bluuebunny/crossref_metadata_2025 huggingface dataset:
Importance of Multidrug Efflux Pumps in the Antimicrobial Resistance Property of Clinical Multidrug-Resistant Isolates of Neisseria gonorrhoeae
Authors: Golparian Daniel , Shafer William M. , Ohnishi Makoto , Unemo Magnus
Published: April 2014

The contribution of drug efflux pumps in clinical isolates of
Neisseria gonorrhoeae
that express extensively drug-resistant or multidrug-resistant phenotypes has heretofore not been examined. Accordingly, we assessed the effect on antimicrobial resistance of loss of the three gonococcal efflux pumps associated with a known capacity to export antimicrobials (MtrC-MtrD-MtrE, MacA-MacB, and NorM) in such clinical isolates. We report that the MIC of several antimicrobials, including seven previously and currently recommended for treatment was significantly impacted.
Significance and Clinical Management of Persistent Low-Level Viremia and Very-Low-Level Viremia in HIV-1-Infected Patients
Authors: Ryscavage Patrick , Kelly Sean , Li Jonathan Z. , Harrigan P. Richard , Taiwo Babafemi
Published: April 2014

A goal of HIV therapy is to sustain suppression of the plasma viral load below the detection limits of clinical assays. However, widely followed treatment guidelines diverge in their interpretation and recommended management of persistent viremia of low magnitude, reflecting the limited evidence base for this common clinical finding. Here, we review the incidence, risk factors, and potential consequences of low-level HIV viremia (LLV; defined in this review as a viremia level of 50 to 500 copies/ml) and very-low-level viremia (VLLV; defined as a viremia level of <50 copies/ml detected by clinical assays that have quantification cutoffs of <50 copies/ml). Using this framework, we discuss practical issues related to the diagnosis and management of patients experiencing persistent LLV and VLLV. Compared to viral suppression at <50 or 40 copies/ml, persistent LLV is associated with increased risk of antiretroviral drug resistance and overt virologic failure. Higher immune activation and HIV transmission may be additional undesirable consequences in this population. It is uncertain whether LLV of <200 copies/ml confers independent risks, as this level of viremia may reflect assay-dependent artifacts or biologically meaningful events during suppression. Resistance genotyping should be considered in patients with persistent LLV when feasible, and treatment should be modified if resistance is detected. There is a dearth of clinical evidence to guide management when genotyping is not feasible. Increased availability of genotypic assays for samples with viral loads of <400 copies/ml is needed.
Predictive Models for Identification of Hospitalized Patients Harboring KPC-Producing Klebsiella pneumoniae
Authors: Tumbarello Mario , Trecarichi Enrico Maria , Tumietto Fabio , Del Bono Valerio , De Rosa Francesco Giuseppe , Bassetti Matteo , Losito Angela Raffaella , Tedeschi Sara , Saffioti Carolina , Corcione Silvia , Giannella Maddalena , Raffaelli Francesca , Pagani Nicole , Bartoletti Michele , Spanu Teresa , Marchese Anna , Cauda Roberto , Viscoli Claudio , Viale Pierluigi
Published: April 2014

The production of
Klebsiella pneumoniae
carbapenemases (KPCs) by
Enterobacteriaceae
has become a significant problem in recent years. To identify factors that could predict isolation of KPC-producing
K. pneumoniae
(KPCKP) in clinical samples from hospitalized patients, we conducted a retrospective, matched (1:2) case-control study in five large Italian hospitals. The case cohort consisted of adult inpatients whose hospital stay included at least one documented isolation of a KPCKP strain from a clinical specimen. For each case enrolled, we randomly selected two matched controls with no KPCKP-positive cultures of any type during their hospitalization. Matching involved hospital, ward, and month/year of admission, as well as time at risk for KPCKP isolation. A subgroup analysis was also carried out to identify risk factors specifically associated with true KPCKP infection. During the study period, KPCKP was isolated from clinical samples of 657 patients; 426 of these cases appeared to be true infections. Independent predictors of KPCKP isolation were recent admission to an intensive care unit (ICU), indwelling urinary catheter, central venous catheter (CVC), and/or surgical drain, ≥2 recent hospitalizations, hematological cancer, and recent fluoroquinolone and/or carbapenem therapy. A Charlson index of ≥3, indwelling CVC, recent surgery, neutropenia, ≥2 recent hospitalizations, and recent fluoroquinolone and/or carbapenem therapy were independent risk factors for KPCKP infection. Models developed to predict KPCKP isolation and KPCKP infection displayed good predictive power, with the areas under the receiver-operating characteristic curves of 0.82 (95% confidence interval [CI], 0.80 to 0.84) and 0.82 (95% CI, 0.80 to 0.85), respectively. This study provides novel information which might be useful for the clinical management of patients harboring KPCKP and for controlling the spread of this organism.
Quinolone Resistance Mechanisms in Salmonella enterica Serovars Hadar, Kentucky, Virchow, Schwarzengrund, and 4,5,12:i:−, Isolated from Humans in Switzerland, and Identification of a Novel
qnrD
Variant,
qnrD2
, in
S
. Hadar
Authors: Abgottspon Helga , Zurfluh Katrin , Nüesch-Inderbinen Magdalena , Hächler Herbert , Stephan Roger
Published: April 2014

Human isolates of
Salmonella enterica
serovars Hadar, Kentucky, Virchow, Schwarzengrund, and the monophasic variant of
S
. Typhimurium,
Salmonella enterica
subsp.
enterica
serovar 4,5,12:i:− were examined for mutations within the quinolone resistance target genes
gyrA
,
gyrB
,
parC
, and
parE
and for plasmid-mediated resistance genes. Differences were observed among the serovars. A novel variant of
qnrD
,
qnrD2
, was detected in an
S
. Hadar isolate.
Preclinical Characterization of BMS-791325, an Allosteric Inhibitor of Hepatitis C Virus NS5B Polymerase
Authors: Lemm Julie A. , Liu Mengping , Gentles Robert G. , Ding Min , Voss Stacey , Pelosi Lenore A. , Wang Ying-Kai , Rigat Karen L. , Mosure Kathleen W. , Bender John A. , Knipe Jay O. , Colonno Richard , Meanwell Nicholas A. , Kadow John F. , Santone Kenneth S. , Roberts Susan B. , Gao Min
Published: April 2014

BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC
50
) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and 1b at 50% effective concentrations (EC
50
s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a. Potency against genotype 6a showed more variability (9 to 125 nM), and activity was weaker against genotype 2 (EC
50
, 87 to 925 nM). Specificity was demonstrated by the absence of activity (EC
50
s of >4 μM) against a panel of mammalian viruses, and cytotoxic concentrations (50%) were >3,000-fold above the HCV EC
50
. Resistance substitutions selected by BMS-791325 in genotype 1 replicons mostly mapped to a single site, NS5B amino acid 495 (P495A/S/L/T). Additive or synergistic activity was observed in combination studies using BMS-791325 with alfa interferon plus ribavirin, inhibitors of NS3 protease or NS5A, and other classes of NS5B inhibitor (palm site 2-binding or nucleoside analogs). Plasma and liver exposures
in vivo
in several animal species indicated that BMS-791325 has a hepatotropic disposition (liver-to-plasma ratios ranging from 1.6- to 60-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥10-fold above the inhibitor EC
50
s observed with HCV genotype 1 replicons. These findings support the evaluation of BMS-791325 in combination regimens for the treatment of HCV. Phase 3 studies are ongoing.
Randomized, Placebo-Controlled, Single-Ascending-Dose Study of BMS-791325, a Hepatitis C Virus (HCV) NS5B Polymerase Inhibitor, in HCV Genotype 1 Infection
Authors: Sims Karen D. , Lemm Julie , Eley Timothy , Liu Menping , Berglind Anna , Sherman Diane , Lawitz Eric , Vutikullird Apinya B. , Tebas Pablo , Gao Min , Pasquinelli Claudio , Grasela Dennis M.
Published: April 2014

BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC
50
], 3 nM) and 1b (EC
50
, 7 nM)
in vitro
. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log
10
copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC
90
for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance
in vitro
were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log
10
IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.)
Efficiency of Incorporation and Chain Termination Determines the Inhibition Potency of 2′-Modified Nucleotide Analogs against Hepatitis C Virus Polymerase
Authors: Fung Amy , Jin Zhinan , Dyatkina Natalia , Wang Guangyi , Beigelman Leo , Deval Jerome
Published: April 2014

Ribonucleotide analog inhibitors of the RNA-dependent RNA polymerase of hepatitis C virus (HCV) represent one of the most exciting recent developments in HCV antiviral therapy. Although it is well established that these molecules cause chain termination by competing at the triphosphate level with natural nucleotides for incorporation into elongating RNA, strategies to rationally optimize antiviral potency based on enzyme kinetics remain elusive. In this study, we used the isolated HCV polymerase elongation complex to determine the pre-steady-state kinetics of incorporation of 2′F-2′C-Me-UTP, the active metabolite of the anti-HCV drug sofosbuvir. 2′F-2′C-Me-UTP was efficiently incorporated by HCV polymerase with apparent

K
d

(equilibrium constant) and
k
pol
(rate of nucleotide incorporation at saturating nucleotide concentration) values of 113 ± 28 μM and 0.67 ± 0.05 s
−1
, respectively, giving an overall substrate efficiency (
k
pol
/

K
d

) of 0.0059 ± 0.0015 μM
−1
s
−1
. We also measured the substrate efficiency of other UTP analogs and found that substitutions at the 2′ position on the ribose can greatly affect their level of incorporation, with a rank order of OH > F > NH
2
> F-C-Me > C-Me > N
3
> ara. However, the efficiency of chain termination following the incorporation of UMP analogs followed a different order, with only 2′F-2′C-Me-, 2′C-Me-, and 2′ara-UTP causing complete and immediate chain termination. The chain termination profile of the 2′-modified nucleotides explains the apparent lack of correlation observed across all molecules between substrate efficiency at the single-nucleotide level and their overall inhibition potency. To our knowledge, these results provide the first attempt to use pre-steady-state kinetics to uncover the mechanism of action of 2′-modified NTP analogs against HCV polymerase.
Phase 1B Study of the Pharmacokinetics and Safety of Posaconazole Intravenous Solution in Patients at Risk for Invasive Fungal Disease
Authors: Maertens Johan , Cornely Oliver A. , Ullmann Andrew J. , Heinz Werner J. , Krishna Gopal , Patino Hernando , Caceres Maria , Kartsonis Nicholas , Waskin Hetty , Robertson Michael N.
Published: April 2014

This was a phase 1B, dose-ranging, multicenter, pharmacokinetics, and safety study of cyclodextrin-based posaconazole intravenous (i.v.) solution administered through a central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3]). Initially, the safety and tolerability of single-dose posaconazole i.v. 200 mg (
n
= 10) were compared with those of a placebo (
n
= 11). Subsequently, 2 doses were evaluated, posaconazole i.v. 200 mg once daily (q.d.) (
n
= 21) and 300 mg q.d. (
n
= 24). The subjects received twice-daily (b.i.d.) posaconazole i.v. on day 1, followed by 13 days of posaconazole i.v. q.d., then 14 days of posaconazole oral suspension 400 mg b.i.d. The steady-state (day 14) exposure target (average concentration [areas under concentration-time curve {AUCs}/24 h, average concentrations at steady state {
C
avg
s}], of ≥500 to ≤2,500 ng/ml in ≥90% of the subjects) was achieved by 94% of the subjects for 200 mg posaconazole q.d. and by 95% of subjects for 300 mg posaconazole q.d. The desired exposure target (mean steady-state
C
avg
, ∼1,200 ng/ml) was 1,180 ng/ml in the 200-mg dosing cohort and was exceeded in the 300-mg dosing cohort (1,430 ng/ml). Posaconazole i.v. was well tolerated. Posaconazole i.v. 300 mg q.d. was selected for the phase 3 study segment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01075984.)
Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules
Authors: Trenholme Katharine , Marek Linda , Duffy Sandra , Pradel Gabriele , Fisher Gillian , Hansen Finn K. , Skinner-Adams Tina S. , Butterworth Alice , Ngwa Che Julius , Moecking Jonas , Goodman Christopher D. , McFadden Geoffrey I. , Sumanadasa Subathdrage D. M. , Fairlie David P. , Avery Vicky M. , Kurz Thomas , Andrews Katherine T.
Published: April 2014

Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity; however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in
Plasmodium falciparum
gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in
P. falciparum
gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology.
Identification of a Diguanylate Cyclase and Its Role in Porphyromonas gingivalis Virulence
Authors: Chaudhuri Swarnava , Pratap Siddharth , Paromov Victor , Li Zhijun , Mantri Chinmay K. , Xie Hua
Published: April 2014

Porphyromonas gingivalis
is a Gram-negative obligate anaerobic bacterium and is considered a keystone pathogen in the initiation of periodontitis, one of the most widespread infectious diseases. Bacterial bis-(3′-5′) cyclic GMP (cyclic di-GMP [c-di-GMP]) serves as a second messenger and is involved in modulating virulence factors in numerous bacteria. However, the role of this second messenger has not been investigated in
P. gingivalis
, mainly due to a lack of an annotation regarding diguanylate cyclases (DGCs) in this bacterium. Using bioinformatics tools, we found a protein, PGN_1932, containing a GGDEF domain. A deletion mutation in the
pgn_1932
gene had a significant effect on the intracellular c-di-GMP level in
P. gingivalis
. Genetic analysis showed that expression of the
fimA
and
rgpA
genes, encoding the major protein subunit of fimbriae and an arginine-specific proteinase, respectively, was downregulated in the
pgn_1932
mutant. Correspondingly, FimA protein production and the fimbrial display on the mutant were significantly reduced. Mutations in the
pgn_1932
gene also had a significant impact on the adhesive and invasive capabilities of
P. gingivalis
, which are required for its pathogenicity. These findings provide evidence that the PGN_1932 protein is both responsible for synthesizing c-di-GMP and involved in biofilm formation and host cell invasion by
P. gingivalis
by controlling the expression and biosynthesis of FimA.
Antiapoptotic Activity of Coxiella burnetii Effector Protein AnkG Is Controlled by p32-Dependent Trafficking
Authors: Eckart Rita A. , Bisle Stephanie , Schulze-Luehrmann Jan , Wittmann Irene , Jantsch Jonathan , Schmid Benedikt , Berens Christian , Lührmann Anja
Published: April 2014

Intracellular bacterial pathogens frequently inhibit host cell apoptosis to ensure survival of their host, thereby allowing bacterial propagation. The obligate intracellular pathogenCoxiella burnetiidisplays antiapoptotic activity which depends on a functional type IV secretion system (T4SS). Accordingly, antiapoptotic T4SS effector proteins, like AnkG, have been identified. AnkG inhibits pathogen-induced apoptosis, possibly by binding to the host cell mitochondrial protein p32 (gC1qR). However, the molecular mechanism of AnkG activity remains unknown. Here, we demonstrate that ectopically expressed AnkG associates with mitochondria and traffics into the nucleus after apoptosis induction, although AnkG lacks a predicted nuclear localization signal. We identified the p32 interaction region in AnkG and constructed an AnkG mutant (AnkGR22/23S) unable to bind to p32. By using this mutant, we found that intracellular localization and trafficking of AnkG into the nucleus are dependent on binding to p32. Furthermore, we demonstrated that nuclear localization of AnkG but not binding to p32 is required for apoptosis inhibition. Thus, the antiapoptotic activity of AnkG is controlled by p32-mediated intracellular trafficking, which, in turn, seems to be regulated by host cell processes that sense stress.
Epidemic Clostridium difficile Strains Demonstrate Increased Competitive Fitness Compared to Nonepidemic Isolates
Authors: Robinson Catherine D. , Auchtung Jennifer M. , Collins James , Britton Robert A.
Published: April 2014

Clostridium difficile
infection is the most common cause of severe cases of antibiotic-associated diarrhea (AAD) and is a significant health burden. Recent increases in the rate of
C. difficile
infection have paralleled the emergence of a specific phylogenetic clade of
C. difficile
strains (ribotype 027; North American pulsed-field electrophoresis 1 [NAP1]; restriction endonuclease analysis [REA] group BI). Initial reports indicated that ribotype 027 strains were associated with increased morbidity and mortality and might be hypervirulent. Although subsequent work has raised some doubt as to whether ribotype 027 strains are hypervirulent, the strains are considered epidemic isolates that have caused severe outbreaks across the globe. We hypothesized that one factor that could lead to the increased prevalence of ribotype 027 strains would be if these strains had increased competitive fitness compared to strains of other ribotypes. We developed a moderate-throughput
in vitro
model of
C. difficile
infection and used it to test competition between four ribotype 027 clinical isolates and clinical isolates of four other ribotypes (001, 002, 014, and 053). We found that ribotype 027 strains outcompeted the strains of other ribotypes. A similar competitive advantage was observed when two ribotype pairs were competed in a mouse model of
C. difficile
infection. Based upon these results, we conclude that one possible mechanism through which ribotype 027 strains have caused outbreaks worldwide is their increased ability to compete in the presence of a complex microbiota.
Role of Intracellular Carbon Metabolism Pathways in Shigella flexneri Virulence
Authors: Waligora E. A. , Fisher C. R. , Hanovice N. J. , Rodou A. , Wyckoff E. E. , Payne S. M.
Published: April 2014

Shigella flexneri
, which replicates in the cytoplasm of intestinal epithelial cells, can use the Embden-Meyerhof-Parnas, Entner-Doudoroff, or pentose phosphate pathway for glycolytic carbon metabolism. To determine which of these pathways is used by intracellular
S. flexneri
, mutants were constructed and tested in a plaque assay for the ability to invade, replicate intracellularly, and spread to adjacent epithelial cells. Mutants blocked in the Embden-Meyerhof-Parnas pathway (
pfkAB
and
pykAF
mutants) invaded the cells but formed very small plaques. Loss of the Entner-Doudoroff pathway gene
eda
resulted in small plaques, but the double
eda edd
mutant formed normal-size plaques. This suggested that the plaque defect of the
eda
mutant was due to buildup of the toxic intermediate 2-keto-3-deoxy-6-phosphogluconic acid rather than a specific requirement for this pathway. Loss of the pentose phosphate pathway had no effect on plaque formation, indicating that it is not critical for intracellular
S. flexneri
. Supplementation of the epithelial cell culture medium with pyruvate allowed the glycolysis mutants to form larger plaques than those observed with unsupplemented medium, consistent with data from phenotypic microarrays (Biolog) indicating that pyruvate metabolism was not disrupted in these mutants. Interestingly, the wild-type
S. flexneri
also formed larger plaques in the presence of supplemental pyruvate or glucose, with pyruvate yielding the largest plaques. Analysis of the metabolites in the cultured cells showed increased intracellular levels of the added compound. Pyruvate increased the growth rate of
S. flexneri
in vitro
, suggesting that it may be a preferred carbon source inside host cells.
Chlamydia trachomatis Polymorphic Membrane Protein D Is a Virulence Factor Involved in Early Host-Cell Interactions
Authors: Kari Laszlo , Southern Timothy R. , Downey Carey J. , Watkins Heather S. , Randall Linnell B. , Taylor Lacey D. , Sturdevant Gail L. , Whitmire William M. , Caldwell Harlan D.
Published: April 2014

Chlamydia trachomatis
is an obligate intracellular mucosotropic pathogen of significant medical importance. It is the etiological agent of blinding trachoma and bacterial sexually transmitted diseases, infections that afflict hundreds of millions of people globally. The
C. trachomatis
polymorphic membrane protein D (PmpD) is a highly conserved autotransporter and the target of broadly cross-reactive neutralizing antibodies; however, its role in host-pathogen interactions is unknown. Here we employed a targeted reverse genetics approach to generate a
pmpD
null mutant that was used to define the role of PmpD in the pathogenesis of chlamydial infection. We show that
pmpD
is not an essential chlamydial gene and the
pmpD
null mutant has no detectable deficiency in cultured murine cells or in a murine mucosal infection model. Notably, however, the
pmpD
null mutant was significantly attenuated for macaque eyes and cultured human cells. A reduction in
pmpD
null infection of human endocervical cells was associated with a deficiency in chlamydial attachment to cells. Collectively, our results show that PmpD is a chlamydial virulence factor that functions in early host-cell interactions. This study is the first of its kind using reverse genetics to evaluate the contribution of a
C. trachomatis
gene to disease pathogenesis.
Orbital trauma and its impact on the heart
Authors: Borumandi Farzad , Rippel Christian , Gaggl Alexander
Published: April 2014

We present the case of a 16-year-old boy, who was hit in the right orbital region during a soccer match. Immediately after the blow, the patient felt nauseous and fell to the ground. The otherwise healthy patient presented with headache, nausea and sinus bradycardia (38 bpm). Clinically there were no obvious signs of fracture of facial bones. There was no sign of injury to the eyes, only the right globe was slightly restricted in movement. With suspicion of head injury, a CT scan was performed revealing a trapdoor fracture of the medial orbital wall. The medial rectus muscle was entrapped within the fracture inducing the oculocardiac reflex. The trapped rectus muscle was released endoscopically on the same day and the heart rate normalised. Early surgical intervention is recommended to avoid prolonged muscle ischaemia and to shorten the vagal symptoms.
Encephalopathy in an infant with infantile spasms: possible role of valproate toxicity
Authors: Sivathanu Shobhana , Sampath Sowmya , Veerasamy Madhubala , Sunderkumar Satheeshkumar
Published: April 2014

An infant presented with global developmental delay and infantile spasms. EEG was suggestive of hypsarrhythmia. She was started on sodium valproate, clonazepam and adrenocorticotropic hormone injection. After an initial improvement the child developed vomiting, altered sensorium and increase in frequency of seizures suggestive of encephalopathy. Valproate-induced hyperammonaemia or hepatic encephalopathy was considered and the drug was withheld following which there was a dramatic improvement. Paradoxically, the liver function tests and serum ammonia were normal. However, a complete reversal of encephalopathy, on withdrawal of the drug, strongly suggested an adverse drug reaction (ADR) due to valproic acid. Marginal elevation of serum valproic acid prompted us to use the Naranjo ADR probability score to confirm the diagnosis. This case highlights the fact that valproate toxicity can manifest with normal liver function and serum ammonia levels. This is the youngest reported case with this rare form of valproate-induced encephalopathy.
Delayed torrential haemorrhage after firearm injury
Authors: Kumar Pankaj , Singhal Maneesh , Sagar Sushma , Gupta Amit
Published: April 2014

A 30-year-old man was referred to us after 48 days of gunshot injury to left groin, with torrential bleeding from a pseudoaneurysm of the left external iliac artery. He was successfully managed with a team of specialists involving trauma surgeon, vascular and plastic surgeon, general surgeons and intervention radiologist with the help of critical care specialists. He required judicious debridement, a transverse rectus abdominis musculocutaneous flap, stenting of the external iliac artery, repair of the external iliac vein and ligation of the bilateral internal iliac artery. He had prolonged intensive care unit stay with open abdomen requiring specialised care. Errors in regular assessment of patient by clinical and radiological examination along with failure in early adequate debridement were responsible for trauma suffered by him. Though it is a rare injury, these devastating complications can occur after any gunshot injury and proper management guidelines must be established.
Symptomatic hepatitis secondary to disseminated coccidioidomycosis in an immunocompetent patient
Authors: Kuprian Mikhail , Schofield Christina , Bennett Steven
Published: April 2014

A young man from California presented with acute onset of cough, fevers, night sweats and pruritus with dark urine. Laboratory studies were notable for moderate transaminitis with elevated bilirubin and eosinophilia. Hepatitis panel, HIV screen and heterophile antibodies were negative. CT scan showed multiple bilateral focal opacities with hilar and mediastinal lymphadenopathy with no ductal dilation or gallbladder stones. The patient had positive coccidioidomycosis serologies and he was started on fluconazole with resolution of symptoms and improvement in transaminitis over the next month. This article highlights a rare manifestation of disseminated coccidioidomycosis with symptomatic hepatitis. Although an increasingly prevalent infection found in southwest USA, dissemination is rare in immunocompetent hosts. Postmortem studies suggest hepatic involvement is common in disseminated infection. However symptomatic hepatitis is rare, with only three cases of symptomatic hepatitis found in the literature.
Isolated suppurative submandibular sialadenitis in a preterm neonate
Authors: Pereira Ester , Lapa Patrícia , Basto Lígia , Afonso Eulália
Published: April 2014

Neonatal isolated suppurative submandibular sialadenitis (NISSS) is rare, with only 21 cases described in the English literature. All cases, with the exception of one, were caused byStaphylococcus aureus. In this case report, we describe a preterm neonate with NISSS due to infection byS aureusandKlebsiella pneumoniapresenting on day 11 of life with submandibular swelling and low-grade fever. Possible contributors for the development of the infection include prematurity, neutropenia, prolonged orogastric feed and bacterial virulence. Antibiotic treatment was effective. To the best of our knowledge, this is the first case report of NISSS caused by a mixed flora.
Breast carcinoma in a prepubertal girl
Authors: Ahmed Syed Tausif , Singh Sudipto Kumar , Mukherjee Tanmoy , Banerjee Manju
Published: April 2014

Breast carcinoma is a very rare disease in children. We present a rare case of breast cancer in an 11-year-old prepubertal girl. Clinically, it was a case of locally advanced breast cancer (T4bN1M0). The core biopsy report showed adenocarcinoma of the not otherwise specified (NOS) variety (oestrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor 2-negative). Diagnosis was late in this case due to lack of suspicion. A modified radical mastectomy was considered to be adequate treatment. Histologically, it was adenocarcinoma NOS, which is rare in young girls (the secretory type being more common). Incidence, differential diagnoses, investigation and management of breast carcinoma in young girls are discussed. The purpose of reporting this case is to highlight that prevention and early detection of breast carcinoma in children is very important.
Concurrent meningococcal and herpes simplex infection in a non-immunocompromised child
Authors: Ali Jasmin , Walsh Hannah , Sanapala Swathi , Syed Nadeem
Published: April 2014

A previously well 11-month-old infant presented with lethargy, a blanching rash, vomiting and diarrhoea. She was diagnosed with suspected gastroenteritis and discharged. The patient deteriorated and re-presented 24 h later with lumbar puncture (LP) confirmingNeisseria meningitidis. Following an initial good response to ceftriaxone, the patient then developed a blistering facial rash on day 3 for which topical aciclovir was started with no improvement. She subsequently developed fever and redeveloped a rising C reactive protein (CRP). A CT of the head on day 6 was normal, however a repeat LP on day 7 showed persistently raised cerebrospinal fluid (CSF), white cell count (WCC), high proteins and low CSF glucose. A CSF viral PCR confirmed concurrent herpes simplex virus (HSV) type 1 for which parenteral aciclovir was started. The patient responded well to bacterial and viral anti-infective treatments and was subsequently discharged on day 16 with no neurological sequelae.
Anti-M antibodies as a cause of intrauterine fetal death and neonatal hyperbilirubinaemia
Authors: Sharma Deepak , Murki Anuradha , Murki Srinivas , Pratap Tejo
Published: April 2014

A preterm male infant (35 weeks), appropriate for gestational age with birth weight of 2.20 kg was born to a 28-year G2 P0 mother. The mother's blood group was A positive and the father's was B positive. Her first pregnancy was an intrauterine fetal death due to immune hydrops. The mother's blood was positive for indirect Coomb's test with 1:32 dilution and anti-M antibodies. This pregnancy was induced at 35 weeks of gestation. Investigations from the cord blood revealed A positive blood group, positive direct Coomb's test, haematocrit of 41.4%, cord reticulocyte count of 5.3% and total serum bilirubin (TSB) of 2.7 mg/dL. Phototherapy was started at 27 h of life for visible jaundice. In view of progressive pallor and a sudden rise of bilirubin, the infant was subjected to exchange transfusion on day 5 of life. The transfusion was given with O negative and anti-M antibodies negative donor blood. Total serum bilirubin (TSB) prior to exchange transfusion was 28 mg/dL and packed cell volume (PCV) was 21%. Phototherapy was continued for a total duration of 8 days.
Xanthoma of the urinary bladder: a rare benign condition which may be mistaken for malignancy
Authors: Hassouna Hussam , Broome James David , Swalem Khalifa , Manikandan Ramaswamy
Published: April 2014

A 77-year-old man was referred with a history of recurrent urinary tract infections and a raised prostate-specific antigen. He was found to have an atypical lesion of the urinary bladder on cystoscopic examination. A preoperative MRI study suggested no evidence of malignancy and histology was consistent with urinary bladder xanthoma. This is a benign and exceedingly rare condition which requires no further treatment or follow-up. Patients should, however, have a lipid profile measured. Our case illustrates the use of MRI as an adjunct to aid operative planning. Although not essential, it may help to avoid an over aggressive initial resection in more precarious areas of the urinary bladder.
Two iniencephaly cases born the same day in the same hospital of Cali, Colombia. Iniencephaly cluster?
Authors: Saldarriaga Wilmar , Isaza De Lourido Carolina , Ruiz Murcia Fabian Andres
Published: April 2014

Two patients with short and hyperextended neck, cervical meningocele and other birth defects, were born the same day at the same hospital, both died. The autopsy report and X-rays show iniencephaly's classic findings. Revision of clinical histories did not show consanguinity between the parents, or exposure to environmental factors.
Republished: Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group?
Authors: Millet Arnaud , Pederzoli-Ribeil Magali , Guillevin Loïc , Witko-Sarsat Véronique , Mouthon Luc
Published: April 2014

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a heterogeneous group of diseases corresponding to necrotising inflammation of small vessels with a wide range of clinical presentations. At least two of the diseases are believed to exhibit a common ground of pathophysiological mechanisms. These are granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis) and microscopic polyangiitis (MPA). ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA, and anti-myeloperoxidase (MPO) ANCA are associated mainly with MPA and eosinophilic GPA (formerly known as Churg-Strauss syndrome). Anti-MPO and anti-PR3 antibodies can activate neutrophils in vitro. In vivo data are available for humans and mice on the pathogenicity of anti-MPO but it is more controversial for PR3-ANCA. A recent genome-wide association study of patients with ANCA-associated vasculitides confirmed the genetic contribution to the pathogenesis of these conditions, with significant association of PR3-ANCA and human leukocyte antigen-DP and the genes encoding α1-antitrypsin and PR3. MPO-ANCA were significantly associated with human leukocyte antigen-DQ. Thus, recent results from epidemiological studies, genome-wide association study and therapeutic trials have suggested that these entities are, in fact, distinct. We have summarised these results and discuss the idea that these two entities should be studied separately as the nature of the two auto-antigens suggests at a molecular level despite shared ANCA involvement.
Building trust on bovine TB
Authors: Woodroffe Rosie
Published: April 2014

Opinion on how best to control bovine TB remains divided, particularly with regard to badgers. Rosie Woodroffe believes that vets have a constructive role to play in the debate and helping farmers locally
Keeping track of illegal medicines residues in food animals
Authors: Craig D.
Published: April 2014

In the first article in an occasional series for Veterinary Record, Dorothy Craig introduces the work of the Veterinary Residues Committee, the independent scientific advisory committee that advises government on the testing of foods from animals to look for residues of veterinary medicines and banned substances.
Rhizopogon kretzerae sp. nov.: the rare fungal symbiont in the tripartite system with Pterospora andromedea and Pinus strobus
Authors: Grubisha Lisa C. , Dowie Nicholas J. , Miller Steven L. , Hazard Christina , Trowbridge Steven M. , Horton Thomas R. , Klooster Matthew R.
Published: April 2014

The first species of Rhizopogon subgenus Amylopogon identified from eastern North America is described here as Rhizopogon kretzerae Grubisha, Dowie, & Mill. sp. nov. In nature, R. kretzerae has been identified only from DNA sequences of the nuclear ribosomal internal transcribed spacer region (ITS) from mycorrhizal roots of Pinus strobus L. and Pterospora andromedea Nutt. Phylogenetic analyses and nucleotide divergence estimates of Rhizopogon ITS sequences from Pterospora roots from Quebec, Michigan, New York, and New Hampshire combined with ITS sequences of Rhizopogon subgenus Amylopogon species type collections suggest R. kretzerae is a sister-group to Rhizopogon salebrosus A.H. Sm. An absence of shared mutations, two informative sequence gaps, and 12 fixed nucleotide differences differentiate R. kretzerae and R. salebrosus. Furthermore, ITS sequences of 40 Pterospora root samples from five populations in the province of Quebec provided the first record of the distribution of R. kretzerae, a potentially rare to endangered species, in eastern Canada.
Age structure of aspen forests on the Uncompahgre Plateau, Colorado
Authors: Binkley Dan , Alsanousi Attia , Romme William H.
Published: April 2014

Aspen forests are one of the most dynamic forest types in western North America, responding to chronic factors of competition for resources, as well as episodes of intense herbivory, drought, and fires. The interactions of these driving factors lead to varying age structures of aspen across landscapes and through time. We characterized the age structure of aspen trees on the Uncompahgre Plateau in western Colorado, USA, to inform collaborative efforts of landscape-scale forest restoration. Over 1000 cores from 51 locations showed few aspen older than 140 years (<0.5% for aspen numbers, <2.5% of aspen basal area). Heavy recruitment in the late 1800s (following the last major fires) led to cohorts from 100 to 140 years of age that account for 15% of current aspen numbers and 40% of current aspen basal area. Perhaps the most important character of the current age structure is a relatively low number of aspen younger than 50 years; normal rates of tree survivorship in coming decades will lead to a substantial decline in aspen on the Plateau as these cohorts progress into older age classes. Patterns of aspen ages on the Uncompahgre Plateau differ substantially from those on the Kaibab Plateau and in Rocky Mountain National Park, owing the varying importance in space and time of driving factors. Landscape-scale increases in aspen regeneration (from major events such as fire) would be necessary to moderate the long-term decline in aspen on the Uncompahgre Plateau.
Movement ecology of amphibians: from individual migratory behaviour to spatially structured populations in heterogeneous landscapes,
Authors: Sinsch Ulrich
Published: April 2014

Both genetic cohesion among local populations of animals and range expansion depend on the frequency of dispersers moving at an interpatch scale. Animal movement has an individual component that reflects behaviour and an ecological component that reflects the spatial organization of populations. The total movement capacity of an individual describes maximum movement distance theoretically achievable during a lifetime, whereas its variation among the members of a local population determines the magnitude of interpatch movements and thus of gene flow between neighbouring patches within metapopulation or patchy population systems. Here, I review information on dispersal and migration as components of the movement capacity of juvenile and adult pond-breeding amphibians and discuss how these components inform the spatial structure of populations. Amphibians disperse as juveniles and adults, but movement distances detected in tracking or capture–mark–recapture studies are usually far below the corresponding estimates based on molecular gene-flow data. This discrepancy reflects the constraints of available tracking methods for free-ranging individuals leading to inappropriate surrogates of annual movement capacity, but can be resolved using probabilistic approaches based on dispersal functions. There is remarkable capacity for and plasticity in movements in amphibians. Annual within-patch movements (migrations) of individuals can be large and likely represent an underestimated capacity for movement at the interpatch scale. Landscape resistance may influence the paths of dispersing amphibians, but rarely impedes interpatch movements. Juveniles emigrating unpredictably far from the natal pond and adults switching from within-patch migrations to dispersal to another patch demonstrate the plasticity of individual movement behaviour. Three basic conclusions can be drawn with respect to the linkage of individual movement behaviour and spatial or genetic structure of local amphibian populations embedded in a heterogeneous landscape: (1) individual movements or consecutive short-term series of movements are misleading surrogate measures of total movement capacity; (2) probabilistic modelling of movement capacity is the best available behavioural predictor of interpatch gene flow; (3) connectivity of local populations in heterogeneous landscapes is less affected by landscape resistance than previously expected.
Mirror dark matter: Cosmology, galaxy structure and direct detection
Authors: Foot R.
Published: April 2014

A simple way to accommodate dark matter is to postulate the existence of a hidden sector. That is, a set of new particles and forces interacting with the known particles predominantly via gravity. In general, this leads to a large set of unknown parameters, however, if the hidden sector is an exact copy of the standard model sector, then, an enhanced symmetry arises. This symmetry, which can be interpreted as space–time parity, connects each ordinary particle (e, ν, p, n, γ, …) with a mirror partner (e′, ν′, p′, n′, γ′, …). If this symmetry is completely unbroken, then the mirror particles are degenerate with their ordinary particle counterparts, and would interact amongst themselves with exactly the same dynamics that govern ordinary particle interactions. The only new interaction postulated is photon–mirror photon kinetic mixing, whose strength ϵ, is the sole new fundamental (Lagrangian) parameter relevant for astrophysics and cosmology. It turns out that such a theory, with suitably chosen initial conditions effective in the very early universe, can provide an adequate description of dark matter phenomena provided that ϵ~10-9. This review focusses on three main developments of this mirror dark matter theory during the last decade: early universe cosmology, galaxy structure and the application to direct detection experiments.
THE HUFFMAN-LIKE ALIGNMENT IN MANIFOLD LEARNING
Authors: MA ZHENGMING , CHEN JING
Published: April 2014

In manifold learning, the neighborhood is often called a patch of the manifold, and the corresponding open set is called the local coordinate of the patch. The so-called alignment is to align the local coordinates in the d-dimensional Euclidean space to get the global coordinate of the manifold. There are two kinds of alignment methods: global and progressive alignment methods. The global alignment methods align the local coordinates of the manifold all at one time by solving an eigenvalue problem. The progressive alignment methods often take the local coordinate of a patch as the basic local coordinate and then attach other local ordinates to the basic local coordinate patch-by-patch until the basic local coordinate evolves into the global coordinate of the manifold. In this paper, a new progressive alignment method is proposed, where only the local coordinates of the two patches with the largest intersection at the current stage of progressive alignment will be aligned into a larger local coordinate. It is inspired by the famous Huffman coding, where two random events with the smallest probabilities at the current phase will be merged into a random event with a larger probability. Therefore, the proposed method is a Huffman-like alignment method. The experiments on benchmark data show that the proposed method outperforms both the global alignment methods and the other progressive alignment methods and is more robust to the changes of data size. The experiments on real-world data show the feasibility of the proposed method.
Quasi-discriminator varieties
Authors: Paoli Francesco , Ledda Antonio , Kowalski Tomasz , Spinks Matthew
Published: April 2014

We generalize the notion of discriminator variety in such a way as to capture several varieties of algebras arising mainly from fuzzy logic. After investigating the extent to which this more general concept retains the basic properties of discriminator varieties, we give both an equational and a purely algebraic characterization of quasi-discriminator varieties. Finally, we completely describe the lattice of subvarieties of the pure pointed quasi-discriminator variety, providing an explicit equational base for each of its members.
Combining Language Modeling and LSA on Greek Song “Words” for Mood Classification
Authors: Kermanidis Katia L. , Karydis Ioannis , Koursoumis Antonis , Talvis Karolos
Published: April 2014

The present work presents a novel approach to song mood classification. Two language models, one absolute and one relative, are experimented with. Two distinct audio feature sets are compared against each other, and the significance of the inclusion of text stylistic features is established. Furthermore, Latent Semantic Analysis is innovatively combined with language modeling, and depicts the discriminative power of the latter. Finally, song “words” are defined in a broader sense that includes lyrics words as well as audio words, and LSA is applied to this augmented vocabulary with highly promising results. The methodology is applied to Greek songs, that are classified into one of four valence and into one of four arousal categories.