The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining ...live birth rates.
We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies.
After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications.
In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).
Nitrous oxide (N2O) is a strong greenhouse gas whose mole fraction in the atmosphere has increased over the industrial period. We present a new set of isotope measurements of N2O in air extracted ...from ice cores covering the last 3,000 years. For the preindustrial (PI) atmosphere, we find an average N2O mole fraction of (267 ± 1) nmol/mol and average tropospheric N2O isotopic values of δ15NavPI = (9.5 ± 0.1)‰, δ18OPI = (47.1 ± 0.2)‰, δ15NαPI = (17.8 ± 0.4)‰, and δ15ΝβPI = (1.2 ± 0.4)‰. From PI to modern times all isotope signatures decreased with a total change of δ15Nav = (−2.7 ± 0.2)‰, δ18O = (−2.5 ± 0.4)‰, δ15Nα = (−2.0 ± 0.7)‰, and δ15Νβ (−3.5 ± 0.7)‰. Interestingly, the temporal evolution is not the same for δ15Nav and δ18O. δ18O trends are relatively larger during the early part, and δ15Nav trends are larger during the late part of the industrial period, implying a decoupling of sources over the industrial period. Using a mass balance model, we determined the isotopic composition of the total average N2O source. Assuming that the total present source is the sum of a constant natural source and an increasing anthropogenic source, this anthropogenic source has an isotopic signature of δ15Navsource,anthrop = (−15.0 ± 2.6)‰, δ18Osource,anthrop = (30.0 ± 2.6)‰, δ15Nαsource,anthrop = (−4.5 ± 1.7)‰, and δ15Nβsource,anthrop = (−24.0 ± 8.4)‰. The 15N site preference of the source has increased since PI times, which is indicative of a relative shift from denitrification to nitrification sources, consistent with agricultural emissions playing a major role in the N2O increase.
Key Points
The isotopic composition of nitrous oxide in the preindustrial period was determined with high precision
The isotopic composition of nitrous oxide changed during the transition to the industrial period
The temporal evolution of δ15Nav is different from that of δ18O implying a decoupling of sources over the industrial period
Coupled equilibria play important roles in controlling information flow in biochemical systems, including allosteric molecules and multidomain proteins. In the simplest case, two equilibria are ...coupled to produce four interconverting states. In this study, we assessed the feasibility of determining the degree of coupling between two equilibria in a four-state system via relaxation dispersion measurements. A major bottleneck in this effort is the lack of efficient approaches to data analysis. To this end, we designed a strategy to efficiently evaluate the smoothness of the target function surface (TFS). Using this approach, we found that the TFS is very rough when fitting benchmark CPMG data to all adjustable variables of the four-state equilibria. After constraining a portion of the adjustable variables, which can often be achieved through independent biochemical manipulation of the system, the smoothness of TFS improves dramatically, although it is still insufficient to pinpoint the solution. The four-state equilibria can be finally solved with further incorporation of independent chemical shift information that is readily available. We also used Monte Carlo simulations to evaluate how well each adjustable parameter can be determined in a large kinetic and thermodynamic parameter space and how much improvement can be achieved in defining the parameters through additional measurements. The results show that in favorable conditions the combination of relaxation dispersion and biochemical manipulation allow the four-state equilibrium to be parameterized, and thus coupling strength between two processes to be determined.
No official document has been published for primary care physicians regarding the management of liver transplant patients. With no official source of reference, primary care physicians often question ...their care of these patients. The following guidelines have been approved by the American Society of Transplantation and represent the position of the association. The data presented are based on formal review and analysis of published literature in the field and the clinical experience of the authors. These guidelines address drug interactions and side effects of immunosuppressive agents, allograft dysfunction, renal dysfunction, metabolic disorders, preventive medicine, malignancies, disability and productivity in the workforce, issues specific to pregnancy and sexual function, and pediatric patient concerns. These guidelines are intended to provide a bridge between transplant centers and primary care physicians in the long‐term management of the liver transplant patient.
These guidelines, intended to assist primary care providers in managing liver transplant patients, address drug interactions and side effects of immunosuppressive agents, allograft dysfunction, renal dysfunction, metabolic disorders, malignancies, productivity in the workforce, pregnancy and sexual function, and pediatric concerns.
Abstract Chronic non-bacterial osteomyelitis (CNO) is an auto-inflammatory disorder that affects the skeletal system. Interleukin (IL-)10 is an immune-modulatory cytokine that controls inflammation, ...and limits inflammatory cytokine responses. Dysregulation of IL-10 expression has been shown to result in autoimmune and infectious diseases. We investigated IL-10 expression by monocytic cells from CNO patients and controls. In response to stimulation with LPS, IL-10 expression from CNO monocytes was reduced ( p < 0.001). This was independent of IL10 promoter polymorphisms. Thus, we investigated Sp1 recruitment to the IL10 promoter and saw markedly reduced binding in CNO monocytes. This was accompanied with reduced phosphorylation of histone H3 serine 10 (H3S10), an activating epigenetic mark. Impaired recruitment of Sp1 to the IL10 promoter, and reduced H3S10 phosphorylation, may be a reflection of deficient MAPK signaling in CNO monocytes in response to LPS stimulation. Thus, we have discovered a mechanism that may be central in the pathophysiology of CNO.
Context. Recent results have revised upwards the total X-ray background (XRB) intensity below similar to 10 keV, therefore an accurate determination of the source counts is needed. There are also ...contradictory results on the clustering of X-ray selected sources. Aims. We have studied the X-ray source counts in four energy bands: soft (0.5-2 keV), hard (2-10 keV), XID (0.5-4.5 keV) and ultra-hard (4.5-7.5 keV) in order to evaluate the contribution of sources at different fluxes to the X-ray background. We have also studied the angular clustering of X-ray sources in those bands. Methods. AXIS (An XMM-Newton International Survey) is a survey of 36 high Galactic latitude XMM-Newton observations covering 4.8 deg super(2) in the Northern sky and containing 1433 serendipitous X-ray sources detected with 5-\sigma significance. This survey has similar depth to the XMM-Newton catalogues and therefore serves as a pathfinder to explore their possibilities. We have combined this survey with shallower and deeper surveys, and fitted the source counts with a Maximum Likelihood technique. Using only AXIS sources we have studied the angular correlation using a novel robust technique. Results. Our source counts results are compatible with most previous samples in the soft, XID, ultra-hard and hard bands. We have improved on previous results in the hard band. The fractions of the XRB resolved in the surveys used in this work are 87%, 85%, 60% and 25% in the soft, hard, XID and ultra-hard bands, respectively. Extrapolation of our source counts to zero flux is not sufficient to saturate the XRB intensity. Only galaxies and/or absorbed AGN could contribute the remaining unresolved XRB intensity. Our results are compatible, within the errors, with recent revisions of the XRB intensity in the soft and hard bands. The maximum fractional contribution to the XRB comes from fluxes within about a decade of the break in the source counts ( similar to 10 super(-14) cgs), reaching similar to 50% of the total in the soft and hard bands. Angular clustering (widely distributed over the sky and not confined to a few deep fields) is detected at 99-99.9% significance in the soft and XID bands, with no detection in the hard and ultra-hard band (probably due to the smaller number of sources). We cannot confirm the detection of significantly stronger clustering in the hard- spectrum hard sources. Conclusions. Medium depth surveys such as AXIS are essential to determine the evolution of the X-ray emission in the Universe below 10 keV.
Several genome-wide association studies (GWAS) have associated variants in late-onset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very ...modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes.
Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education.
Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (β = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (β = -0.44, SE = 0.09, p = 0.009 and β = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (β = 0.26, SE = 0.10, p = 0.010).
MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease.
We introduce and evaluate strain mapping by multidetector computer tomography as a new noninvasive method for assessment of myocardial function. In patients (n = 16) with healed myocardial ...infarction, peak systolic radial strain was measured by automated pixel pattern matching analysis of multiple left ventricular 64-slice multidetector computer tomographic short-axis recordings. For comparison, radial strain and myocardial infarct extent were measured by tagged magnetic resonance imaging (MRI) and late enhancement MRI, respectively. In a linear mixed model analysis, myocardial infarct extent was a strong predictor of segmental strain by multidetector computer tomography (beta = −0.44, p <0.0001). Strain was significantly different among noninfarcted (0%), nontransmurally infarcted (0% to 50%), and transmurally infarcted (>50%) segments (p <0.001) and between infarcted and noninfarcted border zone segments (p <0.001). There was a close relation between strain by multidetector computer tomography and by tagged MRI (mean difference −7.4 ± 11.7%, r = 0.68, p <0.0001). Mean time-to-peak systolic strain was 324 ± 42 ms by multidetector computer tomography and 335 ± 56 ms by tagged MRI (mean difference 11 ± 40 ms). In conclusion, to our knowledge this is the first study to demonstrate that regional myocardial function can be quantified by multidetector computer tomographic imaging, indicating that assessment of radial strain by multidetector computer tomography might be a useful tool in the evaluation of patients with cardiovascular diseases.
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