bluuebunny/crossref_metadata_2025_split huggingface dataset:
Failure of Isoflurane Cardiac Preconditioning in Obese Type 2 Diabetic Mice Involves Aberrant Regulation of MicroRNA-21, Endothelial Nitric-oxide Synthase, and Mitochondrial Complex I
Authors: Ge Zhi-Dong , Li Yingchuan , Qiao Shigang , Bai Xiaowen , Warltier David C. , Kersten Judy R. , Bosnjak Zeljko J. , Liang Mingyu 
Published: October 2017

Abstract

Background
Diabetes impairs the cardioprotective effect of volatile anesthetics, yet the mechanisms are still murky. We examined the regulatory effect of isoflurane on microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I in type 2 diabetic mice.

Methods
Myocardial ischemia/reperfusion injury was produced in obese type 2 diabetic (db/db) and C57BL/6 control mice ex vivo in the presence or absence of isoflurane administered before ischemia. Cardiac microRNA-21 was quantified by real-time quantitative reverse transcriptional–polymerase chain reaction. The dimers and monomers of endothelial nitric-oxide synthase were measured by Western blot analysis. Mitochondrial nicotinamide adenine dinucleotide fluorescence was determined in Langendorff-perfused hearts.

Results
Body weight and fasting blood glucose were greater in db/db than C57BL/6 mice. Isoflurane decreased left ventricular end-diastolic pressure from 35 ± 8 mmHg in control to 23 ± 9 mmHg (P = 0.019, n = 8 mice/group, mean ± SD) and elevated ±dP/dt 2 h after post-ischemic reperfusion in C57BL/6 mice. These beneficial effects of isoflurane were lost in db/db mice. Isoflurane elevated microRNA-21 and the ratio of endothelial nitric-oxide synthase dimers/monomers and decreased mitochondrial nicotinamide adenine dinucleotide levels 5 min after ischemia in C57BL/6 but not db/db mice. MicroRNA-21 knockout blocked these favorable effects of isoflurane, whereas endothelial nitric-oxide synthase knockout had no effect on the expression of microRNA-21 but blocked the inhibitory effect of isoflurane preconditioning on nicotinamide adenine dinucleotide.

Conclusions
Failure of isoflurane cardiac preconditioning in obese type 2 diabetic db/db mice is associated with aberrant regulation of microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I.
Development and use of biochemical markers in osteoarthritis: current update
Authors: Bay-Jensen Anne C. , Thudium Christian S. , Mobasheri Ali 
Published: October 2017

Purpose of review
There is an increasing demand for noninvasive and descriptive biochemical markers (biomarkers) in osteoarthritis; for enabling early drug development (including translational research), evaluating clinical trial at an early stage and for subtyping. Purpose of the review is to review and comment on current availability of such biomarkers.

Recent findings
Many different biomarkers have been tested in the last 18 months. The main focus has been on testing whether the biomarkers, whether is reflect joint tissue turnover or inflammatory status, can differentiate osteoarthritis patients from healthy controls or whether the biomarkers are associated with progression. Less than a handful of studies, investigate the role of the biomarkers as response markers. Thus, there is still a great need for developing biomarkers that reflect disease activity and thereby can be used for treatment response or patient phenotyping.

Summary
Osteoarthritis is the most common form of joint disease. This presents the osteoarthritis research community and pharmaceutical companies developing disease-modifying osteoarthritis drugs (DMOADs) with great opportunities. There are different osteoarthritis subtypes, which complicates the traditional approaches for developing new treatments. If we can identify new markers that can distinguish different subtypes, this can greatly facilitate drug development from early discovery to late clinical development.
Preventing Wedge Deformities When Treating Intertrochanteric Femur Fractures With Intramedullary Devices: A Technical Tip
Authors: Butler Bennet A. , Selley Ryan S. , Summers Hobie D. , Stover Michael D. 
Published: October 2017

Summary:
Intertrochanteric femur fractures are common injuries associated with significant patient morbidity and mortality and high societal costs. Although intramedullary devices have shown promises for treating a wide range of intertrochanteric femur fractures, improper technique can lead to malalignment, fracture displacement, and/or iatrogenic fractures. In particular, a “wedge effect” has been described, in which the passage of conical reamers and the intramedullary nail itself results in the distraction of intertrochanteric fragments with lateralization of the shaft from the femoral neck and varus malalignment. Here, we describe the mechanism by which this deformity is generated and describe techniques for preventing it, including the use of a modified starting point and an alternative to the conical opening reamers.
Is the Best Plate a Nail? A Review of 3230 Unstable Intertrochanteric Fractures of the Proximal Femur
Authors: Tucker Adam , Donnelly Kevin J. , Rowan Clare , McDonald Sinead , Foster Andrew P. 
Published: October 2017

Objectives:
To evaluate the functional outcomes, revision, and mortality rates of 3 implants used for unstable intertrochanteric hip fractures; the sliding hip screw (SHS), with or without a trochanteric stabilization plate (TSP); and a cephalomedullary nail (CMN).

Design:
Multicentre National Prospective Cohort Study.

Setting:
Northern Ireland.

Patient/Participants:
Patients were identified from a prospective database. Fractures were classified according to OTA/AO A31A2.2, A2.3, and A3. All patients had a minimum of 12 months of follow-up.

Intervention:
Patients received either an SHS, an SHS in combination with a TSP, or a CMN. Implant choice was at the discretion of the operating surgeon.

Outcome Measure:
Primary outcome was 12-month mortality analyzed by the Kaplan–Meier survival analysis. Secondary outcomes included 12-month functional status using a validated score and all time revision of implants for any reason.

Results:
In total, 3230 patients met the inclusion criteria (2474 SHS, 158 SHS + TSP, and 598 CMN). CMN use increased over time, with concomitant reduction in SHS use. There was no significant difference in functional outcomes at 12 months (analysis of variance, P = 0.177). Although men were significantly younger, they were at a higher risk of 12-month mortality. CMNs had statistically significantly lower 12-month mortality rates (P = 0.0148). The highest revision rate (4.04%) was seen in patients treated with SHS alone (P = 0.041).

Conclusions:
The use of a CMN in unstable intertrochanteric hip fractures conveys the best results in functional outcomes, 12-month mortality, and has lower revision rates compared with an SHS ± TSP.

Level of Evidence:
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Acetabular Fractures in Children and Adolescents: Comparison of Isolated Acetabular Fractures and Acetabular Fractures Associated With Pelvic Ring Injuries
Authors: Kruppa Christiane G. , Sietsema Debra L. , Khoriaty Justin D. , Dudda Marcel , Schildhauer Thomas A. , Jones Clifford B. 
Published: October 2017

Objectives:
To compare mechanism of injury, fracture pattern, displacement, clinical, and radiographic outcome of isolated acetabular fractures (group 1) versus acetabular fractures associated with a pelvic ring injury (group 2).

Design:
Retrospective cohort comparative analysis.

Setting:
Private orthopaedic practice associated with a level one teaching trauma center.

Main Outcome Measurements:
Mechanism of injury, fracture pattern, displacement and treatment, Glasgow Coma Scale, Injury Severity Score, leg length discrepancy (LLD), and hip dysplasia.

Patients:
Thirty-two children (group 1: 12 fractures; group 2: 25) were classified as 9 A1, 21 A3, 3 B1, 3 B2, and 1 B3 OTA/AO types. Eighteen children (22 fractures) were included with average follow-up of 33.3 months (6–84). The average age was 12.8 years (4–16).

Results:
Main fracture pattern (75%) in group 1 was a posterior wall fracture (A1) caused by falls and sports in 50%. Six socket injuries had a hip dislocation, present only in group 1 (P < 0.001). The majority (84%) in group 2 had anterior wall/column (A3) fractures, caused by traffic accidents (88%). Fracture displacement in group 1 was higher than in group 2 (3.8 vs. 0.8 mm; P = 0.009). Group 2 had a lower Glasgow Coma Scale (P = 0.031) and a higher Injury Severity Score (P < 0.001). Nine (24%) fractures were treated operatively, significantly more were in group 1 (P < 0.001). Three (14%) children had complications including (LLD) (2) or hip dysplasia (2).

Conclusion:
Compared with isolated pediatric acetabular fractures, fractures associated with pelvic ring injuries have less displacement and are less likely to require operative treatment, but they show more associated injuries. Because of potential hip joint growth disturbance, LLD and hip dysplasia can occur.

Level of Evidence:
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Travel Distance as a Barrier to Receipt of Adjuvant Radiation Therapy After Radical Prostatectomy
Authors: Yang David D. , Muralidhar Vinayak , Mahal Brandon A. , Beard Clair J. , Mouw Kent W. , Martin Neil E. , Orio Peter F. , King Martin T. , Nguyen Paul L. 
Published: October 2017

Objectives:
Following radical prostatectomy (RP), adjuvant radiation therapy (RT) decreases biochemical recurrence and potentially improves metastasis-free and overall survival for patients with high-risk pathologic features. Since adjuvant RT typically occurs daily over several weeks, the logistical challenges of extensive traveling may be a significant barrier to its use. We examined the association between distance to treatment facility and use of adjuvant RT.

Materials and Methods:
We identified 97,568 patients in the National Cancer Database diagnosed from 2004 through 2011 with cT1-4N0-xM0-x prostate cancer and found to have high-risk pathologic features (pT3-4 stage and/or positive surgical margins) at RP. Multivariable logistic regression adjusting for sociodemographic and clinicopathologic factors was used to examine the association between travel distance and receipt of adjuvant RT, defined as radiotherapy initiated within 12 months after RP.

Results:
Overall, 10.6% (10,346) of the study cohort received adjuvant RT. On multivariable analysis, increasing travel distance was significantly associated with decreased use of adjuvant RT, with adjusted odds ratios of 1.0 (reference), 0.67, 0.46, 0.39, and 0.32 (all P<0.001) and prevalence of use at 12.6%, 8.8%, 6.3%, 4.9%, and 3.7% for patients living ≤25.0, 25.1 to 50.0, 50.1 to 75.0, 75.1 to 100.0, and >100.0 miles away, respectively.

Conclusions:
Increasing travel distance was strongly associated with decreased use of adjuvant RT in this national cohort of postprostatectomy patients with high-risk pathologic features. These results strongly suggest that the logistical challenges of extensive travel are a significant barrier to the use of adjuvant RT. Efforts aimed at improving access to radiotherapy and reducing treatment time are urgently needed.
Dose Escalation Study of Concurrent Chemoradiotherapy With the Use of Involved-field Conformal Radiotherapy and Accelerated Hyperfractionation in Combination With Cisplatin and Vinorelbine Chemotherapy for Stage III Non–small Cell Lung Cancer
Authors: Yoshimura Naruo , Tada Takuhito , Matsumoto Yoshiya , Sawa Kenji , Yoshimoto Naoki , Suzumura Tomohiro , Tanaka Hidenori , Mitsuoka Shigeki , Kimura Tatsuo , Tamiya Tomohiro , Hirashima Tomonori , Kawaguchi Tomoya , Kudoh Shinzoh , Hosono Masako , Hirata Kazuto 
Published: October 2017

Objectives:
A phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non–small cell lung cancer was conducted.

Materials and Methods:
We used chemotherapy of a cisplatin doublet and 2 dose levels of radiation with accelerated hyperfractionation. The radiation dose levels were: a total dose of 60 Gy in 40 fractions at level 1, and 66 Gy in 44 fractions at level 2. Eligible patients with unresectable stage III non–small cell lung cancer received cisplatin and vinorelbine. Radiation therapy started on day 2 of chemotherapy and was delivered twice daily for 5 days a week.

Results:
Total 12 patients were enrolled, with 6 patients each at dose levels 1 and 2. Dose-limiting toxicity was noted in 2 patients at level 1; one patient had grade 3 febrile neutropenia and the other patient had grade 3 esophagitis. No dose-limiting toxicity was noted in the 6 patients at level 2. Grade 3 to 4 leukopenia, neutropenia, and anemia were noted in 11 (92%), 9 (75%), and 8 (67%) of the total 12 patients, respectively. Grade 3 anorexia and infection were noted in 2 patients (17%) at each level. Grade 3 nausea, fatigue, esophagitis, and febrile neutropenia were noted in 1 patient (8%) at each level. The response rate in the total 12 patients was 83.3%. The median progression-free survival time and the median overall survival time were 10.7 and 24.2 months, respectively.

Conclusions:
Sixty-six gray in 44 fractions is the recommended dose for the following phase II study.
Association of Adverse Childhood Experiences with Co-occurring Health Conditions in Early Childhood
Authors: Bright Melissa A. , Thompson Lindsay A. 
Published: October 2017

ABSTRACT:

Objective:
To understand how adverse childhood experiences (ACEs) are associated with co-occurring physical, mental and developmental problems during early childhood.

Method:
A subsample of 19,957 children aged 2–5 years were selected from the 2011–2012 National Survey for Child Health. Outcomes included 18 health conditions organized in singular condition domains (physical, mental, and developmental), and combinations of condition domains (e.g., physical plus mental, mental plus developmental, etc.). Predictors included 8 ACEs (divorce of a parent, death of a parent, exposure to domestic violence, living with someone with a drug or alcohol abuse problem, household member with a mental illness, parent incarceration, neighborhood violence, discrimination). Multivariable logistic regression was performed controlling for demographic characteristics, having a personal doctor, health insurance coverage, and seeing a health care professional in the previous year.

Results:
Experiencing 3 or more ACEs before the age of 5 years was associated with increased likelihood of nearly every co-occurring condition combination across 3 domains of health. Most notably, experiencing 3 or more ACEs was also associated with a 2-fold increase in likelihood of having ≥1 physical condition and ≥1 developmental condition, a 9-fold increase in likelihood of having ≥1 mental and ≥1 developmental condition, and a 7-fold increase in likelihood of having ≥1 physical, ≥1 mental, and ≥1 developmental condition.

Conclusion:
This study demonstrates that we can identify the health effects of adversity quite early in development and that management should include communication between both health care and early childhood education providers.
Analytical Pitfalls of Therapeutic Drug Monitoring of Thiopurines in Patients With Inflammatory Bowel Disease
Authors: Simsek Melek , Meijer Berrie , Mulder Chris J. J. , van Bodegraven Adriaan A. , de Boer Nanne K. H. 
Published: October 2017

Abstract:
The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) metabolites are monitored and related to therapeutic response and adverse events, respectively. Therapeutic drug monitoring of thiopurines, however, is hampered by several analytical limitations resulting in an impaired translation of metabolite levels to clinical outcome in IBD. Thiopurine metabolism is cell specific and requires nucleated cells and particular enzymes for 6-TGN formation. In the current therapeutic drug monitoring, metabolite levels are assessed in erythrocytes, whereas leukocytes are considered the main target cells of these drugs. Furthermore, currently used methods do not distinguish between active nucleotides and their unwanted residual products. Last, there is a lack of a standardized laboratorial procedure for metabolite assessment regarding the substantial instability of erythrocyte 6-TGN. To improve thiopurine therapy in patients with IBD, it is necessary to understand these limitations and recognize the general misconceptions in this procedure.
Serum Concentrations of Paliperidone After Administration of the Long-Acting Injectable Formulation
Authors: Helland Arne , Spigset Olav 
Published: October 2017

Background:
The pharmacokinetics of long-acting intramuscular paliperidone in a naturalistic setting is not well documented. The objective of this study was to investigate the relationship between dose and serum concentrations of paliperidone using data from a routine therapeutic drug monitoring service.

Methods:
Serum concentration measurements in 310 samples from 110 male and 75 female patients receiving depot injections of paliperidone were retrospectively retrieved from the therapeutic drug monitoring database.

Results:
The median dose was 100 mg every 28 days. The median concentration/dose (C/D) ratio of paliperidone was 16.1 (nmol/L)/(mg/d), with a 10–90 percentile range of 7.8–31.0 (nmol/L)/(mg/d). Dose-adjusted serum concentrations were 33% higher in patients 65 years or older and more than 50% lower in patients taking the p-glycoprotein inducer carbamazepine. There were no significant effects of sex or dose on the C/D ratio. The median serum concentrations of paliperidone at the end of the dose interval were 31 nmol/L at an intramuscular dose of 50 mg/28 d, 53 nmol/L after a dose of 75 mg/28 d, 59 nmol/L after a dose of 100 mg/28 d, and 93 nmol/L after a dose of 150 mg/28 d. Forty-five percent of the measurements were lower than the suggested therapeutic range of 20–60 ng/mL (47–140 nmol/L).

Conclusions:
The data show a 4-fold interindividual difference in dose-adjusted serum concentrations within the 10–90 percentile range and illustrate the significant effects of age and p-glycoprotein induction on the pharmacokinetics of paliperidone. The study also indicates that at least in some patients, it might take longer time than anticipated to reach steady state.
Development of a Liquid Chromatography–Tandem Mass Spectrometric Method for Quantification of Mycophenolic Acid and Its Glucuronides in Dried Blood Spot Samples
Authors: Iboshi Hiromasa , Yamaguchi Hiroaki , Suzuki Hiroyuki , Kikuchi Masafumi , Tanaka Masaki , Takasaki Shinya , Takahashi Akiko , Maekawa Masamitsu , Shimada Miki , Matsuda Yasushi , Okada Yoshinori , Mano Nariyasu 
Published: October 2017

Background:
Personalized immunosuppressive therapy, including accurate drug dosing based on the drug blood level, leads to better clinical outcomes, specifically regarding avoidance of drug-induced adverse effects and maintenance of efficacy. Mycophenolic acid (MPA) is used as an immunosuppressant in transplantation of various solid organs. The aim of this study was to develop a method for quantification of MPA and its metabolites, mycophenolic acid 7-O-glucuronide (MPAG) and mycophenolic acid acyl glucuronide, in dried blood spot (DBS) samples, using liquid chromatography/electrospray ionization/tandem mass spectrometry.

Methods:
For sample preparation, a microwave-drying approach was used to deactivate enzymes and reduce drying time. Blood volume was calculated in a DBS disk of 3 mm diameter. Concentrations of analytes in plasma from patients receiving mycophenolate mofetil were compared with DBS samples after hematocrit correction.

Results:
The method yielded good recoveries of all 3 analytes (90.3%–104.2%). Blood volume in the disk was calculated as 3.0 ± 0.2 μL. Linearity over concentration ranges of 0.1–30 mcg/mL MPA, 0.1–200 mcg/mL MPAG, and 0.125–10 mcg/mL mycophenolic acid acyl glucuronide was obtained with r2 ≥0.999. Intraday and interday variations were less than 14.6%, and accuracy was within ±11.9%. Passing–Bablok analysis showed no significant differences between plasma concentrations and DBS concentrations after hematocrit correction of MPA and MPAG.

Conclusions:
We developed and validated a liquid chromatography/electrospray ionization–tandem mass spectrometry method for analysis of MPA in DBS samples. The method is useful for monitoring the MPA blood level.
AUTOLOGOUS LENS CAPSULAR FLAP TRANSPLANTATION COMBINED WITH AUTOLOGOUS BLOOD APPLICATION IN THE MANAGEMENT OF REFRACTORY MACULAR HOLE
Authors: Peng Jie , Chen Chunli , Jin Haiying , Zhang Hongtao , Zhao Peiquan 
Published: October 2017

Purpose:
To report results of lens capsular flap transplantation (LCFT) and autologous whole blood application in refractory macular hole (MH) treatment.

Methods:
Seven phakic and three aphakic eyes with persistent MH after standard surgery with internal limiting membrane peeling were studied. Lens capsule flap was acquired from the same eye in eight cases (seven phakic and one aphakic). The fellow eye was used in two aphakic eyes without sufficient lens capsule. The fellow eye underwent simultaneous phacoemulsification. All eyes underwent complete vitrectomy, LCFT into the MH, whole blood application, and 15% perfluoropropane (C3F8) tamponade. The patients were instructed to maintain a face-down or prone position for two weeks postoperatively. Structural and functional changes were evaluated.

Results:
The mean preoperative MH diameter was 1,472.78 ± 736.88 μm. The MH was completely closed in nine eyes: eight eyes receiving same-eye LCFT and one receiving fellow-eye LCFT. In the other fellow-eye LCFT recipient, the MH was partially closed. Visual acuity improved from 1.84 ± 0.49 logarithm of the minimum angle of resolution (median Snellen acuity: 20/1,750, range: 20/4,000–20/125) preoperatively to 1.34 ± 0.59 logarithm of the minimum angle of resolution (median Snellen acuity: 20/450, range: 20/4,000–20/63) postoperatively (P = 0.009).

Conclusion:
Lens capsular flap transplantation and autologous whole blood application may improve anatomical and visual outcomes in refractory MH cases. The lens equator and fellow eye may be promising sources of LCF.