bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Pharmacokinetics and Pharmacodynamics of Levofloxacin in Acutely Hospitalized Older Patients with Various Degrees of Renal Function
Authors: Cojutti Pier Giorgio , Ramos-Martin Virginia , Schiavon Isabella , Rossi Paolo , Baraldo Massimo , Hope William , Pea Federico 
Published: December 2016

ABSTRACT

A retrospective study was conducted in a large sample of acutely hospitalized older patients who underwent therapeutic drug monitoring during levofloxacin treatment. The aim was to assess the population pharmacokinetics (popPK) and pharmacodynamics of levofloxacin among older patients. PopPK and Monte Carlo simulation were performed to define the permissible doses in older patients according to various degrees of renal function. Classification and regression tree (CART) analysis was used to detect the cutoff 24-hour area under the concentration-time curve (AUC
24
)/MIC ratio that best correlated with the clinical outcome. The probability of target attainment (PTA) of this value was calculated against different pathogens. A total of 168 patients were included, and 330 trough and 239 peak concentrations were used for the popPK analysis. Creatinine clearance (CrCL) was the only covariate that improved the model fit (levofloxacin CL = 0.399 + 0.051 × CrCL
CKD-EPI
[creatinine clearance estimated by means of the chronic kidney disease epidemiology]). Drug doses ranged between 500 mg every 48 h and 500 mg every 12 h in relation to different renal functions. The identified cutoff AUC
24
/MIC ratio (≥95.7) was the only covariate that correlated with a favorable clinical outcome in multivariate regression analysis (odds ratio [OR], 20.85; 95% confidence interval [CI], 1.56 to 186.73). PTAs were optimal (>80%) against
Escherichia coli
and
Haemophilus influenzae
, borderline against
Staphylococcus aureus
, and suboptimal against
Pseudomonas aeruginosa
. The levofloxacin doses defined in our study may be effective for the treatment of infections due to bacterial pathogens, with an MIC of ≤0.5 mg/liter in older patients with various degrees of renal function, while minimizing the toxicity risk. Conversely, the addition of another active antimicrobial should be considered whenever treating infections caused by less susceptible pathogens.
Otitis-Prone Children Produce Functional Antibodies to Pneumolysin and Pneumococcal Polysaccharides
Authors: Kirkham Lea-Ann S. , Wiertsema Selma P. , Corscadden Karli J. , Mateus Tulia , Mullaney Gemma L. , Zhang Guicheng , Richmond Peter C. , Thornton Ruth B. 
Published: December 2016

ABSTRACT

The pneumococcus is a major otitis media (OM) pathogen, but data are conflicting regarding whether otitis-prone children have impaired humoral immunity to pneumococcal antigens. We and others have shown that otitis-prone and healthy children have similar antibody titers to pneumococcal proteins and polysaccharides (vaccine and nonvaccine types); however, the quality of antibodies from otitis-prone children has not been investigated. Antibody function, rather than titer, is considered to be a better correlate of protection from pneumococcal disease. Therefore, we compared the capacities of antibodies from otitis-prone (cases) and healthy (controls) children to neutralize pneumolysin, the pneumococcal toxin currently in development as a vaccine antigen, and to opsonize pneumococcal vaccine and nonvaccine serotypes. A pneumolysin neutralization assay was conducted on cholesterol-depleted complement-inactivated sera from 165 cases and 61 controls. A multiplex opsonophagocytosis assay (MOPA) was conducted on sera from 20 cases and 20 controls. Neutralizing and opsonizing titers were calculated with antigen-specific IgG titers to determine antibody potency for pneumolysin, pneumococcal conjugate vaccine (PCV) polysaccharides, and non-PCV polysaccharides. There was no significant difference in antibody potencies between cases and controls for the antigens tested. Antipneumolysin neutralizing titers increased with the number of episodes of acute OM, but antibody potency did not. Pneumolysin antibody potency was lower in children colonized with pneumococci than in noncarriers, and this was significant for the otitis-prone group (
P
< 0.05). The production of functional antipneumococcal antibodies in otitis-prone children demonstrates that they respond to the current PCV and are likely to respond to pneumolysin-based vaccines as effectively as healthy children.
Mycobacterium bovis Requires P27 (LprG) To Arrest Phagosome Maturation and Replicate within Bovine Macrophages
Authors: Vázquez Cristina Lourdes , Bianco María Verónica , Blanco Federico Carlos , Forrellad Marina Andrea , Gutierrez Maximiliano Gabriel , Bigi Fabiana 
Published: December 2016

ABSTRACT

Mycobacterium bovis
causes tuberculosis in a wide variety of mammals, with strong tropism for cattle and eventually humans. P27, also called LprG, is among the proteins involved in the mechanisms of the virulence and persistence of
M. bovis
and
Mycobacterium tuberculosis
. Here, we describe a novel function of P27 in the interaction of
M. bovis
with its natural host cell, the bovine macrophage. We found that a deletion in the
p27-p55
operon impairs the replication of
M. bovis
in bovine macrophages. Importantly, we show for the first time that
M. bovis
arrests phagosome maturation in a process that depends on P27. This effect is P27 specific since complementation with wild-type
p27
but not
p55
fully restored the wild-type phenotype of the mutant strain; this indicates that P55 plays no important role during the early events of
M. bovis
infection. In addition, we also showed that the presence of P27 from
M. smegmatis
decreases the association of LAMP-3 with bead phagosomes, indicating that P27 itself blocks phagosome-lysosome fusion by modulating the traffic machinery in the cell host.
Progress in Understanding the Molecular Basis Underlying Functional Diversification of Cyclic Dinucleotide Turnover Proteins
Authors: Römling Ute , Liang Zhao-Xun , Dow J. Maxwell 
Published: December 2016

ABSTRACT
Cyclic di-GMP was the first cyclic dinucleotide second messenger described, presaging the discovery of additional cyclic dinucleotide messengers in bacteria and eukaryotes. The GGDEF diguanylate cyclase (DGC) and EAL and HD-GYP phosphodiesterase (PDE) domains conduct the turnover of cyclic di-GMP. These three unrelated domains belong to superfamilies that exhibit significant variations in function, and they include both enzymatically active and inactive members, with a subset involved in synthesis and degradation of other cyclic dinucleotides. Here, we summarize current knowledge of sequence and structural variations that underpin the functional diversification of cyclic di-GMP turnover proteins. Moreover, we highlight that superfamily diversification is not restricted to cyclic di-GMP signaling domains, as particular DHH/DHHA1 domain and HD domain proteins have been shown to act as cyclic di-AMP phosphodiesterases. We conclude with a consideration of the current limitations that such diversity of action places on bioinformatic prediction of the roles of GGDEF, EAL, and HD-GYP domain proteins.
Proteolytic Cleavage of the Immunodominant Outer Membrane Protein rOmpA in Rickettsia rickettsii
Authors: Noriea Nicholas F. , Clark Tina R. , Mead David , Hackstadt Ted 
Published: December 2016

ABSTRACT

Rickettsia rickettsii
, the causative agent of Rocky Mountain spotted fever, contains two immunodominant proteins, rOmpA and rOmpB, in the outer membrane. Both rOmpA and rOmpB are conserved throughout spotted fever group rickettsiae as members of a family of autotransporter proteins. Previously, it was demonstrated that rOmpB is proteolytically processed, with the cleavage site residing near the autotransporter domain at the carboxy-terminal end of the protein, cleaving the 168-kDa precursor into apparent 120-kDa and 32-kDa fragments. The 120- and 32-kDa fragments remain noncovalently associated on the surface of the bacterium, with implications that the 32-kDa fragment functions as the membrane anchor domain. Here we present evidence for a similar posttranslational processing of rOmpA. rOmpA is expressed as a predicted 224-kDa precursor yet is observed on SDS-PAGE as a 190-kDa protein. A small rOmpA fragment of ∼32 kDa was discovered during surface proteome analysis and identified as the carboxy-terminal end of the protein. A rabbit polyclonal antibody was generated to the autotransporter region of rOmpA and confirmed a 32-kDa fragment corresponding to the calculated mass of a proteolytically cleaved rOmpA autotransporter region. N-terminal amino acid sequencing revealed a cleavage site on the carboxy-terminal side of Ser-1958 in rOmpA. An avirulent strain of
R. rickettsii
Iowa deficient in rOmpB processing was also defective in the processing of rOmpA. The similarities of the cleavage sites and the failure of
R. rickettsii
Iowa to process either rOmpA or rOmpB suggest that a single enzyme may be responsible for both processing events.

IMPORTANCE
Members of the spotted fever group of rickettsiae, including
R. rickettsii
, the etiologic agent of Rocky Mountain spotted fever, express at least four autotransporter proteins that are protective antigens or putative virulence determinants. One member of this class of proteins, rOmpB, is proteolytically processed to a passenger domain and an autotransporter domain that remain associated on the rickettsial outer membrane. The protease responsible for this posttranslation processing remains unknown. Here we show that another autotransporter, rOmpA, is similarly processed by
R. rickettsii
. Similarities in sequence at the cleavage site and predicted secondary protein structure suggest that all four
R. rickettsii
autotransporters may be processed by the same outer membrane protease.
VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System
Authors: Krute Christina N. , Rice Kelly C. , Bose Jeffrey L. 
Published: December 2016

ABSTRACT

In previous studies, we identified the fatty acid kinase virulence factor regulator B (VfrB) as a potent regulator of α-hemolysin and other virulence factors in
Staphylococcus aureus
. In this study, we demonstrated that VfrB is a positive activator of the SaeRS two-component regulatory system. Analysis of
vfrB
,
saeR
, and
saeS
mutant strains revealed that VfrB functions in the same pathway as SaeRS. At the transcriptional level, the promoter activities of SaeRS class I (
coa
) and class II (
hla
) target genes were downregulated during the exponential growth phase in the
vfrB
mutant, compared to the wild-type strain. In addition,
saePQRS
expression was decreased in the
vfrB
mutant strain, demonstrating a need for this protein in the autoregulation of SaeRS. The requirement for VfrB-mediated activation was circumvented when SaeS was constitutively active due to an SaeS (L18P) substitution. Furthermore, activation of SaeS via human neutrophil peptide 1 (HNP-1) overcame the dependence on VfrB for transcription from class I Sae promoters. Consistent with the role of VfrB in fatty acid metabolism,
hla
expression was decreased in the
vfrB
mutant with the addition of exogenous myristic acid. Lastly, we determined that aspartic acid residues D38 and D40, which are predicted to be key to VfrB enzymatic activity, were required for VfrB-mediated α-hemolysin production. Collectively, this study implicates VfrB as a novel accessory protein needed for the activation of SaeRS in
S. aureus
.

IMPORTANCE
The SaeRS two-component system is a key regulator of virulence determinant production in
Staphylococcus aureus
. Although the regulon of this two-component system is well characterized, the activation mechanisms, including the specific signaling molecules, remain elusive. Elucidating the complex regulatory circuit of SaeRS regulation is important for understanding how the system contributes to disease causation by this pathogen. To this end, we have identified the fatty acid kinase VfrB as a positive regulatory modulator of SaeRS-mediated transcription of virulence factors in
S. aureus
. In addition to describing a new regulatory aspect of SaeRS, this study establishes a link between fatty acid kinase activity and virulence factor regulation.
Levels of Antibody against Glycopeptidolipid Core as a Marker for Monitoring Treatment Response in Mycobacterium avium Complex Pulmonary Disease: a Prospective Cohort Study
Authors: Kitada Seigo , Maekura Ryoji , Yoshimura Kenji , Miki Keisuke , Miki Mari , Oshitani Yohei , Nishida Kohei , Sawa Nobuhiko , Mori Masahide , Kobayashi Kazuo 
Published: December 2016

ABSTRACT

The diagnosis of
Mycobacterium avium
complex pulmonary disease (MAC-PD) is sometimes complicated and time-consuming. A serodiagnostic kit that measures the serum levels of IgA antibodies against the glycopeptidolipid (GPL) core is commercially available and has good diagnostic accuracy for MAC-PD. However, the significance of measurement of GPL core IgA antibody levels in monitoring for chemotherapy response in patients with MAC-PD was not well investigated. Thirty-four treatment naive MAC-PD patients who were started on multidrug chemotherapy were enrolled. Their antibody levels were prospectively measured at regular intervals. The relationships between their antibody levels and the therapeutic outcomes were examined. The patients were classified into three groups (conversion, recurrence, and nonconversion) based on the bacteriological outcomes after chemotherapy. There were no significant differences in the antibody levels before treatment between the culture conversion (
n
= 19), recurrence (
n
= 7), and nonconversion (
n
= 8) groups (
P
= 0.9881). The levels decreased significantly after the chemotherapy (
P
< 0.0001). Recurrence and/or worsening of chest radiography findings were observed in cases whose antibody levels subsequently increased after cessation of the chemotherapy. No significant difference in the percent decrease in antibody levels by the chemotherapy was observed between the culture conversion and recurrence groups (
P
= 0.9338). The initial antibody levels are not a predictor of therapeutic outcomes, and also the percent decrease in antibody levels is not a sufficient indicator of the cessation of chemotherapy. However, serial measurements of antibody levels may allow objective monitoring of disease activity in individual MAC-PD patients.
Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses
Authors: Riou Raphaëlle , Bressollette-Bodin Céline , Boutoille David , Gagne Katia , Rodallec Audrey , Lefebvre Maeva , Raffi François , Senitzer David , Imbert-Marcille Berthe-Marie , Retière Christelle 
Published: December 2016

ABSTRACT

Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMV-seronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C
+
NK cells, CD16
+
Vδ2(−) γδ T cells, and conventional HCMV-specific CD8
+
T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals.

IMPORTANCE
HCMV-specific immune responses have been extensively documented in immunocompromised patients and during
in utero
acquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains.
Screening for Novel Small-Molecule Inhibitors Targeting the Assembly of Influenza Virus Polymerase Complex by a Bimolecular Luminescence Complementation-Based Reporter System
Authors: Li Chunfeng , Wang Zining , Cao Yang , Wang Lulan , Ji Jingyun , Chen Zhigao , Deng Tao , Jiang Taijiao , Cheng Genhong , Qin F. Xiao-Feng 
Published: December 2016

ABSTRACT
Influenza virus RNA-dependent RNA polymerase consists of three viral protein subunits: PA, PB1, and PB2. Protein-protein interactions (PPIs) of these subunits play pivotal roles in assembling the functional polymerase complex, which is essential for the replication and transcription of influenza virus RNA. Here we developed a highly specific and robust bimolecular luminescence complementation (BiLC) reporter system to facilitate the investigation of influenza virus polymerase complex formation. Furthermore, by combining computational modeling and the BiLC reporter assay, we identified several novel small-molecule compounds that selectively inhibited PB1-PB2 interaction. Function of one such lead compound was confirmed by its activity in suppressing influenza virus replication. In addition, our studies also revealed that PA plays a critical role in enhancing interactions between PB1 and PB2, which could be important in targeting sites for anti-influenza intervention. Collectively, these findings not only aid the development of novel inhibitors targeting the formation of influenza virus polymerase complex but also present a new tool to investigate the exquisite mechanism of PPIs.

IMPORTANCE
Formation of the functional influenza virus polymerase involves complex protein-protein interactions (PPIs) of PA, PB1, and PB2 subunits. In this work, we developed a novel BiLC assay system which is sensitive and specific to quantify both strong and weak PPIs between influenza virus polymerase subunits. More importantly, by combining
in silico
modeling and our BiLC assay, we identified a small molecule that can suppress influenza virus replication by disrupting the polymerase assembly. Thus, we developed an innovative method to investigate PPIs of multisubunit complexes effectively and to identify new molecules inhibiting influenza virus polymerase assembly.
Nine-year study of US high school soccer injuries: data from a national sports injury surveillance programme
Authors: Khodaee Morteza , Currie Dustin W , Asif Irfan M , Comstock R Dawn 
Published: December 2016

BackgroundResearch on high school soccer injury epidemiology is sparse.AimTo describe high school soccer injury rates, trends and patterns by type of athlete exposure (AE), position and sex.MethodsThis descriptive epidemiological study used data from a large national high school sports injury surveillance programme to describe rates and patterns of soccer-related injuries including concussion sustained from 2005/2006 to 2013/2014. Injury rates are calculated per 1000 AEs.ResultsOverall, 6154 soccer injuries occurred during 2 985 991 AEs; injury rate=2.06 per 1000 AEs. Injury rates were higher during competition (4.42) than practice (1.05; rate ratio (RR)=4.19; 95% CI 3.98 to 4.41), and in girls (2.33) than boys (1.83; RR=1.27, 95% CI 1.21 to 1.34). Boys' non-concussion injury rates decreased significantly (p=0.001) during the study period while reported concussion rates increased significantly (p=0.002). Girls' non-concussion rates were relatively stable and reported concussion rates increased significantly (p=0.004). Player–player contact was the injury mechanism that led to the most competition injuries (injury proportion ratio (IPR)=2.87; 95% CI 2.57 to 3.21), while non-contact injuries were the most common mechanisms among practice injuries (IPR=2.10; 95% CI 1.86 to 2.38). Recovery from concussion was >7 days in a third of the cases. Injury patterns were similar between sexes with respect to position played and location on the field at the time of injury.ConclusionsHigh school soccer injury rates vary by sex and type of exposure, while injury patterns are more similar across sexes. Reported concussion rates increased significantly over the study period in male and female athletes.
Factors associated with influenza vaccination coverage among the elderly in South Korea: the Fourth Korean National Health and Nutrition Examination Survey (KNHANES IV)
Authors: Kwon David Soonil , Kim Kyuwoong , Park Sang Min 
Published: December 2016

ObjectiveThe annual outbreak of influenza is one of the major causes of morbidity and mortality among the elderly population around the world. While there is an annual vaccine available to prevent or reduce the incidence of disease, not all older people in Korea choose to be vaccinated. There have been few previous studies to examine the factors influencing influenza vaccination in Korea. Thus, this study identifies nationwide factors that affect influenza vaccination rates in elderly Koreans.MethodsWe obtained data from the Fourth Korean National Health and Nutrition Examination Survey 2007–2009 (KNHANES IV), a nationwide health survey in Korea. To assess influenza vaccination status, we analysed answers to a single question from the survey. From the respondents, we selected 3567 elderly population aged 65 years or older, to analyse the effects of variables including sociodemographic, health behavioural risk, health status and psychological factors on vaccination coverage. We identified factors that affect vaccination status using a multiple logistic regression analysis.ResultsThe rate of influenza vaccination in this elderly population was 75.8%. Overall, the most significant determinants for choosing influenza vaccination were a recent history of health screening (adjusted OR (aOR) 2.26, 95% CI 1.92 to 2.66) and smoking (aOR 0.78, 95% CI 0.62 to 0.98). Other contributing factors were age, household income, marital status, alcohol consumption, physical activity level, self-reported health status and a limitation in daily activities. In contrast, psychological factors, including self-perceived quality of life, stress and depressive mood, did not show close association with vaccination coverage.ConclusionsTo boost influenza vaccination rates in the elderly, an influenza campaign should focus on under-represented groups, especially smokers. Additionally, promoting routine health screening for the elderly may be an efficient way to help achieve higher vaccination rates. Our results highlight the need for a new strategy for the vaccination campaign.