bluuebunny/crossref_metadata_2025 huggingface dataset:
Small-Molecule Inhibitors Targeting Topoisomerase I as Novel Antituberculosis Agents
Authors: Sandhaus Shayna , Annamalai Thirunavukkarasu , Welmaker Greg , Houghten Richard A. , Paz Carlos , Garcia Pamela K. , Andres Angelo , Narula Gagandeep , Rodrigues Felix Carolina , Geden Sandra , Netherton Mandy , Gupta Rashmi , Rohde Kyle H. , Giulianotti Marc A. , Tse-Dinh Yuk-Ching
Published: April 2016

Bacterial topoisomerase functions are required for regulation of DNA supercoiling and overcoming the DNA topological barriers that are encountered during many vital cellular processes. DNA gyrase and topoisomerase IV of the type IIA bacterial topoisomerase family are important clinical targets for antibacterial therapy. Topoisomerase I, belonging to the type IA topoisomerase family, has recently been validated as a potential antitubercular target. The topoisomerase I activity has been shown to be essential for bacterial viability and infection in a murine model of tuberculosis. Mixture-based combinatorial libraries were screened in this study to identify novel bacterial topoisomerase I inhibitors. Using positional-scanning deconvolution, selective small-molecule inhibitors of bacterial topoisomerase I were identified starting from a polyamine scaffold. Antibacterial assays demonstrated that four of these small-molecule inhibitors of bacterial topoisomerase I are bactericidal against
Mycobacterium smegmatis
and
Mycobacterium tuberculosis
. The MICs for growth inhibition of
M. smegmatis
increased with overexpression of recombinant
M. tuberculosis
topoisomerase I, consistent with inhibition of intracellular topoisomerase I activity being involved in the antimycobacterial mode of action.
Antimicrobial Activities of Ceftazidime-Avibactam and Comparator Agents against Gram-Negative Organisms Isolated from Patients with Urinary Tract Infections in U.S. Medical Centers, 2012 to 2014
Authors: Sader Helio S. , Castanheira Mariana , Flamm Robert K. , Jones Ronald N.
Published: April 2016

A total of 7,272 unique patient clinical isolates were collected from 71 U.S. medical centers from patients with urinary tract infections in 2012 to 2014 and tested for susceptibility to ceftazidime-avibactam and comparators by broth microdilution methods. Ceftazidime-avibactam inhibited >99.9% of all
Enterobacteriaceae
at the susceptible breakpoint of ≤8 μg/ml (there were only three nonsusceptible strains). Ceftazidime-avibactam was also active against
Pseudomonas aeruginosa
isolates (MIC
50
, 2 μg/ml; MIC
90
, 4 μg/ml; 97.7% susceptible), including many isolates not susceptible to meropenem, ceftazidime, and/or piperacillin-tazobactam.
Genomic Appraisal of the Multifactorial Basis forIn VitroAcquisition of Miltefosine Resistance in Leishmania donovani
Authors: Vacchina P. , Norris-Mullins B. , Abengózar M. A. , Viamontes C. G. , Sarro J. , Stephens M. T. , Pfrender M. E. , Rivas L. , Morales M. A.
Published: April 2016

Protozoan parasites of theLeishmania donovanicomplex are the causative agents of visceral leishmaniasis (VL), the most severe form of leishmaniasis, with high rates of mortality if left untreated.Leishmaniaparasites are transmitted to humans through the bite of infected female sandflies (Diptera:Phlebotominae), and approximately 500,000 new cases of VL are reported each year. In the absence of a safe human vaccine, chemotherapy, along with vector control, is the sole tool with which to fight the disease. Miltefosine (hexadecylphosphatidylcholine [HePC]), an antitumoral drug, is the only successful oral treatment for VL. In the current study, we describe the phenotypic traits ofL. donovaniclonal lines that have acquired resistance to HePC. We performed whole-genome and RNA sequencing of these resistant lines to provide an inclusive overview of the multifactorial acquisition of experimental HePC resistance, circumventing the challenge of identifying changes in membrane-bound proteins faced by proteomics. This analysis was complemented by assessment of thein vitroinfectivity of HePC-resistant parasites. Our work underscores the importance of complementary “omics” to acquire the most comprehensive insight for multifaceted processes, such as HePC resistance.
Bactericidal Effect of a Photoresponsive Carbon Monoxide-Releasing Nonwoven against Staphylococcus aureus Biofilms
Authors: Klinger-Strobel Mareike , Gläser Steve , Makarewicz Oliwia , Wyrwa Ralf , Weisser Jürgen , Pletz Mathias W. , Schiller Alexander
Published: April 2016

Staphylococcus aureus
is a leading pathogen in skin and skin structure infections, including surgical and traumatic infections that are associated with biofilm formation. Because biofilm formation is accompanied by high phenotypic resistance of the embedded bacteria, they are almost impossible to eradicate by conventional antibiotics. Therefore, alternative therapeutic strategies are of high interest. We generated nanostructured hybrid nonwovens via the electrospinning of a photoresponsive carbon monoxide (CO)-releasing molecule [CORM-1, Mn
2
(CO)
10
] and the polymer polylactide. This nonwoven showed a CO-induced antimicrobial activity that was sufficient to reduce the biofilm-embedded bacteria by 70% after photostimulation at 405 nm. The released CO increased the concentration of reactive oxygen species (ROS) in the biofilms, suggesting that in addition to inhibiting the electron transport chain, ROS might play a role in the antimicrobial activity of CORMs on
S. aureus
. The nonwoven showed increased cytotoxicity on eukaryotic cells after longer exposure, most probably due to the released lactic acid, that might be acceptable for local and short-time treatments. Therefore, CO-releasing nonwovens might be a promising local antimicrobial therapy against biofilm-associated skin wound infections.
Widespread Dissemination of Carbapenem-Resistant Escherichia coli Sequence Type 167 Strains Harboring
bla
NDM-5
in Clinical Settings in China
Authors: Huang Yonglu , Yu Xiaonan , Xie Miaomiao , Wang Xuan , Liao Kang , Xue Wencheng , Chan Edward Wai-Chi , Zhang Rong , Chen Sheng
Published: April 2016

This study reports the increasing prevalence of clinical
Escherichia coli
of sequence type 167 (ST167) carrying both
bla
NDM-1
and
bla
NDM-5
on the conjugative IncX3 plasmid in various parts of China. Close surveillance is needed to monitor the future dissemination of ST167 strains that harbor
bla
NDM-5
or other
bla
NDM
-like genes.
Adaptation of the [
3
H]Hypoxanthine Uptake Assay for
In Vitro
-Cultured Plasmodium knowlesi Malaria Parasites
Authors: Arnold Megan S. J. , Engel Jessica A. , Chua Ming Jang , Fisher Gillian M. , Skinner-Adams Tina S. , Andrews Katherine T.
Published: April 2016

The zoonotic malaria parasite
Plasmodium knowlesi
has recently been established in continuous
in vitro
culture. Here, the
Plasmodium falciparum
[
3
H]hypoxanthine uptake assay was adapted for
P. knowlesi
and used to determine the sensitivity of this parasite to chloroquine, cycloguanil, and clindamycin. The data demonstrate that
P. knowlesi
is sensitive to all drugs, with 50% inhibitory concentrations (IC
50
s) consistent with those obtained with
P. falciparum
. This assay provides a platform to use
P. knowlesi in vitro
for drug discovery.
Streptococcus oralis Induces Lysosomal Impairment of Macrophages via Bacterial Hydrogen Peroxide
Authors: Okahashi Nobuo , Nakata Masanobu , Kuwata Hirotaka , Kawabata Shigetada
Published: April 2016

Streptococcus oralis
, an oral commensal, belongs to the mitis group of streptococci and occasionally causes opportunistic infections, such as bacterial endocarditis and bacteremia. Recently, we found that the hydrogen peroxide (H
2
O
2
) produced by
S. oralis
is sufficient to kill human monocytes and epithelial cells, implying that streptococcal H
2
O
2
is a cytotoxin. In the present study, we investigated whether streptococcal H
2
O
2
impacts lysosomes, organelles of the intracellular digestive system, in relation to cell death.
S. oralis
infection induced the death of RAW 264 macrophages in an H
2
O
2
-dependent manner, which was exemplified by the fact that exogenous H
2
O
2
also induced cell death. Infection with either a mutant lacking
spxB
, which encodes pyruvate oxidase responsible for H
2
O
2
production, or
Streptococcus mutans
, which does not produce H
2
O
2
, showed less cytotoxicity. Visualization of lysosomes with LysoTracker revealed lysosome deacidification after infection with
S. oralis
or exposure to H
2
O
2
, which was corroborated by acridine orange staining. Similarly, fluorescent labeling of lysosome-associated membrane protein-1 gradually disappeared during infection with
S. oralis
or exposure to H
2
O
2
. The deacidification and the following induction of cell death were inhibited by chelating iron in lysosomes. Moreover, fluorescent staining of cathepsin B indicated lysosomal destruction. However, treatment of infected cells with a specific inhibitor of cathepsin B had negligible effects on cell death; instead, it suppressed the detachment of dead cells from the culture plates. These results suggest that streptococcal H
2
O
2
induces cell death with lysosomal destruction and then the released lysosomal cathepsins contribute to the detachment of the dead cells.
Protection against Streptococcus suis Serotype 2 Infection Using a Capsular Polysaccharide Glycoconjugate Vaccine
Authors: Goyette-Desjardins Guillaume , Calzas Cynthia , Shiao Tze Chieh , Neubauer Axel , Kempker Jennifer , Roy René , Gottschalk Marcelo , Segura Mariela
Published: April 2016

Streptococcus suisserotype 2 is an encapsulated bacterium and one of the most important bacterial pathogens in the porcine industry. Despite decades of research for an efficient vaccine, none is currently available. Based on the success achieved with other encapsulated pathogens, a glycoconjugate vaccine strategy was selected to elicit opsonizing anti-capsular polysaccharide (anti-CPS) IgG antibodies. In this work, glycoconjugate prototypes were prepared by couplingS. suistype 2 CPS to tetanus toxoid, and the immunological features of the postconjugation preparations were evaluatedin vivo. In mice, experiments evaluating three different adjuvants showed that CpG oligodeoxyribonucleotide (ODN) induces very low levels of anti-CPS IgM antibodies, while the emulsifying adjuvants Stimune and TiterMax Gold both induced high levels of IgGs and IgM. Dose-response trials comparing free CPS with the conjugate vaccine showed that free CPS is nonimmunogenic independently of the dose used, while 25 μg of the conjugate preparation was optimal in inducing high levels of anti-CPS IgGs postboost. With an opsonophagocytosis assay using murine whole blood, sera from immunized mice showed functional activity. Finally, the conjugate vaccine showed immunogenicity and induced protection in a swine challenge model. When conjugated and administered with emulsifying adjuvants,S. suistype 2 CPS is able to induce potent IgM and isotype-switched IgGs in mice and pigs, yielding functional activityin vitroand protection against a lethal challengein vivo, all features of a T cell-dependent response. This study represents a proof of concept for the potential of glycoconjugate vaccines in veterinary medicine applications against invasive bacterial infections.
Subdomain 2 of the Autotransporter Pet Is the Ligand Site for Recognizing the Pet Receptor on the Epithelial Cell Surface
Authors: Chavez-Dueñas Lucia , Serapio-Palacios Antonio , Nava-Acosta Raul , Navarro-Garcia Fernando
Published: April 2016

Most autotransporter passenger domains, regardless of their diversity in function, fold or are predicted to fold as right-handed β-helices carrying various loops that are presumed to confer functionality. Our goal here was to identify the subdomain (loop) or amino acid sequence of the Pet passenger domain involved in the receptor binding site on the host cell for Pet endocytosis. Here, we show that d1 and d2 subdomains, as well as the amino acid sequence linking the subdomain d2 and the adjacent β-helix (PDWET), are not required for Pet secretion through the autotransporter system and that none of our deletion mutants altered the predicted long right-handed β-helical structure. Interestingly, Pet lacking the d2 domain (PetΔd2) was unable to bind on the epithelial cell surface, in contrast to Pet lacking d1 (PetΔd1) subdomain or PDWET sequences. Moreover, the purified d1 subdomain, the biggest subdomain (29.8 kDa) containing the serine protease domain, was also unable to bind the cell surface. Thus, d2 sequence (54 residues without the PDWET sequence) was required for Pet binding to eukaryotic cells. In addition, this d2 sequence was also needed for Pet internalization but not for inducing cell damage. In contrast, PetΔd1, which was able to bind and internalize inside the cell, was unable to cause cell damage. Furthermore, unlike Pet, PetΔd2 was unable to bind cytokeratin 8, a Pet receptor. These data indicate that the surface d2 subdomain is essential for the ligand-receptor (Pet-Ck8) interaction for Pet uptake and to start the epithelial cell damage by this toxin.
Early-Life Intranasal Colonization with Nontypeable Haemophilus influenzae Exacerbates Juvenile Airway Disease in Mice
Authors: McCann Jessica R. , Mason Stanley N. , Auten Richard L. , St. Geme Joseph W. , Seed Patrick C.
Published: April 2016

Accumulating evidence suggests a connection between asthma development and colonization with nontypeable
Haemophilus influenzae
(NTHi). Specifically, nasopharyngeal colonization of human infants with NTHi within 4 weeks of birth is associated with an increased risk of asthma development later in childhood. Monocytes derived from these infants have aberrant inflammatory responses to common upper respiratory bacterial antigens compared to those of cells derived from infants who were not colonized and do not go on to develop asthma symptoms in childhood. In this study, we hypothesized that early-life colonization with NTHi promotes immune system reprogramming and the development of atypical inflammatory responses. To address this hypothesis in a highly controlled model, we tested whether colonization of mice with NTHi on day of life 3 induced or exacerbated juvenile airway disease using an ovalbumin (OVA) allergy model of asthma. We found that animals that were colonized on day of life 3 and subjected to induction of allergy had exacerbated airway disease as juveniles, in which exacerbated airway disease was defined as increased cellular infiltration into the lung, increased amounts of inflammatory cytokines interleukin-5 (IL-5) and IL-13 in lung lavage fluid, decreased regulatory T cell-associated
FOXP3
gene expression, and increased mucus production. We also found that colonization with NTHi amplified airway resistance in response to increasing doses of a bronchoconstrictor following OVA immunization and challenge. Together, the murine model provides evidence for early-life immune programming that precedes the development of juvenile airway disease and corroborates observations that have been made in human children.
The Treponema denticola FhbB Protein Is a Dominant Early Antigen That Elicits FhbB Variant-Specific Antibodies That Block Factor H Binding and Cleavage by Dentilisin
Authors: Miller Daniel P. , Oliver Lee D. , Tegels Brittney K. , Reed Lucas A. , O'Bier Nathaniel S. , Kurniyati Kurni , Faust Lindsay A. , Lawson Christine K. , Allard Anna M. , Caimano Melissa J. , Marconi Richard T.
Published: April 2016

The
Treponema denticola
FhbB protein contributes to immune evasion by binding factor H (FH). Cleavage of FH by the
T. denticola
protease, dentilisin, may contribute to the local immune dysregulation that is characteristic of periodontal disease (PD). Although three FhbB phyletic types have been defined (FhbB1, FhbB2, and FhbB3), the
in vivo
expression patterns and antigenic heterogeneity of FhbB have not been assessed. Here, we demonstrate that FhbB is a dominant early antigen that elicits FhbB type-specific antibody (Ab) responses. Using the murine skin abscess model, we demonstrate that the presence or absence of FhbB or dentilisin significantly influences Ab responses to infection and skin abscess formation. Competitive binding analyses revealed that α-FhbB Ab can compete with FH for binding to
T. denticola
and block dentilisin-mediated FH cleavage. Lastly, we demonstrate that dentilisin cleavage sites reside within critical functional domains of FH, including the complement regulatory domain formed by CCPs 1 to 4. Analysis of the FH cleavage products revealed that they lack cofactor activity. The data presented here provide insight into the
in vivo
significance of dentilisin, FhbB and its antigenic diversity, and the potential impact of FH cleavage on the regulation of complement activation.
CTL0511 from Chlamydia trachomatis Is a Type 2C Protein Phosphatase with Broad Substrate Specificity
Authors: Claywell Ja E. , Fisher Derek J.
Published: April 2016

Protein phosphorylation has become increasingly recognized for its role in regulating bacterial physiology and virulence.
Chlamydia
spp. encode two validated Hanks'-type Ser/Thr protein kinases, which typically function with cognate protein phosphatases and appear capable of global protein phosphorylation. Consequently, we sought to identify a Ser/Thr protein phosphatase partner for the chlamydial kinases. CTL0511 from
Chlamydia trachomatis
L2 434/Bu, which has homologs in all sequenced
Chlamydia
spp., is a predicted type 2C Ser/Thr protein phosphatase (PP2C). Recombinant maltose-binding protein (MBP)-tagged CTL0511 (rCTL0511) hydrolyzed
p
-nitrophenyl phosphate (pNPP), a generic phosphatase substrate, in a MnCl
2
-dependent manner at physiological pH. Assays using phosphopeptide substrates revealed that rCTL0511 can dephosphorylate phosphorylated serine (P-Ser), P-Thr, and P-Tyr residues using either MnCl
2
or MgCl
2
, indicating that metal usage can alter substrate preference. Phosphatase activity was unaffected by PP1, PP2A, and PP3 phosphatase inhibitors, while mutation of conserved PP2C residues significantly inhibited activity. Finally, phosphatase activity was detected in elementary body (EB) and reticulate body (RB) lysates, supporting a role for protein dephosphorylation in chlamydial development. These findings support that CTL0511 is a metal-dependent protein phosphatase with broad substrate specificity, substantiating a reversible phosphorylation network in
C. trachomatis
.

IMPORTANCE
Chlamydia
spp. are obligate intracellular bacterial pathogens responsible for a variety of diseases in humans and economically important animal species. Our work demonstrates that
Chlamydia
spp. produce a PP2C capable of dephosphorylating P-Thr, P-Ser, and P-Tyr and that
Chlamydia trachomatis
EBs and RBs possess phosphatase activity. In conjunction with the chlamydial Hanks'-type kinases Pkn1 and PknD, validation of CTL0511 fulfills the enzymatic requirements for a reversible phosphoprotein network. As protein phosphorylation regulates important cellular processes, including metabolism, differentiation, and virulence, in other bacterial pathogens, these results set the stage for elucidating the role of global protein phosphorylation in chlamydial physiology and virulence.
PilZ Domain Protein FlgZ Mediates Cyclic Di-GMP-Dependent Swarming Motility Control in Pseudomonas aeruginosa
Authors: Baker Amy E. , Diepold Andreas , Kuchma Sherry L. , Scott Jessie E. , Ha Dae Gon , Orazi Giulia , Armitage Judith P. , O'Toole George A.
Published: April 2016

The second messenger cyclic diguanylate (c-di-GMP) is an important regulator of motility in many bacterial species. In
Pseudomonas aeruginosa
, elevated levels of c-di-GMP promote biofilm formation and repress flagellum-driven swarming motility. The rotation of
P. aeruginosa
's polar flagellum is controlled by two distinct stator complexes, MotAB, which cannot support swarming motility, and MotCD, which promotes swarming motility. Here we show that when c-di-GMP levels are elevated, swarming motility is repressed by the PilZ domain-containing protein FlgZ and by Pel polysaccharide production. We demonstrate that FlgZ interacts specifically with the motility-promoting stator protein MotC in a c-di-GMP-dependent manner and that a functional green fluorescent protein (GFP)-FlgZ fusion protein shows significantly reduced polar localization in a strain lacking the MotCD stator. Our results establish FlgZ as a c-di-GMP receptor affecting swarming motility by
P. aeruginosa
and support a model wherein c-di-GMP-bound FlgZ impedes motility via its interaction with the MotCD stator.

IMPORTANCE
The regulation of surface-associated motility plays an important role in bacterial surface colonization and biofilm formation. c-di-GMP signaling is a widespread means of controlling bacterial motility, and yet the mechanism whereby this signal controls surface-associated motility in
P. aeruginosa
remains poorly understood. Here we identify a PilZ domain-containing c-di-GMP effector protein that contributes to c-di-GMP-mediated repression of swarming motility by
P. aeruginosa
. We provide evidence that this effector, FlgZ, impacts swarming motility via its interactions with flagellar stator protein MotC. Thus, we propose a new mechanism for c-di-GMP-mediated regulation of motility for a bacterium with two flagellar stator sets, increasing our understanding of surface-associated behaviors, a key prerequisite to identifying ways to control the formation of biofilm communities.
Modulation of the Lytic Activity of the Dedicated Autolysin for Flagellum Formation SltF by Flagellar Rod Proteins FlgB and FlgF
Authors: Herlihey Francesca A. , Osorio-Valeriano Manuel , Dreyfus Georges , Clarke Anthony J.
Published: April 2016

SltF was identified previously as an autolysin required for the assembly of flagella in the alphaproteobacteria, but the nature of its peptidoglycan lytic activity remained unknown. Sequence alignment analyses suggest that it could function as either a muramidase, lytic transglycosylase, or β-
N
-acetylglucosaminidase. Recombinant SltF from
Rhodobacter sphaeroides
was purified to apparent homogeneity, and it was demonstrated to function as a lytic transglycosylase based on enzymatic assays involving mass spectrometric analyses. Circular dichroism (CD) analysis determined that it is composed of 83.4% α-structure and 1.48% β-structure and thus is similar to family 1A lytic transglycosylases. However, alignment of apparent SltF homologs identified in the genome database defined a new subfamily of the family 1 lytic transglycosylases. SltF was demonstrated to be endo-acting, cleaving within chains of peptidoglycan, with optimal activity at pH 7.0. Its activity is modulated by two flagellar rod proteins, FlgB and FlgF: FlgB both stabilizes and stimulates SltF activity, while FlgF inhibits it. Invariant Glu57 was confirmed as the sole catalytic acid/base residue of SltF.

IMPORTANCE
The bacterial flagellum is comprised of a basal body, hook, and helical filament, which are connected by a rod structure. With a diameter of approximately 4 nm, the rod is larger than the estimated pore size within the peptidoglycan sacculus, and hence its insertion requires the localized and controlled lysis of this essential cell wall component. In many beta- and gammaproteobacteria, this lysis is catalyzed by the β-
N
-acetylglucosaminidase domain of FlgJ. However, FlgJ of the alphaproteobacteria lacks this activity and instead it recruits a separate enzyme, SltF, for this purpose. In this study, we demonstrate that SltF functions as a newly identified class of lytic transglycosylases and that its autolytic activity is uniquely modulated by two rod proteins, FlgB and FlgF.
Relapsing peritonitis withBacillus cereusin a patient on continuous ambulatory peritoneal dialysis
Authors: Magnussen Eyð Tausen , Vang Amanda Gratton , á Steig Torkil , Gaini Shahin
Published: April 2016

We present a case whereBacillus cereuswas determined to be the causative agent of relapsing peritonitis in a patient on continuous ambulatory peritoneal dialysis (CAPD). The patient, a 70-year-old man from the Faroe Islands, was admitted with relapsing peritonitis four times over a 3-month period. Peritoneal cultures were positive for growth ofB. cereus, a rare bacterial cause of peritonitis. The cultures demonstrated susceptibility to vancomycin, and therefore the patient was treated with intraperitoneal vancomycin, intraperitoneal gentamycin and oral ciprofloxacin. As a result of the relapsingB. cereusperitonitis diagnosis and a CT scan showing contraction of the peritoneum after longstanding inflammation, the peritoneal catheter was removed and the patient converted to haemodialysis. To date, the patient has not been readmitted due to peritonitis. A lack of proper hygiene when changing the dialysis bag was the suspected source of infection withB. cereus.
Trimethylaminuria
Authors: Sabir Numaera , Jones Elizabeth A , Padmakumar Beena
Published: April 2016

We report the case of a 9-year-old boy referred to secondary care with an unusual presentation of a fishy odour to his hands, feet, saliva and urine. Laboratory investigations including urine analysis and genetic testing confirmed the diagnosis of trimethylaminuria. The patient was referred to a geneticist and dietician, and consequently treated with dietary modification. He now has an arguably much improved quality of life.
Rare case of eosinophilic granulomatosis with polyangiitis in two patients with α-1-antitrypsin deficiency (PiSZ)
Authors: Moxey Jordan Maureen , Low Emma Victoria , Turner Alice Margaret
Published: April 2016

We present two cases of eosinophilic granulomatosis with polyangiitis occurring with α-1-antitrypsin deficiency, both PiSZ phenotype. The simultaneous occurrence of these two conditions has seldom been described in the literature, despite evidence of an association between α-1-antitrypsin deficiency and other forms of vasculitis. Both patients had pulmonary involvement and reported intermittent exacerbations of vasculitic symptoms. Both patients were managed on low-dose oral steroids and azathioprine remaining well with occasional exacerbations. It is important to consider whether there is an association between eosinophilic granulomatosis with polyangiitis and α-1-antitrypsin deficiency, as this may lead to more severe pulmonary symptoms during exacerbations. If a genetic association between the two conditions is found, clinicians should be aware of the possible need to screen for α-1-antitrypsin deficiency in appropriate patients.
Burning vasculitis
Authors: Chadha Priyanka , Hobday Dorian , Fitzgerald O'Connor Edmund , D'Cruz David
Published: April 2016

We present the case of a 69-year-old man who was found collapsed close to a heat source and admitted to hospital for severe sepsis. He was also found to have widespread blistering and ulceration of his right leg; however, a history was unobtainable due to reduced consciousness levels. The leg lesions had the initial appearance of mixed depth burns and a management plan was made to transfer the patient to a burns unit for debridement. It was subsequently noted that the patient had a previous diagnosis of seropositive erosive rheumatoid arthritis. A biopsy of the leg lesion was performed and a diagnosis of rheumatoid vasculitis confirmed. Treatment with systemic steroids, intravenous antibiotics and intravenous immunoglobulin therapy for severe hypogammaglobulinaemia was started, and the patient was not transferred for surgical debridement. Rheumatoid vasculitis is a rare and extremely serious complication of rheumatoid arthritis that can manifest in a number of ways, occasionally mimicking other conditions. This case is essential to raise awareness of rare, severe rheumatoid vasculitis and of the potential for its misdiagnosis as a mixed depth burn.
Convexity subarachnoid haemorrhage secondary to internal carotid stenosis: an indication for revascularisation
Authors: Larrosa Davinia , Ramon Cesar , Benavente Lorena , Calleja Sergio
Published: April 2016

With increasing prevalence due to an ageing population, carotid artery stenosis is a significant cause of stroke morbidity and mortality. The indication for revascularisation treatment in symptomatic carotid stenosis is widely documented and accepted in the scientific community. However, treatment of asymptomatic carotid stenosis remains controversial. We report a case of a 78-year-old woman who was admitted with a convexity subarachnoid haemorrhage (cSAH) secondary to an asymptomatic high-grade carotid artery stenosis. Two months later, she suffered an atherothrombotic ischaemic stroke and was referred to surgery. Transcranial Doppler studies showed impaired cerebral vasoreactivity and, after endarterectomy, the patient developed a reperfusion syndrome; both findings consisting of exhausted collaterals as the underlying mechanism. We propose that cSAH secondary to a high-grade internal carotid artery stenosis is a high risk marker for stroke, and revascularisation therapy should be considered.
Severe acute kidney injury as presentation of Burkitt's lymphoma
Authors: ter Haar Eva , Labarque Veerle , Tousseyn Thomas , Mekahli Djalila
Published: April 2016

We discuss a case of acute kidney injury (AKI) at a very young age caused by primary lymphomatous renal infiltration due to Burkitt's lymphoma and analyse the literature on this rare condition. At presentation, clinical examination showed impressive bilateral nephromegaly and hypertension. Blood analysis indicated severe AKI, mild anaemia and normal serum electrolytes. There were no signs of tumour lysis syndrome. Urine sediment was normal, with neither haematuria nor proteinuria. Abdominal ultrasound demonstrated bilateral renal enlargement (+12 SD), with increased corticomedullar differentiation. MRI demonstrated the presence of a homogenous renal enlargement with features of an infiltrative lesion. Ultimately, microscopic and immunohistochemical analysis of the renal biopsy confirmed the diagnosis of Burkitt's lymphoma. Early and aggressive therapy is the key to ensure a good outcome.
Ocular presentation of natural killer/T-cell lymphoma in a Caucasian man
Authors: Hughes Emily , Fogarty Helen , Fortune Anne , Keegan David
Published: April 2016

Natural killer/T-cell (NK/T-cell) lymphoma—nasal subtype, is a rare form of non-Hodgkin's lymphoma, most common in South East Asia, and can have an ophthalmological presentation. This report describes a 51-year-old Caucasian man with uveitis, recurrent retinal detachment and paraneoplastic features subsequently diagnosed as NK/T-cell lymphoma.
Acute febrile neutrophilic dermatosis associated with JAK-2 positive myeloproliferative disorder
Authors: Smyth Dean , Selwyn Jey
Published: April 2016

We present a case of a 77-year-old man with a history of myeloproliferative disorder. He was admitted with a 2-week history of erythaema, swelling and significant pain of the right forearm following a mechanical fall at home, which had caused a skin laceration. During his admission, he developed ongoing intermittent fever and persistently elevated C reactive protein, and total white cell count. Initially, he was treated with antibiotics for suspected cellulitis. However, symptoms continued to progress, making a suitable management plan challenging. Wound swabs, blood cultures and viral PCR did not confirm infection. A punch biopsy of a skin lesion on the forearm was performed. The histology demonstrated a dense infiltrate of neutrophils and neutrophilic debris in keeping with acute febrile neutrophilic dermatosis (Sweet's syndrome). He was treated with oral steroids and after that he had a complete resolution of symptoms. However, he required a period of rehabilitation before returning home.
Application of the clip method, using thread, for duodenal endoscopic mucosal resection
Authors: Shirai Yuji , Ohki Takeshi , Yamamoto Masakazu
Published: April 2016

Endoscopic mucosal resection (EMR) of a duodenal tumour is associated with a risk of loss of the resected specimen resulting from air introduction, peristaltic motion of the intestines, insertion of the retrieval device or endoscopic operation, or in cases where the specimen is too large to pass the pylorus. There is a high possibility of losing the tumour if the resected tumour is passed through the second portion of the duodenum. Retrieving a specimen after EMR is essential to obtain a pathological finding. The clip method using thread has been useful for endoscopic submucosal dissection of the oesophagus and stomach. We report the effectiveness of the clip method using thread during duodenal EMR.
Influence of age on the prevalence and components of the metabolic syndrome and the association with cardiovascular disease
Authors: Devers Marion C , Campbell Stewart , Simmons David
Published: April 2016

Objective

The significance of the metabolic syndrome (MS) is debated. We investigated whether MS component (by ATPIII and IDF definitions) clustering and any association between MS and prevalent cardiovascular disease (CVD) varied with age.

Research design and methods

In all, 1429 adults (≥25 years) from randomly selected households in rural Victoria, Australia, were assessed for components of MS and prevalent CVD. The expected prevalence of MS was calculated following a simple probabilistic model using the prevalence of each MS component.

Results

The observed prevalence of MS was greater than expected: 27.0% vs 21.2% (ATPIII) and 36.0% vs 30.1% (IDF; p<0.0001), based on the prevalence of individual components. There was significant clustering of 4 and 5 MS components in participants <65 years (p<0.0001). CVD was more prevalent in MS participants, 13.5% (IDF), 14.5% (ATPIII) versus 5.3% (no MS) p<0.0001. The OR for CVD in MS participants was greatest in those <45 years OR (95% CI): IDF 17.5 (1.8 to 172); ATPIII 24.3(2.4 to 241), p<0.001 for both, and was not significant in those >65 years. The prevalence of MS (ATPIII) with normal waist circumference (WC) was less than expected (4.8% vs 7.9%, p<0.002). Low levels of high-density lipoprotein and high triglyceride were less common in older MS participants.

Conclusions

ATPIII MS is rare among those with a normal WC. MS components cluster most markedly among those aged <65 years, who also experience substantially greater rates of CVD. Younger patients with MS may warrant more aggressive CVD preventative treatment than suggested by the summation of their individual risk factors.
Qualitative study exploring surgical team members' perception of patient safety in conflict-ridden Eastern Democratic Republic of Congo
Authors: Labat Francoise , Sharma Anjali
Published: April 2016

Objective

To identify potential barriers to patient safety (PS) interventions from the perspective of surgical team members working in an operating theatre in Eastern Democratic Republic of Congo (DRC).

Design

In-depth interviews were conducted and analysed using qualitative content analysis.

Setting

Governmental referral teaching hospital in Eastern DRC.

Participants

We purposively selected 2–4 national and expatriate surgical team members from each specialisation. Of the 31 eligible surgical health workers (HWs), 17 volunteered to be interviewed.

Results

Economics issues affected PS throughout the entire health system, from human resources and hospital management, to access to healthcare for patients. Surgical team members seemed embedded in a paternalistic organisational structure and blame culture accompanied by perceived inefficient support services and low salaries. The armed conflict did not only worsen these system failures, it also carried direct threats to patients and HWs, and resulted in complex indirect consequences compromising PS. The increased corruption within health organisations, and population impoverishment and substance abuse among health staff adversely altered safe care. Simultaneously, HWs’ reported resilience and resourcefulness to address barrier to PS. Participants had varying views on external aid depending on its relevance.

Conclusions

The complex links between war and PS emphasise the importance of a comprehensive approach including occupational health to strengthen HWs' resilience, external clinical audits to limit corruption, and educational programmes in PS to support patient-centred care and address blame culture. Finally, improvement of equity in the health financing system seems essential to ensure access to healthcare and safe perioperative outcomes for all.
Is poor self-rated health associated with low-grade inflammation in 43 110 late adolescent men of the general population? A cross-sectional study
Authors: Warnoff Carin , Lekander Mats , Hemmingsson Tomas , Sorjonen Kimmo , Melin Bo , Andreasson Anna
Published: April 2016

Objective

Self-rated health is a powerful predictor of long-term health and mortality, hence the importance of a better understanding of its biological determinants. Previous studies have shown that low-grade inflammation is associated with poor self-rated health in clinical and healthy populations, but the evidence is sparse in men and completely lacking for men in late adolescence. The aim of this study was to investigate the association between low-grade inflammation and self-rated health among conscripts. It was hypothesised that high levels of inflammatory factors would be associated with poor self-rated health.

Design

Data from 49 321 men (18–21 years) conscripted for military service in 1969 and 1970 were used. Inflammation had been measured through erythrocyte sedimentation rate (ESR). Self-rated health had been assessed on a five-point scale, and was dichotomised into Good (‘Very good’/‘Good’/‘Fair’) versus Poor (‘Poor’/‘Very poor’). Data from 43 110 conscripts with normal levels of ESR, and who reported self-rated health remained after exclusion of those with ESR <1 and >11 mm/h. Associations were calculated using logistic regression analyses. Adjustments were made for body mass index, socioeconomic position, inflammatory disease, emotion regulation, smoking, risky use of alcohol and physical activity.

Results

High levels of ESR were associated with higher odds for poor self-rated health (OR: 1.077 for each unit mm/h increase in ESR, 95% CI 1.049 to 1.105).

Conclusions

The present study shows for the first time a significant association between a marker of inflammation and self-rated health in late adolescent men, adding to evidence of an association between low-grade inflammation and subjective health perception also in men, as previously demonstrated in women. Further support for inflammation as part of a general psychobiological process that underpins subjective health perception is hereby provided.
Has there been a change in the rates of UK sickness certification for back pain over time? An examination of historical data from 2000 to 2010
Authors: Wynne-Jones Gwenllian , Dunn Kate M
Published: April 2016

Objectives

This paper aims to investigate historical patterns of sickness certification for back pain from 2000 to 2010.

Design

Electronic medical records from 14 practices that are part of the National Institute for Health Research (NIHR) Clinical Research Network: West Midlands were reviewed. All records for back pain consultations from 2000 to 2010 were downloaded and matched, by date, to corresponding sickness certification records.

Setting

Primary Care.

Results

A total of 93 896 back pain consultations were recorded over the 11-year period, resulting in 30 913 sickness certificates. There was a statistically significant decrease in the rate of certification over the period, falling from 376.8 (95% CI 362.1 to 392) per 1000 back pain consultations in 2000 to 246.5 (95% CI 236.5 to 332.9) per 1000 back pain consultations in 2010. There was also a statistically significant difference in certification between males and females, with males issued more certificates than females. There was a statistically significant difference in certification by age, with those aged 60 years and over being less likely to be issued a certificate compared to all other age groups.

Conclusions

Rates of sickness certification for back pain demonstrated a downward trend between 2000 and 2010. While the reasons for this are not transparent, it may be related to changing beliefs around working with back pain.
Clinical validation of hrHPV testing on vaginal and urine self-samples in primary cervical screening (cross-sectional results from the Papillomavirus Dumfries and Galloway—PaVDaG study)
Authors: Stanczuk Grazyna , Baxter Gwendoline , Currie Heather , Lawrence James , Cuschieri Kate , Wilson Allan , Arbyn Marc
Published: April 2016

Objectives

Papillomavirus Dumfries and Galloway (PaVDaG) assessed the performance of a high-risk human papillomavirus (hrHPV) PCR-based assay to detect high-grade cervical intraepithelial neoplasia (CIN2+) in self-collected vaginal and urine samples.

Setting

Women attending routine cervical screening in primary care.

Participants

5318 women aged 20–60 years provided self-collected random urine and vaginal samples for hrHPV testing and a clinician-collected liquid-based cytology (LBC) sample for cytology and hrHPV testing.

Interventions

HrHPV testing. All samples were tested for hrHPV using the PCR-based cobas 4800 assay. Colposcopy was offered to women with high-grade or repeated borderline/low-grade cytological abnormalities; also to those who were LBC negative but hrHPV 16/18 positive.

Primary and secondary outcome measures

The self-tests' absolute sensitivity and specificity for CIN2+ were assessed on all biospecimens; also, their relative sensitivity and specificity compared with clinician-taken samples. Interlaboratory and intralaboratory performance of the hrHPV assay in self-collected samples was also established.

Results

HrHPV prevalence was 14.7%, 16.6% and 11.6% in cervical, vaginal and urine samples, respectively. Sensitivity for detecting CIN2+ was 97.7% (95% to 100%), 94.6% (90.7% to 98.5%) and 63.1% (54.6% to 71.7%) for cervical, vaginal and urine hrHPV detection, respectively. The corresponding specificities were 87.3% (86.4% to 88.2%), 85.4% (84.4% to 86.3%) and 89.8% (89.0% to 90.7%). There was a 38% (24% to 57%) higher HPV detection rate in vaginal self-samples from women over 50 years compared with those ≤29 years. Relative sensitivity and specificity of hrHPV positivity for the detection of CIN2+ in vaginal versus cervical samples were 0.97 (0.94 to 1.00) and 0.98 (0.97 to 0.99); urine versus cervical comparisons were 0.53 (0.42 to 0.67) and 1.03 (1.02 to 1.04). The intralaboratory and interlaboratory agreement for hrHPV positivity in self-samples was high (κ values 0.98 (0.96 to 0.99) and 0.94 (0.92 to 0.97) for vaginal samples and 0.95 (0.93 to 0.98) and 0.90 (0.87 to 0.94) for urine samples).

Conclusions

The sensitivity of self-collected vaginal samples for the detection of CIN2+ was similar to that of cervical samples and justifies consideration of this sample for primary screening.
Does increasing the size of bi-weekly samples of records influence results when using the Global Trigger Tool? An observational study of retrospective record reviews of two different sample sizes
Authors: Mevik Kjersti , Griffin Frances A , Hansen Tonje E , Deilkås Ellen T , Vonen Barthold
Published: April 2016

Objectives

To investigate the impact of increasing sample of records reviewed bi-weekly with the Global Trigger Tool method to identify adverse events in hospitalised patients.

Design

Retrospective observational study.

Setting

A Norwegian 524-bed general hospital trust.

Participants

1920 medical records selected from 1 January to 31 December 2010.

Primary outcomes

Rate, type and severity of adverse events identified in two different samples sizes of records selected as 10 and 70 records, bi-weekly.

Results

In the large sample, 1.45 (95% CI 1.07 to 1.97) times more adverse events per 1000 patient days (39.3 adverse events/1000 patient days) were identified than in the small sample (27.2 adverse events/1000 patient days). Hospital-acquired infections were the most common category of adverse events in both the samples, and the distributions of the other categories of adverse events did not differ significantly between the samples. The distribution of severity level of adverse events did not differ between the samples.

Conclusions

The findings suggest that while the distribution of categories and severity are not dependent on the sample size, the rate of adverse events is. Further studies are needed to conclude if the optimal sample size may need to be adjusted based on the hospital size in order to detect a more accurate rate of adverse events.
Building better research partnerships by understanding how Aboriginal health communities perceive and use data: a semistructured interview study
Authors: Young Christian , Tong Allison , Sherriff Simone , Kalucy Deanna , Fernando Peter , Muthayya Sumithra , Craig Jonathan C
Published: April 2016

Objective

To describe the attitudes and beliefs of health professionals working in Aboriginal Community Controlled Health Services (ACCHS) towards the access, usage and potential value of routinely obtained clinical and research data.

Design, setting and participants

Face-to-face, semistructured interviews were conducted with 35 health professionals from 2 urban and 1 regional ACCHS in New South Wales. The interviews were transcribed and themes were identified using an adapted grounded theory approach.

Results

Six major themes were identified: occupational engagement (day-to-day relevance, contingent on professional capacity, emphasising clinical relevance), trust and assurance (protecting ownership, confidence in narratives, valuing local sources), motivation and empowerment (engaging the community, influencing morale, reassuring and encouraging clients), building research capacity (using cultural knowledge, promoting research aptitude, prioritising specific data), optimising service provision (necessity for sustainable services, guiding and improving services, supporting best practice), and enhancing usability (ensuring ease of comprehension, improving efficiency of data management, valuing accuracy and accessibility).

Conclusions

Participants were willing to learn data handling procedures that could further enhance health service delivery and enable more ACCHS-led research, but busy workloads restrict these opportunities. Staff held concerns regarding the translation of research data into beneficial services, and believed that the outcome and purpose of data collection could be communicated more clearly. Promoting research partnerships, ensuring greater awareness of positive health data and the purposes of data collection, and communicating data in a user-friendly format are likely to encourage greater data use, build research capacity and improve health services within the Aboriginal community.