bluuebunny/crossref_metadata_2025 huggingface dataset:
Conditional Inferential Models: Combining Information for Prior-Free Probabilistic Inference
Authors: Martin Ryan , Liu Chuanhai
Published: May 2014

The inferential model (IM) framework provides valid prior-free probabilistic inference by focusing on predicting unobserved auxiliary variables. But, efficient IM-based inference can be challenging when the auxiliary variable is of higher dimension than the parameter. Here we show that features of the auxiliary variable are often fully observed and, in such cases, a simultaneous dimension reduction and information aggregation can be achieved by conditioning. This proposed conditioning strategy leads to efficient IM inference and casts new light on Fisher's notions of sufficiency, conditioning and also Bayesian inference. A differential-equation-driven selection of a conditional association is developed, and validity of the conditional IM is proved under some conditions. For problems that do not admit a conditional IM of the standard form, we propose a more flexible class of conditional IMs based on localization. Examples of local conditional IMs in a bivariate normal model and a normal variance components model are also given.
Loneliness and health care consumption among older people
Authors: Taube Elin , Kristensson Jimmie , Sandberg Magnus , Midlöv Patrik , Jakobsson Ulf
Published: May 2014

Few studies have investigated loneliness in relation to health care consumption among frail older people. The aim of this study was to examine loneliness, health‐related quality of life (HRQoL), and health complaints in relation to health care consumption of in‐ and outpatient care among frail older people living at home. The study, with a cross‐sectional design, comprised a sample of 153 respondents aged from 65 years (mean age 81.5 years) or older, who lived at home and were frail. Data was collected utilising structured interviews in the respondent's home assessing demographic data, loneliness, HRQoL and health complaints. Patient administrative registers were used to collect data on health care consumption. Loneliness was the dependent variable in the majority of the analyses and dichotomised. For group comparisons Student′s t‐test, Mann–Whitney U‐test and Chi‐square test were used. The results showed that 60% of the respondents had experienced loneliness during the previous year, at least occasionally. The study identified that lonely respondents had a lower HRQoL (p = 0.022), with a higher total number of reported health complaints (p = 0.001), and used more outpatient services including more acute visits at the emergency department, compared to not lonely respondents (p = 0.026). Multiple linear regression analysis showed that a depressed mood was independently associated to total use of outpatient care (B = 7.4, p < 0.001). Therefore, it might not be loneliness, per se, that is the reason for seeking health care. However, reasons for using health care services are difficult to determine due to the complex situation for the frail older person. To avoid emergency department visits and to benefit the well‐being of the frail older person, interventions targeting the complex health situation, including loneliness, are suggested.
First report on the antibody verification of HLA‐ABC epitopes recorded in the website‐based HLA Epitope Registry
Authors: Duquesnoy R. J. , Marrari M. , Mulder A. , da Mata Sousa L. C. D. , da Silva A. S. , do Monte S. J. H.
Published: May 2014

The International Registry of Antibody‐Defined HLA Epitopes (
http://www.epregistry.com.br) has been recently established as a tool to understand humoral responses to human leukocyte antigen (HLA) mismatches. These epitopes are defined structurally by three‐dimensional molecular modeling and amino acid sequence differences between HLA antigens. So‐called eplets represent essential components of HLA epitopes and they are defined by polymorphic residues. A major goal is to identify HLA epitopes that have been verified experimentally with informative antibodies. Our analysis has also included data in many publications. As of 1 November 2013, 95 HLA‐ABC antibody‐verified epitopes have been recorded, 62 correspond to eplets and 33 are defined by eplets paired with other residue configurations. The Registry is still a work‐in‐progress and will become a useful resource for HLA professionals interested in histocompatibility testing at the epitope level and investigating antibody responses to HLA mismatches in transplant patients.
Serological and molecular evidence of a plausible transmission of hepatitis E virus through pooled plasma
Authors: Andonov A. , Rock G. , Lin L. , Borlang J. , Hooper J. , Grudeski E. , Wu J. ,   Members of the Canadian Apheresis Group (CAG)
Published: May 2014

Background and Objectives

Recently, hepatitis E virus has been recognized as a new transfusion‐associated risk; however, its efficiency of transmission through blood products requires further investigation. Asymptomatic viremia of short duration has been observed in blood donors from several European countries to the rate of <1:10 000 and HEV transmission in recipients of blood products has been documented in Japan and Europe. Although HEV RNA was detected in large plasma fractionation pools used for manufacturing of plasma derived products, HEV transmission has not been demonstrated so far. In this study, we investigated the possibility of HEV transmission in patients with thrombotic thrombocytopenic purpura whose treatment included up to 40 l of plasma exchange.

Materials and Methods

Thirty‐six TTP patients received either solvent–detergent‐treated plasma prepared by pooling of 2500 single‐donor or cryosupernatant plasma. Three samples were collected from TTP patients at time 0, 1 and 6 months post‐treatment and tested for anti‐HEV antibodies. Patients with HEV seroconversion were also tested for viremia by PCR.

Results

Two of seventeen TTP patients treated with SDP showed serological evidence of HEV infection. The 1‐month samples from these patients were also positive for HEV RNA. A distinct rise of anti‐HEV IgG level was detected in two other TTP patients with weak pre‐existing immunity to HEV; this observation is indicative of a possible immune response boost due to a breakthrough infection.

Conclusion

This work provides, for the first time, indirect evidence of HEV transmission by pooled plasma and warrants further studies.
Differences in the Microstructure and Biomechanical Properties of the Recurrent Laryngeal Nerve as a Function of Age and Location
Authors: Williams Megan J. , Utzinger Urs , Barkmeier-Kraemer Julie M. , Vande Geest Jonathan P.
Published: May 2014

Idiopathic onset of unilateral vocal fold paralysis (UVP) is caused by damage to the recurrent laryngeal nerve (RLN) and results in difficulty speaking, breathing, and swallowing. This damage may occur in this nerve as it loops around the aortic arch, which is in a dynamic biomechanical environment. The goal of this study is to determine if the location-dependent biomechanical and microstructural properties of the RLN are different in piglets versus adolescent pigs. The neck/distal and thoracic/proximal (near the aortic arch) regions of the RLN from eight adolescent pigs and six piglets were isolated and mechanically assessed in uni-axial tension. Two-photon imaging (second harmonic) data were collected at 5%, 10%, and 15% strain during the mechanical test. The tangential modulus (TM) and the strain energy density (W) were determined at each level of strain. The mean mode of the preferred fiber angle and the full width at half maximum (FWHM, a measure of fiber splay) were calculated from the imaging data. We found significantly larger values of TM, W, and FWHM in the proximal segments of the left RLN when compared to the distal segments (18.51 MPa ± 1.22 versus 10.78 MPa ± 1.22, p < 0.001 for TM, 0.046 MPa ± 0.01 versus 0.026 MPa ± 0.01, p < 0.003 for W, 15.52 deg ± 1.00 versus 12.98 deg ± 1.00, p < 0.001 for FWHM). TM and W were larger in the left segments than the right (15.32 MPa ± 1.20 versus 11.80 MPa ± 1.20, p < 0.002 for TM, 0.038 MPa ± 0.01 versus 0.028 MPa ± 0.01, p < 0.0001 for W). W was larger in piglets when compared to adolescent pigs (0.042 MPa ± 0.01 versus 0.025 MPa ± 0.01, p < 0.04). The proximal region of the left porcine RLN is more stiff than the distal region and has a higher degree of fiber splay. The left RLN of the adolescent pigs also displayed a higher degree of strain stiffening than the right. These differences may develop as a result of the more dynamic environment the left RLN is in as it loops around the aortic arch.
Epitaxial, well-ordered ceria/lanthana high-k gate dielectrics on silicon
Authors: Flege Jan Ingo , Kaemena Björn , Schmidt Thomas , Falta Jens
Published: May 2014

It is shown that the growth of epitaxial lanthana films on silicon may be achieved by substrate prepassivation using an atomic layer of chlorine, which prevents silicon oxide and silicate formation at the oxide–silicon interface. Postdeposition of two layers of cerium oxide facilitates the healing of structural defects within the La2O3 film, strongly increasing its crystallinity at the expense of a slightly more oxidized interfacial layer below. Together, the approach of combining Cl prepassivation and the ceria overgrowth results in an epitaxial, high-quality ceria/lanthana gate stack suitable for high-k integration in a gate-last process.
Oxidation Products of Biogenic Emissions Contribute to Nucleation of Atmospheric Particles
Authors: Riccobono Francesco , Schobesberger Siegfried , Scott Catherine E. , Dommen Josef , Ortega Ismael K. , Rondo Linda , Almeida João , Amorim Antonio , Bianchi Federico , Breitenlechner Martin , David André , Downard Andrew , Dunne Eimear M. , Duplissy Jonathan , Ehrhart Sebastian , Flagan Richard C. , Franchin Alessandro , Hansel Armin , Junninen Heikki , Kajos Maija , Keskinen Helmi , Kupc Agnieszka , Kürten Andreas , Kvashin Alexander N. , Laaksonen Ari , Lehtipalo Katrianne , Makhmutov Vladimir , Mathot Serge , Nieminen Tuomo , Onnela Antti , Petäjä Tuukka , Praplan Arnaud P. , Santos Filipe D. , Schallhart Simon , Seinfeld John H. , Sipilä Mikko , Spracklen Dominick V. , Stozhkov Yuri , Stratmann Frank , Tomé Antonio , Tsagkogeorgas Georgios , Vaattovaara Petri , Viisanen Yrjö , Vrtala Aron , Wagner Paul E. , Weingartner Ernest , Wex Heike , Wimmer Daniela , Carslaw Kenneth S. , Curtius Joachim , Donahue Neil M. , Kirkby Jasper , Kulmala Markku , Worsnop Douglas R. , Baltensperger Urs
Published: May 2014

Out of the Air

New-particle formation from gaseous precursors in the atmosphere is a complex and poorly understood process with importance in atmospheric chemistry and climate. Laboratory studies have had trouble reproducing the particle formation rates that must occur in the natural world.

Riccobono
et al.

(p.
717
) used the CLOUD (Cosmics Leaving Outdoor Droplets) chamber at CERN to recreate a realistic atmospheric environment. Sulfuric acid and oxidized organic vapors in typical natural concentrations caused particle nucleation at similar rates to those observed in the lower atmosphere.
Positive Feedback Within a Kinase Signaling Complex Functions as a Switch Mechanism for NF-κB Activation
Authors: Shinohara Hisaaki , Behar Marcelo , Inoue Kentaro , Hiroshima Michio , Yasuda Tomoharu , Nagashima Takeshi , Kimura Shuhei , Sanjo Hideki , Maeda Shiori , Yumoto Noriko , Ki Sewon , Akira Shizuo , Sako Yasushi , Hoffmann Alexander , Kurosaki Tomohiro , Okada-Hatakeyama Mariko
Published: May 2014

Signaling Dynamics

The signaling pathways that activate the transcription factor NF-κB are key regulatory pathways in cells of the immune system, and their dynamic properties are still being elucidated. In B cells, analysis of single-cell responses has shown that the stimulation of the B cell receptor causes a “digital” all-or-none response of cells to a stimulus.

Shinohara
et al.

(p.
760
) used a combination of mathematical modeling and experiments to show that this property of the system results from the presence of a positive feedback loop among the signaling components activated in response to the receptor. Studies in cells expressing mutated signaling components resolved key phosphorylation events that provide the threshold responses observed and identified potential molecular modifications that might modify the threshold or other aspects of the dynamic response.
Recyclable, Strong Thermosets and Organogels via Paraformaldehyde Condensation with Diamines
Authors: García Jeannette M. , Jones Gavin O. , Virwani Kumar , McCloskey Bryan D. , Boday Dylan J. , ter Huurne Gijs M. , Horn Hans W. , Coady Daniel J. , Bintaleb Abdulmalik M. , Alabdulrahman Abdullah M. S. , Alsewailem Fares , Almegren Hamid A. A. , Hedrick James L.
Published: May 2014

Recyclable Thermoset Polymers

The high mechanical strength and durability of thermoset polymers are exploited in applications such as composite materials, where they form the matrix surrounding carbon fibers. The thermally driven polymerization reaction is usually irreversible, so it is difficult to recycle the constituent monomers and to remove and repair portions of a composite part.

García
et al.

(p.
732
; see the Perspective by

Long

) now describe a family of polymers formed by condensation of paraformaldehyde with bisanilines that could form hard thermoset polymers or, when more oxygenated, produce self-healing gels. Strong acid digestion allowed recovery of the bisaniline monomers.
Comparison of the Immunogenicity and Safety of the Conventional Subunit, MF59-Adjuvanted, and Intradermal Influenza Vaccines in the Elderly
Authors: Seo Yu Bin , Choi Won Suk , Lee Jacob , Song Joon Young , Cheong Hee Jin , Kim Woo Joo
Published: May 2014

The influenza vaccination is known as the most effective method for preventing influenza infection and its complications in the elderly. Conventional subunit (Agrippal S1; Novartis), MF59-adjuvanted (Fluad; Novartis), and intradermal (IDflu15; Sanofi Pasteur) influenza vaccines are widely used throughout South Korea. However, few comparative studies evaluating the safety and immunogenicity of these vaccines are available. Prior to the beginning of the 2011-2012 influenza season, 335 healthy elderly volunteers randomly received one of three seasonal trivalent influenza vaccines, the conventional subunit, MF59-adjuvanted, or intradermal influenza vaccine. Serum hemagglutination-inhibiting antibody levels were measured at the time of vaccination and at 1 and 6 months after vaccination. Adverse events were recorded prospectively. A total of 113 conventional subunit, 111 MF59-adjuvanted, and 111 intradermal influenza vaccine volunteers were followed up during a 6-month postvaccination period. One month after vaccination, all three vaccines satisfied Committee for Medical Products for Human Use (CHMP) immunogenicity criteria for the A/H1N1 and A/H3N2 strains but not for the B strain. Compared with the subunit vaccine, the intradermal vaccine exhibited noninferiority, while the MF59-adjuvanted vaccine exhibited superiority. Furthermore, the MF59-adjuvanted vaccine was more immunogenic against the A/H3N2 strain than was the subunit vaccine up to 6 months postvaccination. The most common local and systemic reactions to the conventional subunit, MF59-adjuvanted, and intradermal influenza vaccines were pain at the injection site (7.1%, 10.8%, and 6.3%, respectively) and generalized myalgia (0.9%, 8.1%, and 5.4%, respectively). Local and systemic reactions were similar among the three vaccine groups. MF59-adjuvanted vaccine exhibited superior immunogenicity compared with a conventional subunit vaccine and had a comparable safety profile. For older adults, the MF59-adjuvanted vaccine is preferable for providing superior immunogenicity.
Detection of Herpesviridae in Whole Blood by Multiplex PCR DNA-Based Microarray Analysis after Hematopoietic Stem Cell Transplantation
Authors: Debaugnies France , Busson Laurent , Ferster Alina , Lewalle Philippe , Azzi Nadira , Aoun Mickael , Verhaegen Godelieve , Mahadeb Bhavna , de Marchin Jérôme , Vandenberg Olivier , Hallin Marie
Published: May 2014

Viral infections are important causes of morbidity and mortality in patients after hematopoietic stem cell transplantation. The monitoring by PCR of
Herpesviridae
loads in blood samples has become a critical part of posttransplant follow-up, representing mounting costs for the laboratory. In this study, we assessed the clinical performance of the multiplex PCR DNA microarray Clart Entherpex kit for detection of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) as a screening test for virological follow-up. Two hundred fifty-five blood samples from 16 transplanted patients, prospectively tested by routine PCR assays, were analyzed by microarray. Routine PCR detected single or multiple viruses in 42% and 10% of the samples, respectively. Microarray detected single or multiple viruses in 34% and 18% of the samples, respectively. Microarray results correlated well with CMV and EBV detections by routine PCR (kappa tests = 0.79 and 0.78, respectively), whereas a weak correlation was observed with HHV-6 (0.43). HHV-7 was also detected in 48 samples by microarray. In conclusion, the microarray is a reliable screening assay for a posttransplant virological follow-up to detect CMV and EBV infections in blood. However, positive samples must be subsequently confirmed and viral loads must be quantified by PCR assays. Limitations were identified regarding HHV-6 detection. Although it is promising, is easy to use as a first-line test, and allows a reduction in the cost of analysis without undue delay in the reporting of the final quantitative result to the clinician, some characteristics of this microarray should be improved, particularly regarding quality control and the targeted virus panel, such that it could then be used as a routine test.
Diarrhea Burden Due to Natural Infection with Enterotoxigenic Escherichia coli in a Birth Cohort in a Rural Egyptian Community
Authors: Mansour A. , Shaheen H. I. , Amine M. , Hassan K. , Sanders J. W. , Riddle M. S. , Armstrong A. W. , Svennerholm A. M. , Sebeny P. J. , Klena J. D. , Young S. Y. N. , Frenck R. W.
Published: May 2014

Enterotoxigenic
Escherichia coli
(ETEC) is commonly associated with diarrhea in Egyptian children. Children less than 3 years old in Abu Homos, Egypt, had approximately five diarrheal episodes per child every year, and at least one of these episodes was due to ETEC. The epidemiology of ETEC diarrhea among children living in a rural Egyptian community was further evaluated in this study. Between January 2004 and April 2007, 348 neonates were enrolled and followed for 2 years. Children were visited twice weekly, and a stool sample was obtained every 2 weeks regardless of symptomatology. A stool sample was obtained whenever a child had diarrhea. From the routine stool culture, five
E. coli
-like colonies were selected and screened for heat-labile and heat-stable toxins by GM1 enzyme-linked immunosorbent assay (ELISA) and further typed for colonization factor antigens by dot blot assay. Incidence of ETEC infection was estimated among children with diarrhea (symptomatic) and without diarrhea (asymptomatic). Incidence of diarrhea and ETEC-associated diarrhea was 7.8 and 1.48 per child-year, respectively. High risk of repeated ETEC diarrhea was associated with being over 6 months of age, warm season, male gender, and crowded sleeping conditions. Exclusive breast-feeding was protective for repeated ETEC infection. ETEC-associated diarrhea remains common among children living in the Nile Delta. The protective role of breast-feeding demonstrates the importance of promoting exclusive breast-feeding during, at least, the first 6 months of life.
Adoption of Lean Principles in a High-Volume Molecular Diagnostic Microbiology Laboratory
Authors: Mitchell P. Shawn , Mandrekar Jayawant N. , Yao Joseph D. C.
Published: May 2014

Clinical laboratories are constantly facing challenges to do more with less, enhance quality, improve test turnaround time, and reduce operational expenses. Experience with adopting and applying lean concepts and tools used extensively in the manufacturing industry is described for a high-volume clinical molecular microbiology laboratory, illustrating how operational success and benefits can be achieved.
Mycobacterium tuberculosis Strains of the Modern Sublineage of the Beijing Family Are More Likely To Display Increased Virulence than Strains of the Ancient Sublineage
Authors: Ribeiro Simone C. M. , Gomes Lia Lima , Amaral Eduardo P. , Andrade Marcelle R. M. , Almeida Fabricio M. , Rezende Andreza L. , Lanes Verônica R. , Carvalho Eulógio C. Q. , Suffys Philip N. , Mokrousov Igor , Lasunskaia Elena B.
Published: May 2014

Strains of the Beijing genotype family of
Mycobacterium tuberculosis
are a cause of particular concern because of their increasing dissemination in the world and their association with drug resistance. Phylogenetically, this family includes distinct ancient and modern sublineages. The modern strains, contrary to the ancestral counterparts, demonstrated increasing prevalence in many world regions that suggest an enhanced bacterial pathogenicity. We therefore evaluated virulence of modern versus ancient Beijing strains with similar epidemiological and genotype characteristics. For this, we selected six strains that had very similar 24-locus mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) typing profiles and belonged to the region of difference 181 (RD181) subgroup but differed using markers (
mutT2
and
mutT4
genes and NTF locus) that discriminate between modern and ancient Beijing sublineages. The strains were isolated from native patients in Brazil and Mozambique, countries with a low prevalence of Beijing strains. The virulence levels of these strains were determined in models of pulmonary infection in mice and
in vitro
macrophage infection and compared with that of a strain from Russia, part of the epidemic and hypervirulent Beijing clone B0/W148, and of the laboratory strain H37Rv. The results showed that two of the three modern Beijing strains were highly pathogenic, exhibiting levels of virulence comparable with that of the epidemic Russian strain. In contrast, all isolates of the ancient sublineage displayed intermediate or low virulence. The data obtained demonstrate that the strains of the modern Beijing sublineage are more likely to exhibit highly virulent phenotypes than ancient strains and suggest that genetic alterations characteristic of the modern Beijing sublineage favor selection of highly virulent bacteria.
Diagnostic Usefulness of Differential Time to Positivity for Catheter-Related Candidemia
Authors: Park Ki-Ho , Lee Mi Suk , Lee Sang-Oh , Choi Sang-Ho , Sung Heungsup , Kim Mi-Na , Kim Yang Soo , Woo Jun Hee , Kim Sung-Han
Published: May 2014

A differential time to positivity (DTP) of ≥120 min is useful for diagnosing catheter-related bacteremia, but data on diagnosing catheter-related candidemia (CRC) in this way are limited. We wished to evaluate the usefulness of the DTP for diagnosing CRC. All adult patients who had the same
Candida
species isolated from blood cultures drawn simultaneously from a central venous catheter (CVC) and a peripheral vein were included at a tertiary care hospital over an 18-month period. A total of 105 patients with candidemia who had positive simultaneous CVC and peripheral vein blood cultures were included in our study. Sixty-one patients (58%) had CRC (47 definite and 14 probable), and 38 (36%) had candidemia from another source (non-CRC). The remaining 6 patients (6%) with indeterminate candidemia were excluded from the final analysis. The overall sensitivity and specificity of a DTP of ≥120 min for diagnosing CRC were 85% (95% confidence interval [CI], 74% to 93%) and 82% (95% CI, 66% to 92%), respectively, and for neutropenic patients, they were 75% (95% CI, 19% to 99%) and 100% (95% CI, 75% to 100%), respectively. For
Candida glabrata
infections, the optimal DTP cutoff was ≥6 h, with a sensitivity of 63% (95% CI, 35% to 85%) and a specificity of 75% (95% CI, 35% to 97%). In summary, DTP is useful for diagnosing CRC, and a DTP of ≥120 min appears to be the optimal cutoff except for CRC caused by
C. glabrata
. For neutropenic patients, DTP may be useful as an adjunct test to rule in CRC and to decide whether a catheter should be removed.
Group A Streptococcus Endometritis following Medical Abortion
Authors: Gendron Nicolas , Joubrel Caroline , Nedellec Sophie , Campagna Jennifer , Agostini Aubert , Doucet-Populaire Florence , Casetta Anne , Raymond Josette , Poyart Claire , Kernéis Solen
Published: May 2014

Medical abortion is not recognized as a high-risk factor for invasive pelvic infection. Here, we report two cases of group A
Streptococcus
(GAS;
Streptococcus pyogenes
) endometritis following medical abortions with a protocol of oral mifepristone and misoprostol.
Multiplex PCR Assay for Identification of Six Different Staphylococcus spp. and Simultaneous Detection of Methicillin and Mupirocin Resistance
Authors: Campos-Peña E. , Martín-Nuñez E. , Pulido-Reyes G. , Martín-Padrón J. , Caro-Carrillo E. , Donate-Correa J. , Lorenzo-Castrillejo I. , Alcoba-Flórez J. , Machín F. , Méndez-Alvarez S.
Published: May 2014

We describe a new, efficient, sensitive, and fast single-tube multiple-PCR protocol for the identification of the most clinically significant
Staphylococcus
spp. and the simultaneous detection of the methicillin and mupirocin resistance loci. The protocol identifies at the species level isolates belonging to
S. aureus
,
S. epidermidis
,
S. haemolyticus
,
S. hominis
,
S. lugdunensis
, and
S. saprophyticus
.
Extraintestinal Microsporidiosis
Authors: Ramanan Poornima , Pritt Bobbi S.
Published: May 2014

Microsporidia are highly specialized obligate intracellular organisms that are closely related to fungi. Although traditionally associated with diarrheal illness in patients with AIDS, extraintestinal infections involving various organs have been reported with increasing frequency in the past decade, particularly in immunocompromised hosts. Diagnosis is usually accomplished by light microscopic identification of spores in body fluids and tissues, using a variety of stains. Transmission electron microscopy, immunofluorescence assays, or molecular methods are necessary for identification to the genus and species level. Early diagnosis is essential for preventing the significant associated morbidity and mortality of extraintestinal microsporidiosis.
Set of Classical PCRs for Detection of Mutations in
Candida glabrata FKS
Genes Linked with Echinocandin Resistance
Authors: Dudiuk Catiana , Gamarra Soledad , Leonardeli Florencia , Jimenez-Ortigosa Cristina , Vitale Roxana G. , Afeltra Javier , Perlin David S. , Garcia-Effron Guillermo
Published: May 2014

Clinical echinocandin resistance among
Candida glabrata
strains is increasing, especially in the United States. Antifungal susceptibility testing is considered mandatory to guide therapeutic decisions. However, these methodologies are not routinely performed in the hospital setting due to their complexity and the time needed to obtain reliable results. Echinocandin failure in
C. glabrata
is linked exclusively to Fks1p and Fks2p amino acid substitutions, and detection of such substitutions would serve as a surrogate marker to identify resistant isolates. In this work, we report an inexpensive, simple, and quick classical PCR set able to objectively detect the most common mechanisms of echinocandin resistance in
C. glabrata
within 4 h. The usefulness of this assay was assessed using a blind collection of 50
C. glabrata
strains, including 16
FKS1
and/or
FKS2
mutants.
Differential Lymphocyte and Antibody Responses in Deer Mice Infected with Sin Nombre Hantavirus or Andes Hantavirus
Authors: Schountz Tony , Quackenbush Sandra , Rovnak Joel , Haddock Elaine , Black William C. , Feldmann Heinz , Prescott Joseph
Published: May 2014

Hantavirus cardiopulmonary syndrome (HCPS) is a rodent-borne disease with a high case-fatality rate that is caused by several New World hantaviruses. Each pathogenic hantavirus is naturally hosted by a principal rodent species without conspicuous disease and infection is persistent, perhaps for life. Deer mice (Peromyscus maniculatus) are the natural reservoirs of Sin Nombre virus (SNV), the etiologic agent of most HCPS cases in North America. Deer mice remain infected despite a helper T cell response that leads to high-titer neutralizing antibodies. Deer mice are also susceptible to Andes hantavirus (ANDV), which causes most HCPS cases in South America; however, deer mice clear ANDV. We infected deer mice with SNV or ANDV to identify differences in host responses that might account for this differential outcome. SNV RNA levels were higher in the lungs but not different in the heart, spleen, or kidneys. Most ANDV-infected deer mice had seroconverted 14 days after inoculation, but none of the SNV-infected deer mice had. Examination of lymph node cell antigen recall responses identified elevated immune gene expression in deer mice infected with ANDV and suggested maturation toward a Th2 or T follicular helper phenotype in some ANDV-infected deer mice, including activation of the interleukin 4 (IL-4) pathway in T cells and B cells. These data suggest that the rate of maturation of the immune response is substantially higher and of greater magnitude during ANDV infection, and these differences may account for clearance of ANDV and persistence of SNV.

IMPORTANCEHantaviruses persistently infect their reservoir rodent hosts without pathology. It is unknown how these viruses evade sterilizing immune responses in the reservoirs. We have determined that infection of the deer mouse with its homologous hantavirus, Sin Nombre virus, results in low levels of immune gene expression in antigen-stimulated lymph node cells and a poor antibody response. However, infection of deer mice with a heterologous hantavirus, Andes virus, results in a robust lymph node cell response, signatures of T and B cell maturation, and production of antibodies. These findings suggest that an early and aggressive immune response to hantaviruses may lead to clearance in a reservoir host and suggest that a modest immune response may be a component of hantavirus ecology.
Continuing Reassortment Leads to the Genetic Diversity of Influenza Virus H7N9 in Guangdong, China
Authors: Lu Jing , Wu Jie , Zeng Xianqiao , Guan Dawei , Zou Lirong , Yi Lina , Liang Lijun , Ni Hanzhong , Kang Min , Zhang Xin , Zhong Haojie , He Xiang , Monagin Corina , Lin Jinyan , Ke Changwen
Published: May 2014

On 30 March 2013, a novel avian influenza A H7N9 virus causing severe human respiratory infections was identified in China. Preliminary sequence analyses have shown that the virus is a reassortant of H7N9 and H9N2 avian influenza viruses. In this study, we conducted enhanced surveillance for H7N9 virus in Guangdong, China, from April to August 2013. We isolated two H7N9 viral strains from environmental samples associated with poultry markets and one from a clinical patient. Sequence analyses showed that the Guangdong H7N9 virus isolated from April to May shared high sequence similarity with other strains from eastern China. The A/Guangdong/1/2013 (H7N9) virus isolated from the Guangdong patient on 10 August 2013 was divergent from previously sequenced H7N9 viruses and more closely related to local circulating H9N2 viruses in the NS and NP genes. Phylogenetic analyses revealed that four internal genes of the A/Guangdong/1/2013 (H7N9) virus—the NS, NP, PB1, and PB2 genes—were in clusters different from those for H7N9 viruses identified previously in other provinces of China. The discovery presented here suggests that continuing reassortment led to the emergence of the A/Guangdong/1/2013 (H7N9) virus as a novel H7N9 virus in Guangdong, China, and that viral adaptation to avian and human hosts must be assessed.

IMPORTANCE
In this study, we isolated and characterized the avian influenza A H7N9 virus in Guangdong, China, from April to August 2013. We show that the viruses isolated from Guangdong environmental samples and chickens from April to May 2013 were highly similar to other H7N9 strains found in eastern China. The H7N9 virus isolated from the clinical patient in Guangdong in August 2013 was divergent from previously identified H7N9 viruses, with the NS and NP genes originating from recent H9N2 viruses circulating in the province. This study provides direct evidence that continuing reassortment occurred and led to the emergence of a novel H7N9 influenza virus in Guangdong, China. These results also shed light on how the H7N9 virus evolved, which is critically important for future monitoring and tracing of viral transmission.
Role of the C Terminus of Lassa Virus L Protein in Viral mRNA Synthesis
Authors: Lehmann Maria , Pahlmann Meike , Jérôme Hanna , Busch Carola , Lelke Michaela , Günther Stephan
Published: May 2014

The N terminus of arenavirus L protein contains an endonuclease presumably involved in “cap snatching.” Here, we employed the Lassa virus replicon system to map other L protein sites that might be involved in this mechanism. Residues Phe-1979, Arg-2018, Phe-2071, Asp-2106, Trp-2173, Tyr-2179, Arg-2200, and Arg-2204 were important for viral mRNA synthesis but dispensable for genome replication. Thus, the C terminus of L protein is involved in the mRNA synthesis process, potentially by mediating cap binding.
CD4
+
T-Cell Help Enhances NK Cell Function following Therapeutic HIV-1 Vaccination
Authors: Jost Stephanie , Tomezsko Phillip John , Rands Keith , Toth Ildiko , Lichterfeld Mathias , Gandhi Rajesh Tim , Altfeld Marcus
Published: May 2014

Increasing data suggest that NK cells can mediate antiviral activity in HIV-1-infected humans, and as such, novel approaches harnessing the anti-HIV-1 function of both T cells and NK cells represent attractive options to improve future HIV-1 immunotherapies. Chronic progressive HIV-1 infection has been associated with a loss of CD4
+
T helper cell function and with the accumulation of anergic NK cells. As several studies have suggested that cytokines produced by CD4
+
T cells are required to enhance NK cell function in various infection models, we hypothesized that reconstitution of HIV-1-specific CD4
+
T-cell responses by therapeutic immunization would restore NK cell activity in infected individuals. Using flow cytometry, we examined the function of CD4
+
T cells and NK cells in response to HIV-1 in subjects with treated chronic HIV-1 infection before and after immunization with an adjuvanted HIV-1 Gp120/NefTat subunit protein vaccine candidate provided by GlaxoSmithKline. Vaccination induced an increased expression of interleukin-2 (IL-2) by Gp120-specific CD4
+
T cells in response to HIV-1 peptides
ex vivo
, which was associated with enhanced production of gamma interferon (IFN-γ) by NK cells. Our data show that reconstitution of HIV-1-specific CD4
+
T-cell function by therapeutic immunization can enhance NK cell activity in HIV-1-infected individuals.

IMPORTANCE
NK cells are effector cells of the innate immune system and are important in the control of viral infection. Recent studies have demonstrated the crucial role played by NK cells in controlling and/or limiting acquisition of HIV-1 infection. However, NK cell function is impaired during progressive HIV-1 infection. We recently showed that therapeutic immunization of treated HIV-1-infected individuals reconstituted strong T-cell responses, measured notably by their production of IL-2, a cytokine that can activate NK cells. The current study suggests that reconstitution of T-cell function by therapeutic vaccination can enhance NK cell activity in individuals with chronic HIV-1 infection. Our findings provide new insights into the interplay between adaptive and innate immune mechanisms involved in HIV-1 immunity and unveil opportunities to harness NK cell function in future therapeutic vaccine strategies to target HIV-1.
Recovery of an HMWP/hmwBP (pUL48/pUL47) Complex from Virions of Human Cytomegalovirus: Subunit Interactions, Oligomer Composition, and Deubiquitylase Activity
Authors: Tullman Jennifer A. , Harmon Mary-Elizabeth , Delannoy Michael , Gibson Wade
Published: May 2014

We report that the human cytomegalovirus (HCMV) high-molecular-weight tegument protein (HMWP, pUL48; 253 kDa) and the HMWP-binding protein (hmwBP, pUL47; 110 kDa) can be recovered as a complex from virions disrupted by treatment with 50 mM Tris (pH 7.5), 0.5 M NaCl, 0.5% NP-40, and 10 mM dithiothreitol [DTT]. The subunit ratio of the complex approximates 1:1, with a shape and structure consistent with an elongated heterodimer. The HMWP/hmwBP complex was corroborated by reciprocal coimmunoprecipitation experiments using antipeptide antibodies and lysates from both infected cells and disrupted virus particles. An interaction of the amino end of pUL48 (amino acids [aa] 322 to 754) with the carboxyl end of pUL47 (aa 693 to 982) was identified by fragment coimmunoprecipitation experiments, and a head-to-tail self-interaction of hmwBP was also observed. The deubiquitylating activity of pUL48 is retained in the isolated complex, which cleaves K11, K48, and K63 ubiquitin isopeptide linkages.

IMPORTANCE
Human cytomegalovirus (HCMV, or human herpesvirus 5 [HHV-5]) is a large DNA-containing virus that belongs to the betaherpesvirus subfamily and is a clinically important pathogen. Defining the constituent elements of its mature form, their organization within the particle, and the assembly process by which it is produced are fundamental to understanding the mechanisms of herpesvirus infection and developing drugs and vaccines against them. In this study, we report isolating a complex of two large proteins encoded by HCMV open reading frames (ORFs) UL47 and UL48 and identifying the binding domains responsible for their interaction with each other and of pUL47 with itself. Our calculations indicate that the complex is a rod-shaped heterodimer. Additionally, we determined that the ubiquitin-specific protease activity of the ORF UL48 protein was functional in the complex, cleaving K11-, K48-, and K63-linked ubiquitin dimers. This information builds on and extends our understanding of the HCMV tegument protein network that is required to interface the HCMV envelope and capsid.
Emergence of CD4 Independence Envelopes and Astrocyte Infection in R5 Simian-Human Immunodeficiency Virus Model of Encephalitis
Authors: Zhuang Ke , Leda Ana Rachel , Tsai Lily , Knight Heather , Harbison Carole , Gettie Agegnehu , Blanchard James , Westmoreland Susan , Cheng-Mayer Cecilia
Published: May 2014

Human immunodeficiency virus type 1 (HIV-1) infection in the central nervous system (CNS) is characterized by replication in macrophages or brain microglia that express low levels of the CD4 receptor and is the cause of HIV-associated dementia and related cognitive and motor disorders that affect 20 to 30% of treatment-naive patients with AIDS. Independent viral envelope evolution in the brain has been reported, with the need for robust replication in resident CD4
low
cells, as well as CD4-negative cells, such as astrocytes, proposed as a major selective pressure. We previously reported giant-cell encephalitis in subtype B and C R5 simian-human immunodeficiency virus (SHIV)-infected macaques (SHIV-induced encephalitis [SHIVE]) that experienced very high chronic viral loads and progressed rapidly to AIDS, with varying degrees of macrophage or microglia infection and activation of these immune cells, as well as astrocytes, in the CNS. In this study, we characterized envelopes (Env) amplified from the brains of subtype B and C R5 SHIVE macaques. We obtained data in support of an association between severe neuropathological changes, robust macrophage and microglia infection, and evolution to CD4 independence. Moreover, the degree of Env CD4 independence appeared to correlate with the extent of astrocyte infection
in vivo
. These findings further our knowledge of the CNS viral population phenotypes that are associated with the severity of HIV/SHIV-induced neurological injury and improve our understanding of the mechanism of HIV-1 cellular tropism and persistence in the brain.

IMPORTANCE
Human immunodeficiency virus type 1 (HIV-1) infection of astrocytes in the brain has been suggested to be important in HIV persistence and neuropathogenesis but has not been definitively demonstrated in an animal model of HIV-induced encephalitis (HIVE). Here, we describe a new nonhuman primate (NHP) model of R5 simian-human immunodeficiency virus (SHIV)-induced encephalitis (SHIVE) with several classical HIVE features that include astrocyte infection. We further show an association between severe neuropathological changes, robust resident microglia infection, and evolution to CD4 independence of viruses in the central nervous system (CNS), with expansion to infection of truly CD4-negative cells
in vivo
. These findings support the use of the R5 SHIVE models to study the contribution of the HIV envelope and viral clades to neurovirulence and residual virus replication in the CNS, providing information that should guide efforts to eradicate HIV from the body.
Livedo reticularis heralding hypercalcaemia of malignancy
Authors: Sundriyal Deepak , Kumar Naveen , Kumar Gaurav , Walia Meenu
Published: May 2014

The term livedo reticularis is used to describe net-like purple rash usually on the lower limbs. It is an important clinical sign with diverse aetiologies. Hypercalcaemia is an uncommon but important clinical entity, sometimes associated with livedo reticularis. Generally, hypercalcaemia of renal failure and secondary hyperparathyroidism has been reported with this condition. We report a case of livedo reticularis heralding onset of hypercalcaemia of malignancy.
Atlantoaxial rotatory subluxation as a cause of torticollis in a 5-year-old girl
Authors: Bagouri Elmunzar , Deshmukh Sandeep , Lakshmanan Palaniappan
Published: May 2014

Many patients present to the emergency department complaining of a sore or stiff neck and lateral flexion of the neck with contralateral rotation. Under the pressure of the breaching time and busy shifts some of the patients are discharged to the care of their general practitioners without adequate investigations. While most of the cases are due to benign causes, torticollis can be due to many congenital and acquired pathologies, some of which may need further investigation and urgent management. Atlantoaxial subluxation (AAS), tumours of the base of the skull and infections are among these causes. Delayed diagnosis may lead to worsening neurology and complicate the management. We report a case of a 5-year-old girl who presented to our fracture clinic with a fractured clavicle and torticollis; her subsequent investigations confirmed the diagnosis of AAS. Our patient responded to non-operative treatment and improved with no neurological complications.
Early experience in high-resolution MRI for large vessel occlusions
Authors: Hui Ferdinand K , Zhu Xianjin , Jones Stephen E , Uchino Ken , Bullen Jennifer A , Hussain M Shazam , Lou Xin , Jiang Wei-Jian
Published: May 2014

Background

Large vessel occlusions are an important cause of ischemic stroke. Imaging goals center on identifying the site of occlusion, the size of the ischemic core and the size of the ischemic penumbra. The etiology of the occlusion is typically inferred by history and demographics, or subacutely during investigation for shunt, hypercoagulable state or other causes. Current generation vascular imaging is based primarily on lumenography. Contours of the vessel lumen on lumenography may suggest the presence of atherosclerosis, dissection or thrombus. High-resolution MRI (HRMRI) techniques can characterize wall morphology in the presence of an occlusion, which may affect clinical care by better definition of intra-occlusion wall characteristics as well as downstream vasculature normally confounded by the lack of antegrade flow.

Methods

The HRMRI databases of Cleveland Clinic and Beijing Tiantan Hospital were reviewed to identify patients with large vessel occlusions on lumenography, performed with a diagnostic quality HRMRI. Clinical data were reviewed for each patient and images were analyzed by experienced neuroradiologists at both institutions. Where possible, conventional angiography/lumenography was reviewed for comparison.

Results

Nine patients with large vessel cerebral artery occlusions were identified in whom HRMRI characteristics were reviewed and categorized. Images were correlated with demographics, risk factors and the working diagnosis of each case.

Conclusions

HRMRI of vascular occlusions can identify wall characteristics and characterize the course and caliber of the vasculature distal to the occluded segment. This information may be useful in determining preferred approaches for endovascular revascularization.
The LVIS/LVIS Jr. stents in the treatment of wide-neck intracranial aneurysms: multicentre registry
Authors: Poncyljusz Wojciech , Biliński Piotr , Safranow Krzysztof , Baron Jan , Zbroszczyk Miłosz , Jaworski Maciej , Bereza Sławomir , Burke Thomas H
Published: May 2014

Background

Wide-necked intracranial aneurysms have been a challenge for endovascular techniques. With the advent of adjunctive devices such as balloons or stents, recanalisation rates have decreased secondary to better packing.

Purpose

The purpose of this registry was to evaluate the safety and effectiveness of the new Low-profiled Visualized Intraluminal Support LVIS and LVIS Jr. stents in the treatment of unruptured wide-neck intracranial aneurysms.

Methods

The LVIS or LVIS Jr. stent-assisted coil embolisation was performed in 78 patients harbouring 78 intracranial aneurysms. There were 59 aneurysms located in the anterior circulation and 19 in the posterior circulation. Clinical data and 6-month follow-up angiograms are presented.

Results

The LVIS and LVIS Jr. stents were successfully delivered to the target aneurysm; however, there were seven cases in which the LVIS/LVIS Jr. stents had suboptimal opening and apposition to the parent vessel wall. The overall technical success for all groups was 91% (71 of 78 stents). There was complete angiographic occlusion in 66 (85%) of 78 cases and residual neck remnants in 12 (15%) cases. All patients had 6-month angiographic follow-up, which demonstrated complete occlusion of the target aneurysm in 64 (82%) cases, residual neck remnants in 5 (6%) cases and there was aneurysm filling in 9 (12%) cases.

Conclusions

The LVIS/LVIS Jr. stent system is safe and effective for the treatment of wide-neck intracranial aneurysms, providing suitable support of the coil mass, which allows for a high level of occlusion with low rates of recanalisation and subsequent treatments.
Anthropogenic food use and diet overlap between red foxes (Vulpesvulpes) and arctic foxes (Vulpeslagopus) in Prudhoe Bay, Alaska
Authors: Savory G.A. , Hunter C.M. , Wooller M.J. , O’Brien D.M.
Published: May 2014

Red foxes (Vulpes vulpes (L., 1758)) recently expanded into the oil fields at Prudhoe Bay, Alaska, USA, and we hypothesized that the availability of anthropogenic foods may contribute to their success and persistence there. This study assessed the importance of anthropogenic foods to the diets of red foxes and arctic foxes (Vulpes lagopus (L., 1758)), and competition for food resources between the two species in Prudhoe Bay. We used stable isotope analysis of fox tissues to infer diet during summer and winter for both red and arctic foxes, and lifetime diet for red fox. While the contribution of anthropogenic foods in late summer for both species’ diets was low (~10% to 15%), the contribution in late winter was higher and varied between species (red foxes = 49%; arctic foxes = 39%). Estimates of lifetime diet in red foxes suggest consistent use of anthropogenic foods. We found moderate overlap of fox diets, although red foxes appeared to be more specialized on lemmings, whereas arctic foxes had a more diverse diet. Availability and consumption of anthropogenic foods by red foxes, particularly in winter, may partially explain their year-round presence in Prudhoe Bay.