bluuebunny/crossref_metadata_2025 huggingface dataset:
Introducing clinical triage for oral surgery referral management in England
Authors: Coulthard P. , Bailey E. , Bridgman C.M.
Published: June 2014

There has been a significant increase in the volume of referrals from general dentists to hospital oral surgery services over the last decade in England. The referral rate also varies between dentists and the referral systems need to become more sophisticated to understand demand and support needs led commissioning of services.

Aim

1. Examine received referrals for hospital oral surgery and explore the reasons for selection to consultant led hospital‐based care or specialist primary care. 2. Determine the minimum data set required for the triager to make decisions for selection.

Materials and methods

Central capture and clinical triage of all referral letters received by the Oral Surgery department of a University Hospital.

Results

One thousand eight hundred and eighty‐five letters were triaged. Nineteen per cent were deflected to primary care including 2% for postgraduate training. Reasons for secondary care triage were anticipated surgical difficulty (43%), teaching and training (21%), need for general anaesthesia (16%), medical co‐morbidities (8%), other indicators (8%) and psychosocial (4%).

Conclusions

The introduction of a central triage system produced a significant amount of data and highlighted several important issues around decision‐making that need to be addressed for future development of the system. The study demonstrated that it is possible to direct a significant proportion of referrals to primary care that were destined for hospital consultant management. However, no account was taken of the quality of the care provided. Review of teaching and training systems in the future can and will be better informed by interrogation of intelligence from a more sophisticated and consistent needs assessment.
Borrowing for College: A Comparison of Long‐Term Debt Financing between Public and Private, Nonprofit Institutions of Higher Education
Authors: Denison Dwight , Fowles Jacob , Moody Michael J.
Published: June 2014

Institutions of higher education provide an excellent opportunity to compare long‐term debt financing in the nonprofit and public sectors. The proposed models explain the long‐term debt per student at public and private‐nonprofit research universities. Student enrollment, enrollment growth, total assets, and revenue variables as a group all influence debt levels. The strongest predictors of debt balances are the fixed characteristics of the universities themselves. Empirical evidence from the university sector also suggests the absence of a powerful arbitrage incentive to issue debt.
Highly interactive nature of flower‐specific enhancers and promoters, and its potential impact on tissue‐specific expression and engineering of multiple genes or agronomic traits
Authors: Wen Zhifeng , Yang Yazhou , Zhang Jinjin , Wang Xiping , Singer Stacy , Liu Zhongchi , Yang Yingjun , Yan Guohua , Liu Zongrang
Published: June 2014

Molecular stacking enables multiple traits to be effectively engineered in crops using a single vector. However, the co‐existence of distinct plant promoters in the same transgenic unit might, like their mammalian counterparts, interfere with one another. In this study, we devised a novel approach to investigate enhancer–promoter and promoter–promoter interactions in transgenic plants and demonstrated that three of four flower‐specific enhancer/promoters were capable of distantly activating a pollen‐ and stigma‐specific Pps promoter (fused to the cytotoxic DT‐A gene) in other tissues, as revealed by novel tissue ablation phenotypes in transgenic plants. The NtAGI1 enhancer exclusively activated stamen‐ and carpel‐specific DT‐A expression, thus resulting in tissue ablation in an orientation‐independent manner; this activation was completely abolished by the insertion of an enhancer‐blocking insulator (EXOB) between the NtAGI1 enhancer and Pps promoter. Similarly, AGL8 and AP1Lb1, but not AP1La, promoters also activated distinct tissue‐specific DT‐A expression and ablation, with the former causing global growth retardation and the latter ablating apical inflorescences. While the tissue specificity of the enhancer/promoters generally defined their activation specificities, the strength of their activity in particular tissues or developmental stages appeared to determine whether activation actually occurred. Our findings provide the first evidence that plant‐derived enhancer/promoters can distantly interact/interfere with one another, which could pose potential problems for the tissue‐specific engineering of multiple traits using a single‐vector stacking approach. Therefore, our work highlights the importance of adopting enhancer‐blocking insulators in transformation vectors to minimize promoter–promoter interactions. The practical and fundamental significance of these findings will be discussed.
Striated Muscle Hamartoma in a Newborn
Authors: Fraile Alonso María del Carmen , Román Curto Concepción , Cañueto Javier , Meseguer Carmen , Santos‐Briz Ángel , Fernández Emilia
Published: June 2014

Striated muscle hamartoma (SMH) is an uncommon benign lesion, that is usually congenital, polypoid, and primarily located on the head and neck. The key histopathologic sign is the existence of individualized fascicles of striated muscle affecting the dermis and subcutaneous fat tissue. Here we report the case of a newborn girl with an SMH, who presented with a congenital infiltrated plaque on her chin without any other associations.
Multiple Familial Pilomatrixomas in Three Generations: An Unusual Clinical Picture
Authors: King Ian C. C. , Rahman Kazi M. A. , Henderson Alex , Ragbir Maniram
Published: June 2014

Pilomatrixomas are benign cutaneous tumors derived from hair matrix cells of unclear etiology. Pilomatrixomas commonly demonstrate somatic mutations in CTNNB1, a gene coding β‐catenin, a protein involved with hair follicle development. Multiple familial pilomatrixomas rarely occur and are most often associated with autosomal dominant conditions such as myotonic dystrophy and familial adenomatous polyposis (FAP). Nine families with multiple familial pilomatrixomas and no demonstrable underlying association have been reported in the literature. We present a tenth family in which five members spanning three generations grew multiple pilomatrixomas in the absence of any previously reported associations. No evidence of myotonic dystrophy, FAP, or other known associations was found. Extreme tiredness, behavioral problems, and sensory disturbances were common features across three generations but bore no temporal relation to the pilomatrixomas. The existence of a germline mutation in CTNNB1 to explain these symptoms has yet to be shown. Pilomatrixomas are potentially cutaneous markers of significant underlying pathologies. Patients presenting with multiple or familial pilomatrixomas should be thoroughly assessed for other pathologies and offered genetic screening to ensure that important diagnoses are not overlooked.
Pediatric Hashimoto's encephalopathy with peripheral nervous system involvement
Authors: Salpietro Vincenzo , Mankad Kshitij , Polizzi Agata , Sugawara Yuji , Granata Francesca , David Emanuele , Ferraù Valeria , Gallizzi Romina , Tortorella Gaetano , Ruggieri Martino
Published: June 2014

Hashimoto encephalopathy is a syndrome of encephalopathy associated with elevated concentration of circulating serum anti‐thyroid antibodies usually responsive to steroid therapy. We report a 13‐year‐old girl with Hashimoto encephalopathy and peripheral nervous system involvement. The child had experienced high‐grade pyrexia, global headache and sleeplessness. After admission she had an ileus with a distended urinary bladder, hallucinations and cognitive impairment. She had reduced deep tendon reflexes and distal sensory deficiency. Anti‐thyroglobulin antibodies were raised at 2121 IU/mL (normal, 0–40) and the anti‐thyroperoxidase was high at 886 IU/mL (normal, 0–50). Progressive neurological and psychiatric remission was noted after i.v. methylprednisolone. Follow‐up magnetic resonance imaging showed complete resolution of the foci of signal abnormality previously yielded. This case report is the first, to the best of our knowledge, to describe peripheral nervous system involvement in a child with a diagnosis of Hashimoto's encephalopathy.
Ultraviolet Erythematic Radiation Dose Received by Golfers in Winter, in Valencia
Authors: Gurrea Ysasi Gonzalo , Moreno Juan Carlos , Serrano María Antonia
Published: June 2014

This article analyzes Ultraviolet Erythematic Radiation (UVER) dose received by several golf players in winter in Valencia. Playing golf involves spending several hours outdoors because of the length of golf matches and training. Moreover, in Valencia there are many golf players coming from northern Europe, with a phototype very sensitive (I–II). For that reason, these people have an increasing risk while playing. This article shows that harmful effects coming from UVER radiation may occur not only in summer time but also in winter, especially at these latitudes. VioSpor dosimeters have been used to develop this analysis over several golf players on January 2013 between 10:00 h and 15:00 h, local time.
Fugu for Logicians
Authors: Sorensen Roy
Published: June 2014

What do you get when you cross a fallacy with a good argument? A fugu, that is, a valid argument that tempts you to reach its conclusion invalidly (named after the dangerous but delicious Japanese puffer fish). You have yielded to the temptation more than you realize. If you are a teacher, you may have served many fugus. They arise systematically through several mechanisms. Fugus are interesting intermediate cases that shed light on the following issues: bare evidentialism, false pleasure, philosophy of education, and the ethics of argument. Normally, a fugu will not yield knowledge from known premises. But if the reasoning is only slightly fallacious, they do yield knowledge. These mild fugus show that we can gain knowledge by invalid reasoning. This is a conservative resource for historians. They want to credit discoveries to Euclid rather than those who made minor corrections to his proofs, such as David Hilbert. We also benefit from this practice of grandfathering in old standards of knowledge attribution. For we can compete spiritedly for priority. We do not need to worry that credit will instead go to future scholars who will make the minor amendments needed to raise present proofs to a future standard of demonstration.
Heritability of cardiac vagal control in 24‐h heart rate variability recordings: Influence of ceiling effects at low heart rates
Authors: Neijts Melanie , Van Lien Rene , Kupper Nina , Boomsma Dorret , Willemsen Gonneke , de Geus Eco J. C.
Published: June 2014

This study estimated the heritability of 24‐h heart rate variability (HRV) measures, while considering ceiling effects on HRV at low heart rates during the night. HRV was indexed by the standard deviation of all valid interbeat intervals (SDNN), the root mean square of differences between valid, successive interbeat intervals (RMSSD), and peak‐valley respiratory sinus arrhythmia (pvRSA). Sleep and waking levels of cardiac vagal control were assessed in 1,003 twins and 285 of their non‐twin siblings. Comparable heritability estimates were found for SDNN (46%–53%), RMSSD (49%–54%), and pvRSA (48%–57%) during the day and night. A nighttime ceiling effect was revealed in 10.7% of participants by a quadratic relationship between mean pvRSA and the interbeat interval. Excluding these participants did not change the heritability estimates. The genetic factors influencing ambulatory pvRSA, RMSSD, and SDNN largely overlap. These results suggest that gene‐finding studies may pool the different cardiac vagal indices and that exclusion of participants with low heart rates is not required.
Apoptosis‐Like Events and In Vitro Fertilization Capacity of Sex‐Sorted Bovine Sperm
Authors: Zhao X‐M , Ren J‐J , Zhao S‐J , Cui L‐S , Hao H‐S , Wang H‐Y , Du W‐H , Qin T , Liu Y , Wang D , Zhu H‐B
Published: June 2014

Contents

This study utilized three staining assays (Annexin V, mitochondrial membrane potential (JC‐1) and TUNEL) for flow cytometric analysis of apoptosis in sex‐sorted sperm from four different bulls (A, B, C and D). Correlations between sperm quality and IVF efficiency were then assessed to determine which assay provided the best prediction of IVF efficiency. The results of the Annexin V assays, as well as measures of viable sperm, early apoptosis, necrotic sperm and mitochondrial membrane potential (∆ψm) showed that the sex‐sorted sperm collected from bull A significantly differed from those of the other three bulls (p < 0.05). In addition, the levels of DNA fragmentation in sex‐sorted sperm from bull A were significantly lower than those from bulls B and C (p < 0.05). The percentage of cells reaching the cleavage and blastocyst stages in sex‐sorted sperm from bull A were significantly greater than those from the other bulls (p < 0.05). A significant positive correlation was observed between viable sperm and the percentage of cells at the cleavage or blastocyst stages (p < 0.05). In contrast, a negative correlation was found between early apoptotic sperm and the percentage of cells at the cleavage or blastocyst stages (p < 0.05). In conclusion, these results indicated that the Annexin V assay was the most reliable technique for the prediction of the IVF success of sex‐sorted bovine sperm.
Principles of Representation: Why You Can't Represent the Same Concept Twice
Authors: Connell Louise , Lynott Dermot
Published: June 2014

As embodied theories of cognition are increasingly formalized and tested, care must be taken to make informed assumptions regarding the nature of concepts and representations. In this study, we outline three reasons why one cannot, in effect, represent the same concept twice. First, online perception affects offline representation: Current representational content depends on how ongoing demands direct attention to modality‐specific systems. Second, language is a fundamental facilitator of offline representation: Bootstrapping and shortcuts within the computationally cheaper linguistic system continuously modify representational content. Third, time itself is a source of representational change: As the content of underlying concepts shifts with the accumulation of direct and vicarious experience, so too does the content of representations that draw upon these concepts. We discuss the ramifications of these principles for research into both human and synthetic cognitive systems.
Association of neonatal red blood cell transfusion with increase in serum bilirubin
Authors: Christensen Robert D. , Baer Vickie L. , Snow Gregory L. , Butler Allison , Ilstrup Sarah J.
Published: June 2014

Background

It is not clear whether red blood cell (RBC) transfusions typically increase a neonate's total serum bilirubin (TSB) level or if so by how much.

Study Design and Methods

In this retrospective analysis, from 2009 through 2012, we collected TSB measurements before and after transfusions, recording blood types of mothers, neonates, and blood donors and whether phototherapy was used before, during, or after transfusion.

Results

Of 7272 neonates admitted during this period, 658 (9%) received 2597 RBC transfusions. TSB levels were drawn before and after 431 transfusions, 255 of which did not have phototherapy at the time the transfusion was administered. The mean increase in TSB was 2.2 mg/dL (95% confidence interval, 1.9‐2.5 mg/dL). Seven percent of all transfusions and 12% of transfusions to very‐low‐birthweight (VLBW) infants (<1500 g) were followed by a TSB increase of at least 5 mg/dL. Transfusions with “universal donor” blood (O–) resulted in a higher TSB increase (p < 0.0001), but the magnitude was clinically insignificant (0.3 mg/dL). Older blood (days since donor draw) did not generate significantly higher posttransfusion TSB levels (p = 0.092). A focused study of the 10 neonates with the highest TSB increases revealed that six were unexplained other than transfusion related.

Conclusions

We describe an association between RBC transfusion and TSB elevation, but we recognize that this does not establish a cause‐and‐effect relationship. However, the observation that an increase of at least 5 mg/dL occurs after 12% of transfusions to VLBW neonates suggests to us that clinicians will want to evaluate jaundice, or measure bilirubin, on VLBW neonates after transfusion.
Current thawing and infusion practice of cryopreserved cord blood: the impact on graft quality, recipient safety, and transplantation outcomes
Authors: Akel Salem , Regan Donna , Wall Donna , Petz Laurence , McCullough Jeffrey
Published: June 2014

Methods of handling, thawing, and infusion of cord blood (CB) products vary substantially among thaw/transplant centers (TCs). This review 1) compares currently available CB product types and thaw methods recommended by CB banks (CBBs), 2) discusses causes of inconsistency in thaw method application at TCs, 3) advises elements to consider in thaw method approval or selection at the TC, 4) provides a procedural template for the traditional thaw methods, and 5) suggests acceptable time from product thaw to infusion and other considerations for safe infusion. It also compares postinfusion adverse reaction and engraftment data as functions of thaw methods. Remarks and suggestions made throughout this review are: 1) not intended to supersede manufacturer's instructions but meant to support the standardization of preparative procedures recommended by CBBs and 2) intended to help TCs to investigate relevant quality issues and handle challenges, especially when the TC is unable to follow recommendations due to foreseeable technical, quality, and/or clinical factors.
Evaluation of Inhibitive Performance of Some Plants Extracts on Low Carbon Steel Corrosion
Authors: Bodude M. A. , Sanni O. S.
Published: June 2014

The corrosion inhibitive potential of Plumeria Alba, Blighia Sapida and Secamone Afezeli plants extracts on heat-treated and non-heat-treated mild steel samples immersed in different concentrations of hydrochloric acid (HCl) were investigated using weight loss technique. The mild steel samples were cut and prepared for the corrosion test in the acid media mixed with the plant extracts obtained by natural drying, grinding and chemical extraction using hexane. The plants were collected from the botanical garden of University of Lagos, Nigeria. Samples of the mild steel were weighed before immersion and at regular interval of 7 days for a period of 56 days after immersion. The experiment was repeated using 0.1 M and 0.2 M of an inorganic inhibitor. Results obtained showed that the extract of Blighia Sapida exhibited the highest inhibitive power, while annealed samples have the least corrosion rate in the Hcl solution.
Mapping and Spectral Analysis of Acoustic Vibration in the Scanning Area of the Weak Field Magnetic Resonance Imager
Authors: Přibil Jiří , Přibilová Anna , Frollo Ivan
Published: June 2014

The paper describes measurement and calculation of 2D distribution of the vibration signal originated by the gradient coil system of the magnetic resonance imaging (MRI) equipment. The measurement experiments were performed at the bottom plastic holder of the scanning area of the open-air weak magnetic field MRI device. Selection of a usable type of a vibration sensor for measurement in a magnetic field with low B0 up to 0.2 T is also discussed. Realized calibration of the chosen sensor (sensitivity and frequency response) together with determination of the propagation time delay between the excitation impulses and the subsequently generated vibration signal is mentioned, too. The picked-up vibration signal exhibits harmonic character so it is suitable to describe it by determined spectral properties and features. Obtained statistical results of spectral analysis will be used to improve image sharpening and reduction of the motion effect in the MR pictures of thin layer samples and phantoms scanned by this MRI system.
Experimental Investigation of Horizontal Gas–Liquid Stratified and Annular Flow Using Wire-Mesh Sensor
Authors: Vieira Ronald E. , Kesana Netaji R. , Torres Carlos F. , McLaury Brenton S. , Shirazi Siamack A. , Schleicher Eckhard , Hampel Uwe
Published: June 2014

Stratified and annular gas–liquid flow patterns are commonly encountered in many industrial applications, such as oil and gas transportation pipelines, heat exchangers, and process equipment. The measurement and visualization of two-phase flow characteristics are of great importance as two-phase flows persist in many fluids engineering applications. A wire-mesh sensor (WMS) technique based on conductance measurements has been applied to investigate two-phase horizontal pipe flow. The horizontal flow test section consisting of a 76.2 mm ID pipe, 18 m long was employed to generate stratified and annular flow conditions. Two 16 × 16 wire configuration sensors, installed 17 m from the inlet of the test section, are used to determine the void fraction within the cross section of the pipe and determine interface velocities between the gas and liquid. These physical flow parameters were extracted using signal processing and cross-correlation techniques. In this work, the principle of WMS and the methodology of flow parameter extraction are described. From the obtained raw data time series of void fraction, cross-sectional mean void fraction, time averaged void fraction profiles, interfacial structures, and velocities of the periodic structures are determined for different liquid and gas superficial velocities that ranged from 0.03 m/s to 0.2 m/s and from 9 m/s to 34 m/s, respectively. The effects of liquid viscosity on the measured parameters have also been investigated using three different viscosities.
Application Conditions of Effective Medium Theory in Near-Field Radiative Heat Transfer Between Multilayered Metamaterials
Authors: Liu X. L. , Bright T. J. , Zhang Z. M.
Published: June 2014

This work addresses the validity of the local effective medium theory (EMT) in predicting the near-field radiative heat transfer between multilayered metamaterials, separated by a vacuum gap. Doped silicon and germanium are used to form the metallodielectric superlattice. Different configurations are considered by setting the layers adjacent to the vacuum spacer as metal–metal (MM), metal–dielectric (MD), or dielectric–dielectric (DD) (where M refers to metallic doped silicon and D refers to dielectric germanium). The calculation is based on fluctuational electrodynamics using the Green's function formulation. The cutoff wave vectors for surface plasmon polaritons (SPPs) and hyperbolic modes are evaluated. Combining the Bloch theory with the cutoff wave vector, the application condition of EMT in predicting near-field radiative heat transfer is presented quantitatively and is verified by exact calculations based on the multilayer formulation.
Exact Solutions for Flexoelectric Response in Nanostructures
Authors: Ray M. C.
Published: June 2014

This paper is concerned with the derivation of the exact solutions for the static responses of the simply supported flexoelectric nanobeams subjected to the applied mechanical load and applied voltage difference across the thickness of the beams. Considering both the direct and the converse flexoelectric effects, the governing equations and the associated boundary conditions of the beams are derived to obtain the exact solutions for the displacements and the electric potential in the beams. Due to the converse flexoelectric effect, the active beams significantly counteract the applied mechanical load. The normal and the transverse shear deformations in the beams are affected by the converse flexoelectric effect in the beams resulting in the coupling of bending and stretching deformations in the beams. For the particular values of the length of the beam and the applied voltage, the deflection of the nanobeam due to the converse flexoelectric effect significantly increases with the decrease in the thickness of the beam. But the deflection of the beam remains invariant with the change in length of the beam for the particular values of the thickness of the beam and the applied voltage. Also, for the particular values of the thickness of the beam and the applied mechanical load, the induced transverse electric polarization on the surface of the beam is independent of the variation of the length of the beam and the value of the polarization increases with the decrease in the thickness of the beam. The benchmark results presented here may be useful for verifying further research and the present study suggests that the flexoelectric nanobeams may be effectively exploited for advanced applications as smart sensors and actuators at nanoscale.
Multimaterial Capability of Laser Induced Plasma Micromachining
Authors: Saxena Ishan , Ehmann Kornel F.
Published: June 2014

Presently surface microtexturing has found many promising applications in the fields of tribology, biomedical engineering, metal cutting, and other functional or topographical surfaces. Most of these applications are material-specific, which necessitates the need for a texturing and machining process that surpasses the limitations posed by a certain class of materials that are difficult to process by laser ablation, owing to their optical or other surface or bulk characteristics. Laser induced plasma micromachining (LIPMM) has emerged as a promising alternative to direct laser ablation for micromachining and microtexturing, which offers superior machining characteristics while preserving the resolution, accuracy and tool-less nature of laser ablation. This study is aimed at understanding the capability of LIPMM process to address some of the issues faced by pulsed laser ablation in material processing. This paper experimentally demonstrates machining of optically transmissive, reflective, and rough surface materials using LIPMM. Apart from this, the study includes machining of conventional metals (nickel and titanium) and polymer (polyimide), to demonstrate higher obtainable depth and reduced heat-affected distortion around microfeatures machined by LIPMM, as compared to laser ablation.
Imaging and Nanomedicine in Inflammatory Atherosclerosis
Authors: Mulder Willem J. M. , Jaffer Farouc A. , Fayad Zahi A. , Nahrendorf Matthias
Published: June 2014

The integration of immunology and cardiovascular medicine with engineering and nanotechnology will yield precision diagnostics and efficient therapeutics for atherosclerosis and its ischemic complications.
Endothelial Insights: The Florian Dialectic
Authors: Edelman Elazer R.
Published: June 2014

In heart healing, engineering technology has driven translation by bridging biology and medicine.
Cardiovascular Genetics: Paying Individual Dividends
Authors: McNally Elizabeth
Published: June 2014

Recently identified genetic variations that underlie cardiovascular disease are changing clinical practice.
Human Stem Cells for Modeling Heart Disease and for Drug Discovery
Authors: Matsa Elena , Burridge Paul W. , Wu Joseph C.
Published: June 2014

This Perspective highlights recent research progress in the use of stem cells and progenitor cells for disease modeling, drug discovery, and cardiac regeneration.
Metabolic Syndrome: A Family Affair
Authors: Haldar Saptarsi M.
Published: June 2014

A rare genetic mutation found to cause human metabolic syndrome may shed light on more common forms of cardiometabolic disease.
Vaping—Vaccine or Virus?
Authors: Kolandaivelu Kumaran
Published: June 2014

Despite the growing popularity of electronic cigarettes, little is known about whether these nicotine-delivery devices hinder or help smokers in their efforts to quit.
Removing the Veil from Cancer Stem Cells
Authors: Lathia Justin D.
Published: June 2014

The evaluation of human patient specimens provides in vivo evidence that cancer stem cells drive myelodysplastic syndromes.
“Brain-Critical” Exons in Autism
Authors: Mefford Heather C.
Published: June 2014

Select brain-expressed exons may be targets for disease-causing mutations in autism.
Invasion of the Central Nervous System by Cryptococcus neoformans Requires a Secreted Fungal Metalloprotease
Authors: Vu Kiem , Tham Rick , Uhrig John P. , Thompson George R. , Na Pombejra Sarisa , Jamklang Mantana , Bautos Jennifer M. , Gelli Angie
Published: June 2014

Cryptococcus
spp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. Why
Cryptococcus neoformans
has this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis of
C. neoformans
revealed a predominantly transcellular migration of cryptococci across the brain endothelium; however, the identities of key fungal virulence factors that function specifically to invade the CNS remain unresolved. Here we found that a novel, secreted metalloprotease (Mpr1) that we identified in the extracellular proteome of
C. neoformans
(CnMpr1) is required for establishing fungal disease in the CNS. Mpr1 belongs to a poorly characterized M36 class of fungalysins that are expressed in only some fungal species. A strain of
C. neoformans
lacking the gene encoding Mpr1 (
mpr1Δ
) failed to breach the endothelium in an
in vitro
model of the human blood-brain barrier (BBB). A mammalian host infected with the
mpr1Δ
null strain demonstrated significant improvement in survival due to a reduced brain fungal burden and lacked the brain pathology commonly associated with cryptococcal disease. The
in vivo
studies further indicate that Mpr1 is not required for fungal dissemination and Mpr1 likely targets the brain endothelium specifically. Remarkably, the sole expression of Cn
MPR1
in
Saccharomyces cerevisiae
resulted in a robust migration of yeast cells across the brain endothelium, demonstrating Mpr1’s specific activity in breaching the BBB and suggesting that Mpr1 may function independently of the hyaluronic acid-CD44 pathway. This distinct role for Mpr1 may develop into innovative treatment options and facilitate a brain-specific drug delivery platform.

IMPORTANCE
Cryptococcus neoformans
is a medically relevant fungal pathogen causing significant morbidity and mortality, particularly in immunocompromised individuals. An intriguing feature is its strong neurotropism, and consequently the hallmark of cryptococcal disease is a brain infection, cryptococcal meningoencephalitis. For
C. neoformans
to penetrate the central nervous system (CNS), it first breaches the blood-brain barrier via a transcellular pathway; however, the identities of fungal factors required for this transmigration remain largely unknown. In an effort to identify extracellular fungal proteins that could mediate interactions with the brain endothelium, we undertook a proteomic analysis of the extracellular proteome and identified a secreted metalloprotease (Mpr1) belonging to the M36 class of fungalysins. Here we found that Mpr1 promotes migration of
C. neoformans
across the brain endothelium and into the CNS by facilitating attachment of cryptococci to the endothelium surface, thus underscoring the critical role of M36 proteases in fungal pathogenesis.
Specialized Transduction Designed for Precise High-Throughput Unmarked Deletions in Mycobacterium tuberculosis
Authors: Jain Paras , Hsu Tsungda , Arai Masayoshi , Biermann Karolin , Thaler David S. , Nguyen Andrew , González Pablo A. , Tufariello Joann M. , Kriakov Jordan , Chen Bing , Larsen Michelle H. , Jacobs William R.
Published: June 2014

Specialized transduction has proven to be useful for generating deletion mutants in most mycobacteria, including virulent
Mycobacterium tuberculosis
. We have improved this system by developing (i) a single-step strategy for the construction of allelic exchange substrates (AES), (ii) a temperature-sensitive shuttle phasmid with a greater cloning capacity than phAE87, and (iii) bacteriophage-mediated transient expression of site-specific recombinase to precisely excise antibiotic markers. The methods ameliorate rate-limiting steps in strain construction in these difficult-to-manipulate bacteria. The new methods for strain construction were demonstrated to generalize to all classes of genes and chromosomal loci by generating more than 100 targeted single- or multiple-deletion substitutions. These improved methods pave the way for the generation of a complete ordered library of
M. tuberculosis
null strains, where each strain is deleted for a single defined open reading frame in
M. tuberculosis.

IMPORTANCE
This work reports major advances in the methods of genetics applicable to all mycobacteria, including but not limited to virulent
M. tuberculosis
, which would facilitate comparative genomics to identify drug targets, genetic validation of proposed pathways, and development of an effective vaccine. This study presents all the new methods developed and the improvements to existing methods in an integrated way. The work presented in this study could increase the pace of mycobacterial genetics significantly and will immediately be of wide use. These new methods are transformative and allow for the undertaking of construction of what has been one of the most fruitful resources in model systems: a comprehensive, ordered library set of the strains, each of which is deleted for a single defined open reading frame.
Dietary Pyridoxine Controls Efficacy of Vitamin B
6
-Auxotrophic Tuberculosis Vaccine Bacillus Calmette-Guérin Δ
ureC
::
hly
Δ
pdx1
in Mice
Authors: Gengenbacher Martin , Vogelzang Alexis , Schuerer Stefanie , Lazar Doris , Kaiser Peggy , Kaufmann Stefan H. E.
Published: June 2014

The only tuberculosis (TB) vaccine in use today, bacillus Calmette-Guérin (BCG), provides insufficient protection and can cause adverse events in immunocompromised individuals, such as BCGosis in HIV
+
newborns. We previously reported improved preclinical efficacy and safety of the recombinant vaccine candidate BCG Δ
ureC
::
hly
, which secretes the pore-forming listeriolysin O of
Listeria monocytogenes
. Here, we evaluate a second-generation construct, BCG Δ
ureC
::
hly
Δ
pdx1
, which is deficient in pyridoxine synthase, an enzyme that is required for biosynthesis of the essential cofactor vitamin B
6
. This candidate was auxotrophic for vitamin B
6
in a concentration-dependent manner, as was its survival
in vivo
. BCG Δ
ureC
::
hly
Δ
pdx1
showed markedly restricted dissemination in subcutaneously vaccinated mice, which was ameliorated by dietary supplementation with vitamin B
6
. The construct was safer in severe combined immunodeficiency mice than the parental BCG Δ
ureC
::
hly
. A prompt innate immune response to vaccination, measured by secretion of interleukin-6, granulocyte colony-stimulating factor, keratinocyte cytokine, and macrophage inflammatory protein-1α, remained independent of vitamin B
6
administration, while acquired immunity, notably stimulation of antigen-specific CD4 T cells, B cells, and memory T cells, was contingent on vitamin B
6
administration. The early protection provided by BCG Δ
ureC
::
hly
Δ
pdx1
in a murine
Mycobacterium tuberculosis
aerosol challenge model consistently depended on vitamin B
6
supplementation. Prime-boost vaccination increased protection against the canonical
M. tuberculosis
H37Rv laboratory strain and a clinical isolate of the Beijing/W lineage. We demonstrate that the efficacy of a profoundly attenuated recombinant BCG vaccine construct can be modulated by external administration of a small molecule. This principle fosters the development of safer vaccines required for immunocompromised individuals, notably HIV
+
infants.

IMPORTANCE
Mycobacterium tuberculosis
can synthesize the essential cofactor vitamin B
6
, while humans depend on dietary supplementation. Unlike the lipophilic vitamins A, D, and E, water-soluble vitamin B
6
is well tolerated at high doses. We generated a vitamin B
6
auxotroph of the phase II clinical tuberculosis vaccine candidate bacillus Calmette-Guérin Δ
ureC
::
hly
. The next-generation candidate was profoundly attenuated compared to the parental strain. Adaptive immunity and protection in mice consistently depended on increased dietary vitamin B
6
above the daily required dose. Control of vaccine efficacy via food supplements such as vitamin B
6
could provide a fast track toward improved safety. Safer vaccines are urgently needed for HIV-infected individuals at high risk of adverse events in response to live vaccines.
Primary uterine osteosarcoma presenting synchronously with bilateral breast carcinomas
Authors: Powell George , Barth Laura , Todd Richard , Ganesan Raji
Published: June 2014

Primary uterine sarcomas are infrequent neoplasms and most commonly leiomyosarcomas or endometrial stromal sarcomas. We report a rare case of primary uterine osteosarcoma discovered in a woman in her 60s following staging CT imaging for bilateral breast carcinomas. Examination of the subsequent hysterectomy specimen showed a tumour composed of malignant spindle cells and osteoclast-like giant cells associated with osteoid and neoplastic bone, in keeping with primary uterine osteosarcoma. Distinction of osteosarcoma from the more common carcinosarcoma is important due to the worse prognosis impacting on treatment decisions. In addition, synchronous presentation of this unusual tumour with bilateral breast carcinomas raises the possibility of a mutual genetic pathogenesis.
Metastatic human epidermal growth factor 2 (HER2/neu) amplified breast cancer with acute fulminant hepatitis responding to trastuzumab, pertuzumab and carboplatin
Authors: Macias Mariela N , Shin Daniel Sanghoon , Ledezma Blanca , Sadeghi Saeed
Published: June 2014

A 30-year-old woman presented to an outside hospital with pain in the right upper abdomen. Imaging revealed over 100 liver lesions, the largest measuring 74 mm×71 mm, and multiple lytic bone lesions. An outpatient liver biopsy showed a poorly differentiated adenocarcinoma favouring a breast primary. The tumour was oestrogen and progesterone receptor negative, but human epidermal growth factor 2 (HER2/neu) amplified. In her second clinic visit she had decompensated liver failure manifested by new-onset ascites and jaundice. Initially, the chemotherapy plan was for docetaxel, pertuzumab and trastuzumab, but given her severe liver dysfunction we used a combination of carboplatin, pertuzumab and trastuzumab as an inpatient. She was hospitalised for 14 days and eventually discharged with a marked improvement of her symptoms and liver tests. She subsequently completed five outpatient chemotherapy cycles. We showed that carboplatin is a possible alternative to docetaxel when severe liver dysfunction precludes docetaxel's use in combination with pertuzumab and trastuzumab.
Acute hepatitis E complicated by acute pancreatitis and multiorgan dysfunction
Authors: Karanth Suman S , Khan Zohaib , Rau Nileshwar Radhakrishna , Rao Karthik
Published: June 2014

We report this rare case of a 27-year-old man who presented with acute hepatitis E and went on to develop acute epigastric pain. He was diagnosed to have acute severe pancreatitis with shock and acute renal failure due to hepatitis E. Such a phenomenon has rarely been reported in the literature, with patients following a benign course and complete recovery after conservative management and analgesia. Awareness of this potentially life-threatening complication, especially in young men from endemic areas with acute hepatitis E presenting with abdomen pain has been highlighted.
Autism: a rare presentation of Bardet-Biedl syndrome
Authors: Chatterjee Seshadri Sekhar , Guha Prathama , Talukdar Arunansu , Dasgupta Gargi
Published: June 2014

Although mental retardation is generally associated with Bardet-Biedl (BBS) syndrome, a rare autosomal recessive disorder with multisystem involvement, autism is an unusual comorbidity. An 8-year-old boy presented to our psychiatry department with poor social skills and night blindness. On further assessment autism, mild mental retardation, retinitis pigmentosa, polydactyly and syndactyly, obesity, micropenis, maldescended testis, hypodontia and high-arched palate were noted and subsequently a diagnosis of BBS was made. To the best of our knowledge, this is the first reported case of BBS with autism from eastern India; it also emphasises the importance of thorough physical examination even in a patient presenting with pure psychiatric symptoms.
Acute peripheral polyneuropathy with multiorgan failure: a diagnostic dilemma
Authors: Hussain Kosar , Abubaker Jawed , Ahmad Dar Javeed , Ahmed Raees
Published: June 2014

We describe the case of a young man who presented with abdominal pain, vomiting and acute symmetric peripheral polyneuropathy. He was noted to have high anion gap metabolic acidosis with high lactate levels and persistently high arterial and venous pO2values. The cerebrospinal fluid was acellular with a high protein and the nerve conduction study was consistent with axonal sensorimotor neuropathy. His clinical condition deteriorated rapidly despite full supportive care and he subsequently died of multiorgan failure. An extensive workup for various infectious, autoimmune and other possible aetiologies was carried out to identify the underlying cause for his fulminant illness. All diagnostic workup was non-conclusive except for a significantly elevated serum aluminium level. We have discussed the possibility of aluminium phosphide poisoning in view of the clinical presentation.
Opioid-induced hyperalgesia: when pain killers make pain worse
Authors: Kaneria Anshuni
Published: June 2014

A 44-year-old woman had a temporal glioma and was admitted to the hospice with pain that was not controlled despite escalating opioids. Her pain levels rose after every dose increase resulting now in continuous pain, making her very low in mood. Her short-term memory had also declined in a stepwise fashion with each increase in opioids. Additionally, her poor health had had a detrimental effect on family life. Physical examination was difficult due to allodynia but no major abnormality was found. The team suspected opioid-induced hyperalgesia and decided to cut the patient's opioids by one-third initially. This immediately improved the overall pain. The opioids continued to be decreased incrementally every 1–2 days until the pain had disappeared completely. She was stabilised on a dose almost one-seventh of her original regime. Mood and memory also improved as opioids decreased and she was discharged home after 8 days.
Moving improvement research closer to practice: the Researcher-in-Residence model
Authors: Marshall Martin , Pagel Christina , French Catherine , Utley Martin , Allwood Dominique , Fulop Naomi , Pope Catherine , Banks Victoria , Goldmann Allan
Published: June 2014

The traditional separation of the producers of research evidence in academia from the users of that evidence in healthcare organisations has not succeeded in closing the gap between what is known about the organisation and delivery of health services and what is actually done in practice. As a consequence, there is growing interest in alternative models of knowledge creation and mobilisation, ones which emphasise collaboration, active participation of all stakeholders, and a commitment to shared learning. Such models have robust historical, philosophical and methodological foundations but have not yet been embraced by many of the people working in the health sector. This paper presents an emerging model of participation, the Researcher-in-Residence. The model positions the researcher as a core member of a delivery team, actively negotiating a body of expertise which is different from, but complementary to, the expertise of managers and clinicians. Three examples of in-residence models are presented: an anthropologist working as a member of an executive team, operational researchers working in a front-line delivery team, and a Health Services Researcher working across an integrated care organisation. Each of these examples illustrates the contribution that an embedded researcher can make to a service-based team. They also highlight a number of unanswered questions about the model, including the required level of experience of the researcher and their areas of expertise, the institutional facilitators and barriers to embedding the model, and the risk that the independence of an embedded researcher might be compromised. The Researcher-in-Residence model has the potential to engage both academics and practitioners in the promotion of evidence-informed service improvement, but further evaluation is required before the model should be routinely used in practice.
AMP kinase (PRKAA1)
Authors: Krishan Sukriti , Richardson Des R , Sahni Sumit
Published: June 2014

ThePRKAA1gene encodes the catalytic α-subunit of 5′ AMP-activated protein kinase (AMPK). AMPK is a cellular energy sensor that maintains energy homeostasis within the cell and is activated when the AMP/ATP ratio increases. When activated, AMPK increases catabolic processes that increase ATP synthesis and inhibit anabolic processes that require ATP. Additionally, AMPK also plays a role in activating autophagy and inhibiting energy consuming processes, such as cellular growth and proliferation. Due to its role in energy metabolism, it could act as a potential target of many therapeutic drugs that could be useful in the treatment of several diseases, for example, diabetes. Moreover, AMPK has been shown to be involved in inhibiting tumour growth and metastasis, and has also been implicated in the pathology of neurodegenerative and cardiac disorders. Hence, a better understanding of AMPK and its role in various pathological conditions could enable the development of strategies to use it as a therapeutic target.
Developmental trajectories of Body Mass Index from infancy to 18 years of age: prenatal determinants and health consequences
Authors: Ziyab Ali H , Karmaus Wilfried , Kurukulaaratchy Ramesh J , Zhang Hongmei , Arshad Syed Hasan
Published: June 2014

Background

Knowledge on the long-term development of adiposity throughout childhood/adolescence and its prenatal determinants and health sequelae is lacking. We sought to (1) identify trajectories of Body Mass Index (BMI) from 1 to 18 years of age, (2) examine associations of maternal gestational smoking and early pregnancy overweight with offspring BMI trajectories and (3) determine whether BMI trajectories predict health outcomes: asthma, lung function parameters (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio), and blood pressure, at 18 years.

Methods

The Isle of Wight birth cohort, a population-based sample of 1456 infants born between January 1989 and February 1990, was prospectively assessed at ages 1, 2, 4, 10 and 18 years. Group-based trajectory modelling was applied to test for the presence of latent BMI trajectories. Associations were assessed using log-binomial and linear regression models.

Results

Four trajectories of BMI were identified: ‘normal’, ‘early persistent obesity’, ‘delayed overweight’, and ‘early transient overweight’. Risk factors for being in the early persistent obesity trajectory included maternal smoking during pregnancy (RR 2.16, 95% CI 1.02 to 4.68) and early pregnancy overweight (3.16, 1.52 to 6.58). When comparing the early persistent obesity to the normal trajectory, a 2.15-fold (1.33 to 3.49) increased risk of asthma, 3.2% (0.4% to 6.0%) deficit in FEV1/FVC ratio, and elevated systolic 11.3 mm Hg (7.1 to 15.4) and diastolic 12.0 mm Hg (8.9 to 15.1) blood pressure were observed at age 18 years.

Conclusions

Maternal prenatal exposures show prolonged effects on offspring's propensity towards overweight-obesity. Distinct morbid BMI trajectories are evident during the first 18 years of life that are associated with higher risk of asthma, reduced FEV1/FVC ratio, and elevated blood pressure.