Pulmonary Vascular Alterations on Computed Tomography Imaging and Outcomes in Heart Failure With Preserved Ejection Fraction: a Preliminary Data.

BACKGROUND: Pulmonary vascular disease may play an important role in the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, no study has demonstrated noninvasive quantification of pulmonary vascular alterations in HFpEF. This study sought to determine the association between pulmonary vascular alterations quantified by chest computed tomography scan and clinical outcomes in HFpEF. METHODS AND RESULTS: Pulmonary vascular alterations were quantified in 151 patients with HFpEF who underwent noncontrast chest computed tomography scan by measuring the percentage of total cross-sectional area (CSA) of pulmonary vessels less than 5 mm2 to the total lung area (%CSA<5). We divided the patients by the median value of %CSA<5 (=1.45%) and examined the association between %CSA<5 and a composite outcome of all-cause mortality or HF hospitalization. During a median follow-up of 17.3 months, there were 44 (29%) composite outcomes. Event rates were significantly higher in patients with higher %CSA<5 than those with lower %CSA<5 (log-rank P = .02). %CSA<5 was associated with an increased risk of the outcome (hazard ratio per 1.0% increment, 1.46; 95% confidence interval 1.06-1.98; P = .02) in an unadjusted Cox model, and was independently and incrementally associated with the outcome over age, the presence of atrial fibrillation, E/e' ratio, and estimated pulmonary artery systolic pressure (global χ2 17.3 vs 11.5, P = .02). CONCLUSIONS: A higher %CSA<5 was associated with an increased risk of all-cause mortality or HF hospitalization in patients with HFpEF, with an incremental prognostic value over age, atrial fibrillation, E/e' ratio, and pulmonary artery systolic pressure.

Kiss1 hexadecapeptide directly regulates gonadotropin-releasing hormone 1 in the scombroid fish, chub mackerel.

Here we report that the Kiss1 hexadecapeptide (Kiss1-16) directly regulates the functional form of gonadotropin-releasing hormone (GnRH) in the preoptic area (POA) of a scombroid fish model. In this study, we analyzed the localization of two kisspeptin (kiss1 and kiss2) neurons and two kisspeptin receptors (kissr1 and kissr2) in the brain of adult chub mackerel using in situ hybridization to determine whether the kisspeptin receptors co-localize with GnRH1 neurons. The kiss1- and kiss2-expressing neurons were mainly localized in the nucleus recessus lateralis (NRL) and the nucleus of the posterior recess (NRP) in the hypothalamus. Kissr1 was present in the anterior POA and the habenular nucleus. Kissr2 was widely distributed, including in the POA, lateral tuberal nucleus, NRL, and NRP. Notably, GnRH1 was expressed in neurons in the POA, and these neurons co-expressed kissr1. In contrast, kissr2 was expressed abundantly in the vicinity of GnRH1 neurons, but their co-expression did not seem to occur. We also characterized the endogenous mature form of the Kiss1 peptide. An in vitro reporter gene assay clearly showed that Kiss1-16 (HQDMSSYNFNSFGLRY-NH2) was more potent at receptor activation than Kiss1 pentadecapeptide (Kiss1-15), which is the form of Kiss1 found in other fish species. This study strongly suggests that kisspeptin signaling, especially Kiss1 signaling, is important for regulating reproduction in scombroid fish.

mRNA levels of kisspeptins, kisspeptin receptors, and GnRH1 in the brain of chub mackerel during puberty.

Kisspeptin (Kiss) and its cognate receptor (Kiss1R), implicated in the neuroendocrine control of GnRH secretion in mammals, have been proposed to be the key factors in regulating puberty. However, the mechanisms underlying the initiation of puberty in fish are poorly understood. The chub mackerel Scomber japonicus expresses two forms of Kiss (kiss1 and kiss2) and two Kiss receptor (kissr1 and kissr2) genes in the brain, which exhibit sexually dimorphic changes during the seasonal reproductive cycle. This indicates that the kisspeptin system plays an important role in gonadal recrudescence of chub mackerel; however, the involvement of the kisspeptin system in the pubertal process has not been identified. In the present study, we examined the mRNA expression of kiss1, kiss2, kissr1, kissr2, and gnrh1 (hypophysiotropic form) in the brain of a chub mackerel during puberty. In male fish, kiss2, kissr1 and kissr2 levels increased significantly at 14weeks post-hatch (wph), synchronously with an increase in type A spermatogonial populations in the testis; kiss2 and gnrh1 levels significantly increased at 22wph, just before the onset of meiosis in the testes. In female fish, kiss2 increased significantly at 14wph, synchronously with an increase in the number of perinucleolar oocytes in the ovary; kiss1 and kiss2 levels significantly increased concomitantly with an increase in the kissr1, kissr2, and gnrh1 levels at 24wph, just before the onset of vitellogenesis in oocytes. The present results suggest positive involvement of the kisspeptin-GnRH system in the pubertal process in the captive reared chub mackerel.

Steroidogenic and maturation-inducing potency of native gonadotropic hormones in female chub mackerel, Scomber japonicus.

BACKGROUND: The gonadotropins (GtHs), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are produced in the pituitary gland and regulates gametogenesis through production of gonadal steroids. However, respective roles of two GtHs in the teleosts are still incompletely characterized due to technical difficulties in the purification of native GtHs. METHODS: Native FSH and LH were purified from the pituitaries of adult chub mackerel, Scomber japonicus by anion-exchange chromatography and immunoblotting using specific antisera. The steroidogenic potency of the intact chub mackerel FSH (cmFSH) and LH (cmLH) were evaluated in mid- and late-vitellogenic stage follicles by measuring the level of gonadal steroids, estradiol-17beta (Ε2) and 17,20beta-dihydroxy-4-pregnen-3-one (17,20beta-P). In addition, we evaluated the maturation-inducing potency of the GtHs on same stage follicles. RESULTS: Both cmFSH and cmLH significantly stimulated E2 production in mid-vitellogenic stage follicles. In contrast, only LH significantly stimulated the production of 17,20beta-P in late-vitellogenic stage follicles. Similarly, cmLH induced final oocyte maturation (FOM) in late-vitellogenic stage follicles. CONCLUSIONS: Present results indicate that both FSH and LH may regulate vitellogenic processes, whereas only LH initiates FOM in chub mackerel.

Prediction of pathological complete response to neoadjuvant chemotherapy in breast cancer using radiomics of pretreatment dynamic contrast-enhanced MRI.

PURPOSE: To investigate if the pretreatment dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-based radiomics machine learning predicts the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: Seventy-eight breast cancer patients who underwent DCE-MRI before NAC and confirmed as pCR or non-pCR were enrolled. Early enhancement mapping images of pretreatment DCE-MRI were created using subtraction formula as follows: Early enhancement mapping = (Signal 1 min - Signal pre)/Signal pre. Images of the whole tumors were manually segmented and radiomics features extracted. Five prediction models were built using five scenarios that included clinical information, subjective radiological findings, first order texture features, second order texture features, and their combinations. In texture analysis workflow, the corresponding variables were identified by mutual information for feature selection and random forest was used for model prediction. In five models, the area under the receiver operating characteristic curves (AUC) to predict the pCR and several metrics for model evaluation were analyzed. RESULTS: The best diagnostic performance based on F-score was achieved when both first and second order texture features with clinical information and subjective radiological findings were used (AUC = 0.77). The second best diagnostic performance was achieved with an AUC of 0.76 for first order texture features followed by an AUC of 0.76 for first and second order texture features. CONCLUSIONS: Pretreatment DCE-MRI can improve the prediction of pCR in breast cancer patients when all texture features with clinical information and subjective radiological findings are input to build the prediction model.

Unveiling a Chemisorbed Crystallographically Heterogeneous Graphene/L10-FePd Interface with a Robust and Perpendicular Orbital Moment.

A crystallographically heterogeneous interface was fabricated by growing hexagonal graphene (Gr) using chemical vapor deposition (CVD) on a tetragonal FePd epitaxial film grown by magnetron sputtering. FePd was alternately arranged with Fe and Pd in the vertical direction, and the outermost surface atom was identified primarily as Fe rather than Pd. This means that FePd has a high degree of L10-ordering, and the outermost Fe bonds to the carbon of Gr at the interface. When Gr is grown by CVD, the crystal orientation of hexagonal Gr toward tetragonal L10-FePd selects an energetically stable structure based on the van der Waals (vdW) force. The atomic relationship of Gr/L10-FePd, which is an energetically stable interface, was unveiled theoretically and experimentally. The Gr armchair axis was parallel to FePd [100]L10, where Gr was under a small strain by chemical bonding. Focusing on the interatomic distance between the Gr and FePd layers, the distance was theoretically and experimentally determined to be approximately 0.2 nm. This shorter distance (≈0.2 nm) can be explained by the chemisorption-type vdW force of strong orbital hybridization, rather than the longer distance (≈0.38 nm) of the physisorption-type vdW force. Notably, depth-resolved X-ray magnetic circular dichroism analyses revealed that the orbital magnetic moment (Ml) of Fe in FePd emerged at the Gr/FePd interface (@inner FePd: Ml = 0.16 µB → @Gr/FePd interface: Ml = 0.32 µB). This interfacially enhanced Ml showed obvious anisotropy in the perpendicular direction, which contributed to interfacial perpendicular magnetic anisotropy (IPMA). Moreover, the interfacially enhanced Ml and interfacially enhanced electron density exhibited robustness. It is considered that the shortening of the interatomic distance produces a robust high electron density at the interface, resulting in a chemisorption-type vdW force and orbital hybridization. Eventually, the robust interfacial anisotropic Ml emerged at the crystallographically heterogeneous Gr/L10-FePd interface. From a practical viewpoint, IPMA is useful because it can be incorporated into the large bulk perpendicular magnetic anisotropy (PMA) of L10-FePd. A micromagnetic simulation assuming both PMA and IPMA predicted that perpendicularly magnetized magnetic tunnel junctions (p-MTJs) using Gr/L10-FePd could realize 10-year data retention in a small recording layer with a circular diameter and thickness of 10 and 2 nm, respectively. We unveiled the energetically stable atomic structure in the crystallographically heterogeneous interface, discovered the emergence of the robust IPMA, and predicted that the Gr/L10-FePd p-MTJ is significant for high-density X nm generation magnetic random-access memory (MRAM) applications.

Functional analysis of kisspeptin peptides in adult immature chub mackerel (Scomber japonicus) using an intracerebroventricular administration method.

In vertebrates (including teleosts), the pivotal hierarchical factor in the control of gonadotropin secretion is the hypothalamic gonadotropin-releasing hormone (GnRH) decapeptide, which regulates the release of pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Recently, kisspeptins encoded by the Kiss1 gene have been shown to act as upstream endogenous regulators of GnRH neurons in mammals. The chub mackerel (Scomber japonicus) brain expresses two kiss genes (kiss1 and kiss2) that show sexually dimorphic expression profiles during the seasonal gonadal cycle. In the present study, we evaluated the biological potency of kisspeptin peptides to induce transcriptional changes in gnrh1 (hypophysiotropic GnRH form in this species), fshß and lhß during the immature stage of adult chub mackerel (2+ years old). Synthetic Kiss1 pentadecapeptide (Kiss1-15) or Kiss2 dodecapeptide (Kiss2-12) at a dose of 100 ng were administered into the intracerebroventricular (ICV) region, and brains were sampled at 6 and 12 h post-injection. In female fish, gnrh1 levels decreased in the presence of both kisspeptin peptides at 12 h post-injection. No significant variation was observed in male fish. In contrast, ICV administration of Kiss2-12 (but not Kiss1-15) significantly increased fshß and lhß mRNAs at 12 h post-injection compared to a saline injected control in both sexes. These results suggested that synthetic Kiss2-12 could induce transcriptional changes in gnrh1 and gths.