bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy
Authors: Hum Julia M. , O’Bryan Linda M. , Tatiparthi Arun K. , Clinkenbeard Erica L. , Ni Pu , Cramer Martin S. , Bhaskaran Manoj , Johnson Robert L. , Wilson Jonathan M. , Smith Rosamund C. , White Kenneth E. 
Published: January 2019

Diabetic nephropathy (DN) is a primary cause of end-stage renal disease and is becoming more prevalent because of the global rise in type 2 diabetes. A model of DN, the db/db uninephrectomized ( db/db-uni) mouse, is characterized by obesity, as well as compromised renal function. This model also manifests defects in mineral metabolism common in DN, including hyperphosphatemia, which leads to severe endocrine disease. The FGF23 coreceptor, α-Klotho, circulates as a soluble, cleaved form (cKL) and may directly influence phosphate handling. Our study sought to test the effects of cKL on mineral metabolism in db/db-uni mice. Mice were placed into either mild or moderate disease groups on the basis of the albumin-to-creatinine ratio (ACR). Body weights of db/db-uni mice were significantly greater across the study compared with lean controls regardless of disease severity. Adeno-associated cKL administration was associated with increased serum Klotho, intact, bioactive FGF23 (iFGF23), and COOH-terminal fragments of FGF23 ( P < 0.05). Blood urea nitrogen was improved after cKL administration, and cKL corrected hyperphosphatemia in the high- and low-ACR db/db-uni groups. Interestingly, 2 wk after cKL delivery, blood glucose levels were significantly reduced in db/db-uni mice with high ACR ( P < 0.05). Interestingly, several genes associated with stabilizing active iFGF23 were also increased in the osteoblastic UMR-106 cell line with cKL treatment. In summary, delivery of cKL to a model of DN normalized blood phosphate levels regardless of disease severity, supporting the concept that targeting cKL-affected pathways could provide future therapeutic avenues in DN. NEW & NOTEWORTHY In this work, systemic and continuous delivery of the “soluble” or “cleaved” form of the FGF23 coreceptor α-Klotho (cKL) via adeno-associated virus to a rodent model of diabetic nephropathy (DN), the db/db uninephrectomized mouse, normalized blood phosphate levels regardless of disease severity. This work supports the concept that targeting cKL-affected pathways could provide future therapeutic avenues for the severe mineral metabolism defects associated with DN.
Exercise-induced hyperemia is associated with knee extensor fatigability in adults with type 2 diabetes
Authors: Senefeld Jonathon W. , Limberg Jacqueline K. , Lukaszewicz Kathleen M. , Hunter Sandra K. 
Published: January 2019

The aim of this study was to compare fatigability, contractile function, and blood flow to the knee extensor muscles after dynamic exercise in patients with type 2 diabetes mellitus (T2DM) and controls. The hypotheses were that patients with T2DM would demonstrate greater fatigability than controls, and greater fatigability would be associated with a lower exercise-induced increase in blood flow and greater impairments in contractile function. Patients with T2DM ( n = 15; 8 men; 62.4 ± 9.0 yr; 30.4 ± 7.7 kg/m2; 7,144 ± 3,294 steps/day) and 15 healthy control subjects (8 men, 58.4 ± 6.9 yr; 28.4 ± 4.6 kg/m2; 7,893 ± 2,323 steps/day) were matched for age, sex, body mass index, and physical activity. Fatigability was quantified as the reduction in knee extensor power during a 6-min dynamic exercise. Before and after exercise, vascular ultrasonography and electrical stimulation were used to assess skeletal muscle blood flow and contractile properties, respectively. Patients with T2DM had greater fatigability (30.0 ± 20.1% vs. 14.6 ± 19.0%, P < 0.001) and lower exercise-induced hyperemia (177 ± 90% vs. 194 ± 79%, P = 0.04) than controls but similar reductions in the electrically evoked twitch amplitude (37.6 ± 24.8% vs. 31.6 ± 30.1%, P = 0.98). Greater fatigability of the knee extensor muscles was associated with postexercise reductions in twitch amplitude ( r = 0.64, P = 0.001) and lesser exercise-induced hyperemia ( r = −0.56, P = 0.009). Patients with T2DM had greater lower-limb fatigability during dynamic exercise, which was associated with reduced contractile function and lower skeletal muscle blood flow. Thus, treatments focused on enhancing perfusion and reversing impairments in contractile function in patients with T2DM may offset lower-limb fatigability and aid in increasing exercise capacity. NEW & NOTEWORTHY Although prior studies compare patients with type 2 diabetes mellitus (T2DM) with lean controls, our study includes controls matched for age, body mass, and physical activity to more closely assess the effects of T2DM. Patients with T2DM demonstrated no impairment in macrovascular endothelial function, evidenced by similar flow-mediated dilation to controls. However, patients with T2DM had greater fatigability and reduced exercise-induced increase in blood flow (hyperemia) after a lower-limb dynamic fatiguing exercise compared with controls.
CREBBP/EP300 Bromodomain Inhibition Affects the Proliferation of AR-Positive Breast Cancer Cell Lines
Authors: Garcia-Carpizo Veronica , Ruiz-Llorente Sergio , Sarmentero Jacinto , González-Corpas Ana , Barrero Maria J. 
Published: January 2019

Abstract

Inhibitors that prevent the binding of bromodomains to acetylated histones hold therapeutic potential. However, the effects of targeting most of the 60 different bromodomains found in the human proteome remain unexplored. Here, we investigate the molecular mechanisms responsible for the antiproliferative properties of CREBBP/EP300 bromodomain inhibition in ER-negative breast cancer cell lines. We show using genetic and chemical approaches that CREBBP/EP300 bromodomains are critical to support the proliferation of the triple-negative breast cancer cell line MDA-MB-453. Analysis of the transcriptional pathways affected by CREBBP/EP300 bromodomain inhibitors reveals that the expression of genes associated with super-enhancers is downregulated, which in turn are occupied by very high levels of androgen receptor (AR) in MDA-MB-453 cells. Treatment of MDA-MB-453 with CREBBP/EP300 bromodomain inhibitors downregulates the expression of an AR-dependent signature distinctive of breast cancer tumors that express AR and causes a decrease in H3K27ac levels at AR-binding sites. In accordance, in prostate cancer cell lines that express AR CREBBP/EP300 bromodomain inhibitors downregulate the expression of genes bound by AR and associated with super-enhancers. In summary, we report that triple-negative breast cancer cell lines that express AR are particularly sensitive to CREBBP/EP300 bromodomain inhibitors and consequently these inhibitors hold potential to treat this type of cancer.

Implications:
AR-dependent cancer cell lines are sensitive to CREBBP/EP300 bromodomain inhibitors
The Tumor Suppressor FBW7 and the Vitamin D Receptor Are Mutual Cofactors in Protein Turnover and Transcriptional Regulation
Authors: Salehi-Tabar Reyhaneh , Memari Babak , Wong Hilary , Dimitrov Vassil , Rochel Natacha , White John H. 
Published: January 2019

Abstract

The E3 ligase and tumor suppressor FBW7 targets drivers of cell-cycle progression such as the oncogenic transcription factor c-MYC, for proteasomal degradation. Vitamin D signaling regulates c-MYC expression and turnover in vitro and in vivo, which is highly significant as epidemiologic data link vitamin D deficiency to increased cancer incidence. We hypothesized that FBW7 and the vitamin D receptor (VDR) controlled each other's function as regulators of protein turnover and gene transcription, respectively. We found that hormonal 1,25-dihydroxyvitamin D3 (1,25D) rapidly enhanced the interaction of FBW7 with VDR and with c-MYC, whereas it blocked FBW7 binding to c-MYC antagonist MXD1. 1,25D stimulated the recruitment of FBW7, SCF complex subunits, and ubiquitin to DNA-bound c-MYC, consistent with 1,25D-regulated c-MYC degradation on DNA. 1,25D also accelerated the turnover of other FBW7 target proteins such as Cyclin E, c-JUN, MCL1, and AIB1, and, importantly, FBW7 depletion attenuated the 1,25D-induced cell-cycle arrest. Although the VDR contains a consensus FBW7 recognition motif in a VDR-specific insertion domain, its mutation did not affect FBW7–VDR interactions, and FBW7 ablation did not stabilize the VDR. Remarkably, however, FBW7 is essential for optimal VDR gene expression. In addition, the FBW7 and SCF complex subunits are recruited to 1,25D-induced genes and FBW7 depletion inhibited the 1,25D-dependent transactivation. Collectively, these data show that the VDR and FBW7 are mutual cofactors, and provide a mechanistic basis for the cancer-preventive actions of vitamin D.

Implications:
The key findings show that the VDR and the E3 ligase FBW7 regulate each other's functions in transcriptional regulation and control of protein turnover, respectively, and provide a molecular basis for cancer-preventive actions of vitamin D.
Visual Overview: http://mcr.aacrjournals.org/content/17/3/709/F1.large.jpg.
Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale
Authors: Rønning Ole Morten , Logallo Nicola , Thommessen Bente , Tobro Håkon , Novotny Vojtech , Kvistad Christopher E. , Aamodt Anne Hege , Næss Halvor , Waje-Andreassen Ulrike , Thomassen Lars 
Published: January 2019

Background and Purpose—
Thrombolysis with alteplase has beneficial effect on outcome and is safe within 4.5 hours. The present study compares the efficacy and safety of tenecteplase and alteplase in patients treated 3 to 4.5 hours after ischemic stroke.

Methods—
The data are from a prespecified substudy of patients included in The NOR-TEST (Norwegian Tenecteplase Stroke Trial), a randomized control trial comparing tenecteplase with alteplase.

Results—
The median admission National Institutes of Health Stroke Scale for this study population was 3 (interquartile range, 2–6). In the intention-to-treat analysis, 57% of patients that received tenecteplase and 53% of patients that received alteplase reached good functional outcome (modified Rankin Scale score of 0–1) at 3 months (odds ratio, 1.19; 95% CI, 0.68–2.10). The rates of intracranial hemorrhage in the first 48 hours were 5.7% in the tenecteplase group and 6.7% in the alteplase group (odds ratio, 0.84; 95% CI, 0.26–2.70). At 3 months, mortality was 5.7% and 4.5%, respectively. After excluding stroke mimics and patients with modified Rankin Scale score of >1 before stroke, the proportion of patients with good functional outcome was 61% in the tenecteplase group and 57% in the alteplase group (odds ratio, 1.24; 95% CI, 0.65–2.37).

Conclusions—
Tenecteplase is at least as effective as alteplase to achieve a good clinical outcome in patients with mild stroke treated between 3 and 4.5 hours after ischemic stroke.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01949948.
Uncertainty Estimates for SeaSonde HF Radar Ocean Current Observations
Authors: Emery Brian , Washburn Libe 
Published: January 2019

Abstract
HF radars typically produce maps of surface current velocities without estimates of the measurement uncertainties. Many users of HF radar data, including spill response and search and rescue operations, incorporate these observations into models and would thus benefit from quantified uncertainties. Using both simulations and coincident observations from the baseline between two operational SeaSonde HF radars, we demonstrate the utility of expressions for estimating the uncertainty in the direction obtained with the Multiple Signal Classification (MUSIC) algorithm. Simulations of radar backscatter using surface currents from the Regional Ocean Modeling System show a close correspondence between direction of arrival (DOA) errors and estimated uncertainties, with mean values of 15° at 10 dB, falling to less than 3° at 30 dB. Observations from two operational SeaSondes have average DOA uncertainties of 2.7° and 3.8°, with a fraction of the observations (10.5% and 7.1%, respectively) having uncertainties of &gt;10°. Using DOA uncertainties for data quality control improves time series comparison statistics between the two radars, with r2=0.6 increasing to r2=0.75 and RMS difference decreasing from 15 to 12 cm s−1. The analysis illustrates the major sources of error in oceanographic HF radars and suggests that the DOA uncertainties are suitable for assimilation into numerical models.
Systematic Review of Hormonal Contraception and Risk of Venous Thrombosis
Authors: Keenan Lynn , Kerr Tyson , Duane Marguerite , Van Gundy Karl 
Published: January 2019

Background: Hormonal contraception (HC) is widely used throughout the world and has been associated with venous thrombosis (VT) such as deep vein thrombosis, pulmonary emboli, and cerebral VT. Objectives: To provide a current comprehensive overview of the risk of objectively confirmed VT with HC in healthy women compared to nonusers. Search methods: PubMed was searched from inception to April 2018 for eligible studies in the English language, with hand searching from past systematic reviews. Selection criteria: We selected original research evaluating risk of objectively confirmed VT in healthy women taking oral or nonoral HC compared with nonusers. Data collection: The primary outcome of interest was a fatal or nonfatal VT in users of HC compared to nonusers or past users. Studies with at least twenty events were eligible. Adjusted relative risks with 95 percent confidence intervals were reported. Three independent reviewers extracted data from selected studies. Results: 1,962 publications were retrieved through the search strategy, with 15 publications included. Users of oral contraception with levonorgesterol had increased risk of VT by a range of 2.79–4.07, while other oral hormonal preparations increased risk by 4.0–48.6. Levonorgestrel intrauterine devices did not increase risk. Etonogestrel/ethinyl estradiol vaginal rings increased the risk of VT by 6.5. Norelgestromin/ethinyl estradiol patches increased risk of VT by 7.9. Etonogestrel subcutaneous implants by 1.4 and depot-medroxyprogesterone by 3.6. The risk of fatal VT was increased in women aged fifteen to twenty-four by 18.8-fold. Conclusion: Users of HC have a significant increased risk of VT compared to nonusers. Current risks would project at least 300–400 healthy young women dying yearly in the United States due to HC. Women should be informed of these risks and offered education in fertility-awareness-based methods with comparable efficacy for family planning. Summary: HC is widely used throughout the world and has been associated with blood clots in the legs and lungs. We searched the literature and found the risks of currently used forms of birth control increased between three- and ninefold for blood clots for healthy women. The risks found would project 300–400 women dying from using HC each year in the United States.
Reliability of Americleft Yardstick Nasolabial Appearance Assessment With/Without Basal View for Japanese Children With Unilateral Complete Cleft Lip and Palate
Authors: Amir Muhammad Subhan , Fuchigami Takao , Kibe Toshiro , Tezuka Masahiro , Ishihata Kiyohide , Nakamura Norifumi 
Published: January 2019

Objective: There is debate on the reliability of the Americleft Yardstick (AY) global nasolabial appearance assessment method. The objective was to analyze the effect of the additional basal view (BV) feature on the reliability of the AY method for Japanese children with complete cleft lip and palate (CUCLP). Design: Blind retrospective analysis of clinical records on 43 patients (5- to 7-year-old) with nonsyndromic CUCLP who underwent primary lip repair from 2005 to 2011. Main Outcome Measure: Color pictures published in AY and Rubin’s studies were used as reference pictures. Patients’ photographs were cropped and rated on a 5-point scale for the vermilion border (VB), nasolabial frontal (NLF), and nasolabial profile (NLP) according to AY with/without BV assessment by Rubin’s methods. Rating was performed twice by 3 oral surgeons. Intra- and inter-rater reliabilities were analyzed using weighted κ, and correlations between BV and other features were analyzed. Results: Overall average assessment scores were 2.742 (0.573) with AY and 2.702 (0.489) with AY+BV methods ( P = .728). Average intra-rater reliabilities were 0.605 and 0.611 and average inter-rater reliabilities were 0.525 and 0.48 with AY and AY+BV, respectively. Inter-rater reliability was the lowest for NLP. ρ scores between BV versus VB, NLF, and NLP were 0.025, 0.659, and 0.092, respectively. Conclusions: Present study demonstrates moderate intra- and inter-rater reliabilities obtained with the AY assessment method for Japanese children with CUCLP. Nasolabial profile standard ambiguity may lead to the poor reliability of AY assessment. Addition of the BV feature does not improve overall reliability.
National survey of telemedicine education and training in medical schools in France
Authors: Yaghobian Sarina , Ohannessian Robin , Mathieu-Fritz Alexandre , Moulin Thierry 
Published: January 2019

Introduction Telemedicine is a remote medical practice using information communication technology (ICT), and has been increasing in France since 2009. With all new forms of medical practice, education and training (ET) is required for quality and safety. To date, implementation of telemedicine ET has not been assessed in France. The objective of this study was to describe the implementation of telemedicine ET and evaluate the knowledge, attitudes and practices (KAP) of deans and associate deans from all medical schools in France. Methods A cross-sectional non-mandatory, descriptive online survey with a self-administered questionnaire was performed from 15 November to 6 December, 2017. Respondents were accessed through the ‘ Conférence des doyens des Facultés de médecine’. Results There were 48 respondents with a 47.4% response rate among deans. Telemedicine ET was limited in France; 10.4% in 1st year medicine (PACES); 4% in the final 3 years of medical school (D.F.A.S.M.) and 18.8% in medical residency. Emergency medicine, dermatology, radiology, neurology and geriatrics were specialties with implemented telemedicine training during residency. Of all respondents, 90% expressed a need to increase telemedicine ET, among which 75% accepted external support. A highly positive attitude towards telemedicine practice was reflected by 60.4% of respondents, and 56.2% practiced telemedicine at least once. Discussion This study was the first to assess national telemedicine ET implementation in France. Telemedicine was integrated into initial medical education; however, telemedicine ET remains limited despite the positive attitudes of deans and associate deans. Further research would need to be conducted on telemedicine ET implementation and KAP of medical students and residents.
Treatment of Mechanical Aortic Valve Thrombosis Fibrinolytic Treatment versus Surgical Intervention: Result of Eight Cases
Authors: Yay Kerem , Boysan Emre , Irdem Ahmet , Cetin Erdem , Altinay Levent , Tutun Ufuk , Cicekcioglu Ferit , Katircioglu Salih Fehmi 
Published: January 2019

Objective Thrombosis of mechanical heart valve prosthesis is a rare fatal complication after heart valve replacement. Although surgical intervention is the suggested treatment in many series, fibrinolytic treatment offers a good alternative. We describe eight cases with mechanical aortic valve thrombosis and compare their results after fibrinolytic treatment or redo aortic valve replacement. Methods Between February 2008 and March 2009, eight patients with previous mechanical prosthetic aortic valve replacement history were admitted to our center with mechanical aortic valve thrombosis. Four patients were operated, and the remaining four patients received low-dose fibrinolytic treatment. All patients’ data were collected prospectively. Results Two of the four operated patients died. In the fibrinolytic group, all patients totally recovered, and there was no mortality or morbidity during the follow-up period. Conclusions We thought that fibrinolytic treatment is a feasible and effective method for thrombosed mechanical aortic valve. However, much more populated patient groups are needed for the vigorous inference.
Video-Assisted Thoracoscopic Lobectomy in Children: Safety and Efficacy Compared with the Conventional Thoracotomy Approach
Authors: Seong Yong Won , Yoo Byung Su , Kim Jin Tae , Park In Kyu , Kang Chang Hyun , Kim Young Tae 
Published: January 2019

Objective There have been only small numbers of reports for video-assisted thoracoscopic surgery (VATS) lobectomy in children because of its technically demanding aspects. This study was performed to evaluate the safety and the efficacy of the VATS lobectomy compared with the conventional lobectomy by thoracotomy and to investigate the risk factors of thoracotomy conversion. Methods From May 2005 to October 2010, a total of 37 pediatric patients underwent VATS lobectomy and 28 pediatric patients underwent conventional lobectomy. The VATS lobectomy group consisted of relatively older patients compared with the thoracotomy group. Clinical outcomes from the two groups were analyzed and compared. Results Of the 37 patients in the VATS group, 8 patients (23%) required thoracotomy conversion and 29 patients (77%) were successfully operated on thoracoscopically. There were no in-hospital mortalities in both groups. Annual thoracotomy conversion rate has decreased from 50% in 2005 to 9% in 2010. There were no significant differences in the outcome between the VATS group and the thoracotomy group. Morbidities in the VATS group included prolonged drainage longer than 7 days (two patients), prolonged air leakage (two patients), and bleeding (one patient). There was no difference in the incidence of morbidities between the two groups. Univariate analyses revealed failure of single-lung ventilation (P = 0.007) and history of pneumonia (P = 0.001) to be risk factors of thoracotomy conversion. Conclusions Video-assisted thoracoscopic surgery lobectomy in children is a safe and effective treatment modality, with results comparable with those of conventional lobectomy. In the univariate analysis, failure of single-lung ventilation and history of pneumonia were the two factors related to thoracotomy conversion.