SummaryA number of FSH Receptor (FSH-R) isoforms with distinct structural motifs and signaling paradigms have been described, including a single transmembrane domain variant that functions as a growth factor type receptor (FSH-R3). This study tested the hypothesis that FSH can stimulate ovarian cancer cell proliferation by acting on FSH-R3, using the tumorigenic mouse ovarian surface epithelial cell (MOSEC) line ID8. FSH enhanced ID8 proliferation in a concentration-dependent fashion. Moreover, FSH-treatment of ID8 elicited intracellular events consistent with activation of FSH-R3 and distinct from those associated with activation of the canonical G-protein coupled FSH-R isoform (FSH-R1). Specifically, the FSH-R3 signaling pathway included cAMP-independent activation of ERK downstream of an SNX-482 sensitive component likely to be the Cav2.3 calcium channel. Northern analysis using probes specific for exons 7 and 11 of FSH-R identified consistently only one 1.9 kb transcript. Immunoblot analysis confirmed expression of FSH-R3 but not FSHR-1 in ID8. Together, these data suggest that FSH-R3 signaling promotes proliferation of ovarian cancer cells.

Interleukin-6 (IL-6) is a multifunctional cytokine that has been shown to play a pivotal role in centrally-mediated physiological responses including activation of the hypothalamic-pituitary-adrenal axis. Cerebral spinal fluid (CSF) concentrations of IL-6 are elevated in multiple pathophysiological conditions including Alzheimer's disease, autoimmune disease, and meningitis. Despite this, the effect of IL-6 on central regulation of sympathetic nerve discharge (SND) remains unknown which limits understanding of sympathetic-immune interactions in health and disease. In the present study we determined the effect of intracerebroventricular (i.c.v, lateral ventricle) administration of IL-6 on splenic SND in urethane-chloralose-anesthetized rats. A second goal was to determine if icv injected IL-6 enters the brain parenchyma and acts as a volume transmission signal to access areas of the brain involved in regulation of sympathetic nerve outflow. i.c.v administration of IL-6 (10 ng, 100 ng, and 400 ng) significantly and progressively increased splenic SND from control levels in baroreceptor-denervated Sprague-Dawley rats. Administration of 100-ng and 400-ng IL-6 resulted in significantly higher SND responses when compared to those elicited with a 10-ng dose. Sixty minutes following icv administration, fluorescently labeled IL-6 was not distributed throughout the parenchyma of the brain but was localized to the periventricular areas of the ventricular system. Brain sections counter-stained for the IL-6 receptor (IL-6R) revealed that IL-6 and the IL-6R were co-localized in periventricular areas adjoining the third ventricle. These results demonstrate that icv IL-6 administration increases splenic SND, an effect likely achieved via signaling mechanisms originating in the periventricular cells.

Summary Despite the ongoing coronavirus disease 2019 (COVID‐19) pandemic, elective paediatric surgery must continue safely through the first, second and subsequent waves of disease. This study presents outcome data from a children's hospital in north‐west England, the region with the highest prevalence of COVID‐19 in England. Children and young people undergoing elective surgery isolated within their household for 14 days, then presented for real‐time reverse transcriptase polymerase chain reaction testing for severe acute respiratory syndrome coronavirus disease‐2 (SARS‐CoV‐2) within 72 h of their procedure (or rapid testing within 24 h in high‐risk cases), and completed a screening questionnaire on admission. Planned surgery resumed on 26 May 2020; in the four subsequent weeks, there were 197 patients for emergency and 501 for elective procedures. A total of 488 out of 501 (97.4%) elective admissions proceeded, representing a 2.6% COVID‐19‐related cancellation rate. There was no difference in the incidence of SARS‐CoV‐2 among children and young people who had or had not isolated for 14 days (p > 0.99). One out of 685 (0.1%) children who had surgery re‐presented to the hospital with symptoms potentially consistent with SARS‐CoV‐2 within 14 days of surgery. Outcomes were similar to those in the same time period in 2019 for length of stay (p = 1.0); unplanned critical care admissions (p = 0.59); and 14‐day hospital re‐admission (p = 0.17). However, the current cohort were younger (p = 0.037); of increased complexity (p < 0.001) and underwent more complex surgery (p < 0.001). The combined use of household self‐isolation, testing and screening questionnaires has allowed the re‐initiation of elective paediatric surgery at high volume while maintaining pre‐COVID‐19 outcomes in children and young people undergoing surgery. This may provide a model for addressing the ongoing challenges posed by COVID‐19, as well as future pandemics.

Helwig BG, Musch TI, Craig RA, Kenney MJ. Increased interleukin-6 receptor expression in the paraventricular nucleus of rats with heart failure. Am J Physiol Regul Integr Comp Physiol 292: R1165-R1173, 2007. First published November 9, 2006; doi:10.1152/ajpregu.00507.2006.-Activation of the hypothalamicpituitary-adrenal (HPA) axis and augmented plasma and tissue levels of IL-6 are hallmarks of heart failure (HF). Within the forebrain, cardiovascular homeostasis is mediated in part by the paraventricular nucleus (PVN) of the hypothalamus. IL-6, via binding to the IL-6 receptor (IL-6R)/glycoprotein 130 (gp130) complex influences cellular and physiological responses. Thus, in the current study, we hypothesized that PVN IL-6R protein and gene expression are upregulated in HF vs. sham-operated rats, whereas gp130 levels in the same tissues remain stable. Six weeks after coronary ligation surgery, hemodynamic measurements were obtained, and HF rats were divided into moderate noncongestive and severe chronic congestive groups based on cardiac indices. Plasma IL-6 levels were determined and changes in gene and protein expression of IL-6R and gp130 between sham-operated and HF rats were determined via real-time PCR and Western blot analyses, respectively. Plasma levels of IL-6 were elevated in rats with severe, but not moderate, HF compared with sham-operated controls. In both moderate and severe HF rats, protein but not gene expression of IL-6R was significantly increased in PVN tissue but not in non-PVN tissue, compared with sham-operated controls. Gene and protein levels of the gp130 subunit were not altered by HF in either tissue analyzed. Collectively, these data suggest that within the brain of HF rats, IL-6R expression is not a global change. Rather the increased IL-6 levels characteristic of HF may alter PVN-mediated physiological responses via enhanced expression of the IL-6R. signal transduction; gp130; hypothalamic-pituitary axis THE PARAVENTRICULAR NUCLEUS (PVN) of the hypothalamus is a forebrain nucleus with projections to brainstem and spinal cord regions regulating cardiovascular homeostasis (10). The PVN is also a key component of the hypothalamic-pituitary-adrenal (HPA) axis. Using cytokines as messengers, bidirectional communication between the nervous and immune systems occurs along the HPA axis (16,17,39,41,54,59). Among the cytokines, IL-6 plays a significant role in HPA activation by stimulating the release of negative feedback hormones, which inhibit cytokine gene expression, resulting in attenuation of immune responses and accompanying inflammation (38,44,51).The initial step in IL-6-mediated responses is interaction of the cytokine with the interleukin-6 receptor (IL-6R), the nonsignaling subunit of the receptor complex. Binding of ligand to the alpha subunit (e.g., IL-6R) results in homodimerization of the signal transducing ␤-subunit, glycoprotein130 (gp130), at the plasma membrane (25,43,55). This recruitment allows the binding of IL-6/IL-6R to gp130, resulting in a functional receptor compl...

To the Editor, Coronavirus disease 2019 due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in sickle cell disease (SCD) is still being described, with vaso-occlusive crisis (VOC) and acute chest syndrome reported. 1 Reports suggest COVID-19 causes hyperinflammation, vasculitis, coagulopathy, 2 acute respiratory distress syndrome, thromboembolism, and multiorgan failure syndrome (MOFS). [3][4][5] We present a case of post-COVID-19 encephalopathy, hyperammonemia, hyperinflammation, and MOFS in SCD.