bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of Uterine Artery Dysfunction in Pregnancy Complications
Authors: Morton Jude S. , Care Alison S. , Davidge Sandra T. 
Published: February 2017

Abstract:
Pregnancy is a unique condition, and the vascular processes that are required for this undertaking are both complex and extensive. In this review, we discuss the vascular adaptations which occur in the maternal uterine arterial bed to maintain blood supply to the fetal-placental unit. In complicated pregnancies, inadequate remodeling of the uterine arteries, hormonal imbalances, and pre-existing conditions such as obesity, hypertension, diabetes etc. may lead to maladaptations of the uterine vasculature that includes increased vasoconstriction and endothelial dysfunction. Ultimately, uterine artery dysfunction results in increased vascular resistance impeding blood flow to the fetal-placental unit and limiting fetal growth and development. A strong association exists between poor fetal development in utero and later life health issues, which can include obesity, poor neurological development, and enhanced susceptibility to cardiovascular disease. Therefore, the detrimental outcomes of a complicated pregnancy are far-reaching and significantly impact the health of the population as a whole. Many treatment options to improve maternal uterine artery function and ameliorate the impact on the fetus are being considered. A particular difficulty in treating complicated pregnancies is the presence of not 1 but (at least) 2 patients. Novel approaches are required to successfully improve pregnancy outcomes and minimize the impact on later life health.
Endothelial and Perivascular Adipose Tissue Abnormalities in Obesity-Related Vascular Dysfunction: Novel Targets for Treatment
Authors: Schinzari Francesca , Tesauro Manfredi , Cardillo Carmine 
Published: February 2017

Abstract:The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. In addition to its well-established role in maintaining vascular homeostasis, the endothelium has been increasingly recognized as a key player in modulating healthy adipose tissue expansion in response to excess calories by providing adipocyte precursors and driving angiogenesis. When this increased storage need is unmet, excessive deposition of fat occurs at ectopic locations, including perivascular adipose tissue (PVAT). PVAT is in intimate contact with the vessel wall, hence affecting vascular function and structure. In lean individuals, PVAT exerts anticontractile and anti-inflammatory activities to protect the vasculature. In obesity, instead, these beneficial properties are lost and PVAT releases inflammatory mediators, promotes oxidative stress, and contributes to vascular dysfunction. The underlying mechanisms elicited by these outside-in signals include resistance to the vasodilator actions of insulin and activation of endothelin (ET)-1-mediated vasoconstriction. A number of adipokines and gut hormones, which are important modulators of food intake, energy balance, glucose and lipid metabolism, insulin sensitivity, and inflammation, have also positive vascular actions. This feature makes them promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant benefits. There is, therefore, real hope that unleashing the power of fat- and gut-derived substances might provide effective dual-action therapies for obesity and its complications.
Deferasirox–Iron Complex Formation Ratio as an Indicator of Long-term Chelation Efficacy in β-Thalassemia Major
Authors: Lu Meng-Yao , Lin Ting-Hao , Chiang Po-Hung , Kuo Pei-Hsin , Wang Ning , Wu Wen-Hsin , Lin Kai-Hsin , Wu Tzu-Hua 
Published: February 2017

Background:
β-Thalassemia major patients with higher total drug levels [deferasirox (DEFR) plus its iron complex] do not yield better serum ferritin (SF) control. This study aimed to determine the concentrations of DEFR and its iron complex (Fe-[DEFR]2) in thalassemia patients to predict the chelation efficacy in terms of SF and cardiac T2* values.

Methods:
Patients' steady-state drug levels at trough (Ctrough) and 2 hours postdose (C2h) were determined. Because iron deposition may cause changes in the hepatic metabolism of amino acids, the concentrations of 40 amino acids in plasma were also assayed at 2 hours postdose.

Results:
A total of 28 patients either dosing daily or twice daily were recruited. After a 1-month DEFR maintenance therapy, 38.8% and 30% of patients from groups of once-daily and twice-daily, respectively, had a plasma DEFR–iron complex formation ratio higher than 0.05 [High Chelation Ratio, (HCR)]. After a 6-month follow-up, those patients who had a HCR (n = 10) at C2h showed more favorable median changes in SF and cardiac T2* values (−388.0, +10.1) than those with a low DEFR–iron complex formation ratio (Low Chelation Ratio; n = 18; +10.5; +4.5) compared with the baseline. The levels of plasma l-arginine, l-alanine, l-glycine, l-norleucine, and l-serine were significantly lower in patients with the low Chelation Ratio condition than the levels in HCR patients.

Conclusions:
This therapeutic drug monitoring study revealed that a DEFR–iron complex formation ratio at C2h might be an applicable indicator of the efficacy of long-term DEFR iron chelation therapy. A better iron-control response to DEFR was observed in the patients with HCRs. The trends for the ratio might have value in dose-setting and need to be validated in a larger cohort.
Quantification of Acetaminophen and Its Metabolites in Plasma Using UPLC-MS: Doors Open to Therapeutic Drug Monitoring in Special Patient Populations
Authors: Flint Robert B. , Mian Paola , van der Nagel Bart , Slijkhuis Nuria , Koch Birgit C. P. 
Published: February 2017

Background:
Acetaminophen (APAP, paracetamol) is the most commonly used drug for pain and fever in both the United States and Europe and is considered safe when used at registered dosages. Nevertheless, differences between specific populations lead to remarkable changes in exposure to potentially toxic metabolites. Furthermore, extended knowledge is required on metabolite formation after intoxication, to optimize antidote treatment. Therefore, the authors aimed to develop and validate a quick and easy analytical method for simultaneous quantification of APAP, APAP-glucuronide, APAP-sulfate, APAP-cysteine, APAP-glutathione, APAP-mercapturate, and protein-derived APAP-cysteine in human plasma by ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry.

Methods:
The internal standard was APAP-D4 for all analytes. Chromatographic separation was achieved with a reversed-phase Acquity ultraperformance liquid chromatography HSS T3 column with a runtime of only 4.5 minutes per injected sample. Gradient elution was performed with a mobile phase consisting of ammonium acetate, formic acid in Milli-Q ultrapure water or in methanol at flow rate of 0.4 mL/minute.

Results:
A plasma volume of only 10 μL was required to achieve both adequate accuracy and precision. Calibration curves of all 6 analytes were linear. All analytes were stable for at least 48 hours in the autosampler; the high quality control of APAP-glutathione was stable for 24 hours. The method was validated according to the U.S. Food and Drug Administration guidelines.

Conclusions:
This method allows quantification of APAP and 6 metabolites, which serves purposes for research, as well as therapeutic drug monitoring. The advantage of this method is the combination of minimal injection volume, a short runtime, an easy sample preparation method, and the ability to quantify APAP and all 6 metabolites.
A Time-Dependent Model Describes Methotrexate Elimination and Supports Dynamic Modification of MRP2/ABCC2 Activity
Authors: Woillard Jean-Baptiste , Debord Jean , Benz-de-Bretagne Isabelle , Saint-Marcoux Franck , Turlure Pascal , Girault Stéphane , Abraham Julie , Choquet Sylvain , Marquet Pierre , Barin-Le Guellec Chantal 
Published: February 2017

Background:Multidrug resistance protein-2 encoded by theABCC2gene (MRP2/ABCC2), an efflux transporter expressed at the proximal renal tubule, is rate-limiting for urine excretion of coproporphyrin (UCP) isomers I and III, translating in high UCP [I/(I + III)] ratio in MRP2-deficient patients presenting with the Dubin–Johnson Syndrome. MRP2 is also a major contributor to methotrexate (MTX) clearance. As MTX is both a substrate and an inhibitor of MRP2, time course of the concentrations of MTX in blood could induce functional modification of MRP2 over time, which in turn can modify its own elimination rate.Methods:A 3-parameter time-dependent MTX population pharmacokinetic (PK) model based on a power function accounting for nonlinearity in its clearance was developed using Pmetrics in a first cohort of 41 patients (76 PK profiles) and compared with a previously published 2-compartment model developed with NONMEM and a 3-compartment model developed with ITSIM. In a second cohort (62 patients and 62 PK profiles), the association between the UCP [I/(I + III)] ratio at 3 periods [before MTX administration (P1), at the end of infusion (P2), and at hospital discharge (P3)] and the time-dependent PK parameters of MTX was investigated. Effects of genetic polymorphisms and of coadministered drugs were also studied.Results:The model developed tightly fitted the data in both cohorts. A significant inverse correlation was found between log (k1) (ie, the rate constant explaining MTX concentration decrease) and the difference in UCP [I/(I + III)] ratio between P3 and P2 (DP3) (β ± SD = −0.025 ± 0.008,P= 0.00443).Conclusions:Self-inhibition of the MRP2-dependent secretion of MTX is a plausible explanation for the time-dependent PKs of this drug. Additional studies specifically designed to evaluate this hypothesis are required.
Menopausal symptom clusters and their correlates in women with and without a history of breast cancer: a pooled data analysis from the Women's Wellness Research Program
Authors: Seib Charrlotte , Porter-Steele Janine , McGuire Amanda , McCarthy Alexandra , Balaam Sarah , Anderson Debra J. 
Published: February 2017

Abstract

Objectives:
This analysis examined climacteric symptoms clusters in women with and without breast cancer, and explored how sociodemographic, health, and modifiable lifestyle factors predicted symptom clusters.

Methods:
This pooled analysis of four Women's Wellness Research Program (WWRP) studies comprised individual-level data from 969 Australian women aged 40 to 63 years, 293 of whom had been previously treated for breast cancer and 678 without a breast cancer history. Climacteric symptoms, menopausal status, sociodemographic characteristics, and health and lifestyle factors were assessed. Principal component analysis was used to determine symptom clusters for each group separately before linear regression with backwards selection was used to identify the significant correlates of the identified clusters.

Results:
Women with a history of breast cancer reported more sleep disturbance (P < 0.01), difficulty concentrating (P < 0.01), muscular/joint pain (P < 0.01), crying (P < 0.01) and irritability (P < 0.01), and vasomotor symptoms (P < 0.01) than women from the noncancer group. Principal component analysis with quartimax rotation revealed two distinct solutions explaining 60.9% and 57.6% of the variance in the groups, respectively. For both groups, symptom clusters were increased among those with unhealthy lifestyle behaviors (and chemotherapy among the after cancer group, P < 0.05 for all), though to a lesser extent in the breast cancer group.

Conclusions:
In this study, women after treatment for breast cancer reported a broad range of bothersome climacteric symptoms. Similar symptom clusters were also noted for women with and without a history of breast cancer, though correlates differed across groups, and might reflect different underlying etiologies.
Subcutaneous testosterone-letrozole therapy before and concurrent with neoadjuvant breast chemotherapy: clinical response and therapeutic implications
Authors: Glaser Rebecca L. , York Anne E. , Dimitrakakis Constantine 
Published: February 2017

Abstract

Objective:
Hormone receptor-positive breast cancers respond favorably to subcutaneous testosterone combined with an aromatase inhibitor. However, the effect of testosterone combined with an aromatase inhibitor on tumor response to chemotherapy was unknown. This study investigated the effect of testosterone-letrozole implants on breast cancer tumor response before and during neoadjuvant chemotherapy.

Methods:
A 51-year-old woman on testosterone replacement therapy was diagnosed with hormone receptor-positive invasive breast cancer. Six weeks before starting neoadjuvant chemotherapy, the patient was treated with subcutaneous testosterone-letrozole implants and instructed to follow a low-glycemic diet. Clinical status was followed. Tumor response to “testosterone-letrozole” and subsequently, “testosterone-letrozole with chemotherapy” was monitored using serial ultrasounds and calculating tumor volume. Response to therapy was determined by change in tumor volume. Cost of therapy was evaluated.

Results:
There was a 43% reduction in tumor volume 41 days after the insertion of testosterone-letrozole implants, before starting chemotherapy. After the initiation of concurrent chemotherapy, the tumor responded at an increased rate, resulting in a complete pathologic response. Chemotherapy was tolerated. Blood counts and weight remained stable. There were no neurologic or cardiac complications from the chemotherapy. Cost of therapy is reported.

Conclusions:
Subcutaneous testosterone-letrozole was an effective treatment for this patient's breast cancer and did not interfere with chemotherapy. This novel combination implant has the potential to prevent side effects from chemotherapy, improve quality of life, and warrants further investigation.
Time since menopause and skeletal muscle estrogen receptors, PGC-1α, and AMPK
Authors: Park Young-Min , Pereira Rocio I. , Erickson Christopher B. , Swibas Tracy A. , Kang Chounghun , Van Pelt Rachael E. 
Published: February 2017

Abstract

Objective:
Short-term administration of estradiol (E2) improves insulin-stimulated glucose disposal rate in early postmenopausal (EPM) women compared with a reduction in late postmenopausal (LPM) women. The underlying mechanisms by which E2 action on glucose disposal rate reversed from beneficial early to harmful late in menopause is unknown, but might include adverse changes in estrogen receptors (ERs) or other biomarkers of cellular energy metabolism with age or duration of estrogen deficiency.

Methods:
We retrospectively analyzed skeletal muscle samples from 27 postmenopausal women who were 6 years or less past menopause (EPM; n = 13) or at least 10 years past menopause (LPM; n = 14). Fasted skeletal muscle (vastus lateralis) samples were collected after 1 week administration of transdermal E2 or placebo, in random cross-over design.

Results:
Compared with EPM, LPM had reduced skeletal muscle ERα and ERβ nuclear protein. Short-term E2 treatment did not change nuclear ERα or ERβ, but decreased cytosolic ERα, so the proportion of ERα in the nucleus compared with the cytosol tended to increase. There was a group-by-treatment interaction (P < 0.05) for nuclear proliferator-activated receptor γ co-activator 1-α and phosphorylated adenosine monophosphate-activated protein kinase, such that E2 increased these proteins in EPM, but decreased these proteins in LPM.

Conclusions:
These preliminary studies of skeletal muscle from early and late postmenopausal women treated with E2 suggest there may be declines in skeletal muscle ER and changes in the E2-mediated regulation of cellular energy homeostasis with increasing time since menopause.
Effects of a dance-based aquatic exercise program in obese postmenopausal women with knee osteoarthritis: a randomized controlled trial
Authors: Casilda-López Jesús , Valenza Marie Carmen , Cabrera-Martos Irene , Díaz-Pelegrina Ana , Moreno-Ramírez Maria Paz , Valenza-Demet Gerald 
Published: February 2017

Abstract

Objective:
To evaluate the effects of a dance-based aquatic exercise program on functionality, cardiorespiratory capacity, postexercise heart rate, and fatigue in obese postmenopausal women with knee osteoarthritis.

Methods:
A randomized controlled trial was performed. In all, 34 obese women diagnosed with knee osteoarthritis participated. Women were randomly allocated to an experimental group (n = 17) or a control group (n = 17). Participants in the experimental group were included in an 8-week dance-based aquatic exercise program conducted in community swimming pools. Those in the control group underwent a global aquatic exercise program. The primary outcome measure was functionality assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes were cardiorespiratory capacity evaluated with the 6-minute walk test, and postexercise heart rate and fatigue assessed using a visual analog scale. Variables were measured at baseline, after the intervention, and at 3-month follow-up.

Results:
A between-group analysis showed significant postintervention differences in functionality (aggregate postintervention WOMAC score of 37.30 ± 16.61 vs 41.83 ± 13.69; P = 0.048) in favor of the experimental group. In addition, significant between-group differences were found after the 8 weeks in cardiorespiratory capacity, postexercise heart rate, and fatigue. Follow-up continued to show significant differences between groups in function (aggregate WOMAC score of 38.60 ± 13.61 vs 42.60 ± 9.05; P = 0.038), postexercise heart rate, and fatigue.

Conclusions:
An 8-week dance-based exercise program significantly improved function and cardiorespiratory capacity, and decreased postexercise heart rate and fatigue. Most of these improvements were maintained at 3-month follow-up in obese postmenopausal women.
Improvements in health-related quality of life, cardio-metabolic health, and fitness in postmenopausal women after a supervised, multicomponent, adapted exercise program in a suited health promotion intervention: a multigroup study
Authors: Godoy-Izquierdo Débora , Guevara Nicolás Mendoza Ladrón de , Toral Mercedes Vélez , Galván Carlos de Teresa , Ballesteros Alberto Salamanca , García Juan F. Godoy 
Published: February 2017

Abstract

Objectives:
This study explored the multidimensional outcomes that resulted from the adherence to regular exercise among previously sedentary postmenopausal women. The exercise was managed through a supervised, multicomponent, adapted approximately 20-week program in a suited health promotion intervention.

Methods:
A multigroup, mixed-design study with between-group (intervention, sedentary, and active women) and within-subject measures (baseline, postintervention, and 3- and 12-month follow-ups) was conducted using intention-to-treat methodology. The Cervantes Scale assessed health-related quality of life (HRQoL), and several indicators of cardio-metabolic status and fitness were also assessed.

Results:
After the intervention, the participants experienced positive changes in short and long-term physical and mental health, with significant enhancements in several HRQoL dimensions, particularly mental well-being and menopause-related health and subdomains. Improvements were maintained or continued (eg, mental well-being) throughout the period, leading up to the 12-month follow-up. These outcomes were accompanied by significant improvements in cardio-metabolic status and fitness, including weight, body mass index, cardio-respiratory fitness, and flexibility.

Conclusions:
Our findings parallel previous empirical evidence showing the benefits associated with regular exercise, and add evidence to the association of positive outcomes in HRQoL with improvements in cardio-metabolic health and fitness status after the adoption of an active lifestyle.
Adam, Eve and the reflux enigma: age and sex differences across the gastro-oesophageal reflux spectrum
Authors: Royston Christine , Bardhan Karna D. 
Published: February 2017

Introduction
We present demographic differences across the gastro-oesophageal reflux disease (GORD) spectrum in a UK District General Hospital.

Patients and methods
Data were prospectively collected over 37 years. At endoscopy patients were categorized as: erosive oesophagitis (EO), Barrett’s oesophagus (BO) or nonerosive reflux disease (NER). Analysis 1: comparison of EO, BO and NER 1977–2001 when the database for GORD without BO closed. Analysis 2: demographic differences in oesophageal adenocarcinoma (OAC) in total BO population diagnosed 1977–2011.

Results
GORD 1977–2001 (n=11 944): sex, male predominance in EO and BO but not NER; male : female ratios, 1.81, 1.65, 0.87, respectively (P<0.0001); mean age at presentation, EO 54 years, BO 62 years, NER 50 years; women were older than men by 10, 7 and 6 years, respectively.
BO 1977–2011: prevalent OAC, 87/1468 (6%); male : female ratio, 4.1 (P<0.0001); incident OAC, 54/1381 (3.9%); male : female ratio, 3.5 (P<0.0001). Among all BO, more men developed OAC (3 vs. 0.9%). Within each sex, proportion of OAC higher among men (4.9 vs. 2.3%); at OAC diagnosis women were slightly but not significantly older (69.9 vs. 72.3 years, P=0.322).

Conclusion
Two views may explain our findings. First, women have either milder reflux, or reduced mucosal sensitivity hence reflux remains silent for longer. Alternatively, women genuinely develop reflux later, that is, are more protected and for longer from developing GORD and its complications. Early evidence is emerging that female sex hormones may indeed have a protective role in GORD during the reproductive period. We suggest reflux and its consequences may be an example of ‘protection’ conferred on Eve.
Carbamazepine Toxicity–Induced Spindle Coma: A Novel Case Report
Authors: Chauhan Bhumir , Patanvadiya Amitkumar , Dash Gopal Krishna 
Published: February 2017

Abstract
A 9-year-old girl presented with alleged history of deliberate ingestion of 4 g of carbamazepine, following which she became comatose. A bedside electroencephalogram (EEG) was performed to rule out nonconvulsive status epilepticus, which showed presence of spindle coma (SC), not reactive to noxious stimuli. Following hemodialysis, a second EEG showed absence of SC and complete clinical recovery. We present this unique case of carbamazepine-induced SC, thereby highlighting the extent of the etiologic spectrum of SC and discussing the literature related to this association.