bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Ceftolozane in an
In Vitro
Infection Model
Authors: VanScoy Brian , Mendes Rodrigo E. , Nicasio Anthony M. , Castanheira Mariana , Bulik Catharine C. , Okusanya Olanrewaju O. , Bhavnani Sujata M. , Forrest Alan , Jones Ronald N. , Friedrich Lawrence V. , Steenbergen Judith N. , Ambrose Paul G. 
Published: April 2013

ABSTRACT

Despite β-lactamase inhibitors being available for clinical use for nearly 30 years, a paucity of data exists describing the pharmacokinetic-pharmacodynamic (PK-PD) determinants of efficacy for these agents. Herein, we describe dose fractionation studies designed to determine the exposure measure most predictive of tazobactam efficacy in combination with ceftolozane and the magnitude of this measure necessary for efficacy in a PK-PD
in vitro
infection model. The challenge organism panel was comprised of an isogenic CTX-M-15-producing
Escherichia coli
triplet set, genetically engineered to transcribe different levels of
bla
CTX-M-15
. These recombinant strains exhibited ceftolozane MIC values of 4, 16, and 64 μg/ml representing low, moderate, and high levels of CTX-M-15, respectively. Different
bla
CTX-M-15
transcription levels were confirmed by relative quantitative real-time PCR (qRT-PCR) and β-lactamase hydrolytic assays. The exposure measure associated with efficacy was the percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold), regardless of enzyme expression (
r
2
= 0.938). The threshold concentrations identified were 0.05 μg/ml for low and moderate and 0.25 μg/ml for the high-β-lactamase expression strain constructs. The magnitudes of %Time>threshold for tazobactam associated with net bacterial stasis and a 1- and 2-log
10
CFU reduction in bacteria at 24 h were approximately 35, 50, and 70%, respectively. These data provide an initial target tazobactam concentration-time profile and a paradigm to optimize tazobactam dosing when combined with ceftolozane.
Ergothioneine Is a Secreted Antioxidant in Mycobacterium smegmatis
Authors: Sao Emani Carine , Williams Monique J. , Wiid Ian J. , Hiten Nicholas F. , Viljoen Albertus J. , Pietersen Ray-Dean D. , van Helden Paul D. , Baker Bienyameen 
Published: April 2013

ABSTRACT

Ergothioneine (ERG) and mycothiol (MSH) are two low-molecular-weight thiols synthesized by mycobacteria. The role of MSH has been extensively investigated in mycobacteria; however, little is known about the role of ERG in mycobacterial physiology. In this study, quantification of ERG at various points in the growth cycle of
Mycobacterium smegmatis
revealed that a significant portion of ERG is found in the culture media, suggesting that it is actively secreted. A mutant of
M. smegmatis
lacking
egtD
(
MSMEG_6247
) was unable to synthesize ERG, confirming its role in ERG biosynthesis. Deletion of
egtD
from wild-type
M. smegmatis
and an MSH-deficient mutant did not affect their susceptibility to antibiotics tested in this study. The ERG- and MSH-deficient double mutant was significantly more sensitive to peroxide than either of the single mutants lacking either ERG or MSH, suggesting that both thiols play a role in protecting
M. smegmatis
against oxidative stress and that ERG is able to partly compensate for the loss of MSH.
Pharmacokinetics of First-Line Tuberculosis Drugs in Tanzanian Patients
Authors: Tostmann Alma , Mtabho Charles M. , Semvua Hadija H. , van den Boogaard Jossy , Kibiki Gibson S. , Boeree Martin J. , Aarnoutse Rob E. 
Published: April 2013

ABSTRACTEast Africa has a high tuberculosis (TB) incidence and mortality, yet there are very limited data on exposure to TB drugs in patients from this region. We therefore determined the pharmacokinetic characteristics of first-line TB drugs in Tanzanian patients using intensive pharmacokinetic sampling. In 20 adult TB patients, plasma concentrations were determined just before and at 1, 2, 3, 4, 6, 8, 10, and 24 h after observed drug intake with food to estimate the areas under the curve from 0 to 24 h (AUC0–24) and peak plasma concentrations (Cmax) of isoniazid, rifampin, pyrazinamide, and ethambutol. Acetylator status for isoniazid was assessed phenotypically using the isoniazid elimination half-life and the acetylisoniazid/isoniazid metabolic ratio at 3 h postdose. The geometric mean AUC0–24s were as follows: isoniazid, 11.0 h · mg/liter; rifampin, 39.9 h · mg/liter; pyrazinamide, 344 h · mg/liter; and ethambutol, 20.2 h · mg/liter. TheCmaxwas below the reference range for isoniazid in 10/19 patients and for rifampin in 7/20 patients. In none of the patients were theCmaxs for pyrazinamide and ethambutol below the reference range. Elimination half-life and metabolic ratio of isoniazid gave discordant phenotyping results in only 2/19 patients. A substantial proportion of patients had an isoniazid and/or rifampinCmaxbelow the reference range. Intake of TB drugs with food may partly explain these low drug levels, but such a drug intake reflects common practice. The finding of low TB drug concentrations is concerning because low concentrations have been associated with worse treatment outcome in several other studies.
Rho Kinase Regulates Induction of T-Cell Immune Dysfunction in Abdominal Sepsis
Authors: Hasan Z. , Palani K. , Zhang S. , Lepsenyi M. , Hwaiz R. , Rahman M. , Syk I. , Jeppsson B. , Thorlacius Henrik 
Published: April 2013

ABSTRACT

T-cell dysfunction increases susceptibility to infections in patients with sepsis. In the present study, we hypothesized that Rho kinase signaling might regulate induction of T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were treated with the specific Rho kinase inhibitor Y-27632 (5 mg/kg of body weight) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation, and percentage of regulatory T cells (CD4
+
CD25
+
Foxp3
+
) were determined by flow cytometry. Formation of gamma interferon (IFN-γ) and interleukin 4 (IL-4) in the spleen and plasma levels of HMBG1, IL-17, and IL-6 were quantified by use of enzyme-linked immunosorbent assay (ELISA). It was found that CLP evoked apoptosis and decreased proliferation in splenic CD4 T cells. Inhibition of Rho kinase activity decreased apoptosis and enhanced proliferation of CD4 T cells in septic animals. In addition, CLP-evoked induction of regulatory T cells in the spleen was abolished by Rho kinase inhibition. CLP reduced the levels of IFN-γ and IL-4 in the spleen. Pretreatment with Y-27632 inhibited the sepsis-induced decrease in IFN-γ but not IL-4 formation in the spleen. CLP increased plasma levels of high-mobility group box 1 (HMGB1) by 20-fold and IL-6 by 19-fold. Inhibition of Rho kinase decreased this CLP-evoked increase of HMGB1, IL-6, and IL-17 levels in the plasma by more than 60%, suggesting that Rho kinase regulates systemic inflammation in sepsis. Moreover, we observed that pretreatment with Y-27632 abolished CLP-induced bacteremia. Together, our novel findings indicate that Rho kinase is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, targeting Rho kinase signaling might be a useful strategy to improve T-cell immunity in patients with abdominal sepsis.
The Stimulated Innate Resistance Event in Bordetella pertussis Infection Is Dependent on Reactive Oxygen Species Production
Authors: Zurita E. , Moreno G. , Errea A. , Ormazabal M. , Rumbo M. , Hozbor D. 
Published: April 2013

ABSTRACTThe exacerbated induction of innate immune responses in airways can abrogate diverse lung infections by a phenomenon known as stimulated innate resistance (StIR). We recently demonstrated that the enhancement of innate response activation can efficiently impairBordetella pertussiscolonization in a Toll-like receptor 4 (TLR4)-dependent manner. The aim of this work was to further characterize the effect of lipopolysaccharide (LPS) on StIR and to identify the mechanisms that mediate this process. Our results showed that bacterial infection was completely abrogated in treated mice when the LPS ofB. pertussis(1 μg) was added before (48 h or 24 h), after (24 h), or simultaneously with theB. pertussischallenge (107CFU). Moreover, we detected that LPS completely cleared bacterial infection as soon as 2 h posttreatment. This timing suggests that the observed StIR phenomenon should be mediated by fast-acting antimicrobial mechanisms. Although neutrophil recruitment was already evident at this time point, depletion assays using an anti-GR1 antibody showed thatB. pertussisclearance was achieved even in the absence of neutrophils. To evaluate the possible role of free radicals in StIR, we performed animal assays using the antioxidantN-acetyl cysteine (NAC), which is known to inactivate oxidant species. NAC administration blocked theB. pertussisclearance induced by LPS. Nitrite concentrations were also increased in the LPS-treated mice; however, the inhibition of nitric oxide synthetases did not suppress the LPS-induced bacterial clearance. Taken together, our results show that reactive oxygen species (ROS) play an essential role in the TLR4-dependent innate clearance ofB. pertussis.
Pasteurella multocida Toxin as a Transporter of Non-Cell-Permeating Proteins
Authors: Bergmann Stefan , Jehle Doris , Schwan Carsten , Orth Joachim H. C. , Aktories Klaus 
Published: April 2013

ABSTRACT

The protein toxin
Pasteurella multocida
toxin (PMT) is the causative agent of atrophic rhinitis in pigs, leading to atrophy of the nasal turbinate bones by affecting osteoblasts and osteoclasts. The mechanism of PMT-induced intoxication is a deamidation of α-subunits of heterotrimeric G proteins, including Gα
q
, Gα
13
, and Gα
i
, thereby causing persistent activation of the G proteins. Here we utilized PMT as a transporter of the non-cell-permeating A domain of diphtheria toxin (DTa). Fusion proteins of PMT and DTa ADP-ribosylated elongation factor 2, the natural target of diphtheria toxin, leading to cell toxicity. PMT-DTa effects were competed by PMT, indicating binding to the same cell surface receptor. Fluorescently labeled PMT-DTa and PMT colocalized with specific markers of early and late endosomes. Bafilomycin A, which inhibits vacuolar H
+
-ATPase, blocked PMT-DTa-induced intoxication of HEK-293 cells. By constructing various PMT-DTa chimeras, we identified a minimal region of PMT necessary for uptake of DTa. The data suggest that PMT is able to transport cargo proteins into eukaryotic cells by utilizing the PMT-specific uptake route.
A cholestatic diagnostic dilemma
Authors: Kalinke Lukas , Rashid Mohammed 
Published: April 2013

A 28-year-old man with hereditary spherocytosis presented with abdominal pain and jaundice. He had severe, mainly conjugated (642 μmol/l), hyperbilirubinaemia (1033 μmol/l), with elevated liver enzymes: alkaline phosphatase (ALP) (163 IU/l), γ-glutamyltransferase (gGT) (277 IU/l) and aspartate transaminase (AST) (358 IU/l). Abdominal ultrasound and magnetic resonance cholangiopancreatography (MRCP) showed gallstones in the gallbladder but an absence of biliary duct dilation. Liver biopsy was consistent with cholestasis but showed no large duct obstruction. The cause of the cholestasis was unclear, was it a primary intrahepatic pathology or secondary to a posthepatic cause?He presented with similar symptoms days later with gallstones in the bile duct (choledocholithiasis) and underwent endoscopic retrograde cholangiopancreatography (ERCP) and cholecystectomy. This report guides one through the assessment of jaundice and serves as an example whereby the diagnosis of a common cause of illness is blurred by an atypical clinical presentation and relevant comorbidities. A diagnosis of benign recurrent intrahepatic cholestasis (BRIC) is also considered.
Inhaled hypertonic saline+hyaluronic acid in cystic fibrosis with asthma-like symptoms: a new therapeutic chance
Authors: Cresta Federico , Naselli Aldo , Favilli Federica , Casciaro Rosaria 
Published: April 2013

The aim of the paper is to report the case of a boy affected by cystic fibrosis, with non-ABPA-related recurrent wheezing and frequent pulmonary exacerbation during childhood, who had been inhaling 7% NaCl+0.1% hyaluronic acid (HA) as a maintenance therapy. We reviewed patient database and, analysing a 7-year follow-up, considered pulmonary exacerbation, antibiotic and steroid courses, pulmonary function (forced expiratory volume in one second; FEV1) and microbiological data. After starting 7% NaCl+0.1% HA treatment, we observed a dramatic decrease of oral antibiotic need (0.55 courses/month during the pretreatment period against 0.10 courses/month in the treatment period), associated with a good initial recovery and a stability of FEV1. In our opinion this case could suggest an extended indication for inhaled 7% NaCl+0.1% HA use in CF, not only in patients who did not tolerate hypertonic saline, but also in patients with coexistent asthma-like symptoms.
‘Eye is a window to the pulse’: bilateral ocular ischaemic syndrome as a presenting manifestation of Takayasu arteritis
Authors: Shailaja S , Vivek G , Shetty Ranjan , Kamath Yogish 
Published: April 2013

A 22-year-old lady presented with gradually progressive visual loss and chronic pain in both the eyes of 3 months duration. The clinical examination and fundus fluorescein angiography were suggestive of bilateral ocular ischaemic syndrome. Her upper limb pulses were feeble and blood pressure was not recordable in the same. Carotid Doppler revealed a bilateral carotid artery occlusion. Systemic markers for inflammation were elevated. Diagnosis of Takayasu arteritis was made on the basis of clinical and laboratory findings.Takayasu arteritis should be considered in the differential diagnosis of ocular ischaemic syndrome, particularly in young Asian women.
Pattern and Timing of the Coronary Sinus Activation to Guide Rapid Diagnosis of Atrial Tachycardia After Atrial Fibrillation Ablation
Authors: Pascale Patrizio , Shah Ashok J. , Roten Laurent , Scherr Daniel , Komatsu Yuki , Jadidi Amir S. , Ramoul Khaled , Daly Matthew , Denis Arnaud , Wilton Stephen B. , Derval Nicolas , Sacher Frédéric , Hocini Mélèze , Haïssaguerre Michel , Jaïs Pierre 
Published: April 2013

Background—
Atrial tachycardias (AT) during or after ablation of atrial fibrillation frequently pose a diagnostic challenge. We hypothesized that both the patterns and the timing of coronary sinus (CS) activation could facilitate AT mapping.

Methods and Results—

A total of 140 consecutive postpersistent atrial fibrillation ablation patients with sustained AT were investigated by conventional mapping. CS activation pattern was defined as chevron or reverse chevron when the activations recorded on both the proximal and the distal CS dipoles were latest or earliest, respectively. The local activation of mid-CS was timed with reference to P
peak
–P
peak
(P–P) interval in lead V1. A ratio, mid-CS activation time to AT cycle length, was computed. Of 223 diagnosed ATs, 124 were macroreentrant (56%) and 99 were centrifugal (44%). When CS activation was chevron/reverse chevron (n=44; 20%), macroreentries were mostly roof dependent. With reference to P–P interval, mid-CS activation timing showed specific consistency for peritricuspid and perimitral AT. Proximal to distal CS activation pattern and mid-CS activation at 50% to 70% of the P–P interval (n=30; 13%) diagnosed peritricuspid AT with 81% sensitivity and 89% specificity. Distal to proximal CS activation and mid-CS activation at 10% to 40% of the P–P interval (n=44; 20%) diagnosed perimitral AT with 88% sensitivity and 75% specificity.

Conclusions—
The analysis of the patterns and timing of CS activation provides a rapid stratification of most likely macroreentrant ATs and points toward the likely origin of centrifugal ATs. It can be included in a stepwise diagnostic approach to rapidly select the most critical mapping maneuvers.
Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-Induced Obesity and Glucose Intolerance
Authors: Matsuura Hirohide , Ichiki Toshihiro , Inoue Eriko , Nomura Masatoshi , Miyazaki Ryohei , Hashimoto Toru , Ikeda Jiro , Takayanagi Ryoichi , Fong Guo-Hua , Sunagawa Kenji 
Published: April 2013

Background—

Recent studies suggest that the oxygen-sensing pathway consisting of transcription factor hypoxia-inducible factor and prolyl hydroxylase domain proteins (PHDs) plays a critical role in glucose metabolism. However, the role of adipocyte PHD in the development of obesity has not been clarified. We examined whether deletion of
PHD2
, the main oxygen sensor, in adipocytes affects diet-induced obesity and associated metabolic abnormalities.

Methods and Results—

To delete
PHD2
in adipocyte,
PHD2
-floxed mice were crossed with aP2-Cre transgenic mice (
Phd2

f/f

/aP2-Cre)
.
Phd2

f/f

/aP2-Cre
mice were resistant to high-fat diet–induced obesity (36.7±1.7 versus 44.3±2.0 g in control;
P
<0.01) and showed better glucose tolerance and homeostasis model assessment–insulin resistance index than control mice (3.6±1.0 versus 11.1±2.1;
P
<0.01). The weight of white adipose tissue was lighter (epididymal fat, 758±35 versus 1208±507 mg in control;
P
<0.01) with a reduction in adipocyte size. Macrophage infiltration into white adipose tissue was also alleviated in
Phd2

f/f

/aP2-Cre
mice. Target genes of hypoxia-inducible factor, including glycolytic enzymes and adiponectin, were upregulated in adipocytes of
Phd2

f/f

/aP2-Cre
mice. Lipid content was decreased and uncoupling protein-1 expression was increased in brown adipose tissue of
Phd2

f/f

/aP2-Cre
mice. Knockdown of PHD2 in 3T3L1 adipocytes induced a decrease in the glucose level and an increase in the lactate level in the supernatant with upregulation of glycolytic enzymes and reduced lipid accumulation.

Conclusions—
PHD2 in adipose tissue plays a critical role in the development of diet-induced obesity and glucose intolerance. PHD2 might be a novel target molecule for the treatment of obesity and associated metabolic abnormalities.
Video‐Assisted Harvesting of Anterolateral Thigh Free Flap: Technique Validation and Initial Results
Authors: Moreno Mauricio Alejandro 
Published: April 2013

ObjectiveTo provide a description of a minimally invasive, video‐assisted technique (VAT) to identify the cutaneous perforators of the anterolateral thigh (ALT). The objective of the study was to compare this technique with standard open exploration of the thigh and to describe the learning curve for the procedure.Study DesignCase series with chart review.SettingAcademic tertiary institution.Subjects and MethodsTwenty‐six cases operated between December 2009 and June 2012. In all of these cases, an open thigh exploration, considered the gold standard, was performed immediately after the VAT. Data retrieved included surgical findings, demographics, and outcomes.ResultsThere were 17 men and 9 women with a mean age of 60 years. The average flap size was 91 cm2 (range, 39‐264 cm2), and a chimeric double skin paddle flap was harvested in 6 cases. Forty‐nine of 53 total perforators were successfully identified endoscopically. Findings on endoscopic and open exploration were highly correlated (r = 0.92, P =. 000). The overall sensitivity for the technique was 92.4% (confidence interval, 80.9‐97.5) but reached 100% for perforators located at the midpoint of the anterior‐superior iliac spine–patella line. All flaps survived, and there were no technique‐related complications. The learning curve plateaued after 15 cases, with a mean endoscopic operative time of 18.2 minutes for the last 10 procedures.ConclusionThis VAT is a safe and reliable method to identify cutaneous perforators of the lateral thigh. The procedure is straightforward and has a moderate learning curve. This approach has a role in minimizing donor site morbidity and assisting in flap design.
Preliminary Results of Diode Laser Surgery for Early Glottic Cancer
Authors: Tunçel Ümit , Cömert Ela 
Published: April 2013

ObjectiveTo analyze the complications and preliminary oncologic results of microscopic diode laser surgery.Study DesignProspective research.SettingAnkara Oncology Education and Research Hospital.Subjects and MethodsThis prospective study was conducted on a series of 64 patients with glottic carcinoma (Tis, T1, T2) treated with microscopic endolaryngeal diode laser surgery.ResultsFour patients had local recurrence (6.2%). Local control and larynx preservation rates were 93.8% and 100%, respectively, for all groups of patients. Two‐year disease‐free survival after primary surgery was 100% for the Tis group, 96.4% for the T1 group, and 89.7% for the T2 group. When considering anterior commissure involvement, 2‐year disease‐free survival after primary surgery was 100% for the AC0 group, 85.7% for the AC1 group, and 85.7% for the AC2 group.ConclusionOur study of microscopic diode laser resection of Tis, T1, and T2 glottic tumors showed similar oncologic results to previous reports about CO2 laser surgery. In anterior commissure tumors, both techniques had high complication and recurrence rates.
Risk factors for pulmonary tuberculosis in patients with chronic obstructive airway disease in Taiwan: a nationwide cohort study
Authors: Lee Chih-Hsin , Lee Ming-Chia , Shu Chin-Chung , Lim Chor-Shen , Wang Jann-Yuan , Lee Li-Na , Chao Kun-Mao 
Published: April 2013

Abstract

Background
An association between chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) has been described, mainly due to smoking and corticosteroid use. Whether inhaled corticosteroid (ICS) therapy is associated with an increased risk of TB remains unclear.

Methods
We selected COPD cases by using six diagnostic scenarios and control subjects from a nationwide health insurance database, and applied time-dependent Cox regression analysis to identify the risk factors for TB.

Results
Among 1,000,000 beneficiaries, 23,594 COPD cases and 47,188 non-COPD control subjects were selected. Cox regression analysis revealed that age, male gender, diabetes mellitus, end-stage renal disease, and cirrhosis, as well as COPD (hazard ratio = 2.468 [2.205–2.762]) were independent risk factors for TB. Among the COPD cases, those who developed TB received more oral corticosteroids and oral β-agonists. Time-dependent Cox regression analysis revealed that age, male gender, diabetes mellitus, low income, oral corticosteroid dose, and oral β-agonist dose, but not ICS dose, were independent risk factors for TB. The identified risk factors and their hazard ratios were similar among the COPD cases selected using different scenarios.

Conclusion
Keeping a high suspicion and regularly monitoring for the development of pulmonary TB in COPD patients are necessary, especially for those receiving higher doses of oral corticosteroids and other COPD medications. Although ICS therapy has been shown to predispose COPD patients to pneumonia in large randomized clinical trials, it does not increase the risk of TB in real world practice.