Search

We confirm prior evidence that bonds on average are offered at prices below their immediate post-offer secondary market prices. However, in cases where banks lead–manage their own bond offerings the underpricing is significantly less as compared with other non-self-marketed offerings. These findings are robust across various matched samples and selection models. Our results suggest that the bond offering process is characterized by substantive agency conflicts between shareholders of corporations (issuers) and underwriters. [ABSTRACT FROM AUTHOR]

Objectives: Immune checkpoint inhibitors (ICIs) are associated with immunerelated adverse events (irAEs), of which endocrinopathies are common. We characterized endocrine and non-endocrine irAEs in cancer patients receiving ICIs, identified risk factors for their development and established whether endocrine and non-endocrine irAEs were differentially associated with improved cancer prognosis. Design and methods: Single-center, retrospective cohort study of patients with advanced or metastatic solid tumors receiving at least one ICI treatment cycle (242 men, 151 women, median age 65 years). Main outcome measures were incidence of any irAE during the study period, overall survival and time to treatment failure. Results: Non-endocrine irAEs occurred in 32% and endocrine irAEs in 12% of patients. Primary thyroid dysfunction was the most common endocrine irAE (9.5%) and the majority of endocrinopathies required permanent hormone replacement. Women had an increased risk of developing endocrine irAEs (p = 0.017). The biggest survival advantage occurred in patients who developed both endocrine and non-endocrine irAEs (overall survival: HR 0.16, CI 0.09-0.28). Time to treatment failure was also significantly improved in patients who developed endocrine irAEs (HR 0.49, CI 0.34 – 0.71) or both (HR 0.41, CI 0.25 – 0.64) but not in those who only developed non-endocrine irAEs. Conclusions: Women may have increased risk of endocrine irAEs secondary to ICI treatment. This is the first study to compare the effects of endocrine irAEs with non-endocrine irAEs on survival. Development of endocrine irAEs may confer survival benefit in ICI treatment and future, prospective studies are needed to elucidate this. [ABSTRACT FROM AUTHOR]

Aim: The regulation of osteoclasts (OCs) by inhibitory immunoreceptors maintains bone homeostasis and is considered an important determinant of the extent of periodontal pathology. The aim of this study was to investigate the role of the inhibitory immunoreceptor CD300lf and its ligand ceramide in osteoclastogenesis in periodontitis. Materials and Methods: The expression of CD300lf was measured in vitro and in a ligature‐induced periodontitis model. The effect of CD300lf ablation on osteoclastogenesis was examined in ligature‐retained and ligature removal periodontitis models. The effect of ceramide, the ligand of CD300lf, was examined in osteoclastogenesis in vitro and in vivo by smearing 20 μg of ceramide dissolved in carboxymethylcellulose on teeth and gingiva every other day in an experimental periodontitis model and ligature removal model. Results: CD300lf expression was downregulated during osteoclastogenesis. Ablation of CD300lf in the ligature‐induced periodontitis model increased the number of OCs and exacerbated bone damage. Bone resorption caused by CD300lf ablation was reversible following ligature removal. CD300lf‐ceramide binding suppressed osteoclastogenesis in vitro and inhibited alveolar bone loss in a mouse periodontitis model. Conclusions: Our findings reveal that CD300lf‐ceramide binding plays a critical negative role in alveolar bone loss in periodontitis by inhibiting OCs differentiation. [ABSTRACT FROM AUTHOR]

Examined illustrations for portrayal of older adult characters in Caldecott Medal-winning picture books, comparing 1972-83 and 1984-95 winners. Found that recent books portray elderly in a more positive manner than earlier winners. In addition, only two significant gender differences in a field of 36 possibilities were found over the entire 23-year period of Caldecott award-winners. (HTH)

Background: Delayed puberty in males is almost invariably associated with constitutional delay of growth and puberty (CDGP) or congenital hypogonadotrophic hypogonadism (CHH). Establishing the cause at presentation is challenging, with "red flag" features of CHH commonly overlooked. Thus, several markers have been evaluated in both the basal state or after stimulation e.g. with gonadotrophin releasing hormone agonist (GnRHa).Insulin-like peptide 3 (INSL3) is a constitutive secretory product of Leydig cells and thus a possible candidate marker, but there have been limited data examining its role in distinguishing CDGP from CHH. In this manuscript, we assess INSL3 and inhibin B (INB) in two cohorts: 1. Adolescent boys with delayed puberty due to CDGP or CHH and 2. Adult men, both eugonadal and having CHH. Materials and methods: Retrospective cohort studies of 60 boys with CDGP or CHH, as well as 44 adultmen who were either eugonadal or had CHH, in whom INSL3, INB, testosterone and gonadotrophins were measured.Cohort 1: Boys with delayed puberty aged 13-17 years (51 with CDGP and 9 with CHH) who had GnRHa stimulation (subcutaneous triptorelin 100mcg), previously reported with respect to INB.Cohort 2: Adult cohort of 44 men (22 eugonadal men and 22 men with CHH), previously reported with respect to gonadotrophin responses to kisspeptin-54. Results: Median INSL3 was higher in boys with CDGP than CHH (0.35 vs 0.15 ng/ml; p=0.0002). Similarly, in adult men, median INSL3 was higher in eugonadal men than CHH (1.08 vs 0.05 ng/ml; p<0.0001). However, INSL3 more accurately differentiated CHH in adult men than in boys with delayed puberty (auROC with 95% CI in adult men: 100%, 100-100%; boys with delayed puberty: 86.7%, 77.7-95.7%).Median INB was higher in boys with CDGP than CHH (182 vs 59 pg/ml; p<0.0001). Likewise, in adult men, median INB was higher in eugonadal men than CHH (170 vs 36.5 pg/ml; p<0.0001). INB performed better than INSL3 in differentiating CHH in boys with delayed puberty (auROC 98.5%, 95.9-100%), than in adult men (auROC 93.9%, 87.2-100%). Conclusion: INSL3 better identifies CHH in adult men, whereas INB better identifies CHH in boys with delayed puberty. [ABSTRACT FROM AUTHOR]

The neuropeptide kisspeptin is now well-established as the master regulator of the mammalian reproductive axis. Beyond the hypothalamus, kisspeptin and its cognate receptor are also extensively distributed in extra-hypothalamic brain regions. An expanding pool of animal and human data demonstrates that kisspeptin sits within an extensive neuroanatomical and functional framework through which it can integrate a range of internal and external cues with appropriate neuroendocrine and behavioural responses. In keeping with this, recent studies reveal wide-reaching effects of kisspeptin on key behaviours such as olfactory-mediated partner preference, sexual motivation, copulatory behaviour, bonding, mood, and emotions. In this review, we provide a comprehensive update on the current animal and human literature highlighting the far-reaching behaviour and mood-altering roles of kisspeptin. A comprehensive understanding of this important area in kisspeptin biology is key to the escalating development of kisspeptin-based therapies for common reproductive and related psychological and psychosexual disorders. [ABSTRACT FROM AUTHOR]

Context: Osteoporosis results from disturbances in bone formation and resorption. Recent nonhuman data suggest that the reproductive hormone kisspeptin directly stimulates osteoblast differentiation in vitro and thus could have clinical therapeutic potential. However, the effects of kisspeptin on human bone metabolism are currently unknown. Objective: To assess the effects of kisspeptin on human bone metabolism in vitro and in vivo. Methods: In vitro study: of Mono- and cocultures of human osteoblasts and osteoclasts treated with kisspeptin. Clinical study: Randomized, placebo-controlled, double-blind, 2-way crossover clinical study in 26 men investigating the effects of acute kisspeptin administration (90 minutes) on human bone metabolism, with blood sampling every 30 minutes to +90 minutes. Cells for the in vitro study were from 12 male blood donors and 8 patients undergoing hip replacement surgery. Twenty-six healthy eugonadal men (age 26.8 ± 5.8 years) were included in the clinical study. The intervention was Kisspeptin (vs placebo) administration. The main outcome measures were changes in bone parameters and turnover markers. Results: Incubation with kisspeptin in vitro increased alkaline phosphatase levels in human bone marrow mesenchymal stem cells by 41.1% (P = .0022), and robustly inhibited osteoclastic resorptive activity by up to 53.4% (P < .0001), in a dose-dependent manner. Kisspeptin administration to healthy men increased osteoblast activity, as evidenced by a 20.3% maximal increase in total osteocalcin (P = .021) and 24.3% maximal increase in carboxylated osteocalcin levels (P = .014). Conclusion: Collectively, these data provide the first human evidence that kisspeptin promotes osteogenic differentiation of osteoblast progenitors and inhibits bone resorption in vitro. Furthermore, kisspeptin acutely increases the bone formation marker osteocalcin but not resorption markers in healthy men, independent of downstream sex steroid levels. Kisspeptin could therefore have clinical therapeutic application in the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Milk protein is recognised as one of the eight most common food allergens in the United States, and one of the most common causes of fatal or near-fatal food-induced anaphylactic reactions globally. Undeclared allergens in food products are the leading cause of the U.S. Food and Drug Administration (FDA) requests for food recalls, with undeclared milk protein as the most frequently cited allergen. The purpose of this study was to evaluate the prevalence of milk protein contamination in milk-alternative ice cream products sold as frozen dessert in the U.S. and labelled as 'non-dairy', 'dairy-free', and/or 'vegan', and to characterise the potential risk for allergic individuals consuming these products. Thirty-two unique milk-alternative frozen dessert products, including flavours with and without inclusions, from 16 different brands, were tested for the presence of milk proteins using enzyme-linked immunosorbent assay. Milk protein was detected in three of the tested products: two contained solid inclusions, and one did not have inclusions. One of the three products with detectable milk protein had an advisory statement indicating the product was made in a facility that processed milk. Although no consensus exists as to the minimal dose of milk protein necessary to elicit an adverse effect in a milk-sensitised individual, the milk protein quantities in one serving of each of the three products exceeded some of the published thresholds. These results suggest that one serving of certain milk-alternative frozen dessert products could potentially elicit an allergic response in highly sensitive individuals. [ABSTRACT FROM AUTHOR]

Context: Antenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all 3 trimesters in women with antenatal complications. Objective: We aimed to assess whether kisspeptin levels are altered in women with antenatal complications. Methods: Women with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed. Results: Third-trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking, and parity were increased by 30% (95% CI, 16%-47%; P < 0.0001), and of FGR were reduced by 28% (95% CI, 4-46%; P = 0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (P = 0.014) and lower in those with GDM (P = 0.020), but not significantly on multivariable analysis. Conclusion: We delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications. [ABSTRACT FROM AUTHOR]

Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as primary ovarian insufficiency, hypothalamic amenorrhea, congenital hypogonadotropic hypogonadism, and early menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evidence relating to traditional reproductive hormones and the recent discovery of newer reproductive neuropeptides and hormones has deepened our understanding of the interaction between bone and the reproductive system. In this review, we provide a contemporary summary of the literature examining the relationship between bone biology and reproductive signals that extend beyond estrogens and androgens, and include kisspeptin, gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, progesterone, inhibin, activin, and relaxin. A comprehensive and up-to-date review of the recent basic and clinical research advances is essential given the prevalence of clinical reproductive disorders, the emerging roles of upstream reproductive hormones in bone physiology, as well as the urgent need to develop novel safe and effective therapies for bone fragility in a rapidly aging population. [ABSTRACT FROM AUTHOR]

Background: Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pituitary dysfunction. While gonadotropin-releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH release and thus could be used to specifically interrogate hypothalamic function. Congenital HH (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration or function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. Methods: Men with CHH (n = 21) and healthy eugonadal men (n = 21) received an intravenous bolus of either GnRH (100 μg) or KP54 (6.4 nmol/kg), on 2 occasions, and were monitored for 6 h after administration of each neuropeptide. Results: Maximal luteinizing hormone (LH) rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; p < 0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (area under receiver operating characteristic curve KP54: 1.0, 95% CI 1.0–1.0; GnRH: 0.88, 95% CI 0.76–0.99). Indeed, all CHH men had an LH rise <2.0 iU/L following KP54, whereas all healthy men had an LH rise >4.0 iU/L. Anosmic men with CHH (i.e., Kallmann syndrome) had even lower LH rises after KP54 than did normosmic men with CHH (p = 0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH rises after KP54 than other men with CHH (p = 0.035). Conclusion: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with CHH. [ABSTRACT FROM AUTHOR]

Context: The hormone kisspeptin has crucial and well-characterized roles in reproduction. Emerging data from animal models also suggest that kisspeptin has important metabolic effects including modulation of food intake. However, to date there have been no studies exploring the effects of kisspeptin on brain responses to food stimuli in humans.Objective: This work aims to investigate the effects of kisspeptin administration on brain responses to visual food stimuli and psychometric parameters of appetite, in healthy men.Design: A double-blinded, randomized, placebo-controlled, crossover study was conducted.Participants: Participants included 27 healthy, right-handed, eugonadal men (mean ± SEM: age 26.5 ± 1.1 years; body mass index 23.9 ± 0.4 kg/m2).Intervention: Participants received an intravenous infusion of 1 nmol/kg/h of kisspeptin or rate-matched vehicle over 75 minutes.Main Outcome Measures: Measurements included change in brain activity on functional magnetic resonance imaging in response to visual food stimuli and change in psychometric parameters of appetite, during kisspeptin administration compared to vehicle.Results: Kisspeptin administration at a bioactive dose did not affect brain responses to visual food stimuli or psychometric parameters of appetite compared to vehicle.Conclusions: This is the first study in humans investigating the effects of kisspeptin on brain regions regulating appetite and demonstrates that peripheral administration of kisspeptin does not alter brain responses to visual food stimuli or psychometric parameters of appetite in healthy men. These data provide key translational insights to further our understanding of the interaction between reproduction and metabolism. [ABSTRACT FROM AUTHOR]

Microglial/macrophage activation plays a dual role in response to brain injury after a stroke, promoting early neuroinflammation and benefit for neurovascular recovery. Therefore, the dynamics of stroke-induced cerebral microglial/macrophage activation are of substantial interest. This study used novel anti-Iba-1-targeted superparamagnetic iron–platinum (FePt) nanoparticles in conjunction with magnetic resonance imaging (MRI) to measure the spatiotemporal changes of the microglial/macrophage activation in living rat brain for four weeks post-stroke. Ischemic lesion areas were identified and measured using T2-weighted MR images. After injection of the FePt-nanoparticles, T2*-weighted MR images showed that the nanoparticles were seen solely in brain regions that coincided with areas of active microglia/macrophages detected by post-mortem immunohistochemistry. Good agreement in morphological and distributive dynamic changes was also observed between the Fe+-cells and the Iba-1+-microglia/macrophages. The spatiotemporal changes of nanoparticle detected by T2*-weighted images paralleled the changes of microglial/macrophage activation and phenotypes measured by post-mortem immunohistochemistry over the four weeks post-stroke. Maximum microglial/macrophage activation occurred seven days post-stroke for both measures, and the diminished activation found after two weeks continued to four weeks. Our results suggest that nanoparticle-enhanced MRI may constitute a novel approach for monitoring the dynamic development of neuroinflammation in living animals during the progression and treatment of stroke. [ABSTRACT FROM AUTHOR]

Background: It has been reported that the polyadenylate‐binding protein‐interacting protein 1 (PAIP1) pathway is closely connected with the progression of some malignant tumors. Here we examined the potential functional mechanism of PAIP1 in tongue squamous cell carcinoma (TSCC). Methods: PAIP1 was knocked down in TSCC cell lines and proliferation and apoptosis in vitro analyzed. The molecular features of TSCC were determined using quantitative proteome and succinylome analyses. The results were confirmed in the mouse model. Results: PAIP1 promoted cell proliferation and inhibited apoptosis. Its knockdown decreased Ki67 and Pcna expressions and increased Bax/Bcl2 index and Caspase‐3 expression. Bioinformatics analysis for proteomics revealed that PAIP1 knockdown correlated with the changes in differential protein expression. Conclusions: Upregulation of PAIP1 induces cell proliferation and inhibits apoptosis in TSCC; PAIP1 might be a diagnostic biomarker and a significant drug target. [ABSTRACT FROM AUTHOR]

γδ T cells are a small subset of unconventional T cells that are enriched in the mucosal areas, and are responsible for pathogen clearance and maintaining integrity. However, the role of γδ T cells in head and neck squamous cell carcinoma (HNSCC) is largely unknown. Here, by using RNA-seq data from The Cancer Genome Atlas (TCGA), we discovered that HNSCC patients with higher levels of γδ T cells were positively associated with lower clinical stages and better overall survival, and high abundance of γδ T cells was positively correlated with CD8+/CD4+ T cell infiltration. Gene ontology and pathway analyses showed that genes associated with T cell activation, proliferation, effector functions, cytotoxicity, and chemokine production were enriched in the group with a higher γδ T cell abundance. Furthermore, we found that the abundance of γδ T cells was positively associated with the expression of the butyrophilin (BTN) family proteins BTN3A1/BTN3A2/BTN3A3 and BTN2A1, but only MICB, one of the ligands of NKG2D, was involved in the activation of γδ T cells, indicating that the BTN family proteins might be involved in the activation and proliferation of γδ T cells in the tumor microenvironment of HNSCC. Our results indicated that γδ T cells, along with their ligands, are promising targets in HNSCC with great prognostic values and treatment potentials. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans. Materials and methods: In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells). Results: Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. Conclusions: Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Recurrent hypoglycemia is common, but its presentation is often insidious resulting in delays in diagnosis and significant morbidity. We describe a case of an insulinoma presenting with falls and confusion in a patient with tuberous sclerosis, demonstrating the importance of early hypoglycemia identification and a potential shared molecular pathogenesis. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to measure and characterize breathing-induced motion artifacts in fast helical free-breathing CT scans. Methods Ten lung cancer patients were scanned using fast helical CT during free breathing. In each case, 25 low-dose CT scans were acquired in alternating craniocaudal and caudocranial directions. A bellow-based breathing surrogate was simultaneously acquired. A published breathing motion model was used to estimate the diaphragm craniodaudal velocity at each CT scan. The Hounsfield unit ( HU) profiles passing through a small square (7 × 7 mm2) portion of the diaphragm were examined and fit to error functions, which were used to characterize the motion blur. The HU profiles that intersected diaphragm-adjacent non-parenchymal tissue were excluded from analysis. The five profiles for each scan that were best isolated from non-parenchymal tissue were used to determine the amount of blurring. A convolution-based blurring model was also employed to compare against the human data. Results There was a distinct relationship between blurring and diaphragm speed. The convolution model well described the blurring behavior in the patients. Most of the CT scans were acquired at tissue velocities less than 20 mm s−1, which was the threshold where blurring exceeded 1 mm (corresponding to the slice spacing in this study). Conclusions Breathing motion-induced blurring occurs even for relatively fast modern helical CT scans. Measurable motion-induced blurring occurs for velocities greater than 15 mm s−1 and greater than 1 mm for velocities greater than 20 mm s−1. Methods to manage the residual blurring artifacts will need to be developed to maximize the image quality for free-breathing CT protocols. [ABSTRACT FROM AUTHOR]