bluuebunny/crossref_metadata_2025 huggingface dataset:
System architecture for functional characterization of devices to mitigate hearing impairment
Authors: Byrne Jennifer , Sarkani Shahram , Mazzuchi Thomas
Published: June 2013

Since 2000, claims of hearing loss by warfighters have doubled. It is the most frequently identified combat-related disability. Conventional audibility enhancement relies heavily on hearing aids, which do not provide sufficient sound intelligibility for a sizable subset of the hearing-impaired population. For them, there is a surgical option called a ‘cochlear implant’, a device which bypasses the damaged portions of the inner ear (cochlea) and provides direct neural stimulation. In this paper, we review the current state of the art in hearing aids and cochlear implants. A new device which has the potential for high spectral and temporal fidelity, the optical cochlear implant, is currently being tested in the laboratory. The projected development timeline spans many years: from point testing in the laboratory, through the approval process for limited human testing, with control gates for application to human candidates. A model-based development approach could potentially shorten this timeline. In this paper, we describe models and simulations that we developed to extend laboratory measurements in order to evaluate intelligibility impacts. Specifically, we describe our development of the Cochlear Laser Transduction Model, a physics-based simulator that evaluates tonotopic specificity; the Optical Cochlear Implant Simulator (OCIS), which can extend the laboratory measurements via simulation using the results of the Cochlear Laser Transduction Model; and the configuration of an off-the-shelf speech recognition tool to quickly assess intelligibility impacts, predicting system level impacts of varying optical cochlear implant design parameters. Results from the system-level modeling and simulation approach indicate that significant intelligibility improvements could be realized with the optical cochlear implant, with potential to offer upwards of 40 channels of spectral resolution compared with 10 channels with electrode-based implants.
The Epilepsy Phenome/Genome Project
Authors:   The EPGP Collaborative, McGovern Kathleen , Stillman Nora , McKenna Kevin , Mays Vickie , Williams Michael , Carpenter Alan , Miller Kevin , Agarwal Prashant , Ayala Jennifer , Bakey Cate , Borkowski Thomas , Boyd Riann , Camuto Alicia , Carrasco Cendy , Cassarly Jennifer , Collins Yong , Collon Kevin , Collon Sean , Eckman Heather , Fogarty Susan , Morón Dolores González , Grayson La June , Hagopian Samantha , Hayden Emily , Heggeli Kristin , Hennessy Rachel , Hessling Jody , Hirschfield Emily , Howell Jennifer , Klingerman Sherry , Lopez Maritza , Marinelli Heather , Maschhaupt Brandy , Minnick Jennie , Misajon Jade , Monahan Jennifer , Oliver Karen , Parulkar Isha , Przepiorka Laura , Pyzik Paula , Regan Brigid , Shain Catherine , Slingerland Lexie , Stanton Caitlin , Taylor Kelly , Thompson Stacy , Turczyk Jennifer , Vara Alexander , Wesolowski Cindy , Yourich Andrew
Published: July 2013

Background

Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies.

Study design

The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype–genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy.

Results

EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants.

Conclusions

EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.
In vitro inflammatory responses elicited by isolates of Alloiococcus otitidis obtained from children with otitis media with effusion
Authors: Ashhurst-Smith Christopher , Hall Sharron T , Burns Christine J , Stuart John , Blackwell C Caroline
Published: June 2013

Alloiococcus otitidis is usually detected in children with otitis media (OM) by PCR as it is not often detected by routine culture. Our improved method for its isolation obtained A. otitidis from nearly 50% of 78 children with OM with effusion. The role of A. otitidis in pathogenesis of OM is unclear. This study tested two hypothesis: (1) that fresh isolates of A. otitidis would elicit pro-inflammatory cytokines from THP-1 monocytic cells equivalent to those induced by Streptococcus pneumoniae; (2) priming THP-1 cells with interferon-gamma (IFN-γ) a surrogate for virus infection, would enhance pro-inflammatory responses. Recent clinical isolates of A. otitidis, S. pneumoniae (ATCC 49619) and a blood culture isolate of S. pneumoniae (SP2) were used in the assays. Cytokines were quantified by BioRad bead assay and Luminex 200. IFN-γ priming enhanced cytokine responses. S. pneumoniae ATCC 49619 induced lower responses than SP2 for IL-1β, IL-6, TNF-α. A. otitidis LW 27 elicited higher IL-1β and TNF-α responses than either pneumococcal isolate. Small green colony types of A. otitidis induced higher responses than large white colony types for IL-8 and IL-1β. The hypothesis that A. otitidis elicits cytokines observed in middle ear effusions was supported; the need to use recent clinical isolates in studies of pathogenesis was highlighted.
Unprotected left main coronary stenting as alternative therapy to coronary bypass surgery in high surgical risk acute coronary syndrome patients
Authors: Abdelmalak Hany D. , Omar Hesham R. , Mangar Devanand , Camporesi Enrico M.
Published: June 2013

Acute coronary syndrome has a high mortality rate that dramatically increases in the presence of left main coronary artery (LMCA) disease. Over the past decades, coronary artery bypass graft (CABG) surgery has been commonly accepted as the standard of care for patients with LMCA stenosis and is still considered the first-line treatment in current practice guidelines. Percutaneous coronary intervention (PCI) of protected and unprotected LMCA has gained popularity and is increasingly utilized with comparable outcomes to CABG in randomized controlled trials. In-stent restenosis and the need for revascularization provide the main obstacle to LMCA revascularization. The advent of better PCI equipment, stents, ablative devices, intravascular ultrasound, hemodynamic support devices and antithrombotic agents have ignited a renewed interest in the practice of LMCA PCI, especially for high surgical risk patients who are neither candidates nor agreeable to CABG surgery. Herein, we review the studies comparing unprotected LMCA stenting with CABG surgery in regard to 3 main endpoints: mortality, major adverse events and the incidence of repeat revascularization.
The Total Ankle Arthroplasty Learning Curve With Third-Generation Implants
Authors: Clement R. Carter , Krynetskiy Evgeny , Parekh Selene G.
Published: June 2013

Background. Renewed interest in total ankle arthroplasty (TAA) has developed globally as a result of recent literature supporting new-generation implants as a viable alternative to arthrodesis. The literature also demonstrates a learning curve among surgeons adopting TAA. The purpose of this study is to better define this learning curve for surgeons using third-generation implants. Methods. Charts and radiographs were reviewed for the initial 26 TAA procedures performed by the senior author. Three third-generation implants were used: SBi (Small Bone Innovations) STAR, Salto Talaris, and Wright Medical INBONE. We report perioperative and early postoperative complications. Results. Two perioperative fractures occurred in the first 9 cases, and the incidence subsequently dropped to 0 ( P = .0431). Two cases of component malalignment occurred in the first 3 patients receiving the STAR implant, and the incidence then dropped to 0 ( P = .0034). Five wound complications (4 minor and 1 major) occurred, all in the final 14 patients. No cases of nerve injury, tendon laceration, or deep vein thrombosis occurred. Two patients returned to the operating room as a result of complications, and the total perioperative and early postoperative complication rate was 27%. Conclusion. The observed rate of perioperative and early postoperative complications in this case series was low relative to other similar-sized studies, suggesting that third-generation implants can reduce adverse events. Our results demonstrate that some common complications could be avoided altogether (nerve/tendon injuries), some decreased quickly with experience (intraoperative fractures and component malpositioning), and some persisted unchanged throughout this study (wound complications). These findings should influence surgical training, surgeon willingness to adopt this procedure, and patient counseling.

Levels of Evidence: Therapeutic, Level IV, Retrospective Case Series.
Ultrasound-Guided First Metatarsophalangeal Joint Injections
Authors: Sahler Christopher S. , Spinner David A. , Kirschner Jonathan S.
Published: June 2013

Objective. To describe a longitudinal ultrasound-guided in-plane approach for injection into the first metatarsophalangeal (MTP) joint and assess its accuracy in a cadaveric model. Design. A prospective anatomical cadaver study model was used. A total of 10 first MTP joints using the described technique were injected with 0.5 mL of dye under ultrasound guidance. The joints were later dissected, and accuracy was classified as accurate, accurate with overflow, or inaccurate with no injectate in the target area. Results. Of the injections, 9 were classified as accurate injections, and 1 was classified accurate with overflow. Conclusion. This cadaveric study suggests that ultrasound-guided injections of the first MTP joint can be accurately and reproducibly performed with a gel standoff, long-axis in-plane approach. This technique attempts to minimize the collateral damage to the surrounding tissue, specifically the articular cartilage. Clinicians should consider using this technique when performing ultrasound-guided injections to the first MTP joint.

Level of Evidence: Cadaveric, Level V
Writer’s cramp: is focal dystonia the best explanation?
Authors: Pritchard Michael H
Published: June 2013

Often considered no more than an historical curiosity, writer’s cramp remains an important disability in the workplace and the mechanism, which has puzzled the best medical minds for generations, remains contentious. A remarkable range of hypotheses has been put forward to try and explain a disability which periodically reached epidemic and economically worrying levels, but in the end medical opinion has accepted the explanation put forward by neurologists Sheehy and Marsden in 1983 that this was caused by a form of focal dystonia. However, the majority of the historical descriptions of writer’s cramp do not fit the classical parameters of focal dystonia and are more accurately described as a progressive forearm muscle fatigue. Today’s keyboard operators continue to complain of symptoms identical to their clerical forebears demonstrating that this is a problem which has evolved but not disappeared; this has the paradoxical advantage that modern research techniques enable this complaint to be revisited. The result shows that two varieties of writer’s cramp have always existed and while focal dystonia remains a valid explanation for a minority of cases, the much more common fatigue-based complaint is better explained by chronic compartment syndrome of the forearm.
Current state of medical device nomenclature and taxonomy systems in the UK: spotlight on GMDN and SNOMED CT
Authors: White Judith , Carolan-Rees Grace
Published: June 2013

A standardised terminology for describing medical devices can enable safe and unambiguous exchange of information. Proposed changes to EU-wide medical devices regulations mandate the use of such a system. This article reviews two important classification systems for medical devices in the UK. The Global Medical Device Nomenclature (GMDN) provides a classification system specifically for medical devices and diagnostics, and facilitates data exchange between manufacturers and regulators. SNOMED CT is the terminology of choice in the NHS for communicating, sharing and storing information about patients’ healthcare episodes. Harmonisation of GMDN and SNOMED CT will encourage use of single terminology throughout the lifetime of a device; from regulatory approval through clinical use and post-marketing surveillance. Manufacturers will be required to register medical devices with a European device database (Eudamed) and to fit certain devices with a Unique Device Identifier; both are efforts to improve transparency and traceability of medical devices. Successful implementation of these elements depends on having a consistent nomenclature for medical devices.
Stabbing and safeguarding in children and young people: a Pan-London service evaluation and audit
Authors: Apps John R , Williams Carrie , McGuinness Anne , Gabbie Susie , Sutcliffe Alastair G
Published: June 2013

Objectives

To characterize paediatric presentations of stabbing to emergency departments across London and to audit existing referral rates to the police and social services against the new standard set by the General Medical Council.

Design

Retrospective multi-centre service evaluation/audit.

Setting

All emergency departments within London.

Participants

Patients under 18 years of age presenting to emergency departments with non-accidental stabbing between 1 April 2007 and 30 April 2009.

Main outcome measures

Patient age, nature of assault, assailant, injuries and management. Rates of documented referral to police and social services, as mandated by GMC guidance.

Results

A total of 381 presentations were identified from 20 out of the 32 hospitals in London, 160 of whom were less than 16 years old. The majority were seen only by emergency department staff and only a minority (28%) were admitted. Three died in the departments. A knife was the commonest weapon and the limbs the most common site of injury. Referrals to police were documented in only 30% of patients (43% if <16 years old) and to social services in 16% (31% if <16 years old) of those discharged. In the majority, there was no documentation (police 64%, social services 79%).

Conclusions

A significant number of paediatric stabbings present to emergency departments across London. The majority of these are discharged directly from departments. Of those discharged, documentation regarding referral rates to Police and Social Services was poor, and documented referral rates low. This study covered a period prior to the introduction of new General Medical Council guidance and a repeat audit to assess subsequent documented referrals is required.
Dermatology, an interdisciplinary approach between community and hospital care
Authors: Mashayekhi Soudeh , Hajhosseiny Reza
Published: June 2013

Skin lesions are extremely common, with 54% of the UK population being affected by skin disease annually. As such, dermatological conditions can be brought to light following admission to hospital for different underlying conditions, with 57% of the dermatological diagnoses made on the hospital wards, unrelated to previous patient history or reasons for admission. The role of the dermatologist is therefore comprehensive and inherently important in the hospital. General practitioners play an integral role in managing skin conditions in the community, with up to 24% of consultations relating to skin disease, referring patients to dermatology mainly for the management of more complex conditions, and diagnosis of certain skin lesions. It is therefore essential to further analyse these roles and to better understand the extent of inpatient and outpatient activity to better plan the provision of dermatological services whether in the community, or in the hospital.
Hedgehog inhibition reduces angiogenesis by downregulation of tumoral VEGF‐A expression in hepatocellular carcinoma
Authors: Pinter Matthias , Sieghart Wolfgang , Schmid Monika , Dauser Bernhard , Prager Gerald , Dienes Hans Peter , Trauner Michael , Peck‐Radosavljevic Markus
Published: June 2013

Background

Dysregulation and activation of Hedgehog (Hh) signalling may contribute to tumorigenesis, angiogenesis, and metastatic seeding in several solid tumours.

Objective

We investigated the impact of Hh inhibition on tumour growth and angiogenesis using in‐vitro and in‐vivo models of hepatocellular carcinoma (HCC).

Methods

The effect of the Hh pathway inhibitor GDC‐0449 on tumour growth was investigated using an orthotopic rat model. Effects on angiogenesis were determined by immunohistochemical staining of von Willebrand factor antigen and by assessing the mRNA expression of several angiogenic factors. In vitro, HCC cell lines were treated with GDC‐0449 and evaluated for viability and expression of vascular endothelial growth factor (VEGF). Endothelial cells were evaluated for viability, migration, and tube formation.

Results

In the orthotopic HCC model, GDC‐0449 significantly decreased tumoral VEGF expression which was accompanied by a significant reduction of microvessel density and tumour growth. In HCC cells, GDC‐0449 had no effect on cell growth but significantly reduced target gene regulation and VEGF expression while having no direct effect on endothelial cell viability, migration, and tube formation.

Conclusions

Hh inhibition with GDC‐0449 downregulates tumoral VEGF production in vitro and reduces tumoral VEGF expression, angiogenesis, and tumour growth in an orthotopic HCC model.
Cystectomy for obstructive uropathy secondary to lupus cystitis: a learning point for urologists?
Authors: De Siqueira J , Mangera A , Venugopal S , Edhem I
Published: June 2013

We present the case of a 72-year-old woman with obstructive uropathy secondary to interstitial cystitis-like pathology as the presenting features of systemic lupus erythematosus (SLE). After her initial presentation with visible haematuria, she was shown to have hydroureteronephrosis and a bulky bladder mass. Histology of bladder biopsies demonstrated severe inflammation. Following unsuccessful attempts to stent the ureters, worsening renal function and a concern regarding possible malignancy, a cystectomy and ileal conduit were performed. Final histology showed her bladder had only benign inflammatory changes. Subsequent investigations led to a diagnosis of SLE. We suggest that in cases of obstructive uropathy in association with severe inflammation of the bladder, lupus cystitis should be considered at an early stage and managed with steroids in the first instance. This may lead to resolution of the underlying pathology and thus avoid the need for urinary diversion and cystectomy.
Identifying Gender Differences in an Australian Youth Offender Population
Authors: Shepherd Stephane M. , Luebbers Stefan , Dolan Mairead
Published: June 2013

The study examined gender differences in risk factors for violence in a sample of 213 male and female youths held in Youth Justice Centres in Victoria, Australia. Although violence risk factors are considered to be commensurate across gender, a growing body of international literature is categorizing gender-specific criminal trajectories. The study aimed to investigate this concept in an Australian juvenile context. Through the use of a widely validated youth violence risk assessment inventory, the prevalence of salient risk items was compared across gender. Young female offenders were found to present with higher levels of family dysfunction, peer rejection and self-injurious behavior reflecting international female offending pathways literature.
Multimodal imaging reveals structural and functional heterogeneity in different bone marrow compartments: functional implications on hematopoietic stem cells
Authors: Lassailly Francois , Foster Katie , Lopez-Onieva Lourdes , Currie Erin , Bonnet Dominique
Published: June 2013

Key Points

Comparative analysis of epiphyses, diaphyses, and calvaria in terms of homeostatic HSC content, homing, and early reconstitution is described. Noninvasive intravital imaging of intact bones and assessment of BVF, BRA, and hypoxia are reported.
Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK–mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma
Authors: McDonnell Scott R. P. , Hwang Steven R. , Rolland Delphine , Murga-Zamalloa Carlos , Basrur Venkatesha , Conlon Kevin P. , Fermin Damian , Wolfe Thomas , Raskind Alexander , Ruan Chunhai , Jiang Jian-Kang , Thomas Craig J. , Hogaboam Cory M. , Burant Charles F. , Elenitoba-Johnson Kojo S. J. , Lim Megan S.
Published: June 2013

Key Points

NPM-ALK induces a metabolic shift toward biomass production. NPM-ALK phosphorylates Y105-PKM2 to regulate metabolism and tumorigenesis.
PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia
Authors: Tung Stephanie , Shi Yonghong , Wong Karry , Zhu Fang , Gorczynski Reg , Laister Robert C. , Minden Mark , Blechert Anne-Kareen , Genzel Yvonne , Reichl Udo , Spaner David E.
Published: June 2013

Key Points

Glucocorticoids downregulate PKM2 and metabolism in CLL cells, impairing access to bioenergetic programs needed to repair cell damage. PPARα and fatty acid oxidation antagonists potentiate the cytotoxic effects of glucocorticoids.
Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy
Authors: Jodele Sonata , Licht Christoph , Goebel Jens , Dixon Bradley P. , Zhang Kejian , Sivakumaran Theru A. , Davies Stella M. , Pluthero Fred G. , Lu Lily , Laskin Benjamin L.
Published: June 2013

Key Points

Genetic variations in the alternative pathway of complement may be associated with thrombotic microangiopathy in children receiving HSCT. These findings may guide the development of novel treatment interventions for this poorly understood transplant complication.
Disruption of rimP-SC, encoding a ribosome assembly cofactor, markedly enhances the production of several antibiotics in Streptomyces coelicolor
Authors: Pan Yuanyuan , Lu Cheng , Dong Hailing , Yu Lingjun , Liu Gang , Tan Huarong
Published: July 2013

Background

Ribosome assembly cofactor RimP is one of the auxiliary proteins required for maturation of the 30S subunit in Escherichia coli. Although RimP in protein synthesis is important, its role in secondary metabolites biosynthesis has not been reported so far. Considering the close relationship between protein synthesis and the production of secondary metabolites, the function of ribosome assembly cofactor RimP on antibiotics production was studied in Streptomyces coelicolor and Streptomyces venezuelae.

Results

In this study, the rimP homologue rimP-SC was identified and cloned from Streptomyces coelicolor. Disruption of rimP-SC led to enhanced production of actinorhodin and calcium-dependent antibiotics by promoting the transcription of act II-ORF4 and cdaR. Further experiments demonstrated that MetK was one of the reasons for the increment of antibiotics production. In addition, rimP-SC disruption mutant could be used as a host to produce more peptidyl nucleoside antibiotics (polyoxin or nikkomycin) than the wild-type strain. Likewise, disruption of rimP-SV of Streptomyces venezuelae also significantly stimulated jadomycin production, suggesting that enhanced antibiotics production might be widespread in many other Streptomyces species.

Conclusion

These results established an important relationship between ribosome assembly cofactor and secondary metabolites biosynthesis and provided an approach for yield improvement of secondary metabolites in Streptomyces.
Trimethoxy-benzaldehyde levofloxacin hydrazone inducing the growth arrest and apoptosis of human hepatocarcinoma cells
Authors: Sun Jin-ping , Shi Zhen-yu , Liu Shi-meng , Kang Yu-hua , Hu Guo-qiang , Huangfu Chao-shen , Deng Jin-bo , Liu Bin
Published: July 2013

Background

In order to search for new structural modification strategies on fluoroquinolones, we have designed and synthesized a series of fluoroquinolone derivatives by linking various hydrazine compounds to the C-3 carboxyl group of levofloxacin and assessed their anticancer activities. Several novel levofloxacin derivatives displayed potent cytotoxicity against the tested cancer cell lines in vitro. In the present study, we investigated the effect of 1-Cyclopropyl-6-fluoro-4-oxo-7- piperazin-1, 4-dihydro- quinoline- 3-carboxylic acid benzo [1,3] dioxol-5- ylmethylene- hydrazide (QNT11) on the apoptosis of human hepatocarcinoma cells in vitro.

Methods

The inhibition effects of QNT11 on cell proliferation were examined by MTT assay. Cell apoptosis was determined by TUNEL and DNA agarose gel electrophoresis method. The topoisomerase ΙΙ activity was measured by agarose gel electrophoresis using Plasmid pBR322 DNA as the substrate. Cell cycle progression was analyzed using flow cytometry in conjunction with ethanol fixation and propidium iodide staining. Mitochondrial membrane potential (△ψm) was measured by high content screening image system. The caspase-9, caspase-8, caspase-3, Bcl-2, Bax, CDK1, Cyclin B1and cytochrome c protein expressions were detected by Western blot analysis.

Results

QNT11 showed selective cytotoxicity against Hep3B, SMMC-7721, MCF-7 and HCT-8 cell lines with IC50 values of 2.21 μM, 2.38 μM, 3.17 μM and 2.79 μM, respectively. In contrast, QNT11 had weak cytotoxicity against mouse bone marrow mesenchymal stem cells (BMSCs) with IC50 value of 7.46 μM. Treatment of Hep3B cells with different concentrations of QNT11 increased the percentage of the apoptosis cells significantly, and agarose gel electrophoresis revealed the ladder DNA bands typical of apoptotic cells, with a decrease in the mitochondrial membrane potential. Compared to the control group, QNT11 could influence the DNA topoisomerase IIactivity and inhibit the religation of DNA strands, thus keeping the DNA in fragments. There was a significant increase of cytochrome c in the cytosol after 24 h of treatment with QNT11 and a decrease in the mitochondrial compartment. Observed changes in cell cycle distribution by QNT11 treated might be caused by insufficient preparation for G2/M transition. In addition, QNT11 increased the protein expression of Bax, caspase-9, caspase-8, caspase-3, as well as the cleaved activated forms of caspase-9, caspase-8 and caspase-3 significantly, whereas the expression of Bcl-2 decreased.

Conclusions

Our results showed that QNT11 as a fluoroquinolone derivative exerted potent and selectively anticancer activity through the mechanism of eukaryotic topoisomerase II poisoning. The growth inhibition was in large part mediated via apoptosis-associated mitochondrial dysfunction and regulation of Bcl-2 signaling pathways.
Feasibility and safety study of a new device (Odón device) for assisted vaginal deliveries: study protocol
Authors:   The World Health Organization Odon Device Research Group
Published: July 2013

Background

Intrapartum complications are responsible for approximately half of all maternal deaths, and two million stillbirth and neonatal deaths per year. Prolonged second stage of labour is associated with potentially fatal maternal complications such as haemorrhage and infection and it is a major cause of stillbirth and newborn morbidity and mortality. Currently, the three main options for managing prolonged second stage of labour are forceps, vacuum extractor and caesarean section. All three clinical practices require relatively expensive equipment (e.g., a surgical theatre for caesarean section) and/or highly trained staff which are often not available in low resource settings. The specific aim of the proposed study is to test the safety and feasibility of a new device (Odón device) to effectively deliver the fetus during prolonged second stage of labour. The Odón device is a low-cost technological innovation to facilitate operative vaginal delivery and designed to minimize trauma to the mother and baby. These features combined make it a potentially revolutionary development in obstetrics, particularly for improving intrapartum care and reducing maternal and perinatal morbidity and mortality in low resource settings.

Methods/design

This will be a hospital-based, multicenter prospective phase 1 cohort study with no control group. Delivery with the Odón device will be attempted under normal labour and non-emergency conditions on all the women enrolled in the study. One-hundred and thirty pregnant women will be recruited in tertiary care facilities in Argentina. Safety will be assessed by examining maternal and infant outcomes until discharge. Feasibility will be evaluated by observing successful expulsion of the fetal head after one-time application of the device under standardized conditions (full cervical dilation, anterior presentation, +2 station, normal fetal heart rate).

Trial registration

Australian New Zealand Clinical Trials Registry (ANZCTR). Identifier:ACTRN12613000141741
A wild-type Botrytis cinerea strain co-infected by double-stranded RNA mycoviruses presents hypovirulence-associated traits
Authors: Potgieter Christiaan A , Castillo Antonio , Castro Miguel , Cottet Luis , Morales Angélica
Published: July 2013

Background

Botrytis cinerea CCg378 is a wild-type strain infected with two types of double-stranded RNA (dsRNA) mycoviruses and which presents hypovirulence-associated traits. The objectives of the present study were to characterize the mycoviruses and investigate their relationship with the low virulence degree of the fungal host.

Results

B. cinerea CCg378 contains five dsRNA molecules that are associated with two different types of isometric viral particles of 32 and 23 nm in diameter, formed by structural polypeptides of 70-kDa and 48-kDa, respectively.

The transfection of spheroplasts of a virus-free strain, B. cinerea CKg54, with viral particles purified from the CCg378 strain revealed that the 2.2-kbp dsRNAs have no dependency on the smaller molecules for its stable maintenance in the fungal cytoplasm, because a fungal clone that only contains the 2.2-kbp dsRNAs associated with the 32-nm particles was obtained, which we named B. cinerea CKg54vi378. One of the 2.2 kbpdsRNA segments (2219 bp) was sequenced and corresponds to the gene encoding the capsid protein of B. cinerea CCg378 virus 1 (Bc378V1), a putative new member of the Partitiviridae family.

Furthermore, physiological parameters related to the degree of virulence of the fungus, such as the sporulation rate and laccase activity, were lower in B. cinerea CCg378 and B. cinerea CKg54vi378 than in B. cinerea CKg54. Additionally, bioassays performed on grapevine leaves showed that the CCg378 and CKg54vi378 strains presented a lower degree of invasiveness on the plant tissue than the CKg54 strain.

Conclusions

The results show that B. cinerea CCg378 is coinfected by two mycoviruses and that the 2.2-kbp dsRNAs correspond to the 32-nm mycovirus genome, which would be a new member of the Partitiviridae family as it has the typical pattern of partitiviruses. On the other hand, the results suggest that the hypovirulence of B. cinerea CCg378 could be conferred by both mycoviruses, since the fungal clone B. cinerea CKg54vi378 presents an intermediate virulence between the CKg54 and CCg378 strains. Therefore, the putative partitivirus would be partially contributing to the hypovirulence phenotype of the CCg378 strain.
Dual organism design cycle reveals small subunit substitutions that improve [NiFe] hydrogenase hydrogen evolution
Authors: Yonemoto Isaac T , Matteri Christopher W , Nguyen Thao Amy , Smith Hamilton O , Weyman Philip D
Published: July 2013

Background

Photosynthetic microorganisms that directly channel solar energy to the production of molecular hydrogen are a potential future biofuel system. Building such a system requires installation of a hydrogenase in the photosynthetic organism that is both tolerant to oxygen and capable of hydrogen production. Toward this end, we have identified the [NiFe] hydrogenase from the marine bacterium Alteromonas macleodii “Deep ecotype” that is able to be heterologously expressed in cyanobacteria and has tolerance to partial oxygen. The A. macleodii enzyme shares sequence similarity with the uptake hydrogenases that favor hydrogen uptake activity over hydrogen evolution. To improve hydrogen evolution from the A. macleodii hydrogenase, we examined the three Fe-S clusters found in the small subunit of many [NiFe] uptake hydrogenases that presumably act as a molecular wire to guide electrons to or from the active site of the enzyme. Studies by others altering the medial cluster of a Desulfovibrio fructosovorans hydrogenase from 3Fe-4S to 4Fe-4S resulted in two-fold improved hydrogen evolution activity.

Results

We adopted a strategy of screening for improved hydrogenase constructs using an Escherichia coli expression system before testing in slower growing cyanobacteria. From the A. macleodii enzyme, we created a mutation in the gene encoding the hydrogenase small subunit that in other systems is known to convert the 3Fe-4S medial cluster to 4Fe-4S. The medial cluster substitution did not improve the hydrogen evolution activity of our hydrogenase. However, modifying both the medial cluster and the ligation of the distal Fe-S cluster improved in vitro hydrogen evolution activity relative to the wild type hydrogenase by three- to four-fold. Other properties of the enzyme including thermostability and tolerance to partial oxygen did not appear to be affected by the substitutions.

Conclusions

Our results show that substitution of amino acids altering the ligation of Fe-S clusters in the A. macleodii [NiFe] uptake hydrogenase resulted in increased hydrogen evolution activity. This activity can be recapitulated in multiple host systems and with purified protein. These results validate the approach of using an E. coli-cyanobacteria shuttle system for enzyme expression and improvement.
The use of HE4, CA125 and CA72-4 biomarkers for differential diagnosis between ovarian endometrioma and epithelial ovarian cancer
Authors: Anastasi Emanuela , Granato Teresa , Falzarano Renato , Storelli Paola , Ticino Adele , Frati Luigi , Panici Pierluigi Benedetti , Porpora Maria Grazia
Published: July 2013

Background

Endometriosis is frequently associated with high levels of CA125. This marker is therefore not useful for discriminating ovarian endometrioma from ovarian malignancy. The aim of this study was to establish a panel of complementary biomarkers that could be helpful in the differential diagnosis between ovarian endometriosis or other ovarian benign masses and ovarian cancer.

Methods

Blood samples from 50 healthy women, 17 patients with benign ovarian tumors, 57 patients with ovarian endometrioma and 39 patients with ovarian cancer were analyzed and serum values were measured for the following biomarkers: CA125, HE4 and CA72-4.

Results

Serum CA125 concentration was elevated in both patients with ovarian endometriosis and ovarian cancer but not in patients with other benign ovarian masses. HE4 was never increased in patients with endometriosis or benign masses whereas it was significantly higher in all patients with ovarian cancer (p < 0.05). A marked difference in CA72-4 values was observed between women with ovarian cancer (67%) and those with endometriosis (p < 0.05).

Conclusions

The results of the study suggest that HE4 and CA72-4 determination is the best approach to confirm the benign nature of ovarian endometrioma in women with high CA125 levels.
Analysis of hairpin RNA transgene-induced gene silencing in Fusarium oxysporum
Authors: Schumann Ulrike , Smith Neil A , Kazan Kemal , Ayliffe Michael , Wang Ming-Bo
Published: July 2013

Background

Hairpin RNA (hpRNA) transgenes can be effective at inducing RNA silencing and have been exploited as a powerful tool for gene function analysis in many organisms. However, in fungi, expression of hairpin RNA transcripts can induce post-transcriptional gene silencing, but in some species can also lead to transcriptional gene silencing, suggesting a more complex interplay of the two pathways at least in some fungi. Because many fungal species are important pathogens, RNA silencing is a powerful technique to understand gene function, particularly when gene knockouts are difficult to obtain. We investigated whether the plant pathogenic fungus Fusarium oxysporum possesses a functional gene silencing machinery and whether hairpin RNA transcripts can be employed to effectively induce gene silencing.

Results

Here we show that, in the phytopathogenic fungus F. oxysporum, hpRNA transgenes targeting either a β-glucuronidase (Gus) reporter transgene (hpGus) or the endogenous gene Frp1 (hpFrp) did not induce significant silencing of the target genes. Expression analysis suggested that the hpRNA transgenes are prone to transcriptional inactivation, resulting in low levels of hpRNA and siRNA production. However, the hpGus RNA can be efficiently transcribed by promoters acquired either by recombination with a pre-existing, actively transcribed Gus transgene or by fortuitous integration near an endogenous gene promoter allowing siRNA production. These siRNAs effectively induced silencing of a target Gus transgene, which in turn appeared to also induce secondary siRNA production. Furthermore, our results suggested that hpRNA transcripts without poly(A) tails are efficiently processed into siRNAs to induce gene silencing. A convergent promoter transgene, designed to express poly(A)-minus sense and antisense Gus RNAs, without an inverted-repeat DNA structure, induced consistent Gus silencing in F. oxysporum.

Conclusions

These results indicate that F. oxysporum possesses functional RNA silencing machineries for siRNA production and target mRNA cleavage, but hpRNA transgenes may induce transcriptional self-silencing due to its inverted-repeat structure. Our results suggest that F. oxysporum possesses a similar gene silencing pathway to other fungi like fission yeast, and indicate a need for developing more effective RNA silencing technology for gene function studies in this fungal pathogen.
The role of viruses in autoreactive B cell activation within tertiary lymphoid structures in autoimmune diseases
Authors: Lucchesi Davide , Bombardieri Michele
Published: June 2013

TLS, characterized by the formation of ectopic B/T cell follicles with FDCs supporting an ectopic GC response, have been described in the target organs of several autoimmune diseases, including MS, RA, SS, and autoimmune thyroiditis. These structures represent functional niches, whereby autoreactive B cells undergo in situ affinity maturation and differentiation to autoantibody-producing cells, thus contributing to the progression and persistence of autoimmunity. Increasing evidence demonstrates that TLS can also develop in the context of cancer, as well as chronic infections. In this review, we collect recent evidences that highlights the relationship between persistent viral infection and the development of ectopic lymphoid structures in animal models and patients. Furthermore, we shall discuss the concept that whereas in physiological conditions, inducible TLS are critical for viral clearance and the establishment of protective immunity, but in the context of susceptible individuals, persistent viral infections may contribute, directly or indirectly, to the development of breach of tolerance against self-antigens and the development of autoimmunity through the formation of TLS.
Analysis of Molecular Motion of Proton-conductive Imidazolium Hydrogen Succinate Crystal Using Solid-state NMR
Authors: Umiyama Tsuyoshi , Ohashi Ryutaro , Ida Tomonori , Mizuno Motohiro
Published: July 2013

The dynamics of imidazolium ion and its influence on proton conductivity were investigated for imidazolium hydrogen succinate crystal using solid-state 2H and 13C NMR. A 180° flip and libration (rotational vibration) of the imidazolium ion were observed from 2H NMR broad line spectra, quadrupole Carr–Purcell–Meiboom–Gill (QCPMG) spectra and high-resolution 13C NMR spectra. From a comparison of the rates of these motions and proton transfer, the libration of imidazolium ion is important for the proton conductive process.
Heterogeneous Enantioselective Hydrogenation: pH Dependence and Interplay between Catalytic Efficacy and Surface Composition
Authors: Osawa Tsutomu , Kizawa Tomoko , Ikeda Shinji , Kitamura Takayuki , Inoue Yoshihisa , Borovkov Victor
Published: July 2013

The performance of a catalytic system consisting of metallic Ni powder, tartaric acid (TA), and NaBr in the enantioselective hydrogenation of methyl acetoacetate was strongly influenced by the pH of TA solution upon chiral modification, which is attributable to the pH-induced change in the surface composition of Ni catalyst as unambiguously confirmed by X-ray photoelectron spectroscopy for the first time.
PLASMA SPRAYED HYDROXYAPATITE COATINGS MODIFIED WITH SILVER NANOPARTICLES
Authors: Ignatev Mikhail
Published: July 2013

Metallic silver, silver nanoparticles (AgNp) and nanocomposites based on silver are widely usedin medicine, due to their antibacterial and antiseptic properties. The main goals of the presentwork were: (1) research of various types of liquids containing AgNp (including AgNp producedby biosynthesis technology using dessert plants (nopal, agave) extracts to reduce the silver); (2)research of sedimentation from liquids of AgNp on the surface of Hydroxyapatite (HA) implantcoatings deposited by plasma spraying; (2) preliminary evaluation of antibacterial properties ofHA coating modified with AgNp. The first test shows significant antibacterial activity of HAcoatings containing AgNp produced by biosynthesis technology.
FAILURE MODES OF PVD COATINGS IN MOLTEN Al-ALLOY CONTACT
Authors: Lorusso Massimo , Ugues Daniele
Published: July 2013

This paper deals with a study of the failure mode of thin PVD coatings in alternated contact withmolten aluminum alloy. CrN and ZrN monolayer coatings deposited through cathodic arcevaporation were used. The coatings morphology was assessed by SEM and their mechanicalproperties evaluated by nanohardness test performed at room temperature. An experimental testrig which cyclically immerses coated steel samples in molten Al-alloy and in a cooling bath wasapplied. The thermal gradient from the coating to the steel core was exalted by internal coolingchannels placed in the internal cavity of samples. Periodical SEM inspections were performed toassess the damaging levels introduced by the test and to study the related decrease of substrateprotection capability. Descriptions and interpretations of the damages evolutions were derived.The main conclusions achieved are that both coatings suffered by the formation of corrosionpits, which were due to a corrosion attack of the steel substrate localized at coating defects sites.In particular, at pores locations the corrosion was fast, whereas at droplets sites it required acertain incubation time. Once corrosion pits were formed they exhibited an initial tendency toexpand laterally, but they did rapidly stabilize in terms of lateral dimensions. Later on twodifferent failure modes acted in ZrN and in CrN. Extended delamination due to a markedmismatch of mechanical properties between the coating and the steel substrate developed inZrN. On the contrary, thermal cracking due to lower hardness levels developed in CrN, but withlimited delamination. Accordingly the steel substrate protection capability was evaluated to behigher in CrN than in ZrN.Keywords: PVD
Singular Control and Optimal Stopping of SPDEs, and Backward SPDEs with Reflection
Authors: Øksendal Bernt , Sulem Agnès , Zhang Tusheng
Published: June 2013

We consider general singular control problems for random fields given by a stochastic partial differential equation (SPDE). We show that under some conditions the optimal singular control can be identified with the solution of a coupled system of SPDE and a reflected backward SPDE (RBSPDE). As an illustration we apply the result to a singular optimal harvesting problem from a population whose density is modeled as a stochastic reaction-diffusion equation. Existence and uniqueness of solutions of RBSPDEs are established, as well as comparison theorems. We then establish a relation between RBSPDEs and optimal stopping of SPDEs, and apply the result to a risk-minimizing stopping problem.
Excursion-Based Universal Approximations for the Erlang-A Queue in Steady-State
Authors: Gurvich Itai , Huang Junfei , Mandelbaum Avishai
Published: June 2013

We revisit many-server approximations for the well-studied Erlang-A queue. This is a system with a single pool of i.i.d. servers that serve one class of impatient i.i.d. customers. Arrivals follow a Poisson process and service times are exponentially distributed as are the customers' patience times. We propose a diffusion approximation that applies simultaneously to all existing many-server heavy-traffic regimes: quality and efficiency driven, efficiency driven, quality driven, and nondegenerate slowdown. We prove that the approximation provides accurate estimates for a broad family of steady-state metrics. Our approach is “metric-free” in that we do not use the specific formulas for the steady-state distribution of the Erlang-A queue. Rather, we study excursions of the underlying birth-and-death process and couple these to properly defined excursions of the corresponding diffusion process. Regenerative process and martingale arguments, together with derivative bounds for solutions to certain ordinary differential equations, allow us to control the accuracy of the approximation. We demonstrate the appeal of universal approximation by studying two staffing optimization problems of practical interest.
Mimicking P450 processes and the use of
metalloporphyrins
Authors: Simões Mário M. Q. , Neves Cláudia M. B. , Pires Sónia M. G. , Neves M. Graça P. M. S. , Cavaleiro José A. S.
Published: June 2013

Metalloporphyrins (MPs) are known to catalyze in vitro a broad range of
cytochrome P450-mediated reactions occurring in vivo. Most of the
biomimetic research using MPs in oxidative catalysis has been directed towards
the oxidation of organic compounds presenting significant reactivity features in
one functional group. Much less effort has been made to imitate the oxidation of
more complex molecules, with a range of functionalities, such as drugs or other
xenobiotics. By varying the structure of the porphyrin, the metal ion, the
oxidant, and the reaction conditions, it is possible to modulate the
regioselectivity of the oxidation reactions. Recently, and along with studies on
the synthesis and reactivity of porphyrins, chlorins, and phthalocyanines, our
group was able to develop an interesting line of research in the field of
biomimetic oxidation of organic compounds using environmentally benign hydrogen
peroxide as oxidant and Mn(III) or Fe(III) porphyrin complexes as catalysts. The
more up to date results obtained in such work are reviewed here.