(1) Background: Aorta hemodynamics have been associated with aortic remodeling, but the reproducibility of its assessment has been evaluated marginally in patients with thoracic aortic aneurysm ...(TAA). The current study evaluated intra- and interobserver reproducibility of 4D flow MRI-derived hemodynamic parameters (normalized flow displacement, flow jet angle, wall shear stress (WSS) magnitude, axial WSS, circumferential WSS, WSS angle, vorticity, helicity, and local normalized helicity (LNH)) in TAA patients; (2) Methods: The thoracic aorta of 20 patients was semi-automatically segmented on 4D flow MRI data in 5 systolic phases by 3 different observers. Each time-dependent segmentation was manually improved and partitioned into six anatomical segments. The hemodynamic parameters were quantified per phase and segment. The coefficient of variation (COV) and intraclass correlation coefficient (ICC) were calculated; (3) Results: A total of 2400 lumen segments were analyzed. The mean aneurysm diameter was 50.8 ± 2.7 mm. The intra- and interobserver analysis demonstrated a good reproducibility (COV = 16–30% and ICC = 0.84–0.94) for normalized flow displacement and jet angle, a very good-to-excellent reproducibility (COV = 3–26% and ICC = 0.87–1.00) for all WSS components, helicity and LNH, and an excellent reproducibility (COV = 3–10% and ICC = 0.96–1.00) for vorticity; (4) Conclusion: 4D flow MRI-derived hemodynamic parameters are reproducible within the thoracic aorta in TAA patients.
To determine the effects of pre-synchronization and delayed fixed-time artificial insemination (TAI) on pregnancy rates (PR/AI) with sexed semen, 1,844 beef heifers were enrolled in a completely ...randomized design at 12 locations. Within a location, the heifers were randomly assigned to one of the five treatments: (1 and 2), heifers were administered prostaglandin F
2α
(PGF) on Day -7, gonadotropin-releasing hormone (GnRH), and a controlled internal drug releasing (CIDR) insert on Day 0, PGF at CIDR removal on Day 7, and a second injection of GnRH at TAI 72 h later with either conventional (CTRL72-CNV) or sexed semen (CTRL72-SEX); (3 and 4), treated the same as CTRL72 but received a CIDR insert on Day -7 at PGF administration and TAI at 60 h with either conventional (CIDR60-CNV) or sexed semen (CIDR60-SEX); (5), treated the same as CIDR60 but had TAI delayed to 72 h with sexed semen (CIDR72-SEX). Estrus detection patches were applied to all heifers on Day 7 and were evaluated for activation at TAI. Estrus expression did not differ (
p
= 0.92) between CIDR60 and CIDR72 heifers, but was greater (
p
< 0.001) in CIDR60 and CIDR72 heifers compared with CTRL72 heifers. Among treatments, PR/AI differed (
p
< 0.001) and were greater (
p
≤ 0.003) in CTRL72-CNV and CIDR60-CNV heifers than CIDR60-SEX and CIDR72-SEX heifers (51.6 and 48.1 vs. 37.5 and 25.3%, respectively). In addition, PR/AI were greater (
p
< 0.001) in CTRL72-SEX and CIDR60-SEX heifers when compared with CIDR72-SEX (42.0 and 37.5 vs. 25.3%, respectively) heifers but only tended (
p
= 0.09) to differ between CTRL72-SEX and CIDR60-CNV heifers. No differences (
p
= 0.33) were determined between CTRL72-CNV and CIDR60-CNV or between CTRL72-SEX and CIDR60-SEX heifers (
p
= 0.22). In conclusion, no differences were determined between heifers pre-synchronized with only PGF and those pre-synchronized with PGF and a CIDR insert when inseminated with either conventional or sexed semen. Therefore, the use of a CIDR insert for an additional 7 days was not beneficial to PR/AI when heifers were TAI at 60 h with either conventional or sexed semen. Furthermore, delaying TAI to 72 h with sexed semen after pre-synchronization with both PGF and a CIDR insert had a negative impact on PR/AI.
Chronic kidney disease is a major contributor to human and companion animal morbidity and mortality. Renal complications are sequelae of canine and human visceral leishmaniasis (VL). Despite the high ...incidence of infection-mediated glomerulonephritis, little is known about pathogenesis of VL-associated renal disease. Leishmania infantum –infected dogs are a naturally occurring model of VL-associated glomerulonephritis. Membranoproliferative glomerulonephritis type I 24 of 25 (96%), with interstitial lymphoplasmacytic nephritis 23 of 25 (92%), and glomerular and interstitial fibrosis 12 of 25 (48%) were predominant lesions. An ultrastructural evaluation of glomeruli from animals with VL identified mesangial cell proliferation and interposition. Immunohistochemistry demonstrated significant Leishmania antigen, IgG, and C3b deposition in VL dog glomeruli. Asymptomatic and symptomatic dogs had increased glomerular nucleotide-binding domain leucine-rich repeat–containing-like receptor family, pyrin domain containing 3 and autophagosome-associated microtubule-associated protein 1 light chain 3 associated with glomerular lesion severity. Transcriptional analyses from symptomatic dogs confirmed induction of autophagy and inflammasome genes within glomeruli and tubules. On the basis of temporal VL staging, glomerulonephritis was initiated by IgG and complement deposition. This deposition preceded presence of nucleotide-binding domain leucine-rich repeat–containing-like receptor family, pyrin domain containing 3–associated inflammasomes and increased light chain 3 puncta indicative of autophagosomes in glomeruli from dogs with clinical VL and renal failure. These findings indicate potential roles for inflammasome complexes in glomerular damage during VL and autophagy in ensuing cellular responses.
Purpose The 2012 American Urological Association (AUA) vasectomy guidelines recommend the finding of rare nonmotile sperm, representing 100,000 or fewer nonmotile sperm per ml, as a metric of ...post-vasectomy success. At our institution success was previously defined as 2 sequential azoospermic centrifuged semen pellets. The criteria change of including rare nonmotile sperm as a success end point may simplify post-vasectomy followup and decrease the number of post-vasectomy semen analyses required to assure occlusive success. Materials and Methods In the context of the new 2012 guidelines we retrospectively reviewed and analyzed the records of 972 of the 1,740 vasectomies (55.9%) performed between January 2000 and June 2012 after which at least 1 post-vasectomy semen analysis was done. Results A total of 1,919 post-vasectomy semen analyses were obtained from 972 patients with a mean ± SE age of 39.7 ± 0.2 years. Occlusive success was evident in 337 azoospermic men (36.4%), while 514 (52.9%) underwent 2 or more post-vasectomy semen analyses and 458 (47.1%) returned for a single post-vasectomy semen analysis but were lost to followup. Of these noncompliant patients 76.0% were azoospermic, 19.7% had rare nonmotile sperm, 1.5% had greater than 100,000 nonmotile sperm per ml and 2.8% had motile sperm. Three patients underwent repeat vasectomy for persistent rare nonmotile sperm. If the criteria defined by the 2012 guidelines had been used to monitor these men, the occlusive success rate would have improved to 97.6% (949 patients) (p <0.05). Repeat vasectomies as well as 896 subsequent post-vasectomy semen analyses would have been avoided. Conclusions The AUA vasectomy guidelines provide clear, evidence-based criteria for vasectomy success. The guidelines simplify followup protocols, improve patient compliance and help avoid unnecessary post-vasectomy semen analyses and repeat vasectomies.
Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first ...known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.
Experts recommend screening for albuminuria in patients at risk for kidney disease.
To systematically review evidence about the diagnostic accuracy of point-of-care (POC) tests for detecting ...albuminuria in individuals for whom guidelines recommend such detection.
Cochrane Library, EMBASE, Medion database, MEDLINE, and Science Citation Index from 1963 through 5 December 2013; hand searches of other relevant journals; and reference lists.
Cross-sectional studies, published in any language, that compared the accuracy of machine-read POC tests of urinary albumin-creatinine ratio with that of laboratory measurement.
Two independent reviewers extracted study data and assessed study quality using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool.
Sixteen studies (n = 3356 patients) that evaluated semiquantitative or quantitative POC tests and used random urine samples collected in primary or secondary ambulatory care settings met inclusion criteria. Pooling results from a bivariate random-effects model gave sensitivity and specificity estimates of 76% (95% CI, 63% to 86%) and 93% (CI, 84% to 97%), respectively, for the semiquantitative test. Sensitivity and specificity estimates for the quantitative test were 96% (CI, 78% to 99%) and 98% (CI, 93% to 99%), respectively. The negative likelihood ratios for the semiquantitative and quantitative tests were 0.26 (CI, 0.16 to 0.40) and 0.04 (CI, 0.01 to 0.25), respectively.
Accuracy estimates were based on data from single-sample urine measurement, but guidelines require that diagnosis of albuminuria be based on at least 2 of 3 samples collected in a 6-month period.
A negative semiquantitative POC test result does not rule out albuminuria, whereas quantitative POC testing meets required performance standards and can be used to rule out albuminuria.
None.
The extractable activity ofL-phenylalanine ammonia-lyase (PAL; EC 4.3.1.5) in cell suspension cultures of bean (Phaseolus vulgaris) is greatly induced following exposure to an elicitor preparation ...from the cell walls of the phytopathogenic fungusColletotrichum lindemuthianum. Following exogenous application oftrans-cinnamic acid (the product of the PAL reaction) to elicitor-induced cells, the activity of the enzyme rapidly declines. Loss of enzyme activity is accompanied by inhibition of the rate of synthesis of PAL subunits, as determined by (35)Smethionine pulse-labelling followed by specific immunoprecipitation; this is insufficient to account for the rapid loss of PAL enzyme activity. Pulse-chase and immune blotting experiments indicate that cinnamic acid does not affect the rate of degradation of enzyme subunits, but rather mediates inactivation of the enzyme. A non-dialysable factor from cinnamicacid-treated bean cells stimulates removal of PAL activity from enzyme extracts in vitro; this effect is dependent on the presence of cinnamic acid. Such loss of enzyme activity in vitro is accompanied by an apparent loss or reduction of the dehydroalanine residue of the enzyme's active site, as detected by active-site-specific tritiation, although levels of immunoprecipitable enzyme subunits do not decrease. Furthermore, cinnamic-acid-mediated loss of enzyme activity in vivo is accompanied, in pulse-chase experiments, by a greater relative loss of(35)S-labelled enzyme subunits precipitated by an immobilised active-site affinity ligand than of subunits precipitated with anti-immunoglobulin G. It is therefore suggested that a possible mechanism for cinnamic-acid-mediated removal of PAL activity may involve modification of the dehydroalanine residue of the enzyme's active site.
Multivariate extreme value models are used to estimate joint risk in a number of applications, with a particular focus on environmental fields ranging from climatology and hydrology to oceanography ...and seismic hazards. The semi‐parametric conditional extreme value model of Heffernan and Tawn involving a multivariate regression provides the most suitable of current statistical models in terms of its flexibility to handle a range of extremal dependence classes. However, the standard inference for the joint distribution of the residuals of this model suffers from the curse of dimensionality because, in a d‐dimensional application, it involves a d−1‐dimensional nonparametric density estimator, which requires, for accuracy, a number points and commensurate effort that is exponential in d. Furthermore, it does not allow for any partially missing observations to be included, and a previous proposal to address this is extremely computationally intensive, making its use prohibitive if the proportion of missing data is nontrivial. We propose to replace the d−1‐dimensional nonparametric density estimator with a model‐based copula with univariate marginal densities estimated using kernel methods. This approach provides statistically and computationally efficient estimates whatever the dimension, d, or the degree of missing data. Evidence is presented to show that the benefits of this approach substantially outweigh potential misspecification errors. The methods are illustrated through the analysis of UK river flow data at a network of 46 sites and assessing the rarity of the 2015 floods in North West England.
After treatment with cisplatin-based chemotherapy for testicular cancer (TC), patients have higher prevalence of cardiovascular complications after long-term follow up. Little is known about acute ...cardiovascular effects of cisplatin-based chemotherapy. The aim of this study was to explore acute effects of chemotherapy on cardiac function in patients treated for TC.
Fourteen TC patients (age 34.6 ± 12.3 years) were studied before and 3 months after start with cisplatin-based chemotherapy. Cardiac function was assessed with magnetic resonance imaging. Fasting glucose and insulin levels were measured and insulin sensitivity, reflected by the quantitative insulin sensitivity index (Quicki index), was calculated.
Left ventricular (LV) end-diastolic volume and LV stroke volume (SV) significantly decreased from 192 ± 27 to 175 ± 26 ml (P<0.05) and 109 ± 18 to 95 ± 16 ml (P<0.05), respectively. The ratio of early and atrial filling velocities across the mitral valve, a parameter of diastolic heart function, decreased after chemotherapy from 1.87 ± 0.43 to 1.64 ± 0.45 (P<0.01). Metabolic parameters were unfavourably changed, reflected by a decreased Quicki index, which reduced from 0.39 ± 0.05 to 0.36 ± 0.05 (P<0.05).
Chemotherapy for TC induces acute alterations in diastolic heart function, paralleled by unfavourable metabolic changes. Therefore, early after chemotherapy, metabolic treatment may be indicated to possibly reduce long-term cardiovascular complications.
To determine if differences exist in ovarian response and pregnancy rates between Asian and Caucasian donors.
Retrospective cohort study.
University-based clinic.
Anonymous oocyte donors of ...self-reported Asian (n=63) or Caucasian (n=156) ethnicity who began ovarian stimulation between February 2000 and March 2008 and their matched recipients.
None.
Recipient pregnancy rates and oocyte donor ovarian responsiveness.
Baseline characteristics were similar between Asian and Caucasian donors. Asian donors had peak serum estradiol levels that were 23% higher than their Caucasian counterparts (3715±220 vs. 3013±114 pg/mL). Adjusted estradiol levels per follicle measured and per oocyte retrieved were elevated in Asian donors (17% and 23% higher, respectively), and these differences were unchanged after adjusting for body mass index. No differences were noted in implantation rates (47.4% vs. 40.9%), clinical pregnancy rates (60.3% vs. 62.4%), or live-birth rates (55.5% vs. 59.9%) achieved using Asian vs. Caucasian oocyte donors.
In contrast to autologous fresh in vitro fertilization cycles, Asian ethnicity is not associated with a lower pregnancy rate in recipient women using controlled hormone replacement when anonymous donor oocytes are used. Asian donors achieved statistically significantly higher serum estradiol levels during gonadotropin stimulation, suggesting an ethnic difference in steroid production and/or metabolism.
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