Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators.

Cushing's disease (CD) is a serious endocrine disorder attributed to an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that that subsequently leads to chronic hypercortisolemia. PitNET regression has been reported following treatment with the investigational selective glucocorticoid receptor (GR) modulator relacorilant, but the mechanisms behind that effect remain unknown. Human PitNET organoid models were generated from induced human pluripotent stem cells (iPSCs) or fresh tissue obtained from CD patient PitNETs (hPITOs).

Increased expression of blood muscarinic receptors in patients with reflex syncope.

Aims: Pathophysiology of reflex syncope is not fully understood but a vagal overactivity might be involved in this syncope. Previously, overexpression of muscarinic M2 receptors and acetylcholinesterase was found in particular in the heart and in lymphocytes of rabbits with vagal overactivity as well as in hearts of Sudden Infant Death Syndromes. The aim of this present study was to look at M2 receptor expression in blood of patients with reflex syncope.

Peculiar Clinical Presentation of Coxsackievirus B4 Infection: Neonatal Restrictive Cardiomyopathy.

 Restrictive cardiomyopathy in fetuses and neonates is extremely rare and has a poor outcome. Its etiology in neonates is elusive: metabolic diseases (e.g.

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland.

As a key component of the vertebrate neuroendocrine system, the pituitary gland relies on the progressive and coordinated development of distinct hormone-producing cell types and an invading vascular network. The molecular mechanisms that drive formation of the pituitary vasculature, which is necessary for regulated synthesis and secretion of hormones that maintain homeostasis, metabolism, and endocrine function, remain poorly understood. Here, we report that expression of integrin β1 in embryonic pituitary epithelial cells is required for angiogenesis in the developing mouse pituitary gland.

Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.

Background: Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity.

Cardiac muscarinic receptor overexpression in sudden infant death syndrome.

Background: Sudden infant death syndrome (SIDS) remains the leading cause of death among infants less than 1 year of age. Disturbed expression of some neurotransmitters and their receptors has been shown in the central nervous system of SIDS victims but no biological abnormality of the peripheral vago-cardiac system has been demonstrated to date. The present study aimed to seek vago-cardiac abnormalities in SIDS victims.

[Value of MRI in the evaluation of congenital anomalies of the heart and great vessels].

Management of congenital heart diseases (CHD) frequently is a diagnostic challenge. MRI, as a complement to echocardiography, plays an important role in the non-invasive evaluation of these anomalies. MRI allows high resolution anatomical evaluation of these structures in multiple planes as well as functional evaluation.

Daily on-line haemodiafiltration: a pilot trial in children.

Background: Despite major improvements in paediatric dialysis over the last two decades, cardiovascular outcome is often poor. As France gives priority to kidney transplantation over dialysis, children in chronic haemodialysis are generally pre-adolescents or adolescents with long medical histories and low compliance. In them, the usual weekly schedule of dialysis is often unsuitable.

PPAR gamma signaling exacerbates mammary gland tumor development.

Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR gamma ligands. To evaluate the therapeutic potential of increased PPAR gamma signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR gamma in mammary gland. These mice are indistinguishable from their wild-type littermates.

Hepatitis C virus NS5A and subgenomic replicon activate NF-kappaB via tyrosine phosphorylation of IkappaBalpha and its degradation by calpain protease.

Hepatitis C virus nonstructural protein 5A (NS5A) has been implicated in the HCV antiviral resistance, replication, and transactivation of cellular gene expression. We have recently shown that HCV NS5A activates NF-kappaB via oxidative stress (22). In this study, we investigate the molecular mechanism(s) of NF-kappaB activation in response to oxidative stress induced by NS5A protein.

First model of spontaneous vagal hyperreactivity and its mode of genetic transmission.

Background: The main purpose of our study was to define an animal model of vagal hyperreactivity and its genetic transmission.

Methods And Results: We first investigated the vagal reactivity with phenylephrine in conscious rabbits. Barosensitivity and the maximal bradycardic response were measured at the upper mean blood pressure plateau.

[Role of gastroesophageal reflux in asthma in infants and young children].

Gastroesophageal reflux (GER) occurs more frequently in asthmatic children than in general population. Esophageal pH recording data may be somewhat particular. The debate on GER increasing bronchial obstruction or GER being a parallel phenomenon remains controversial.

[Thoracic aortic coarctation: MRI evaluation and follow-up].

Purpose: Report our experience in the evaluation and follow-up of thoracic aortic coarctation with MRI and describe its role to estimate trans-stenotic flow.

Material And Methods: 43 MR examinations were performed in 30 patients (age range 15 days to 73 years) referred to our institution in the last 7 years.

Results: MRI visualized the ascending, horizontal and descending portions of the aorta and the supra-aortic vessels in 42/43 patients.

[Tetralogy of Fallot in monozygotic twins].

Unlabelled: The causative mechanisms of congenital heart defects remain unclear and little is known about the respective implication of chance, genetics and environment, though recent findings in molecular biology may provide further insight into understanding the pathophysiologic basis of congenital heart diseases.

Case Report: We report the exceptional but significant case of monozygotic twins both affected by tetralogy of Fallot, for whom prenatal diagnosis ruled out 22q11 microdeletion.

Conclusion: We discuss how far this observation is consistent with the latest hypothesis, which emphasizes the leading role of genetic factors.

Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha.

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-kappaB (NFkappaB). We investigated the effect of NGF on the expression of Bcl-xL, an anti-apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.

Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases.

Phosphorylation of the N-terminal domain of I kappa B inhibitory subunits induces activation of the transcription factor NF-kappa B. Although serine phosphorylation has been shown to induce ubiquitination and subsequent proteasome-mediated degradation of I kappa B-alpha, little is known about the mechanisms that lead to release of active NF-kappa B in T cells as a consequence of tyrosine phosphorylation of I kappa B-alpha [Imbert, V., Rupec, R.

Cleavage and relocation of the tyrosine kinase P59FYN during Fas-mediated apoptosis in T lymphocytes.

Ligation of Fas with its natural ligand or with anti-Fas antibodies induces an apoptotic program in Fas sensitive cells. We report here the identification of the tyrosine kinase p59Fyn as a substrate for CPP32-like proteinases and more particularly caspase 3 during Fas-mediated apoptosis in Jurkat T cells. Inhibition of CPP32-like proteinases by Ac-Asp-Glu-Val-Asp-aldehyde but not by Ac-Tyr-Val-Ala-Asp-aldehyde prevents CPP32, PARP and p59Fyn cleavage indicating that CPP32 or CPP32-like proteinases are responsible for the cleavage of p59Fyn.

Structural analysis, expression, and chromosomal localization of the mouse ikba gene.

The pleiotropic transcription factor NF-kappaB is localized in the cytoplasm bound to its inhibitory subunit IkappaB. The predominant form of NF-kappaB is a p50/p65 heterodimer which can be released from IkappaB-alpha and migrate to the nucleus. Previous studies have shown that IkappaB-alpha-/- mice die 8 to 10 days postnatally, showing runting and a severe dermatitis.

Tumor necrosis factor alpha-mediated inhibition of melanogenesis is dependent on nuclear factor kappa B activation.

Melanogenesis is a physiological process resulting in the synthesis of melanin pigments which play a crucial protective role against skin photocarcinogenesis. In vivo, solar ultraviolet light triggers the secretion of numerous keratinocyte-derived factors that are implicated in the regulation of melanogenesis. Among these, tumor necrosis factor alpha (TNFalpha), a cytokine implicated in the pro-inflammatory response, down-regulates pigment synthesis in vitro.

Tumor necrosis factor-alpha activation of nuclear transcription factor-kappaB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of Ikappa Balpha.

Tumor necrosis factor-alpha (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-kappa B (NF-kappaB). NF-kappaB is sequestered in the cytosol by Ikappa Balpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation. In contrast, we find TNF induction of NF-kappaB in murine bone marrow macrophages (BMMs), is mediated, by c-Src, in a cell, and cytokine specific manner.

Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha.

The transcription factor NF-kappa B regulates genes participating in immune and inflammatory responses. In T lymphocytes, NF-kappa B is sequestered in the cytosol by the inhibitor I kappa B-alpha and released after serine phosphorylation of I kappa B-alpha that regulates its ubiquitin-dependent degradation. We report an alternative mechanism of NF-kappa B activation.

Mediastinal stabilization by an expansion prosthesis in postoperative congenital diaphragmatic hernia with severe pulmonary hypoplasia.

The authors illustrate a case of right neonatal congenital diaphragmatic hernia (CDH) of Bochdalek with major pulmonary hypoplasia and postoperative massive mediastinal displacement to the right, leading to tracheal compression and recurrent respiratory distress at every attempt to wean the infant from the ventilator. Mediastinal stabilization was obtained by placing an expansion prosthesis (of the cutaneous type) in the right hemithorax, to prevent mediastinal obstruction of the main airways. This procedure may prove to be an original and efficient solution for the critical postoperative respiratory obstruction due to severe pulmonary hypoplasia and mediastinal mass effect in the newborn with CDH.