bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship of vitamin D status with lung function and exercise capacity in COPD
Authors: Jung Ji Ye , Kim Young Sam , Kim Se Kyu , Kim Ha Yan , Oh Yeon Mok , Lee Sang Min , Seo Joon Beom , Lee Sang‐Do ,   KOLD Study
Published: April 2015

AbstractBackground and objectiveThe relationship between blood vitamin D level and clinical parameters in patients with chronic obstructive pulmonary disease (COPD) has been reported with conflicting results. We explored the effects of vitamin D on clinical characteristics of patients with COPD in Korea.MethodsThe study population comprised 193 patients with COPD from Korean Obstructive Lung Disease Cohort. The plasma level of 25‐OH vitamin D3 (25‐OH‐VitD3) was measured every year along with various clinical parameters such as lung function, 6‐min walking (6MW) distance, quality of life, exacerbations and emphysema index. Generalized estimating equations and linear mixed model were used for statistical analysis.ResultsOf the 193 patients, 12 (6.2%), 28 (14.5%) and 153 (79.3%) were categorized into normal, insufficiency and deficiency groups. Clustered analysis showed that the plasma 25‐OH‐VitD3 level was associated with the post‐bronchodilator ratio of force expiratory volume in 1 s/forced vital capacity (FEV1/FVC) (estimated = 0.001; P = 0.022). The vitamin D deficiency group showed lower FEV1 (estimated = −0.129, P = 0.043), FEV1 % predicted (estimated = −4.994, P = 0.029) and FEV1/FVC ratio (estimated = −0.048, P = 0.001) than did the non‐deficiency group. The 6MW distance tended to be shorter in deficiency group (estimated = −17.26, P = 0.069) than in non‐deficiency group. Quality of life, exacerbation and emphysema index were not associated with plasma 25‐OH‐VitD3 level.ConclusionsWe demonstrated a high prevalence of vitamin D deficiency in Korean patients with COPD and a significant relationship between vitamin D deficiency and airflow limitation. The exercise capacity tended to be decreased in the vitamin D deficiency group.
High levels of soluble MICA are significantly related to increased disease‐free and disease‐specific survival in patients with cervical adenocarcinoma
Authors: Samuels S. , Ferns D. M. , Meijer D. , van Straalen J. P. , Buist M. R. , Zijlmans H. J. , Kenter G. G. , Jordanova E. S. 
Published: April 2015

AbstractDownregulation of major histocompatibility complex class I chain‐related molecule A (MICA) and upregulation of human leukocyte antigen G (HLA‐G) on the tumor cells are important immune escape mechanisms for different epithelial tumors. In addition, upregulation of the soluble forms of the latter molecules in serum leads to peripheral T‐cell and natural killer (NK)‐cell tolerance. As for cervical cancer, it remains unknown whether soluble MICA (sMICA) and soluble HLA‐G (sHLA‐G) concentrations are related to tumor characteristics or patient survival rates. We measured sMICA and sHLA‐G in pre‐treatment sera of a large cohort of cervical cancer patients (n = 366) by enzyme‐linked immunosorbent assay (ELISA). We detected a median sMICA of 174.73 pg/ml and a median sHLA‐G of 5.35 U/ml. We did not find an association between sHLA‐G levels and clinicopathological characteristics. In adenocarcinoma, low sMICA concentration was positively related to recurrent disease, a higher International Federation of Gynecology and Obstetrics (FIGO) stage and vaginal involvement (Mann–Whitney U‐test; P = 0.018, P = 0.042 and P = 0.013, respectively). In the latter patient group, high sMICA levels were associated with better disease‐free survival (DFS) and disease‐specific survival (DSS) (P = 0.011 and P = 0.047). After adjusting for confounding factors, high sMICA proved to be an independent predictor for a better DFS and DSS [HR 0.16; 95% confidence interval (CI) 0.04–0.64; P = 0.009 and HR 0.12; 95% CI 0.03–0.50; P = 0.004]. sHLA‐G did not influence survival in cervical cancer patients, regardless of histology. We conclude that cervical adenocarcinoma patients with high sMICA levels have an increased DFS and DSS. This data warrants a prospective trial to study the functional role of sMICA in cervical adenocarcinoma.
Red cell alloimmunisation in regularly transfused beta thalassemia patients in Pakistan
Authors: Zaidi U. , Borhany M. , Ansari S. , Parveen S. , Boota S. , Shamim I. , Zahid D. , Shamsi T. 
Published: April 2015

SUMMARYBackgroundIn Pakistan routine blood group typing of thalassemia patients identifies ABO and Rh(D) antigens only. Therefore, other antigen incompatibilities between blood donor and blood recipient may cause alloimmunisation.ObjectiveThe aim of this study was to estimate the frequency of alloimmunisation and to evaluate the risk factors associated with its development in beta (β)‐thalassemia patients receiving regular blood transfusions.Materials and MethodsIn total 162 β thalassemia patients were included in this study. An extended red cell antigen panel was performed to detect antibodies. Patients received red cell concentrates, which were matched for ABO and Rh(D) antigens. Clinical and laboratory data were collected and analysed to estimate the frequency of alloantibodies and the factors influencing immunisation in patients on regular blood transfusion.ResultsThe median age of patients was 6·7 (range: 0·5–25) years. A total of 14 (8·6%) patients developed alloantibodies against red cell antigens. The most frequently occurring alloantibodies was anti‐E (2·5%), anti‐K (1·8%), anti‐e (1·2%) and anti‐D (0·6%). Five (3·1%) patients developed more than one red blood cell (RBC) alloantibody. Age at first transfusion in alloimmunised patients was 1·22 ± 0·87 years. The frequency of blood transfusion in alloimmunised patients was 23 ± 8·81 days and in those without alloimmunisation was 31·8 ± 16 days (p = 0·02). Logistic regression analysis showed no independent risk factor associated with alloimmunisation.ConclusionThe frequency of transfusion was increased in patients who developed alloantibodies. Typing patients and donors to match for Rh and Kell antigens would prevent more than 90% of RBC alloantibodies and reduce the frequency of transfusion in thalassemia patients.
Development and Validation of a High-Throughput Cell-Based Screen To Identify Activators of a Bacterial Two-Component Signal Transduction System
Authors: van Rensburg Julia J. , Fortney Kate R. , Chen Lan , Krieger Andrew J. , Lima Bruno P. , Wolfe Alan J. , Katz Barry P. , Zhang Zhong-yin , Spinola Stanley M. 
Published: April 2015

ABSTRACT

CpxRA is a two-component signal transduction system (2CSTS) found in many drug-resistant Gram-negative bacteria. In response to periplasmic stress, CpxA autophosphorylates and donates a phosphoryl group to its cognate response regulator, CpxR. Phosphorylated CpxR (CpxR-P) upregulates genes involved in membrane repair and downregulates multiple genes that encode virulence factors, which are trafficked across the cell membrane. Mutants that constitutively activate CpxRA in
Salmonella enterica
serovar Typhimurium and
Haemophilus ducreyi
are avirulent in mice and humans, respectively. Thus, the activation of CpxRA has high potential as a novel antimicrobial/antivirulence strategy. Using a series of
Escherichia coli
strains containing a CpxR-P-responsive
lacZ
reporter and deletions in genes encoding CpxRA system components, we developed and validated a novel cell-based high-throughput screen (HTS) for CpxRA activators. A screen of 36,000 compounds yielded one hit compound that increased reporter activity in wild-type cells. This is the first report of a compound that activates, rather than inhibits, a 2CSTS. The activity profile of the compound against CpxRA pathway mutants in the presence of glucose suggested that the compound inhibits CpxA phosphatase activity. We confirmed that the compound induced the accumulation of CpxR-P in treated cells. Although the hit compound contained a nitro group, a derivative lacking this group retained activity in serum and had lower cytotoxicity than that of the initial hit. This HTS is amenable for the screening of larger libraries to find compounds that activate CpxRA by other mechanisms, and it could be adapted to find activators of other two-component systems.
Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation
Authors: Roy Sujayita , He Ran , Kapoor Arun , Forman Michael , Mazzone Jennifer R. , Posner Gary H. , Arav-Boger Ravit 
Published: April 2015

ABSTRACT

Artemisinin-derived monomers and dimers inhibit human cytomegalovirus (CMV) replication in human foreskin fibroblasts (HFFs). The monomer artesunate (AS) inhibits CMV at micromolar concentrations, while dimers inhibit CMV replication at nanomolar concentrations, without increased toxicity in HFFs. We report on the variable anti-CMV activity of AS compared to the consistent and reproducible CMV inhibition by dimer 606 and ganciclovir (GCV). Investigation of this phenomenon revealed that the anti-CMV activity of AS correlated with HFFs synchronized to the G
0
/G
1
stage of the cell cycle. In contact-inhibited serum-starved HFFs or cells arrested at early/late G
1
with specific checkpoint regulators, AS and dimer 606 efficiently inhibited CMV replication. However, in cycling HFFs, in which CMV replication was productive, virus inhibition by AS was significantly reduced, but inhibition by dimer 606 and GCV was maintained. Cell cycle analysis in noninfected HFFs revealed that AS induced early G
1
arrest, while dimer 606 partially blocked cell cycle progression. In infected HFFs, AS and dimer 606 prevented the progression of cell cycle toward the G
1
/S checkpoint. AS reduced the expression of cyclin-dependent kinases (CDK) 2, 4, and 6 in noninfected cycling HFFs, while the effect of dimer 606 on these CDKs was moderate. Neither compound affected CDK expression in noninfected contact-inhibited HFFs. In CMV-infected cells, AS activity correlated with reduced CDK2 levels. CMV inhibition by AS and dimer 606 also correlated with hypophosphorylation (activity) of the retinoblastoma protein (pRb). AS activity was strongly associated with pRb hypophosphorylation, while its reduced anti-CMV activity was marked by pRb phosphorylation. Roscovitine, a CDK2 inhibitor, antagonized the anti-CMV activities of AS and dimer 606. These data suggest that cell cycle modulation through CDKs and pRb might play a role in the anti-CMV activities of artemisinins. Proteins involved in this modulation may be identified and targeted for CMV inhibition.
Bactericidal Activities of Cathelicidin LL-37 and Select Cationic Lipids against the Hypervirulent Pseudomonas aeruginosa Strain LESB58
Authors: Wnorowska Urszula , Niemirowicz Katarzyna , Myint Melissa , Diamond Scott L. , Wróblewska Marta , Savage Paul B. , Janmey Paul A. , Bucki Robert 
Published: April 2015

ABSTRACT

Pseudomonas aeruginosa
Liverpool epidemic strain (LES) infections in cystic fibrosis (CF) patients are associated with transmissibility and increased patient morbidity. This study was designed to assess the
in vitro
activities of cathelicidin LL-37 peptide (LL-37) and select cationic lipids against
Pseudomonas aeruginosa
LESB58 in CF sputum and in a setting mimicking the CF airway. We found that LL-37 naturally present in airway surface fluid and some nonpeptide cationic lipid molecules such as CSA-13, CSA-90, CSA-131, and D2S have significant, but broadly differing, bactericidal activities against
P. aeruginosa
LESB58. We observed strong inhibition of LL-37 bactericidal activity in the presence of purified bacteriophage Pf1, which is highly expressed by
P. aeruginosa
LES, but the activities of the cationic lipids CSA-13 and CSA-131 were not affected by this polyanionic virus. Additionally, CSA-13 and CSA-131 effectively prevent LESB58 biofilm formation, which is stimulated by Pf1 bacteriophage, DNA, or F-actin. CSA-13 and CSA-131 display strong antibacterial activities against different clinical strains of
P. aeruginosa
, and their activities against
P. aeruginosa
LESB58 and Xen5 strains were maintained in CF sputum. These data indicate that synthetic cationic lipids (mimics of natural antimicrobial peptides) are suitable for developing an effective treatment against CF lung
P. aeruginosa
infections, including those caused by LES strains.
Evaluation of a Modified EUCAST Fragmented-Mycelium Inoculum Method for
In Vitro
Susceptibility Testing of Dermatophytes and the Activity of Novel Antifungal Agents
Authors: Risslegger B. , Lass-Flörl C. , Blum G. , Lackner M. 
Published: April 2015

ABSTRACT

For antifungal susceptibility testing of nonsporulating or poorly sporulating dermatophytes, a fragmented-mycelium inoculum preparation method was established and compared to broth microdilution testing according to CLSI and EUCAST guidelines. Moreover, the
in vitro
activity of new antifungal agents against dermatophytes was evaluated. Agreement between the mycelial inoculum method and the CLSI broth microdilution method was high (93% to 100%). Echinocandins (minimal effective concentration [MEC], ≤0.5 mg/liter) and posaconazole (MIC, ≤3.00 mg/liter) showed good activity against all tested dermatophytes.
War Wound Treatment Complications Due to Transfer of an IncN Plasmid Harboring
bla
OXA-181
from Morganella morganii to CTX-M-27-Producing Sequence Type 131 Escherichia coli
Authors: McGann Patrick , Snesrud Erik , Ong Ana C. , Appalla Lakshmi , Koren Michael , Kwak Yoon I. , Waterman Paige E. , Lesho Emil P. 
Published: April 2015

ABSTRACT

A 22-year-old male developed a recurrent sacral abscess associated with embedded shrapnel following a blast injury. Cultures grew extended-spectrum β-lactamase (ESBL)-producing, carbapenem-susceptible
Escherichia coli
. Ertapenem was administered, but the infection recurred after each course of antibiotics. Initial surgical interventions were unsuccessful, and subsequent cultures yielded
E. coli
and
Morganella morganii
, both nonsusceptible to carbapenems. The isolates were Carba NP test negative, gave ambiguous results with the modified Hodge test, and amplified the
bla
OXA48
-like gene by real-time PCR. All
E. coli
isolates were sequence type 131 (ST131), carried nine resistance genes (including
bla
CTX-M-27
) on an IncF plasmid, and were identical by genome sequencing, except for 150 kb of plasmid DNA in carbapenem-nonsusceptible isolates only. Sixty kilobases of this was shared by
M. morganii
and represented an IncN plasmid harboring
bla
OXA-181
. In
M. morganii
, the gene was flanked by IS
3000
and IS
Kpn19
, but in all but one of the
E. coli
isolates containing
bla
OXA-181
, a second copy of IS
Kpn19
had inserted adjacent to IS
3000
. To the best of our knowledge, this is the first report of
bla
OXA-181
in the virulent ST131 clonal group and carried by the promiscuous IncN family of plasmids. The tendency of
M. morganii
to have high MICs of imipenem, a
bla
OXA-181
substrate profile that includes penicillins but not extended-spectrum cephalosporins, and weak carbapenemase activity almost resulted in the presence of
bla
OXA-181
being overlooked. We highlight the importance of surveillance for carbapenem resistance in all species, even those with intrinsic resistances, and the value of advanced molecular techniques in detecting subtle genetic changes.
Dissemination of the Same
cfr
-Carrying Plasmid among Methicillin-Resistant Staphylococcus aureus and Coagulase-Negative Staphylococcal Isolates in China
Authors: Cai Jia Chang , Hu Yan Yan , Zhou Hong Wei , Chen Gong-Xiang , Zhang Rong 
Published: April 2015

ABSTRACT

Six
cfr
-harboring methicillin-resistant
Staphylococcus aureus
(MRSA) isolates, which belonged to the same clone of sequence type 5 (ST5)-staphylococcal cassette chromosome
mec
element II (SCC
mec
II)-
spa
t311, were investigated in this study. Complete sequencing of a
cfr
-carrying plasmid, pLRSA417, revealed an 8,487-bp fragment containing a Tn
4001
-like transposon,
cfr
,
orf1
, and IS
Enfa4
. This segment, first identified in an animal plasmid, pSS-01, was observed in several plasmids from clinical coagulase-negative staphylococci in China, suggesting that the
cfr
gene, which might originate from livestock, was located in the same mobile element and disseminated among different clinical staphylococcal species.
Safety and Pharmacokinetics of Solithromycin in Subjects with Hepatic Impairment
Authors: Jamieson Brian D. , Ciric Sabrina , Fernandes Prabhavathi 
Published: April 2015

ABSTRACT

Solithromycin, a new macrolide and the first fluoroketolide, is in late-stage clinical development and, like older macrolides, is primarily metabolized and excreted through liver-dependent mechanisms. This study evaluated the safety and pharmacokinetics of solithromycin in patients with chronic liver disease. This open-label, multiple-dose study in subjects with hepatic impairment and in healthy control subjects (matched for age, weight, and sex) enrolled 8 Child-Pugh class A (mild), 8 class B (moderate), and 8 class C (severe) patients and 9 healthy controls. Subjects (
n
= 33) received one 800-mg dose on day 1 followed by once-daily doses of 400 mg on days 2 through 5. The most commonly reported adverse events were mild diarrhea and mild headache, and no significant differences were noted between hepatically impaired subjects and healthy controls. The pharmacokinetics of plasma solithromycin in subjects with mild and moderate impairment was similar to that in control subjects. In subjects with severe impairment, total exposure to solithromycin at steady state (area under the plasma concentration-time curve [AUC
0–tau
]) was decreased compared to that in control subjects, which may have been related to the higher body mass index of individuals in this group. No greater accumulation was noted in any hepatically impaired cohort on day 5 compared to that in control subjects. No decrease in dosage is therefore needed when administering solithromycin to patients with mild, moderate, or severe hepatic impairment. Solithromycin was well tolerated in this patient population, and no significant differences in safety, compared to healthy controls, were noted.
Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects
Authors: Zhu Li , Hruska Matthew , Hwang Carey , Shah Vaishali , Furlong Michael , Hanna George J. , Bertz Richard , Savant Landry Ishani 
Published: April 2015

ABSTRACTBMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+T cells. This open-label, multiple-dose, four-sequence, crossover study addressed potential two-way drug-drug interactions following coadministration of BMS-663068 (BMS-626529 is a CYP3A4 substrate), atazanavir (ATV), and ritonavir (RTV) (ATV and RTV are CYP3A4 inhibitors). Thirty-six healthy subjects were randomized 1:1:1:1 to receive one of four treatment sequences with three consecutive treatments: BMS-663068 at 600 mg twice daily (BID), BMS-663068 at 600 mg BID plus RTV at 100 mg once daily (QD), ATV at 300 mg QD plus RTV at 100 mg QD (RTV-boosted ATV [ATV/r]), or BMS-663068 at 600 mg BID plus ATV at 300 mg QD plus RTV at 100 mg QD. Compared with the results obtained by administration of BMS-663068 alone, coadministration of BMS-663068 with ATV/r increased the BMS-626529 maximum concentration in plasma (Cmax) and the area under the concentration-time curve in one dosing interval (AUCtau) by 68% and 54%, respectively. Similarly, coadministration of BMS-663068 with RTV increased the BMS-626529Cmaxand AUCtauby 53% and 45%, respectively. Compared with the results obtained by administration of ATV/r alone, ATV and RTV systemic exposures remained similar following coadministration of BMS-663068 with ATV/r. BMS-663068 was generally well tolerated, and there were no adverse events (AEs) leading to discontinuation, serious AEs, or deaths. Moderate increases in BMS-626529 systemic exposure were observed following coadministration of BMS-663068 with ATV/r or RTV. However, the addition of ATV to BMS-663068 plus RTV did not further increase BMS-626529 systemic exposure. ATV and RTV exposures remained similar following coadministration of BMS-663068 with either ATV/r or RTV. BMS-663068 was generally well tolerated alone or in combination with either RTV or ATV/r.
Narrow-Spectrum Inhibitors of Campylobacter jejuni Flagellar Expression and Growth
Authors: Johnson Jeremiah G. , Yuhas Caroline , McQuade Thomas J. , Larsen Martha J. , DiRita Victor J. 
Published: April 2015

ABSTRACT

Campylobacter jejuni
is a major cause of food-borne illness due to its ability to reside within the gastrointestinal tracts of chickens. Multiple studies have identified the flagella of
C. jejuni
as a major determinant of chicken colonization. An inhibitor screen of approximately 147,000 small molecules was performed to identify compounds that are able to inhibit flagellar expression in a reporter strain of
C. jejuni
. Several compounds that modestly inhibited motility of wild-type
C. jejuni
in standard assays were identified, as were a number of small molecules that robustly inhibited
C. jejuni
growth,
in vitro
. Examination of similar bacterial screens found that many of these small molecules inhibited only the growth of
C. jejuni
. Follow-up assays demonstrated inhibition of other strains of
C. jejuni
and
Campylobacter coli
but no inhibition of the closely related
Helicobacter pylori
. The compounds were determined to be bacteriostatic and nontoxic to eukaryotic cells. Preliminary results from a day-of-hatch chick model of colonization suggest that at least one of the compounds demonstrates promise for reducing
Campylobacter
colonization loads
in vivo
, although further medicinal chemistry may be required to enhance bioavailability.
Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis
Authors: Kumar Rohitashw , Saraswat Darpan , Tati Swetha , Edgerton Mira 
Published: April 2015

ABSTRACT

Candida albicans
, a commensal fungus of the oral microbiome, causes oral candidiasis in humans with localized or systemic immune deficiencies. Secreted aspartic proteinases (Saps) are a family of 10 related proteases and are virulence factors due to their proteolytic activity, as well as their roles in adherence and colonization of host tissues. We found that mice infected sublingually with
C. albicans
cells overexpressing Sap6 (
SAP6
OE and a Δ
sap8
strain) had thicker fungal plaques and more severe oral infection, while infection with the Δ
sap6
strain was attenuated. These hypervirulent strains had highly aggregative colony structure
in vitro
and higher secreted proteinase activity; however, the levels of proteinase activity of
C. albicans
Saps did not uniformly match their abilities to damage cultured oral epithelial cells (SCC-15 cells). Hyphal induction in cells overexpressing Sap6 (
SAP6
OE and Δ
sap8
cells) resulted in formation of large cell-cell aggregates. These aggregates could be produced in germinated wild-type cells by addition of native or heat-inactivated Sap6. Sap6 bound only to germinated cells and increased
C. albicans
adhesion to oral epithelial cells. The adhesion properties of Sap6 were lost upon deletion of its integrin-binding motif (RGD) and could be inhibited by addition of RGD peptide or anti-integrin antibodies. Thus, Sap6 (but not Sap5) has an alternative novel function in cell-cell aggregation, independent of its proteinase activity, to promote infection and virulence in oral candidiasis.