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The exact link between systemic and ocular endogenous corticoids (steroidome) is unclear and whether the ocular steroidome is altered in CSCR eyes is unknown. The aims of this study were to analyze the human steroidome in the aqueous humor as a function of age, sex and time of the day, to correlate systemic and ocular steroidome and to analyze the ocular steroidome in long lasting complex inactive CSCR. Based on our results, we present two CSCR cases treated by the combination of oral mineralocorticoid antagonist and glucocorticoids drops. In a cross-sectional study, aqueous humor (AH) was collected between 8am and 6 pm from 50 unaffected individuals (25 men and 25 women) and from 14 patients with chronic CSCR, during cataract surgery. In addition, simultaneous serum and AH were collected from 27 individuals undergoing cataract surgery and, simultaneous AH and vitreous were collected from 9 patients undergoing cataract and vitrectomy to estimate corticoids levels in the different compartments. The steroidome was determined using a LC–MS/MS method that quantifies 13 endogenous corticoids from the gluco, mineralocorticoid and androgen pathways. In AH and vitreous, the highest corticoid level is reached by cortisol (F), that represents less than 10% of F serum level. The cortisol levels in the serum did not correlate with ocular cortisol levels. Serum and ocular cortisone (E) levels correlate, although less than 5% of circulating E reaches the eye. The only mineralocorticoids measured in the AH were corticosterone (B) and its inactive form, the 11-desoxycorticosterone (A). There was no influence of circadian rhythm on cortisol ocular levels and there was no correlation between the age or the sex and the level of F, E, A, and B. In eyes with chronic inactive CSCR, the levels of the active glucocorticoid form F was lower than in control eyes and the F/E ratio was reduced by 50% but the B/A ratio was higher indicating imbalance towards active mineralocorticoids. Base on this observation, we propose to combine an antagonist of the mineralocorticoid receptor together with topical glucocorticoids in two CSCR patients, resistant to all other treatments, with favorable outcome. Our results indicate that the ocular psteroidome is highly regulated suggesting a local metabolism of ocular corticoids. In eyes with long-lasting complex inactive CSCR, the steroidome analysis shows lower active glucocorticoids and higher active mineralocorticoids.

Hypoglycemia is a recognized feature of severe malaria but its diagnosis and management remain problematic in resource-limited settings. There is limited data on the burden and prognosis associated with glycemia dysregulation in non-neonate children in non-malaria areas. We prospectively assessed the abnormal blood glucose prevalence and the outcome and risk factors of deaths in critically ill children admitted to a national referral hospital in Laos. Consecutive children (1 month-15 years) admitted to the pediatric ward of Mahosot hospital, were categorized using the integrated management of childhood illness (IMCI). Blood glucose was assessed once on admission through a finger prick using a bedside glucometer. Glycemia levels: hypoglycemia: < 2.2 mmol/L (< 40 mg⁄ dl), low glycemia: 2.2-4.4 mmol/L (40-79 mg⁄ dl), euglycemia: 4.4-8.3 mmol/L (80-149 mg⁄ dl), and hyperglycemia: > 8.3 mmol/L (≥150 mg⁄ dl), were related to the IMCI algorithm and case fatality using univariate and multivariate analysis. Of 350 children, 62.2% (n = 218) were severely ill and 49.1% (n = 172) had at least one IMCI danger sign. A total of 15 (4.2%, 95%CI: 2.4-6.9) had hypoglycemia, 99 (28.2%, 95%CI: 23.6-33.3) low glycemia, 201 (57.4%, 95% CI: 52.0-62.6) euglycemia and 35 (10.0%, 95% CI: 7.0-13.6) hyperglycemia. Hypoglycemia was associated with longer fasting (p = 0.001) and limited treatment before admission (p = 0.09). Hypoglycemia and hyperglycemia were associated with hypoxemia (SaO2) (p = 0.001). A total of 21 (6.0%) of the children died: 66.6% with hypoglycemic, 6.0% with low glycemic, 5.7% with hyperglycemic and 1.4% with euglycemic groups. A total of 9 (2.5%) deaths occurred during the first 24 hours of admission and 5 (1.7%) within 3 days of hospital discharge. Compared to euglycemic children, hypoglycemic and low glycemic children had a higher rate of early death (20%, p<0.001 and 5%, p = 0.008; respectively). They also had a higher risk of death (OR: 132; 95%CI: 29.0-596.5; p = 0.001; and OR: 4.2; 95%CI: 1.1-15.6; p = 0.02; respectively). In multivariate analyses, hypoglycemia (OR: 197; 95%CI: 33-1173.9), hypoxemia (OR: 5.3; 95%CI: 1.4-20), presence of hepatomegaly (OR: 8.7; 95%CI: 2.0-37.6) and having an illiterate mother (OR: 25.9; 95%CI: 4.2-160.6) were associated with increased risk of death. Hypoglycemia is linked with a high risk of mortality for children in non malaria tropical settings. Blood sugar should be monitored and treatment provided for sick children, especially with danger signs and prolonged fasting. Further evaluations of intervention using thresholds including low glycemia is recommended in resource-limited settings. Research is also needed to determine the significance, prognosis and care of hyperglycemia.

Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media. Human RPE cells derived from induced pluripotent stem cells (iRPE) were used to analyze the pan-transcriptional regulations induced by aldosterone—an MR-specific agonist, or cortisol or cortisol + RU486—a GR antagonist. The retinal phenotype of transgenic mice that overexpress the human MR (P1.hMR) was analyzed. In the human eye, the main ligand for GR and MR is cortisol. The iRPE cells express functional GR and MR. The subset of genes regulated by aldosterone and by cortisol + RU-486, and not by cortisol alone, mimics an imbalance toward MR activation. They are involved in extracellular matrix remodeling (CNN1, MGP, AMTN), epithelial–mesenchymal transition, RPE cell proliferation and migration (ITGB3, PLAUR and FOSL1) and immune balance (TNFSF18 and PTX3). The P1.hMR mice showed choroidal vasodilation, focal alteration of the RPE/choroid interface and migration of RPE cells together with RPE barrier function alteration, similar to human retinal diseases within the pachychoroid spectrum. RPE is a corticosteroid-sensitive epithelium. MR pathway activation in the RPE regulates genes involved in barrier function, extracellular matrix, neural regulation and epithelial differentiation, which could contribute to retinal pathology.

In the neonatal period, the human kidney is characterized by an impaired ability to regulate water and sodium homeostasis, resembling partial aldosterone resistance. The aim of our study was to assess this hormonal insensitivity in newborn infants and to determine its relationship with neonatal sodium handling. We conducted a prospective study in 48 healthy newborns and their mothers. Aldosterone, renin, and electrolyte concentrations were measured in umbilical cords and in maternal plasma. Urinary aldosterone concentrations and sodium excretion were determined at urination within 24 h after birth. A significant difference was observed between aldosterone and renin levels in newborn infants compared with their mothers (817 ± 73 versus 575 ± 55 pg/mL and 79 ± 10 versus 15 ± 2 pg/mL, respectively, p < 0.001). This hyperactivation of the renin-angiotensin-aldosterone system was associated with hyponatremia and hyperkalemia in the newborn infants, and high urinary sodium loss, consistent with a partial aldosterone resistance at birth. Unlike plasma aldosterone, urinary aldosterone concentration was found highly correlated with plasma potassium concentrations, thus representing the best index for accurate evaluation of mineralocorticoid sensitivity. Our study represents a comprehensive characterization of the renin-aldosterone axis in newborn infants and provides evidence for physiologic partial aldosterone resistance in the neonatal period.

SUMOylation is a dynamic posttranslational modification, that provides fine-tuning of protein function involved in the cellular response to stress, differentiation, and tissue development. In the adrenal cortex, an emblematic endocrine organ that mediates adaptation to physiological demands, the SUMOylation gradient is inversely correlated with the gradient of cellular differentiation raising important questions about its role in functional zonation and the response to stress. Considering that SUMO-specific protease 2 (SENP2), a deSUMOylating enzyme, is upregulated by Adrenocorticotropic Hormone (ACTH)/cAMP-dependent Protein Kinase (PKA) signalling within the zona fasciculata , we generated mice with adrenal-specific Senp2 loss to address these questions. Disruption of SENP2 activity in steroidogenic cells leads to specific hypoplasia of the zona fasciculata , a blunted reponse to ACTH and isolated glucocorticoid deficiency. Mechanistically, overSUMOylation resulting from SENP2 loss shifts the balance between ACTH/PKA and WNT/β-catenin signalling leading to repression of PKA activity and ectopic activation of β-catenin. At the cellular level, this blocks transdifferentiation of β-catenin-positive zona glomerulosa cells into fasciculata cells and sensitises them to premature apoptosis. Our findings indicate that the SUMO pathway is critical for adrenal homeostasis and stress responsiveness. SUMOylation is a mechanism of posttranslational modification involved in eukaryotic cell homeostasis. Here the authors report that mice unable to control SUMOylation in the adrenal cortex develop a selective defect in glucocorticoid production due to disrupted differentiation of cells involved in steroid hormone synthesis.

Renal and cardiovascular complications of prematurity are well established, notably the development of hypertension in adulthood. However, the underlying molecular mechanisms remain poorly understood. Our objective was to investigate the impact of prematurity on the ontogenesis of renal corticosteroid pathways, to evaluate its implication in perinatal renal complications and in the emergence of hypertension in adulthood. Swiss CD1 pregnant mice were injected with lipopolysaccharides at 18 days of gestation (E18) to induce prematurity at E18.5. Pups were sacrificed at birth, 7 days and 6 months of life. Second (F2) and third (F3) generations, established by mating prematurely born adult females with wild-type males, were also analyzed. Former preterm males developed hypertension at M6 (P < 0.0001). We found robust activation of renal corticosteroid target gene transcription at birth in preterm mice (αENaC (+45%), Gilz (+85%)), independent of any change in mineralocorticoid or glucocorticoid receptor expression. The offspring of the preterm group displayed increased blood pressure in F2 and F3, associated with increased renal Gilz mRNA expression, despite similar MR or GR expression and plasma corticosteroid levels measured by LC-MS/MS. Gilz promoter methylation measured by methylated DNA immunoprecipitation-qPCR was reduced with a negative correlation between methylation and expression (P = 0.0106). Our study demonstrates prematurity-related alterations in renal corticosteroid signaling pathways, with transgenerational inheritance of blood pressure dysregulation and epigenetic Gilz regulation up to the third generation. This study provides a better understanding of the molecular mechanisms involved in essential hypertension, which could partly be due to perinatal epigenetic programming from previous generations.High blood pressure: Exploring inheritanceA propensity towards high blood pressure may be passed down through several generations from adults who were born preterm. People who are born prematurely often suffer from kidney (renal) problems, high blood pressure and cardiovascular disease as they age. Recent research suggests adults born prematurely can pass dysregulated blood pressure to their children. Laetitia Martinerie at INSERM Unit 1185, Le Kremlin Bicêtre and Robert Debré Hospital in Paris, France, and co-workers studied generations of mice to explore how epigenetic alterations, DNA modifications that do not change the DNA code, affect blood pressure from birth through to adulthood. The team identified tissue-specific alterations in renal signaling pathways in premature mice. They also traced the associated overexpression of a gene called Gilz, known to play a role in blood pressure maintenance, through second and third generation mice born to the first generation preterms.

High myopia (HM) and posterior staphyloma (PS) are major causes of vision loss worldwide. Genetic and environmental factors, especially light exposure, influence myopia. This study shows that low-density lipoprotein-related receptor type 2 (LRP2) levels are decreased in the vitreous of patients with HM and PS, and that in human donor eyes affected by PS, LRP2 expression was reduced in the neural retina and retinal pigment epithelium (RPE), with morphologic changes similar to those observed in the Foxg1-Cre-Lrp2fl/fl mouse that also develops PS. In human induced pluripotent stem cell-derived RPE cells, LRP2 silencing regulated genes involved in eye and neuronal development, visual perception, tissue remodeling, hormone metabolism, and RPE structure. Its expression increased under light exposure, particularly red light, but was downregulated by cortisol. These findings establish a link between LRP2, myopization, and environmental factors, highlighting its crucial role in nonsyndromic HM and PS. LRP2 appears to be a promising therapeutic target for HM treatment.

Hypoglycemia is a defining feature of severe malaria and several other infectious diseases in children but the prevalence, significance, and prognosis of abnormal blood glucose, including hyperglycemia, have rarely been addressed in severely ill children in non-malaria endemic areas. In Madagascar, consecutive children (1 month-15 years) admitted to the pediatric ward of a referral hospital, were categorized using the integrated management of childhood illness (IMCI). Samples were taken once on admission for measuring blood glucose concentration. Glycemia levels (hypoglycemia <2.2 mmol/l; low glycemia: 2.2-4.4 mmol/l; normoglycemia >4.4-8.3 mmol/l; and hyperglycemia >8.3 mmol/l) were related to the IMCI algorithm and case fatality. Factors associated with blood glucose concentration and case fatality were analysed using univariate and multivariate analysis. Of 420 children, 48.1% (n = 202) were severely ill; 3.1% (n = 13) had hypoglycemia; 20.0% (n = 84) low glycemia; 65.9% (n = 277) normoglycemia; and 10.9% (n = 46) hyperglycemia. In univariate analysis, hypoglycemia and hyperglycemia both showed significant increase in the risk of death, as compared to normal blood glucose (RR: 12.2, 95% CI: 6.2-23.7 and RR: 2.5, 95% CI: 1.0-6.2, respectively). Children with low glycemia had no increased risk of death (RR: 1.2, 95% CI: 0.4-3.2) despite a poorer IMCI status on admission. After logistic regression, hypoglycemia (RR: 19.4, 95% CI: 5.0-.74.7, hepatomegaly (RR: 12.2, 95% CI: 3.3-44.9) and coma (RR: 4.8, 95% CI: 1.3-17.6) were the features on admission associated with an increased risk of death. Dysglycemia in non-neonates is associated with increased mortality. These findings underline the need for the use of rapid screening tests to initiate early treatment. Alternative treatments such as oral or sublingual administration of glucose should be developed in structures with limited resources.

Glucocorticoid hormones play a major role in fetal organ maturation. Yet, excessive glucocorticoid exposure in utero can result in a variety of detrimental effects, such as growth retardation and increased susceptibility to the development of hypertension. To protect the fetus, maternal glucocorticoids are metabolized into inactive compounds by placental 11beta-hydroxysteroid dehydrogenase type2 (11βHSD2). This enzyme is also expressed in the kidney, where it prevents illicit occupation of the mineralocorticoid receptor by glucocorticoids. We investigated the role of renal 11βHSD2 in the control of neonatal glucocorticoid metabolism in the human and mouse. Cortisol (F) and cortisone (E) concentrations were measured in maternal plasma, umbilical cord blood and human newborn urine using HPLC. 11βHSD2 activity was indirectly assessed by comparing the F/E ratio between maternal and neonatal plasma (placental activity) and between plasma and urine in newborns (renal activity). Direct measurement of renal 11βHSD2 activity was subsequently evaluated in mice at various developmental stages. Renal 11βHSD2 mRNA and protein expression were analyzed by quantitative RT-PCR and immunohistochemistry during the perinatal period in both species. We demonstrate that, at variance with placental 11βHSD2 activity, renal 11βHSD2 activity is weak in newborn human and mouse and correlates with low renal mRNA levels and absence of detectable 11βHSD2 protein. We provide evidence for a weak or absent expression of neonatal renal 11βHSD2 that is conserved among species. This temporal and tissue-specific 11βHSD2 expression could represent a physiological window for glucocorticoid action yet may constitute an important predictive factor for adverse outcomes of glucocorticoid excess through fetal programming.

Background Critically ill patients including trauma patients are at high risk of urinary tract infection (UTI). The composition of urine in trauma patients may be modified due to inflammation, systemic stress, rhabdomyolysis, life support treatment and/or urinary catheter insertion. Methods Prospective, single-centre, observational study conducted in patients with severe trauma and without a history of UTIs or recent antibiotic treatment. The 24-hour urine samples were collected on the first and the fifth days and the growth of Escherichia coli in urine from patients and healthy volunteers was compared. Biochemical and hormonal modifications in urine that could potentially influence bacterial growth were explored. Results Growth of E. coli in urine from trauma patients was significantly higher on days 1 and 5 than in urine of healthy volunteers. Several significant modifications of urine composition could explain these findings. On days 1 and 5, trauma patients had an increase in glycosuria, in urine iron concentration, and in the concentrations of several amino acids compared to healthy volunteers. On day 1, the urinary osmotic pressure was significantly lower than for healthy volunteers. Conclusion We showed that urine of trauma patients facilitated growth of E. coli when compared to urine from healthy volunteers. This effect was present in the first 24 hours and until at least the fifth day after trauma. This phenomenon may be involved in the pathophysiology of UTIs in trauma patients. Further studies are required to define the exact causes of such modifications.