-mediated trafficking of naked and enveloped alphaherpesvirus capsids.

IMPORTANCE
The alphaherpesviruses include several important human pathogens. These viruses utilize microtubule-mediated transport to travel through the cell cytoplasm; however, the molecular mechanisms of trafficking are not well understood. In this study, we have used a cell-free system to examine the requirements for microtubule trafficking and have attempted to distinguish between the movement of so-called “naked” and membrane-associated cytoplasmic alphaherpesvirus capsids.
Shortness of breath in a patient with inflammatory bowel disease
Authors: Abbey Aoife , Elsmore Amy C
Published: October 2014

Cytomegalovirus (CMV) is an important cause of morbidity and mortality in immunocompromised patients. Although immunosuppressive therapy is the mainstay of medical treatment for patients with inflammatory bowel disease, the importance of CMV as a cause of pneumonia in this group is less well recognised. This case report presents a case of shortness of breath, dyspnoea and fever in a 51-year-old man with Crohn's disease on azathioprine and highlights the importance of considering CMV as a cause of pneumonia in this group.
A generalised sensation of coldness following introduction of rosuvastatin therapy
Authors: Huynh Niem Tu , Huot Philippe
Published: October 2014

Rosuvastatin is the most potent 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor commercially available to lower low-density lipoprotein cholesterol. Rosuvastatin has been associated with several adverse effects, including rhabdomyolysis and arthralgias. Here, we report an unusual adverse effect occurring on treatment with rosuvastatin, a ‘continuous sensation of coldness’. A 60-year-old man began experiencing this peculiar feeling shortly after introduction of rosuvastatin treatment. The gentleman had to wear extra pair of socks and cover himself with blankets while reading, even during summer with surrounding temperature above 30°C. The abnormal sensation persisted for the 26 months during which he was treated with rosuvastatin, and disappeared within a week after discontinuing treatment. Physical examination, including thorough neurological examination, was entirely normal, as were haematological and biochemical parameters. While the pathophysiology of this phenomenon remains unknown, we hope that this case will encourage others to report similar symptomatology, perhaps enabling to gain more insight on the condition.
Parasitised large intestinal diverticulum of the spermatic cord
Authors: Grigor Thomas , Ahmad Sheikh
Published: October 2014

We present a 70-year-old male patient with an unusual incidental finding at an elective repair of an indirect left inguinal hernia (LIH). A black nodule resembling a melanoma metastasis in a lymph node was discovered attached to the spermatic cord. There was no contiguity with the large bowel on the same side. Histological examination showed an isolated, detached colonic diverticulum containing a faecolith. We postulate derivation from an incarcerated colonic diverticulum that became ‘parasitised’ onto the spermatic cord.
Medical thoracoscopic removal of a metal needle from the pleural space
Authors: Gupta Richa , James Prince , Thangakunam Balamugesh , Christopher Devasahayam Jesudas
Published: October 2014

Medical thoracoscopy is an excellent diagnostic and therapeutic tool for management of pleural diseases. There have been case reports of removal of foreign bodies from pleural spaces with video-assisted thoracoscopic surgery under general anaesthesia by thoracic surgeons. We present a case of successful removal of an 8 cm long metal needle from the pleural space with single port medical semirigid thoracoscopy under local anaesthesia by a chest physician. Removal of a foreign body from the pleural space is one more indication for medical thoracoscopy, however, an experienced chest physician and proper case selection are very important for safety and a successful outcome of this procedure.
Breaking the taboo: an interpretative phenomenological analysis of healthcare professionals’ experience of caring for palliative patients with disgusting symptoms
Authors: Muggleton Joshua , Guy Helen , Howard Ruth
Published: October 2014

Objectives

Disgusting symptoms are common in healthcare settings. Previous research has identified that healthcare professionals systematically avoid contact with patients with disgusting symptoms, potentially compromising patient care. Furthermore, research has highlighted disgust in healthcare professionals as a possible contributory factor to dehumanisation and abuse of patients. Given that healthcare professionals often feel that disgust is unprofessional, they may also feel unable to express or process disgust in their work, potentially impacting their emotional health, and contributing to burning out. Given the ubiquity of disgust in palliative care, we investigated how palliative healthcare professionals' experience and cope with disgust in their work, and how they are supported in doing so.

Methods and Results

We interviewed six palliative healthcare professionals and analysed their transcripts using Interpretative Phenomenological Analysis, from which four themes are discussed.

Conclusions

Three key findings emerged. Firstly, participants were uncomfortable talking about disgust at work, reducing their access to support for disgust. Secondly, participants often neglected their own emotional needs, and as a result, sometimes become emotionally entangled with patients. Finally, participants were at risk of reducing vital socio-emotional support for patients with disgusting symptoms. Based on our analysis, we suggest interventions to counteract these effects.
Trends in the TD-DFT calculations of porphyrin and phthalocyanine analogs
Authors: Mack John , Stone Justin , Nyokong Tebello
Published: October 2014

In 2005, Kobayashi and coworkers reported trends in the TD-DFT spectra of 17 Zn ( II ) porphyrinoids [J. Am. Chem. Soc. 2005; 127: 17697] that were analyzed using Michl's perimeter model as part of a study of the anomalous magnetic circular dichroism (MCD) spectroscopy of zinc tetraphenyltetraacenaphthoporphyrin. In recent years, it has become increasingly clear that TD-DFT calculations with the commonly used hybrid B3LYP exchange-correlation functional of the Gaussian software package are problematic in the B -band region of porphyrinoid spectra, since the degree of configurational interaction between the B and higher energy ππ* state appears to be significantly overestimated. The CAM-B3LYP functional is now often preferred for analyzing the optical properties of porphyrinoids, since it includes a long-range correction of the exchange potential, which incorporates an increasing fraction of Hartree–Fock (HF) exchange as the interelectronic separation increases, making it better suited for studying compounds where there is significant charge transfer in the electronic excited states. The trends in the TD-DFT calculations are reexamined with a wider range porphyrinoid compounds including several with pyrazino moieties and are found to provide a closer agreement with the experimental in the B -band region for complexes such as zinc tetraphenylporphyrin and phthalocyanine.
A new porphyrin dimer as an unexpected side-product
Authors: Pereira Ana M.V.M. , Jeandon Christophe , Cavaleiro José A.S. , Neves Maria G.P.M.S. , Ruppert Romain
Published: October 2014

The synthesis of new diporphyrinylamines is described. In particular, the possibility to use the Buchwald or Ullmann amination reactions to obtain these compounds is detailed. Attempts to obtain symmetrical diporphyrinylamines linked by a tertiary amine are exposed and the obtention as side-product of an unexpected unsymmetrical porphyrin dimer with a meso–β linkage is described.
Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway
Authors: Zhao Liang , Li Ai Q. , Zhou Teng F. , Zhang Meng Q. , Qin Xiao M.
Published: October 2014

Vascular aging has been implicated in the progression of diabetes and age-related cardiovascular disorders. Glucagon-like peptide-1 (GLP-1) is an incretin hormone capable of cytoprotective actions in addition to its glucose-lowering effect. The present study was undertaken to examine whether Exendin-4, a specific ligand for the GLP-1 receptor, could prevent angiotensin (ANG) II-induced premature senescence in vascular smooth muscle cells (VSMCs) and to determine the underlying mechanism involved. Senescence-associated β-galactosidase (SA β-gal) assay showed that ANG II induced premature senescence of VSMCs. Pretreatment with Exendin-4 significantly attenuated ANG II-induced generation of H2O2 and the subsequent VSMC senescence. These effects were, however, reversed in the presence of exendin fragment 9–39, a GLP-1 receptor antagonist, or PKI14-22. Moreover, a marked increase in the levels of p53 and p21 induced by ANG II was blunted by the treatment with Exendin-4. Nevertheless, Exendin-4 failed to decrease ANG II-induced expression of NAD(P)H oxidase 1 (Nox1), NAD(P)H oxidase 4 (Nox4), p22phox, or p47phox in VSMCs. Mechanistically, Exendin-4 blocked ANG II-induced Rac1 activation through the cAMP/PKA signaling cascade. Specifically, NSC23766, a Rac1 inhibitor, abrogated the suppressive effects of Exendin-4 on ANG II-induced premature senescence and H2O2 generation, respectively. Thus Exendin-4 confers resistance to ANG II-induced superoxide anion generation from NAD(P)H oxidase and the resultant VSMC senescence by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. These findings demonstrate that GLP-1 as well as its analogs (GLP-1-related reagents) may hold therapeutic potential in the treatment of diabetes with cardiovascular disease.
Gene expression and cellular localization of ROMKs in the gills and kidney of Mozambique tilapia acclimated to fresh water with high potassium concentration
Authors: Furukawa Fumiya , Watanabe Soichi , Kakumura Keigo , Hiroi Junya , Kaneko Toyoji
Published: October 2014

Regulation of plasma K+levels in narrow ranges is vital to vertebrate animals. Since seawater (SW) teleosts are loaded with excess K+, they constantly excrete K+from the gills. However, the K+regulatory mechanisms in freshwater (FW)-acclimated teleosts are still unclear. We aimed to identify the possible K+regulatory mechanisms in the gills and kidney, the two major osmoregulatory organs, of FW-acclimated Mozambique tilapia ( Oreochromis mossambicus). As a potential molecular candidate for renal K+handling, a putative renal outer medullary K+channel (ROMK) was cloned from the tilapia kidney and tentatively named “ROMKb”; another ROMK previously cloned from the tilapia gills was thus renamed “ROMKa”. The fish were acclimated to control FW or to high-K+(H-K) FW for 1 wk, and we assessed physiological responses of tilapia to H-K treatment. As a result, urinary K+levels were slightly higher in H-K fish, implying a role of the kidney in K+excretion. However, the mRNA expression levels of both ROMKa and ROMKb were very low in the kidney, while that of K+/Cl−cotransporter 1 (KCC1) was robust. In the gills, ROMKa mRNA was markedly upregulated in H-K fish. Immunofluorescence staining showed that branchial ROMKa was expressed at the apical membrane of type I and type III ionocytes, and the ROMKa immunosignals were more intense in H-K fish than in control fish. The present study suggests that branchial ROMKa takes a central role for K+regulation in FW conditions and that K+excretion via the gills is activated irrespective of environmental salinity.
Hypoxia-sensitive pathways in inflammation-driven fibrosis
Authors: Manresa Mario C. , Godson Catherine , Taylor Cormac T.
Published: October 2014

Tissue injury can occur for a variety of reasons, including physical damage, infection, and ischemia. The ability of tissues to effectively recover from injury is a cornerstone of human health. The healing response in tissues is conserved across organs and typically involves distinct but overlapping inflammatory, proliferative, and maturation/resolution phases. If the inflammatory phase is not successfully controlled and appropriately resolved, an excessive healing response characterized by scar formation can lead to tissue fibrosis, a major clinical complication in disorders such as Crohn's disease (CD). As a result of enhanced metabolic and inflammatory processes during chronic inflammation, profound changes in tissue oxygen levels occur leading to localized tissue hypoxia. Therefore, inflammation, fibrosis, and hypoxia are coincidental events during inflammation-driven fibrosis. Our current understanding of the mechanism(s) underpinning fibrosis is limited as are the therapeutic options available. In this review, we discuss what is known about the cellular and molecular mechanisms underpinning inflammation-driven fibrosis and how hypoxia may play a role in shaping this process.
Simultaneous assessment of glomerular filtration and barrier function in live zebrafish
Authors: Kotb Ahmed M. , Müller Tobias , Xie Jing , Anand-Apte Bela , Endlich Karlhans , Endlich Nicole
Published: October 2014

The zebrafish pronephros is a well-established model to study glomerular development, structure, and function. A few methods have been described to evaluate glomerular barrier function in zebrafish larvae so far. However, there is a need to assess glomerular filtration as well. In the present study, we extended the available methods by simultaneously measuring the intravascular clearances of Alexa fluor 647-conjugated 10-kDa dextran and FITC-conjugated 500-kDa dextran as indicators of glomerular filtration and barrier function, respectively. After intravascular injection of the dextrans, mean fluorescence intensities of both dextrans were measured in the cardinal vein of living zebrafish (4 days postfertilization) by confocal microscopy over time. We demonstrated that injected 10-kDa dextran was rapidly cleared from the circulation, became visible in the lumen of the pronephric tubule, quickly accumulated in tubular cells, and was detectably excreted at the cloaca. In contrast, 500-kDa dextran could not be visualized in the tubule at any time point. To check whether alterations in glomerular function can be quantified by our method, we injected morpholino oligonucleotides (MOs) against zebrafish nonmuscle myosin heavy chain IIA (zMyh9) or apolipoprotein L1 (zApol1). While glomerular filtration was reduced in zebrafish nonmuscle myosin heavy chain IIA MO-injected larvae, glomerular barrier function remained intact. In contrast, in zebrafish apolipoprotein L1 MO-injected larvae, glomerular barrier function was compromised as 500-kDa dextran disappeared from the circulation and became visible in tubular cells. In summary, we present a novel method that allows to simultaneously assess glomerular filtration and barrier function in live zebrafish.
Serelaxin reduces oxidative stress and asymmetric dimethylarginine in angiotensin II-induced hypertension
Authors: Sasser Jennifer M. , Cunningham Mark W. , Baylis Chris
Published: October 2014

Recent findings suggest the therapeutic action of relaxin during hypertension is dependent on nitric oxide synthase (NOS) activation; however, the mechanisms underlying the beneficial effects of relaxin on the NOS system have not been fully elucidated. We hypothesized that the protective effects of relaxin include reducing both oxidative stress and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). We examined the effect of Serelaxin [human recombinant relaxin-2 (RLX)] in male Sprague-Dawley rats given high-dose angiotensin (ANG) II (400 ng·kg−1·min−1 sc) for 6 wk or shams. RLX was administered (4 μg/h sc) to half of the rats in each group after 2 wk of ANG II for the remaining 4 wk. ANG II induced hypertension and proteinuria, reduced NO oxidation products (NOx), and increased oxidative stress (NADPH oxidase activity, thiobarbituric acid-reactive substances, and 8-isoprostane excretion) and plasma ADMA. While RLX had no effect on sham rats, RLX attenuated the ANG II-dependent hypertension (165 ± 5 vs. 135 ± 13 mmHg, P < 0.05) and proteinuria at 6 wk (62 ± 6 vs. 41 ± 4 mg·day−1·100 g−1, P < 0.05) and normalized oxidative stress and circulating ADMA, in association with restored NOx excretion and kidney cortex NOx. We found that RLX had no impact on the ADMA-regulatory enzymes protein arginine methyltransferase and dimethylarginine-dimethylaminohydrolase (DDAH). Furthermore, RLX treatment did not increase DDAH activity in kidney cortex or liver. These data suggest that benefits of RLX treatment include reduced ADMA levels and increased NO bioavailability, possibly due to its antioxidant effects.
Differences in respiratory muscle activity during cycling and walking do not influence dyspnea perception in obese patients with COPD
Authors: Ciavaglia Casey E. , Guenette Jordan A. , Langer Daniel , Webb Katherine A. , Alberto Neder J. , O'Donnell Denis E.
Published: October 2014

In patients with combined obesity and chronic obstructive pulmonary disease (COPD), dyspnea intensity at matched work rates during weight-supported cycling and weight-bearing walking is similar, despite consistent metabolic differences between test modalities. The present study examined the influence of differences in activity of the diaphragm and abdominal muscles during cycling and walking on intensity and quality of dyspnea at matched ventilation in obese patients with COPD. We compared respiratory muscle activity patterns and dyspnea ratings during incremental cycle and treadmill exercise tests, where work rate was matched, in 12 obese (body mass index 36.6 ± 5.4 kg/m2; mean ± SD) patients with moderate COPD. We used a multipair electrode-balloon catheter to compare electromyography of the diaphragm and esophageal, gastric, and transdiaphragmatic pressures during the two exercise tests. Ventilation, breathing pattern, operating lung volumes, global respiratory effort, and electrical activation of the diaphragm were similar across exercise modalities for a given work rate. The cycling position was associated with greater neuromuscular efficiency of the diaphragm ( P < 0.01), greater diaphragm use ( P < 0.01) measured by the ventilatory muscle recruitment index, and less expiratory muscle activity compared ( P < 0.01) with treadmill walking. However, intensity and quality of dyspnea were similar between exercise modalities. In obese patients with COPD, altered respiratory muscle activity due to body position differences between cycling and walking did not modulate perceived dyspnea when indirect measures of respiratory neural drive were unchanged.
Suppression of putative tinnitus-related activity by extra-cochlear electrical stimulation
Authors: Noreña A. J. , Mulders W. H. A. M. , Robertson D.
Published: October 2014

Studies on animals have shown that noise-induced hearing loss is followed by an increase of spontaneous firing at several stages of the central auditory system. This central hyperactivity has been suggested to underpin the perception of tinnitus. It was shown that decreasing cochlear activity can abolish the noise-induced central hyperactivity. This latter result further suggests that an approach consisting of reducing cochlear activity may provide a therapeutic avenue for tinnitus. In this context, extra-cochlear electric stimulation (ECES) may be a good candidate to modulate cochlear activity and suppress tinnitus. Indeed, it has been shown that a positive current applied at the round window reduces cochlear nerve activity and can suppress tinnitus reliably in tinnitus subjects. The present study investigates whether ECES with a positive current can abolish the noise-induced central hyperactivity, i.e., the putative tinnitus-related activity. Spontaneous and stimulus-evoked neural activity before, during and after ECES was assessed from single-unit recordings in the inferior colliculus of anesthetized guinea pigs. We found that ECES with positive current significantly decreases the spontaneous firing rate of neurons with high characteristic frequencies, whereas negative current produces the opposite effect. The effects of the ECES are absent or even reversed for neurons with low characteristic frequencies. Importantly, ECES with positive current had only a marginal effect on thresholds and tone-induced activity of collicular neurons, suggesting that the main action of positive current is to modulate the spontaneous firing. Overall, cochlear electrical stimulation may be a viable approach for suppressing some forms of (peripheral-dependent) tinnitus.
Predictors of Survival in HIV-Infected Patient after Initiation of HAART in Zewditu Memorial Hospital, Addis Ababa, Ethiopia
Authors: Mengesha Shibre , Belayihun Bekele , Kumie Abera
Published: October 2014

Introduction. ART has improved the survival of HIV-infected patients. However, patients in resource-poor countries have higher mortality rates, particularly the first months after initiating ART. In this study we tried to determine the survival factors in HIV-infected patients treated with HAART in Zewditu Memorial Hospital. Methods. A retrospective cohort study was conducted from 2008 to 2012. All HIV-infected patients above the age of 14 took first line ART. Data were collected, entered, and analyzed using Epi Info 7 and SPSS Version 20. Life table was used to estimate mortality after initiation of ART, and Kaplan-Meier was used to compare survival curves. Cox proportional hazards model was used to assess the predictors of mortality. Results. The incidence of mortality was 3.8/100 person-years. Independent predictors of mortality were WHO clinical stages 3-4 (HR=2.39 at 95% CI (1.26, 5.31)), anemia (hemoglobin level < 10 gm/dL (HR=5.54 at 95% CI (2.58, 11.86)). Conclusion. Incidence of mortality was found relatively low, majority of deaths occurring within 3 months of starting ART. WHO stages 3-4, anemia (hemoglobin count < 10 gm/dL), and past TB coinfection were the main predictors of mortality. The underlying causes for early death in patients presenting at late stages should be investigated.
Adult Ocular Toxocariasis Mimicking Ciliary Body Malignancy
Authors: Mansour Ahmad M. , Abiad Bachir , Boulos Fouad I. , Alameddine Ramzi , Maalouf Fadi C. , Bu Ghannam Alaa , Hamam Rola N.
Published: October 2014

Purpose. To discuss an unusual presentation of ocular toxocariasis.Methods. Case report.Results. A 40-year-old woman presented with decreased vision in the left eye with a long history of recurrent red eye from uveitis. Eosinophilia and positive ELISA titers forToxocara canisfavored the diagnosis of ocular toxocariasis. Over 3 months, an anterior scleral mass had a rapid growth raising the possibility of medulloepithelioma, which rarely can mimic uveitic syndromes. Surgical plan changed from local excision to enucleation. Histopathology demonstrated a large homogeneous mass of chronic inflammatory cells with inflammation of the overlying thinned out sclera, medial rectus insertion, and limbal cornea. The triad of peripheral granuloma, eosinophilia, and positive blood serology established the diagnosis of ocular toxocariasis.Conclusions. Ocular toxocariasis can mimic ocular malignancy such as medulloepithelioma in adults and rarely presents as an anterior scleral mass.
Self-Expandable Metal Stent Placement for Closure of a Leak after Total Gastrectomy for Gastric Cancer: Report on Three Cases and Review of the Literature
Authors: Raimondo Dario , Sinagra Emanuele , Facella Tiziana , Rossi Francesca , Messina Marco , Spada Massimiliano , Martorana Guido , Marchesa Pier Enrico , Squatrito Rosario , Tomasello Giovanni , Lo Monte Attilio Ignazio , Pompei Giancarlo , La Rocca Ennio
Published: October 2014

In the setting of the curative oncological surgery, the gastric surgery is exposed to complicated upper gastrointestinal leaks, and consequently the management of this problem has become more critically focused than was previously possible. We report here three cases of placement of a partially silicone-coated SEMS (Evolution Controlled Release Esophageal Stent System, Cook Medical, Winston-Salem, NC, USA) in patients who underwent total gastrectomy with Roux-en-Y end-to-side esophagojejunostomy for a gastric adenocarcinoma. The promising results of our report, despite the small number of patients, suggest that early stenting (through a partially silicone-coated SEMS) is a feasible alternative to surgical treatment in this subset of patients. In fact, in the treatment of leakage after total gastrectomy, plastic stents and totally covered metallic stents may not adhere sufficiently to the esophagojejunal walls and, as a result, migrate beyond the anastomosis. However, prospective studies with a larger number of patients might assess the real effectiveness and safety of this procedure.
Cashew Nut Quality as Influenced by Microwave Heating Used for Stored Grain Insect Control
Authors: Das Ipsita , Shah Narendra G. , Kumar Girish
Published: October 2014

The objective of this work is to investigate the effect of microwave power levels (240, 360, and 480 W) and exposure time (30, 60, 90, 120, 180, and 240 s) on various properties of cashew nuts being used for disinfestation. The nuts were analyzed for moisture content, temperature rise, colour, free fatty acid (FFA) and peroxide value (PV). Experiments were conducted according to the response surface methodology. Increase in microwave power level and exposure time caused a decrease in moisture content, increase in temperature, and change in colour. Microwave treatment to target temperatures of 50–55°C (unfavorable for insect survival) made the PV of cashew nut decrease to 1.10 to 1.66 meq O2/Kg (from an initial value of 2.08 ± 0.05) and FFA value to 0.11 to 0.51% (from an initial value of 0.68 ± 0.03). Though PV and FFA values of microwave treated cashew nut were found to increase after 6 months of storage at room conditions, the values were within the limits for acceptable quality. Microwave treated cashew nuts were free from infestation and rancidity even after 6 months of storage while the untreated nuts were found to be heavily infested at the end of 1 month of storage.
Increasing Resistance of Coagulase-Negative Staphylococci in Total Hip Arthroplasty Infections: 278 THA-Revisions due to Infection Reported to the Norwegian Arthroplasty Register from 1993 to 2007
Authors: Lutro Olav , Langvatn Håkon , Dale Håvard , Schrama Johannes Cornelis , Hallan Geir , Espehaug Birgitte , Sjursen Haakon , Engesæter Lars B.
Published: October 2014

We investigated bacterial findings from intraoperative tissue samples taken during revision due to infection after total hip arthroplasty (THA). The aim was to investigate whether the susceptibility patterns changed during the period from 1993 through 2007. Reported revisions due to infection in the Norwegian Arthroplasty Register (NAR) were identified, and 10 representative hospitals in Norway were visited. All relevant information on patients reported to the NAR for a revision due to infection, including bacteriological findings, was collected from the medical records. A total of 278 revision surgeries with bacterial growth in more than 2 samples were identified and included. Differences between three 5-year time periods were tested by the chi-square test for linear trend. The most frequent isolates were coagulase-negative staphylococci (CoNS) (41%, 113/278) andStaphylococcus aureus(19%, 53/278). The proportion of CoNS resistant to the methicillin-group increased from 57% (16/28) in the first period, 1993–1997, to 84% (52/62) in the last period, 2003–2007 (P= 0.003). There was also significant increase in resistance for CoNS to cotrimoxazole, quinolones, clindamycin, and macrolides. AllS. aureusisolates were sensitive to both the methicillin-group and the aminoglycosides. For the other bacteria identified no changes in susceptibility patterns were found.