bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breathing pattern and breathlessness in idiopathic pulmonary fibrosis: An observational study
Authors: Olukogbon Kasope L. , Thomas Paul , Colasanti Ricardo , Hope‐Gill Ben , Williams Edgar Mark 
Published: November 2015

AbstractBackground and objectiveIdiopathic pulmonary fibrosis (IPF) is characterized by progressive decline in lung function and increasing dyspnoea. The aim of this study was to investigate the relationship among IPF, pulmonary function, resting tidal breathing patterns and level of breathlessness.MethodsThirty‐one participants with IPF and 17 matched healthy controls underwent lung function testing, followed by a 2‐min period of resting tidal breathing. The IPF cohort was stratified according to disease severity, based on their forced vital capacity and diffusion capacity for carbon monoxide.ResultsIn comparison to the healthy controls, the IPF cohort showed a higher tidal volume, VT, of 0.22 L (P = 0.026) and a raised minute ventilation in the severest IPF group, while no differences in the timing of inspiration or expiration were observed. In the IPF cohort, the ratio of VT to forced vital capacity was around 15% higher. These changes corresponded with an increase in the self‐reported sensation of breathlessness.ConclusionThose with IPF increased their depth of breathing with worsening disease severity, with IPF‐induced changes in pulmonary function and breathlessness associated with an altered tidal breathing pattern.
Bisphosphonate‐related osteonecrosis of the jaws: Report of a case using conservative protocol
Authors: Heggendorn Fabiano Luiz , Leite Taiana Campos , Cunha Karin Soares Gonçalves , Junior Arley Silva , Gonçalves Lucio Souza , da Costa Karla Bianca Fernandes Fontes , Dias Eliane Pedra 
Published: November 2015

ABSTRACTBisphosphonates have been the first‐line treatment option for osteometabolic diseases, such as osteoporosis, hypercalcaemia in malignant bone diseases, and in bone metastasis. It is possible to observe a growing number of cases of osteonecrosis of the jaws in patients using this medication, called bisphosphonate‐related osteonecrosis of the jaws. The purpose of this study was to report a conservative treatment for bisphosphonate‐related osteonecrosis of the jaws—Stage 2, using antibacterial solution and low‐level laser therapy. At the end of the treatment, the patient presented improvement of the lesion with the healing of the mucosa. The literature still lacks successful definite protocols, thus the present case may contribute with another option for conservative management for bisphosphonate‐related osteonecrosis of the jaws. More research is necessary in order to develop a good protocol management for bisphosphonate‐related osteonecrosis of the jaws.
Diagnosis of HIV infection on the basis of histoplasmosis‐related oral ulceration
Authors: Klein Isadora Peres , Martins Marco Antonio Trevizani , Martins Manoela Domingues , Carrard Vinicius Coelho 
Published: November 2015

ABSTRACTHistoplasmosis is an endemic systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. In immunocompromised patients, histoplasmosis generally occurs as an opportunistic disease, with dissemination to various organs. Cutaneous involvement is observed in 38% to 85% of cases, with oral mucosal involvement in 30% to 60% of cases. This article describes the case study of a 32‐year‐old woman who presented an extensive tongue ulcer due to histoplasmosis and had the HIV infection diagnosis based on laboratory tests requested by the dentist.
Genetic factors influencing ferritin levels in 14,126 blood donors: results from the Danish Blood Donor Study
Authors: Sørensen Erik , Rigas Andreas S. , Thørner Lise W. , Burgdorf Kristoffer S. , Pedersen Ole B. , Petersen Mikkel S. , Hjalgrim Henrik , Erikstrup Christian , Ullum Henrik 
Published: November 2015

BACKGROUNDMany biologic functions depend on sufficient iron levels, and iron deficiency is especially common among blood donors. Genetic variants associated with iron levels have been identified, but the impact of genetic variation on iron levels among blood donors remains unclear.STUDY DESIGN AND METHODSThe effect of six single‐nucleotide polymorphisms (SNPs) on ferritin levels in 14,126 blood donors were investigated in four genes: in Human Hemochromatosis Protein gene (HFE; rs1800562 and rs179945); in Transmembrane Protease gene, Serine 6 (TMPRSS6‐regulating hepcidin; rs855791); in BTB domain containing protein gene (BTBD9—associated with restless legs syndrome; rs9357271); and in the Transferrin gene (TF; rs2280673 and rs1830084). Multiple linear and logistic regression analyses were used to evaluate the effect of each SNP on ferritin levels and the risk of iron deficiency (ferritin < 15 ng/mL).RESULTSIn HFE, the G‐allele of rs1800562 was associated with lower iron stores in both sexes. This was also true for the C‐allele of rs179945, but in men only. Also, the T‐allele of TMPRSS6 rs855791 was negatively associated with iron stores in men. Homozygocity for C in rs1799945 was associated with iron deficiency in women. Results for all other genetic variants were insignificant.CONCLUSIONGenetic variants associated with hemochromatosis may protect donors against depleted iron stores. In addition, we showed that presence of the T‐allele at rs855791 in TMPRSS6 was associated with lower iron stores in men.
The costs of producing a unit of blood in Zimbabwe
Authors: Mafirakureva Nyashadzaishe , Nyoni Herbert , Nkomo Sisodwa Z. , Jacob Jeffery S. , Chikwereti Radhi , Musekiwa Zamile , Khoza Star , Mvere David A. , Emmanuel Jean C. , Postma Maarten J. , van Hulst Marinus 
Published: November 2015

BACKGROUNDThere is lack of published data on the costs of blood and blood transfusion in sub‐Saharan Africa. This study aimed to assess the unit costs of producing blood in Zimbabwe using an activity‐based costing (ABC) method.STUDY DESIGN AND METHODSA management accounting approach, based on the ABC method, was used to develop a cost model for blood. The production of blood was broken down into recruitment, collection, testing, processing, and storage plus distribution. Data for the year 2013 were collected retrospectively from budgets, financial and expenditure reports, databases, and interviews with transfusion personnel and managers. All direct and indirect costs, in 2013 US$, were allocated, accordingly, to the activities of blood acquisition.RESULTSThe total cost of producing safe blood in Zimbabwe for the year 2013 was US$8.6 million. Variable costs accounted for 51.2% of the total cost of production. The unit production costs for red blood cells (RBCs) were US$15.94 for recruitment, US$34.62 for collection, US$17.88 for testing, US$11.49 for processing, and US$3.06 for storage plus distribution. The overall cost of production of one unit of whole blood was US$118.42 and RBCs was US$130.94 constituting 12.4 and 13.7% of the country's annual GDP per capita.CONCLUSIONSThe high unit cost of producing blood relative to the annual GDP per capita demonstrates that acquiring safe blood is a burden on the health care sector in Zimbabwe. Introducing additional safety measures, such as nucleic acid amplification testing and pathogen reduction technology, although desirable, will further increase this burden.
Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases
Authors: Schad Caroline , Baum Ulrike , Frank Benjamin , Dietzel Uwe , Mattern Felix , Gomes Carlos , Ponte-Sucre Alicia , Moll Heidrun , Schurigt Uta , Schirmeister Tanja 
Published: November 2015

ABSTRACTLeishmaniasis is one of the major neglected tropical diseases of the world. Druggable targets are the parasite cysteine proteases (CPs) of clan CA, family C1 (CAC1). In previous studies, we identified two peptidomimetic compounds, the aziridine-2,3-dicarboxylate compounds 13b and 13e, in a series of inhibitors of the cathepsin L (CL) subfamily of the papain clan CAC1. Both displayed antileishmanial activityin vitrowhile not showing cytotoxicity against host cells. In further investigations, the mode of action was characterized inLeishmania major. It was demonstrated that aziridines 13b and 13e mainly inhibited the parasitic cathepsin B (CB)-like CPC enzyme and, additionally, mammalian CL. Although these compounds induced cell death ofLeishmaniapromastigotes and amastigotesin vitro, the induction of a proleishmanial T helper type 2 (Th2) response caused by host CL inhibition was observedin vivo. Therefore, we describe here the synthesis of a new library of more selective peptidomimetic aziridine-2,3-dicarboxylates discriminating between host and parasite CPs. The new compounds are based on 13b and 13e as lead structures. One of the most promising compounds of this series is compound s9, showing selective inhibition of the parasite CPsLmaCatB (a CB-like enzyme ofL. major; also namedL. majorCPC) andLmCPB2.8 (a CL-like enzyme ofLeishmania mexicana) while not affecting mammalian CL and CB. It displayed excellent leishmanicidal activities againstL. majorpromastigotes (50% inhibitory concentration [IC50] = 37.4 μM) and amastigotes (IC50= 2.3 μM). In summary, we demonstrate a new selective aziridine-2,3-dicarboxylate, compound s9, which might be a good candidate for futurein vivostudies.
New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with Trypanosoma cruzi: a Pilot Short-Term Follow-Up Study with Adult Patients
Authors: Álvarez María Gabriela , Hernández Yolanda , Bertocchi Graciela , Fernández Marisa , Lococo Bruno , Ramírez Juan Carlos , Cura Carolina , Albizu Constanza Lopez , Schijman Alejandro , Abril Marcelo , Sosa-Estani Sergio , Viotti Rodolfo 
Published: November 2015

ABSTRACT

There is a clinical need to test new schemes of benznidazole administration that are expected to be at least as effective as the current therapeutic scheme but safer. This study assessed a new scheme of benznidazole administration in chronic Chagas disease patients. A pilot study with intermittent doses of benznidazole at 5 mg/kg/day in two daily doses every 5 days for a total of 60 days was designed. The main criterion of response was the comparison of quantitative PCR (qPCR) findings prior to and 1 week after the end of treatment. The safety profile was assessed by the rate of suspensions and severity of adverse effects. Twenty patients were analyzed for safety, while qPCR was tested for 17 of them. The average age was 43 ± 7.9 years; 55% were female. Sixty-five percent of treated subjects showed detectable qPCR results prior to treatment of 1.45 (0.63 to 2.81) and 2.1 (1.18 to 2.78) parasitic equivalents per milliliter of blood (par.eq/ml) for kinetoplastic DNA (kDNA) qPCR and nuclear repetitive sequence satellite DNA (SatDNA) qPCR, respectively. One patient showed detectable PCR at the end of treatment (1/17), corresponding to 6% treatment failure, compared with 11/17 (65%) patients pretreatment (
P
= 0.01). Adverse effects were present in 10/20 (50%) patients, but in only one case was treatment suspended. Eight patients showed mild adverse effects, whereas moderate reactions with increased liver enzymes were observed in two patients. The main accomplishment of this pilot study is the promising low rate of treatment suspension. Intermittent administration of benznidazole emerges a new potential therapeutic scheme, the efficacy of which should be confirmed by long-term assessment posttreatment.
Role of Mitochondrial RNA Polymerase in the Toxicity of Nucleotide Inhibitors of Hepatitis C Virus
Authors: Feng Joy Y. , Xu Yili , Barauskas Ona , Perry Jason K. , Ahmadyar Shekeba , Stepan George , Yu Helen , Babusis Darius , Park Yeojin , McCutcheon Krista , Perron Michel , Schultz Brian E. , Sakowicz Roman , Ray Adrian S. 
Published: November 2015

ABSTRACTToxicity has emerged during the clinical development of many but not all nucleotide inhibitors (NI) of hepatitis C virus (HCV). To better understand the mechanism for adverse events, clinically relevant HCV NI were characterized in biochemical and cellular assays, including assays of decreased viability in multiple cell lines and primary cells, interaction with human DNA and RNA polymerases, and inhibition of mitochondrial protein synthesis and respiration. NI that were incorporated by the mitochondrial RNA polymerase (PolRMT) inhibited mitochondrial protein synthesis and showed a corresponding decrease in mitochondrial oxygen consumption in cells. The nucleoside released by the prodrug balapiravir (R1626), 4′-azido cytidine, was a highly selective inhibitor of mitochondrial RNA transcription. The nucleotide prodrug of 2′-C-methyl guanosine, BMS-986094, showed a primary effect on mitochondrial function at submicromolar concentrations, followed by general cytotoxicity. In contrast, NI containing multiple ribose modifications, including the active forms of mericitabine and sofosbuvir, were poor substrates for PolRMT and did not show mitochondrial toxicity in cells. In general, these studies identified the prostate cell line PC-3 as more than an order of magnitude more sensitive to mitochondrial toxicity than the commonly used HepG2 cells. In conclusion, analogous to the role of mitochondrial DNA polymerase gamma in toxicity caused by some 2′-deoxynucleotide analogs, there is an association between HCV NI that interact with PolRMT and the observation of adverse events. More broadly applied, the sensitive methods for detecting mitochondrial toxicity described here may help in the identification of mitochondrial toxicity prior to clinical testing.
In Vivo
Microdialysis To Determine Subcutaneous Interstitial Fluid Penetration and Pharmacokinetics of Fluconazole in Intensive Care Unit Patients with Sepsis
Authors: Sinnollareddy Mahipal G. , Roberts Michael S. , Lipman Jeffrey , Lassig-Smith Melissa , Starr Therese , Robertson Thomas , Peake Sandra L. , Roberts Jason A. 
Published: November 2015

ABSTRACT

The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean
in vivo
fluconazole recovery rates ± standard deviation (SD) for microdialysis were 51.4% ± 16.1% with a mean (±SD) fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC
0–24
) was significantly higher than the median ISF AUC
0–24
(340.4 versus 141.1 mg · h/liter;
P
= 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78;
P
= 0.106). Both minimum and the maximum concentrations of drug in serum (
C
max
and
C
min
) showed a significant correlation with the fluconazole plasma exposure (
C
max
,
R
2
=
0.86,
P
< 0.0001;
C
min
,
R
2
= 0.75,
P
< 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.
The GraS Sensor in Staphylococcus aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action
Authors: Chaili Siyang , Cheung Ambrose L. , Bayer Arnold S. , Xiong Yan Q. , Waring Alan J. , Memmi Guido , Donegan Niles , Yang Soo-Jin , Yeaman Michael R. 
Published: November 2015

ABSTRACT

Staphylococcus aureus
uses the two-component regulatory system GraRS to sense and respond to host defense peptides (HDPs). However, the mechanistic impact of GraS or its extracellular sensing loop (EL) on HDP resistance is essentially unexplored. Strains with null mutations in the GraS holoprotein (Δ
graS
) or its EL (ΔEL) were compared for mechanisms of resistance to HDPs of relevant immune sources: neutrophil α-defensin (human neutrophil peptide 1 [hNP-1]), cutaneous β-defensin (human β-defensin 2 [hBD-2]), or the platelet kinocidin congener RP-1. Actions studied by flow cytometry included energetics (ENR); membrane permeabilization (PRM); annexin V binding (ANX), and cell death protease activation (CDP). Assay conditions simulated bloodstream (pH 7.5) or phagolysosomal (pH 5.5) pH contexts.
S. aureus
strains were more susceptible to HDPs at pH 7.5 than at pH 5.5, and each HDP exerted a distinct effect signature. The impacts of Δ
graS
and ΔΕL on HDP resistance were peptide and pH dependent. Both mutants exhibited defects in ANX response to hNP-1 or hBD-2 at pH 7.5, but only hNP-1 did so at pH 5.5. Both mutants exhibited hyper-PRM, -ANX, and -CDP responses to RP-1 at both pHs and hypo-ENR at pH 5.5. The actions correlated with Δ
graS
or ΔΕL hypersusceptibility to hNP-1 or RP-1 (but not hBD-2) at pH 7.5 and to all study HDPs at pH 5.5. An exogenous EL mimic protected mutant strains from hNP-1 and hBD-2 but not RP-1, indicating that GraS and its EL play nonredundant roles in
S. aureus
survival responses to specific HDPs. These findings suggest that GraS mediates specific resistance countermeasures to HDPs in immune contexts that are highly relevant to
S. aureus
pathogenesis in humans.
Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice
Authors: Lujan Eduardo , Pajon Rolando , Granoff Dan M. 
Published: November 2015

ABSTRACT

Neisserial surface protein A (NspA) is a highly conserved outer membrane protein previously investigated as a meningococcal vaccine candidate. Despite eliciting serum bactericidal activity in mice, a recombinant NspA vaccine failed to elicit serum bactericidal antibodies in a phase 1 clinical trial in humans. The discordant results may be explained by the recent discovery that NspA is a human-specific ligand of the complement inhibitor factor H (FH). Therefore, in humans but not mice, NspA would be expected to form a complex with FH, which could impair human anti-NspA protective antibody responses. To investigate this question, we immunized human FH transgenic BALB/c mice with three doses of recombinant NspA expressed in
Escherichia coli
microvesicles, with each dose being separated by 3 weeks. Three of 12 (25%) transgenic mice and 13 of 14 wild-type mice responded with bactericidal titers of ≥1:10 in postimmunization sera (
P
= 0.0008, Fisher's exact test). In contrast, human FH transgenic and wild-type mice immunized with a control meningococcal native outer membrane vesicle vaccine had similar serum bactericidal antibody responses directed at PorA, which is not known to bind human FH, and a mutant factor H binding protein (FHbp) antigen with a >50-fold lower level of FH binding than wild-type FHbp antigen binding.Thus, human FH can impair anti-NspA serum bactericidal antibody responses, which may explain the poor immunogenicity of the NspA vaccine previously tested in humans. A mutant NspA vaccine engineered to have decreased binding to human FH may increase protective antibody responses in humans.
Systemic Cytokine Profiles in Strongyloides stercoralis Infection and Alterations following Treatment
Authors: Anuradha Rajamanickam , Munisankar Saravanan , Bhootra Yukti , Jagannathan Jeeva , Dolla Chandrakumar , Kumaran Paul , Shen Kui , Nutman Thomas B. , Babu Subash 
Published: November 2015

ABSTRACT

Strongyloides stercoralis
is a soil-transmitted helminth organism that infects ∼50 to 100 million people worldwide. Despite its widespread prevalence, very little is known about the immune response that characterizes human
S. stercoralis
infection. To study the systemic cytokine profile characteristic of
Strongyloides
infection, we measured the circulating levels of a large panel of pro- and anti-inflammatory cytokines in asymptomatic, infected individuals (
n
= 32) and compared them to those in uninfected, controls (
n
= 24). Infected individuals exhibited significantly lower circulating levels of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-1β [IL-1β]) and significantly higher levels of anti-inflammatory cytokines (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and transforming growth factor β [TGF-β]). Moreover, treatment of
Strongyloides
infection resulted in a significant reversal of the cytokine profile, with increased levels of proinflammatory (IFN-γ, TNF-α, IL-2, IL-17A, IL-17F, IL-22, IL-23, and IL-1β) and decreased levels of anti-inflammatory (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and TGF-β) cytokines following treatment. Thus,
S. stercoralis
infection is characterized by alterations in the levels of systemic cytokines, reflecting major alterations in the underlying immune response to this chronic helminth infection.
csrT
Represents a New Class of
csrA
-Like Regulatory Genes Associated with Integrative Conjugative Elements of Legionella pneumophila
Authors: Abbott Zachary D. , Flynn Kaitlin J. , Byrne Brenda G. , Mukherjee Sampriti , Kearns Daniel B. , Swanson Michele S. 
Published: November 2015

ABSTRACT

Bacterial evolution is accelerated by mobile genetic elements. To spread horizontally and to benefit the recipient bacteria, genes encoded on these elements must be properly regulated. Among the legionellae are multiple integrative conjugative elements (ICEs) that each encode a paralog of the broadly conserved regulator
csrA
. Using bioinformatic analyses, we deduced that specific
csrA
paralogs are coinherited with particular lineages of the type IV secretion system that mediates horizontal spread of its ICE, suggesting a conserved regulatory interaction. As a first step to investigate the contribution of
csrA
regulators to this class of mobile genetic elements, we analyzed here the activity of the
csrA
paralog encoded on
Legionella pneumophila
ICE-βox. Deletion of this gene, which we name
csrT
, had no observed effect under laboratory conditions. However, ectopic expression of
csrT
abrogated the protection to hydrogen peroxide and macrophage degradation that ICE-βox confers to
L. pneumophila
. When ectopically expressed,
csrT
also repressed
L. pneumophila
flagellin production and motility, a function similar to the core genome's canonical
csrA
. Moreover,
csrT
restored the repression of motility to
csrA
mutants of
Bacillus subtilis
, a finding consistent with the predicted function of CsrT as an mRNA binding protein. Since all known ICEs of legionellae encode coinherited
csrA
-type IV secretion system pairs, we postulate that CsrA superfamily proteins regulate ICE activity to increase their horizontal spread, thereby expanding
L. pneumophila
versatility.

IMPORTANCE
ICEs are mobile DNA elements whose type IV secretion machineries mediate spread among bacterial populations. All surveyed ICEs within the
Legionella
genus also carry paralogs of the essential life cycle regulator
csrA
. It is striking that the
csrA
loci could be classified into distinct families based on either their sequence or the subtype of the adjacent type IV secretion system locus. To investigate whether ICE-encoded
csrA
paralogs are bona fide regulators, we analyzed ICE-βox as a model system. When expressed ectopically, its
csrA
paralog inhibited multiple ICE-βox phenotypes, as well as the motility of not only
Legionella
but also
Bacillus subtilis
. Accordingly, we predict that CsrA regulators equip legionellae ICEs to promote their spread via dedicated type IV secretion systems.