Frequency Change Detection in Human Auditory Cortex

We offer a model of how human cortex detects changes in the auditory environment. Auditory change detection has recently been the object of intense investigation via the mismatch negativity (MMN). MMN is a preattentive response to sudden changes in stimulation, measured noninvasively in the electroencephalogram (EEG) and the magnetoencephalogram (MEG). It is elicited in the oddball paradigm, where infrequent deviant tones intersperse a series of repetitive standard tones. However, little apart from the participation of tonotopically organized auditory cortex is known about the neural mechanisms underlying change detection and the MMN. In the present study, we investigate how poststimulus inhibition might account for MMN and compare the effects of adaptation with those of lateral inhibition in a model describing tonotopically organized cortex. To test the predictions of our model, we performed MEG and EEG measurements on human subjects and used both small- (<1/3 octave) and large- (>5 octaves) frequency differences between the standard and deviant tones. The experimental results bear out the prediction that MMN is due to both adaptation and lateral inhibition. Finally, we suggest that MMN might serve as a probe of what stimulus features are mapped by human auditory cortex.     

A Population Rate Code of Auditory Space in the Human Cortex

Background

Previous work on the human auditory cortex has revealed areas specialized in spatial processing but how the neurons in these areas represent the location of a sound source remains unknown.

Methodology/Principal Findings

Here, we performed a magnetoencephalography (MEG) experiment with the aim of revealing the neural code of auditory space implemented by the human cortex. In a stimulus-specific adaptation paradigm, realistic spatial sound stimuli were presented in pairs of adaptor and probe locations. We found that the attenuation of the N1m response depended strongly on the spatial arrangement of the two sound sources. These location-specific effects showed that sounds originating from locations within the same hemifield activated the same neuronal population regardless of the spatial separation between the sound sources. In contrast, sounds originating from opposite hemifields activated separate groups of neurons.

Conclusions/Significance

These results are highly consistent with a rate code of spatial location formed by two opponent populations, one tuned to locations in the left and the other to those in the right. This indicates that the neuronal code of sound source location implemented by the human auditory cortex is similar to that previously found in other primates.     

Glycomics of bone marrow-derived mesenchymal stem cells can be used to evaluate their cellular differentiation stage

Human mesenchymal stem cells (MSCs) are adult multipotent progenitor cells. They hold an enormous therapeutic potential, but at the moment there is little information on the properties of MSCs, including their surface structures. In the present study, we analyzed the mesenchymal stem cell glycome by using mass spectrometric profiling as well as a panel of glycan binding proteins. Structural verifications were obtained by nuclear magnetic resonance spectroscopy, mass spectrometric fragmentation, and glycosidase digestions. The MSC glycome was compared to the glycome of corresponding osteogenically differentiated cells. More than one hundred glycan signals were detected in mesenchymal stem cells and osteoblasts differentiated from them. The glycan profiles of MSCs and osteoblasts were consistently different in biological replicates, indicating that stem cells and osteoblasts have characteristic glycosylation features. Glycosylation features associated with MSCs rather than differentiated cells included high-mannose type N-glycans, linear poly-N-acetyllactosamine chains and α2-3-sialylation. Mesenchymal stem cells expressed SSEA-4 and sialyl Lewis x epitopes. Characteristic glycosylation features that appeared in differentiated osteoblasts included abundant sulfate ester modifications. The results show that glycosylation analysis can be used to evaluate MSC differentiation state.     

Separating parental and treatment contributions to perinatal health after fresh and frozen embryo transfer in assisted reproduction: A cohort study with within-sibship analysis

BackgroundCompared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors.Methods and findingsThis registry-based cohort study with nationwide data from Denmark (1994–2014), Norway (1988–2015), and Sweden (1988–2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (<37 weeks, versus ≥37), and very preterm birth (<32 weeks, versus ≥32). Singletons born after fresh-ET had lower mean birthweight (−51 g, 95% CI −58 to −45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (−1.0 days, 95% CI −1.2 to −0.8, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking.ConclusionsWe found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias.Trial registrationClinicalTrials.gov ISRCTN11780826.

Kjersti Westvik-Johari and co-workers report on perinatal outcomes following fresh and frozen embryo transfer.     

Cardiovascular disease,obesity, and type 2 diabetes in children born after assisted reproductive technology: A population-based cohort study

BackgroundSome earlier studies have found indications of significant changes in cardiometabolic risk factors in children born after assisted reproductive technology (ART). Most of these studies are based on small cohorts with high risk of selection bias. In this study, we compared the risk of cardiovascular disease, obesity, and type 2 diabetes between singleton children born after ART and singleton children born after spontaneous conception (SC).Methods and findingsThis was a large population-based cohort study of individuals born in Norway, Sweden, Finland, and Denmark between 1984 and 2015. Data were obtained from national ART and medical birth registers and cross-linked with data from national patient registers and other population-based registers in the respective countries. In total, 122,429 children born after ART and 7,574,685 children born after SC were included. Mean (SD) maternal age was 33.9 (4.3) years for ART and 29.7 (5.2) for SC, 67.7% versus 41.8% were primiparous, and 45.2% versus 32.1% had more than 12 years of education. Preterm birth (<37 weeks 0 days) occurred in 7.9% of children born after ART and 4.8% in children born after SC, and 5.7% versus 3.3% had a low birth weight (<2,500 g). Mean (SD) follow-up time was 8.6 (6.2) years for children born after ART and 14.0 (8.6) years for children born after SC. In total, 135 (0.11%), 645 (0.65%), and 18 (0.01%) children born after ART were diagnosed with cardiovascular disease (ischemic heart disease, cardiomyopathy, heart failure, or cerebrovascular disease), obesity or type 2 diabetes, respectively. The corresponding values were 10,702 (0.14%), 30,308 (0.74%), and 2,919 (0.04%) for children born after SC. In the unadjusted analysis, children born after ART had a significantly higher risk of any cardiovascular disease (hazard ratio [HR] 1.24; 95% CI 1.04–1.48; p = 0.02), obesity (HR 1.13; 95% CI 1.05–1.23; p = 0.002), and type 2 diabetes (HR 1.71; 95% CI 1.08–2.73; p = 0.02). After adjustment, there was no significant difference between children born after ART and children born after SC for any cardiovascular disease (adjusted HR [aHR]1.02; 95% CI 0.86–1.22; p = 0.80) or type 2 diabetes (aHR 1.31; 95% CI 0.82–2.09; p = 0.25). For any cardiovascular disease, the 95% CI was reasonably narrow, excluding effects of a substantial magnitude, while the 95% CI for type 2 diabetes was wide, not excluding clinically meaningful effects. For obesity, there was a small but significant increased risk among children born after ART (aHR 1.14; 95% CI 1.06–1.23; p = 0.001). Important limitations of the study were the relatively short follow-up time, the limited number of events for some outcomes, and that the outcome obesity is often not considered as a disease and therefore not caught by registers, likely leading to an underestimation of obesity in both children born after ART and children born after SC.ConclusionsIn this study, we observed no difference in the risk of cardiovascular disease or type 2 diabetes between children born after ART and children born after SC. For obesity, there was a small but significant increased risk for children born after ART.Trial registration numberISRCTN11780826.

Emma Norrman and co-workers study the health of children born with and without assisted reproductive technology.     

Fatty acid esterification of lipoprotein-associated estrone in human plasma and follicular fluid

Estrogen fatty acid esters constitute a unique family of extremely hydrophobic hormonal derivatives which are exclusively transported in lipoprotein particles in plasma. In estradiol, the fatty acyl residues are conjugated at the 17beta-hydroxyl of the steroid D-ring, leaving the phenolic 3-hydroxyl group unsubstituted and, therefore, preserving antioxidative efficacy. The 17beta-fatty acid derivative of estradiol is proposedly an even more efficient antioxidant protecting LDL and HDL than the parent steroid. Previous studies have established that the enzyme lecithin:cholesterol acyltransferase which catalyzes the fatty acid esterification of 3beta-hydroxyl group of cholesterol, also catalyzes the formation of estrogen 17beta-esters. Estrone, the principal estrogen in the postmenopausal female, has a keto group at carbon-17 and has been thought unable to form fatty acid esters. However, we detected hydrophobic derivatives of estrone following incubations with human plasma and ovarian follicular fluid. These derivatives accumulated in HDL and LDL during incubation showing chemical characteristics similar to estrone-3-fatty acid esters. Liquid chromatographic-mass spectrometric analyses established the presence of unhydrolyzed estrone esters consisting of different fatty acid species, the major one being estrone-3-linoleate, in human HDL particles following incubation of estrone with plasma. These extremely hydrophobic estrone conjugates could, in theory, represent a storage form of this estrogen.     

Interruption of CXCL13-CXCR5 Axis Increases Upper Genital Tract Pathology and Activation of NKT Cells following Chlamydial Genital Infection

Background

Regulation of immune responses is critical for controlling inflammation and disruption of this process can lead to tissue damage. We reported that CXCL13 was induced in fallopian tube tissue following C. trachomatis infection. Here, we examined the influence of the CXCL13-CXCR5 axis in chlamydial genital infection.

Methodology and Principal Findings

Disruption of the CXCL13-CXCR5 axis by injecting anti-CXCL13 Ab to BALB/c mice or using Cxcr5−/− mice increased chronic inflammation in the upper genital tract (UGT; uterine horns and oviducts) after Chlamydia muridarum genital infection (GT). Further studies in Cxcr5−/− mice showed an elevation in bacterial burden in the GT and increased numbers of neutrophils, activated DCs and activated NKT cells early after infection. After resolution, we noted increased fibrosis and the accumulation of a variety of T cells subsets (CD4-IFNγ, CD4-IL-17, CD4-IL-10 & CD8-TNFα) in the oviducts. NKT cell depletion in vitro reduced IL-17α and various cytokines and chemokines, suggesting that activated NKT cells modulate neutrophils and DCs through cytokine/chemokine secretion. Further, chlamydial glycolipids directly activated two distinct types of NKT cell hybridomas in a cell-free CD1d presentation assay and genital infection of Cd1d−/− mice showed reduced oviduct inflammation compared to WT mice. CXCR5 involvement in pathology was also noted using single-nucleotide polymorphism analysis in C. trachomatis infected women attending a sub-fertility clinic. Women who developed tubal pathology after a C. trachomatis infection had a decrease in the frequency of CXCR5 SNP +10950 T>C (rs3922).

Conclusions/Significance

These experiments indicate that disruption of the CXCL13-CXCR5 axis permits increased activation of NKT cells by type I and type II glycolipids of Chlamydia muridarum and results in UGT pathology potentially through increased numbers of neutrophils and T cell subsets associated with UGT pathology. In addition, CXCR5 appears to contribute to inter-individual differences in human tubal pathology following C. trachomatis infection.     

Sexual function and fertility in adult females and males with congenital adrenal hyperplasia

Female patients with classic 21-hydroxylase deficiency (21-OHD) present with decreased fertility and low childbirth rates, women with a salt-wasting form of 21-OHD being most severely affected. In cases of undersubstitution with glucocorticoids, tonic androgen secretion disturbs ovulation. However, even adequately substituted females may present with apparent infertility. Despite adrenal androgen suppression, adrenal progesterone secretion can prevent thickening of the endometrium in the follicular phase. Furthermore, functional ovarian hyperandrogenism is a common finding even in women with well-controlled classic 21-OHD. Psychosexual factors may also contribute significantly to decreased childbirth rates found in these patients. Genital ambiguity may lead to a disturbed body image and the patients have been found to feel less feminine than healthy control women. The repeated psychological insult caused by frequent genital examinations and operations is also important, though its exact impact has been difficult to determine. Finally, prenatal androgen excess can cause masculinization of the central nervous system leading to boyish behavior in childhood and decreased heterosexual activity in adulthood. Some recent reports show a high rate of infertility also in men with 21-OHD. They are at risk of benign testicular tumors, adrenal rests, which can lead to permanent infertility. Also, raised adrenal androgen production leading to increased estrogen concentrations can suppress gonadotropin secretion and may lead to a hypogonadotropic state.     

Cancer in children born after frozen-thawed embryo transfer: A cohort study

BackgroundThe aim was to investigate whether children born after assisted reproduction technology (ART), particularly after frozen-thawed embryo transfer (FET), are at higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception.Methods and findingsWe performed a registry-based cohort study using data from the 4 Nordic countries: Denmark, Finland, Norway, and Sweden. The study included 7,944,248 children, out of whom 171,774 children were born after use of ART (2.2%) and 7,772,474 children were born after spontaneous conception, representing all children born between the years 1994 to 2014 in Denmark, 1990 to 2014 in Finland, 1984 to 2015 in Norway, and 1985 to 2015 in Sweden. Rates for any cancer and specific cancer groups in children born after each conception method were determined by cross-linking national ART registry data with national cancer and health data registries and population registries. We used Cox proportional hazards models to estimate the risk of any cancer, with age as the time scale.After a mean follow-up of 9.9 and 12.5 years, the incidence rate (IR) of cancer before age 18 years was 19.3/100,000 person-years for children born after ART (329 cases) and 16.7/100,000 person-years for children born after spontaneous conception (16,184 cases). Adjusted hazard ratio (aHR) was 1.08, 95% confidence interval (CI) 0.96 to 1.21, p = 0.18. Adjustment was performed for sex, plurality, year of birth, country of birth, maternal age at birth, and parity. Children born after FET had a higher risk of cancer (48 cases; IR 30.1/100,000 person-years) compared to both fresh embryo transfer (IR 18.8/100,000 person-years), aHR 1.59, 95% CI 1.15 to 2.20, p = 0.005, and spontaneous conception, aHR 1.65, 95% CI 1.24 to 2.19, p = 0.001. Adjustment either for macrosomia, birth weight, or major birth defects attenuated the association marginally. Higher risks of epithelial tumors and melanoma after any assisted reproductive method and of leukemia after FET were observed.The main limitation of this study is the small number of children with cancer in the FET group.ConclusionsChildren born after FET had a higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception. The results should be interpreted cautiously based on the small number of children with cancer, but the findings raise concerns considering the increasing use of FET, in particular freeze-all strategies without clear medical indications.Trial registrationTrial registration number: ISRCTN 11780826.

Nona Sargisian and colleagues investigate the risk of childhood cancer in children born after Frozen-Thawed Embryo Transfer in Denmark, Finland, Norway, and Sweden.