Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum.

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.

Control of Glucocorticoid Receptor Levels by PTEN Establishes a Failsafe Mechanism for Tumor Suppression.

The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. While the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Here, using knockin (KI) mice harboring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. Thus, we find that the dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN loss-driven cancers.

Novel mineralocorticoid receptor mechanisms regulate cardiac tissue inflammation in male mice.

MR activation in macrophages is critical for the development of cardiac inflammation and fibrosis. We previously showed that MR activation modifies macrophage pro-inflammatory signalling, changing the cardiac tissue response to injury via both direct gene transcription and JNK/AP-1 second messenger pathways. In contrast, MR-mediated renal electrolyte homeostasis is critically determined by DNA-binding-dependent processes. Hence, ascertaining the relative contribution of MR actions via DNA binding or alternative pathways on macrophage behaviour and cardiac inflammation may provide therapeutic opportunities which separate the cardioprotective effects of MR antagonists from their undesirable renal potassium-conserving effects. We developed new macrophage cell lines either lacking MR or harbouring a mutant MR incapable of DNA binding. Western blot analysis demonstrated that MR DNA binding is required for lipopolysaccharide (LPS), but not phorbol 12-myristate-13-acetate (PMA), induction of the MAPK/pJNK pathway in macrophages. Quantitative RTPCR for pro-inflammatory and pro-fibrotic targets revealed subsets of LPS- and PMA-induced genes that were either enhanced or repressed by the MR via actions that do not always require direct MR-DNA binding. Analysis of the MR target gene and profibrotic factor MMP12 identified promoter elements that are regulated by combined MR/MAPK/JNK signalling. Evaluation of cardiac tissue responses to an 8-day DOC/salt challenge in mice selectively lacking MR DNA-binding in macrophages demonstrated levels of inflammatory markers equivalent to WT, indicating non-DNA binding-dependent MR signalling in macrophages is sufficient for DOC/salt-induced tissue inflammation. Our data demonstrate that the MR regulates a macrophage pro-inflammatory phenotype and cardiac tissue inflammation, partially via pathways that do not require DNA binding.

The science of steroids.

Steroids are complex lipophilic molecules that have many actions in the body to regulate cellular, tissue and organ functions across the life-span. Steroid hormones such as cortisol, aldosterone, estradiol and testosterone are synthesised from cholesterol in specialised endocrine cells in the adrenal gland, ovary and testis, and released into the circulation when required. Steroid hormones move freely into cells to activate intracellular nuclear receptors that function as multi-domain ligand-dependent transcriptional regulators in the cell nucleus. Activated nuclear receptors modify expression of hundreds to thousands of specific target genes in the genome. Steroid hormone actions in the fetus include developmental roles in the respiratory system, brain, and cardiovascular system. The synthetic glucocorticoid steroid betamethasone is used antenatally to reduce the complications of preterm birth. Development of novel selective partial glucocorticoid receptor agonists may provide improved therapies to treat the respiratory complications of preterm birth and spare the deleterious effects of postnatal glucocorticoids in other organs.

In vivo evidence that RBM5 is a tumour suppressor in the lung.

Cigarette smoking is undoubtedly a risk factor for lung cancer. Moreover, smokers with genetic mutations on chromosome 3p21.3, a region frequently deleted in cancer and notably in lung cancer, have a dramatically higher risk of aggressive lung cancer. The RNA binding motif 5 (RBM5) is one of the component genes in the 3p21.3 tumour suppressor region. Studies using human cancer specimens and cell lines suggest a role for RBM5 as a tumour suppressor. Here we demonstrate, for the first time, an in vivo role for RBM5 as a tumour suppressor in the mouse lung. We generated Rbm5 loss-of-function mice and exposed them to a tobacco carcinogen NNK. Upon exposure to NNK, Rbm5 loss-of-function mice developed lung cancer at similar rates to wild type mice. As tumourigenesis progressed, however, reduced Rbm5 expression lead to significantly more aggressive lung cancer i.e. increased adenocarcinoma nodule numbers and tumour size. Our data provide in vivo evidence that reduced RBM5 function, as occurs in a large number of patients, coupled with exposure to tobacco carcinogens is a risk factor for an aggressive lung cancer phenotype. These data suggest that RBM5 loss-of-function likely underpins at least part of the pro-tumourigenic consequences of 3p21.3 deletion in humans.

Fresh Noncultured Endothelial Progenitor Cells Improve Neonatal Lung Hyperoxia-Induced Alveolar Injury.

Treatment of preterm human infants with high oxygen can result in disrupted lung alveolar and vascular development. Local or systemic administration of endothelial progenitor cells (EPCs) is reported to remedy such disruption in animal models. In this study, the effects of both fresh (enriched for KDR) and cultured bone marrow (BM)-derived cell populations with EPC characteristics were examined following hyperoxia in neonatal mouse lungs. Intraperitoneal injection of fresh EPCs into five-day-old mice treated with 90% oxygen resulted in full recovery of hyperoxia-induced alveolar disruption by 56 days of age. Partial recovery in septal number following hyperoxia was observed following injection of short-term cultured EPCs, yet aberrant tissue growths appeared following injection of long-term cultured cells. Fresh and long-term cultured cells had no impact on blood vessel development. Short-term cultured cells increased blood vessel number in normoxic and hyperoxic mice by 28 days but had no impact on day 56. Injection of fresh EPCs into normoxic mice significantly reduced alveolarization compared with phosphate buffered saline-injected normoxic controls. These results indicate that fresh BM EPCs have a higher and safer corrective profile in a hyperoxia-induced lung injury model compared with cultured BM EPCs but may be detrimental to the normoxic lung. The appearance of aberrant tissue growths and other side effects following injection of cultured EPCs warrants further investigation. Stem Cells Translational Medicine 2017;6:2094-2105.

Aldosterone-Mediated Renal Sodium Transport Requires Intact Mineralocorticoid Receptor DNA-Binding in the Mouse.

The classic role of mineralocorticoid receptor (MR) is to promote sodium transport in epithelial tissues. However, the MR is also expressed in a range of tissues in which its role appears unrelated to sodium transport, and under normal physiological conditions, it may be responding to cortisol (corticosterone in rodents) rather than aldosterone. The relative importance of transcriptional mechanisms such as classical genomic signaling via a hormone response element, transrepression of other transcription factors, and nongenomic signaling is not clear, particularly in nonepithelial tissues. The goal of the present study was to define the role of the different signaling pathways for the MR by separating the functional role of classic genomic signaling, mediated by DNA binding, from these two other mechanisms. We used gene targeting to generate mice in which serine is substituted for cysteine at codon 603 in the MR; this mutation precludes DNA binding. These MR C603S mutant mice either die at birth or fail to thrive, lose weight, and die between days 10 and 13 in a manner similar to that observed previously for mice null for the MR gene. Renal expression and cellular localization of MR C603S by immunohistochemistry was equivalent to control mice. MR C603S mice were rescued by twice-daily saline injections. Despite increased aldosterone levels, renal expression of aldosterone-induced genes was not increased. This unique mouse model demonstrates that DNA binding is essential for the epithelial MR response and will provide the basis for analysis of nonclassical signaling of the MR in nonepithelial tissues.

Trop2: from development to disease.

BACKGROUND: Trop2 was first discovered as a biomarker of invasive trophoblast cells. Since then most research has focused on its role in tumourigenesis because it is highly expressed in the vast majority of human tumours and animal models of cancer. It is also highly expressed in stem cells and in many organs during development. RESULTS: We review the multifaceted role of Trop2 during development and tumourigenesis, including its role in regulating cell proliferation and migration, self-renewal, and maintenance of basement membrane integrity. We discuss the evolution of Trop2 and its related protein Epcam (Trop1), including their distinct roles. Mutation of Trop2 leads to gelatinous drop-like corneal dystrophy, whereas over-expression of Trop2 in human tumours promotes tumour aggressiveness and increases mortality. Although Trop2 expression is sufficient to promote tumour growth, the surprising discovery that Trop2-null mice have an increased risk of tumour development has highlighted the complexity of Trop2 signaling. Recently, studies have begun to identify the mechanisms underlying TROP2's functions, including regulated intramembrane proteolysis or specific interactions with integrin b1 and claudin proteins. CONCLUSIONS: Understanding the mechanisms underlying TROP2 signaling will clarify its role during development, aid in the development of better cancer treatments and unlock a promising new direction in regenerative medicine.

The glucocorticoid receptor 1A3 promoter correlates with high sensitivity to glucocorticoid-induced apoptosis in human lymphocytes.

Glucocorticoids (GCs) are powerful inhibitors of inflammation and immunity. Although glucocorticoid-induced cell death (GICD) is an important part of GCs actions, the cell types and molecular mechanisms involved are not well understood. Untranslated exon 1A3 of the human glucocorticoid receptor (GR) gene is a major determinant of GICD in GICD-sensitive human cancer cell lines, operating to dynamically upregulate GR levels in response to GCs. We measured the GICD sensitivity of freshly isolated peripheral blood mononuclear cells and thymocytes to dexamethasone in vitro, relating this to GR exon 1A3 expression. A clear GICD sensitivity hierarchy was detected: B cells>thymocytes/natural killer (NK) cells>peripheral T cells. Within thymocyte populations, GICD sensitivity decreased with maturation. Interestingly, NK cell subsets were differentially sensitive to GICD, with CD16(+)CD56(int) (cytotoxic) NK cells being highly resistant to GICD, whereas CD16(-)CD56(hi) (cytokine producing) NK cells were highly sensitive (similar to B cells). B-cell GICD was rescued by co-culture with interleukin-4. Strikingly, although no significant increases in GR protein were observed during 48 h of culture of GICD-sensitive and -resistant cells alike, GR 1A3 expression was increased over pre-culture levels in a manner directly proportional to the GICD sensitivity of each cell type. Accordingly, this is the first evidence that the GR exon 1A3 promoter is differentially regulated during thymic development and maturation of human T cells. Furthermore, human peripheral blood B cells are exquisitely GICD-sensitive in vitro, giving new insight into how GCs may downregulate immunity. Collectively, these data show that GR 1A3 expression is tied with GICD sensitivity in human lymphocytes, underscoring the potential for GR 1A3 expression to be used as a biomarker for sensitivity to GICD.

Trop2 regulates motility and lamellipodia formation in cultured fetal lung fibroblasts.

Proliferation and migration of fibroblasts are vital for fetal lung development. However, the regulatory mechanisms are poorly understood. We have previously shown that TROP2 gene expression is closely associated with fetal lung cell proliferation in vivo and that TROP2 knockdown decreases proliferation of fetal lung fibroblasts in culture. We hypothesized that the Trop2 protein also regulates the morphology and motility of fetal lung fibroblasts. Fibroblasts isolated from fetal rat lungs (gestational age embryonic day 19) adopted a myofibroblast-like morphology in culture. Trop2 protein was localized to lamellipodia. TROP2 siRNA significantly decreased: TROP2 mRNA levels by 77%, the proportion of cells containing Trop2 protein by 70%, and cell proliferation by 50%. TROP2 siRNA also decreased the degree of motility as determined by the number of gridlines that cells moved across (2.2 ± 0.2 vs. 3.2 ± 0.2; P < 0.001). TROP2 knockdown altered cell morphology, causing a notable absence of lamellipodia and abnormal localization of components of the cell migration apparatus, and it reduced phosphorylated ERK1 and ERK2 levels. In contrast, TROP2 overexpression significantly increased: TROP2 mRNA levels by 40-fold, cell proliferation by 40%, the proportion of cells that were motile by 20%, and the number of gridlines that cells moved across (2.1 ± 0.2 vs. 1.6 ± 0.1; P < 0.001). Our data suggest that Trop2 regulates cell proliferation and motility and that it does so by regulating the ERK pathway and several critical components of the cell migration apparatus.

cAMP response element binding protein1 is essential for activation of steroyl co-enzyme a desaturase 1 (Scd1) in mouse lung type II epithelial cells.

Cyclic AMP Response Element-Binding Protein 1 (Creb1) is a transcription factor that mediates cyclic adenosine 3', 5'-monophosphate (cAMP) signalling in many tissues. Creb1(-/-) mice die at birth due to respiratory failure and previous genome-wide microarray analysis of E17.5 Creb1(-/-) fetal mouse lung identified important Creb1-regulated gene targets during lung development. The lipogenic enzymes stearoyl-CoA desaturase 1 (Scd1) and fatty acid synthase (Fasn) showed highly reduced gene expression in Creb1(-/-) lungs. We therefore hypothesized that Creb1 plays a crucial role in the transcriptional regulation of genes involved in pulmonary lipid biosynthetic pathways during lung development. In this study we confirmed that Scd1 and Fasn mRNA levels were down regulated in the E17.5 Creb1(-/-) mouse lung while the lipogenic-associated transcription factors SrebpF1, C/ebpα and Pparγ were increased. In vivo studies using germline (Creb1(-/-) ) and lung epithelial-specific (Creb1(EpiΔ/Δ) ) Creb1 knockout mice showed strongly reduced Scd1, but not Fasn gene expression and protein levels in lung epithelial cells. In vitro studies using mouse MLE-15 epithelial cells showed that forskolin-mediated activation of Creb1 increased both Scd1 gene expression and protein synthesis. Additionally, MLE15 cells transfected with a dominant-negative ACreb vector blocked forskolin-mediated stimulation of Scd1 gene expression. Lipid profiling in MLE15 cells showed that dominant-negative ACreb suppressed forskolin-induced desaturation of ether linked lipids to produce plasmalogens, as well as levels of phosphatidylethanolamine, ceramide and lysophosphatidylcholine. Taken together these results demonstrate that Creb1 is essential for the induction and maintenance of Scd1 in developing fetal mouse lung epithelial cells.

Nfil3 is a glucocorticoid-regulated gene required for glucocorticoid-induced apoptosis in male murine T cells.

Glucocorticoids (GCs) have essential roles in the regulation of development, integrated metabolism, and immune and neurological responses, and act primarily via the glucocorticoid receptor (GR). In most cells, GC treatment results in down-regulation of GR mRNA and protein levels via negative feedback mechanisms. However, in GC-treated thymocytes, GR protein levels are maintained at a high level, increasing sensitivity of thymocytes to GCs, resulting in apoptosis termed glucocorticoid-induced cell death (GICD). CD4(+)CD8(+) double-positive thymocytes and thymic natural killer T cells in particular are highly sensitive to GICD. Although GICD is exploited via the use of synthetic GC analogues in the treatment of hematopoietic malignancies, the intracellular molecular pathway of GICD is not well understood. To explore GICD in thymocytes, the authors performed whole genome expression microarray analysis in mouse GR exon 2 null vs wild-type thymus RNA 3 hours after dexamethasone treatment. Identified and validated direct GR targets included P21 and Bim, in addition to an important transcriptional regulator Nfil3, which previously has been associated with GICD and is essential for natural killer cell development in vivo. Immunostaining of NFIL3 in whole thymus localized NFIL3 primarily to the medullary region, and double labeling colocalized NFIL3 to apoptotic cells. In silico analysis revealed a putative GC response element 5 kb upstream of the Nfil3 promoter that is strongly conserved in the rat genome and was confirmed to bind GR by chromatin immunoprecipitation. The knockdown of Nfil3 mRNA levels to 20% of normal using specific small interfering RNAs abrogated GICD, indicating that NFIL3 is required for normal GICD in CTLL-2 T cells.

Prevalence and persistence of sleep disordered breathing symptoms in young children: a 6-year population-based cohort study.

STUDY OBJECTIVES: To describe the prevalence, persistence, and characteristics associated with sleep disordered breathing (SDB) symptoms in a population-based cohort followed from 6 months to 6.75 years. DESIGN: Avon Longitudinal Study of Parents and Children (ALSPAC). SETTING: England, 1991-1999. PARTICIPANTS: 12,447 children in ALSPAC with parental report of apnea, snoring, or mouth-breathing frequency on any one of 7 questionnaires. MEASUREMENTS: Symptom prevalence rates-assessed as "Always" and "Habitually"-are reported at 0.5, 1.5, 2.5, 3.5, 4.75, 5.75, and 6.75 years of age. The proportion of children in whom symptoms develop, persist or abate between observation points is reported. Exploratory multivariate analyses identified SDB risk factors at 1.5, 4.75, and 6.75 years. RESULTS: The prevalence of apnea ("Always") is 1%-2% at all ages assessed. In contrast, snoring "Always" ranges from 3.6% to 7.7%, and snoring "Habitually" ranges from 9.6% to 21.2%, with a notable increase from 1.5- 2.5 years. At 6 years old, 25% are habitual mouth-breathers. The "Always" and "Habitual" incidence of each symptom between time points is 1%-5% and 5%-10%, respectively. In multivariate analyses of combined symptoms, socioeconomic factors have stronger, more persistent effects upon increased SDB risk than gestational age, gender, or race (aside from 1.5 years); adenoidectomy decreases risk by 40%-50%. CONCLUSIONS: This is the first natural history study of the primary symptoms of SDB across a key 6-year period in the development of SDB symptoms. Snoring rates are higher and spike earlier than previously reported. Symptoms are dynamic, suggesting the need for early and continued vigilance in early childhood.

The oncogene Trop2 regulates fetal lung cell proliferation.

The factors regulating growth of the developing lung are poorly understood, although the degree of fetal lung expansion is critical. The oncogene Trop2 (trophoblast antigen 2) is upregulated during accelerated fetal lung growth, and we hypothesized that it may regulate normal fetal lung growth. We investigated Trop2 expression in the fetal and neonatal sheep lung during accelerated and delayed lung growth induced by alterations in fetal lung expansion, as well as in response to glucocorticoids. Trop2 expression was measured using real-time PCR and localized spatially using in situ hybridization and immunofluorescence. During normal lung development, Trop2 expression was higher at 90 days gestational age (GA; 4.0 ± 0.8) than at 128 days GA (1.0 ± 0.1), decreased to 0.5 ± 0.1 at 142 days GA (full term ∼147 days GA), and was positively correlated to lung cell proliferation rates (r = 0.953, P < 0.005). Trop2 expression was regulated by fetal lung expansion, but not by glucocorticoids. It was increased nearly threefold by 36 h of increased fetal lung expansion (P < 0.05) and was reduced to ∼55% of control levels by reduced fetal lung expansion (P < 0.05). Trop2 expression was associated with lung cell proliferation during normal and altered lung growth, and the TROP2 protein colocalized with Ki-67-positive cells in the fetal lung. TROP2 was predominantly localized to fibroblasts and type II alveolar epithelial cells. Trop2 small interfering RNA decreased Trop2 expression by ∼75% in cultured fetal rat lung fibroblasts and decreased their proliferation by ∼50%. Cell viability was not affected. This study demonstrates that TROP2 regulates lung cell proliferation during development.

cAMP response element binding protein is required for differentiation of respiratory epithelium during murine development.

The cAMP response element binding protein 1 (Creb1) transcription factor regulates cellular gene expression in response to elevated levels of intracellular cAMP. Creb1(-/-) fetal mice are phenotypically smaller than wildtype littermates, predominantly die in utero and do not survive after birth due to respiratory failure. We have further investigated the respiratory defect of Creb1(-/-) fetal mice during development. Lungs of Creb1(-/-) fetal mice were pale in colour and smaller than wildtype controls in proportion to their reduced body size. Creb1(-/-) lungs also did not mature morphologically beyond E16.5 with little or no expansion of airway luminal spaces, a phenotype also observed with the Creb1(-/-) lung on a Crem(-/-) genetic background. Creb1 was highly expressed throughout the lung at all stages examined, however activation of Creb1 was detected primarily in distal lung epithelium. Cell differentiation of E17.5 Creb1(-/-) lung distal epithelium was analysed by electron microscopy and showed markedly reduced numbers of type-I and type-II alveolar epithelial cells. Furthermore, immunomarkers for specific lineages of proximal epithelium including ciliated, non-ciliated (Clara), and neuroendocrine cells showed delayed onset of expression in the Creb1(-/-) lung. Finally, gene expression analyses of the E17.5 Creb1(-/-) lung using whole genome microarray and qPCR collectively identified respiratory marker gene profiles and provide potential novel Creb1-regulated genes. Together, these results demonstrate a crucial role for Creb1 activity for the development and differentiation of the conducting and distal lung epithelium.

Glucocorticoids stimulate hepatic and renal catecholamine inactivation by direct rapid induction of the dopamine sulfotransferase Sult1d1.

During the stress response and metabolic fasting, glucocorticoids acting via the glucocorticoid receptor (GR) stimulate hepatic glucose production by activating specific gluconeogenic enzyme target genes. To characterize novel direct GR-regulated hepatic target genes under glucocorticoid control, we performed a whole genome gene expression microarray using dexamethasone-treated GR-null mice. Strongly induced previously characterized genes included phosphoenolpyruvate carboxykinase, serine dehydratase, tyrosine oxygenase, lipin 1, metallothionine, and cdkn1A. Novel induced genes included Ddit4, Fkbp5, Megf9, Sult1e1, and Sult1d1, and all were verified by real-time PCR. Sult1d1, a sulfotransferase, is a member of a large superfamily of detoxification enzymes and has an important role in the inactivation of endogenous dopamine-derived compounds, including the catecholamines. Treatment of primary mouse hepatocytes with dexamethasone for 6 h dramatically increased Sult1d1 mRNA levels, whereas cotreatment with RU-486, a GR antagonist, blocked induction by dexamethasone. Sult1d1 mRNA levels were also increased by dexamethasone in the kidney, a major site of Sult1d1 synthesis. Sult1d1 mRNA was localized by in situ hybridization to renal collecting ducts and was rapidly induced by glucocorticoids in renal inner medullary collecting duct (IMCD3) cells. Hepatic and renal Sult1d1 enzymatic activity was significantly induced in vivo in wild-type mice 6 h after dexamethasone treatment. Chromatin immunoprecipitation assay analysis upstream of the Sult1d1 gene promoter identified a glucocorticoid response element close to the neighboring glucocorticoid-responsive estrogen sulfotransferase Sult1e1 gene, indicating that both genes potentially share a common glucocorticoid response element. These results suggest that Sult1d1 in mice is directly induced by glucocorticoids and may attenuate elevated catecholamine activity during the stress response.

Referencias de peso y estatura desde el nacimiento hasta la madurez para niñas y niños argentinos: Incorporación de datos de la OMS de 0 a 2 años, recálculo de percentilos para obtención de valores LMS / Growth references for weight and height for Argentinian girls and boys from birth to maturity: Incorporation of data from the World Health Organisation from birth to 2 years and calculation of new percentiles and LMS values

Las tablas de crecimiento nacionales se han estado empleando por más de 20 años. En este período mostraron dos carencias: la falta de datos de niños alimentados a pecho en los primeros años de vida y la dificultad de calcular puntajes “z”. Afortunadamente, la OMS publicó recientemente datos longitudinales de crecimiento en niños amamantados de 0 a 2 años, información que hemos incorporadoa las tablas nacionales en este intervalo etario. La segunda carencia fue resuelta mediante el método LMS para el cálculo de nuevos percentilos. Los valores de mediana (M), coeficientes de variación(S) y asimetría (L) se suavizaron ajustando splines cúbicos. Se publican los percentilos seleccionados y los valores de L, M y S para edades en intervalos anuales. Los pediatras y otros usuarios pueden ahora calcular los puntajes “z” automáticamente en el sitio correspondiente de Internet provisto por el Servicio de Crecimiento y Desarrollo del Hospital Garrahan, que permite usar el programa LMS growth: www.garrahan.gov.ar/tdecrecimiento.Se prepararon nuevos gráficos con el mismo formato anterior, para rangos etarios de 0-19 y de 0-6 años para cada sexo. Se incorporaron los percentilos 3° y 97° de la edad de comienzo del estadio II de Tanner para genitales, mamas y vello pubiano en niñas y niños argentinos y edad de la menarca. Pensamos que las nuevas tablas representan un progreso para la evaluación del crecimiento y la nutrición de niños en nuestro país.

Argentine growth references have been widely used by paediatricians in the country for the last 20 years. Two main difficulties were detected during this period: the lack of data on breast-fed children in the first months of age, and problems in the calculation of “z” scores. On these basis, local data on weight and height during the first two years of life were replaced by data from the longitudinal international studyrecently carried out by WHO. L, M and S values were obtained from the original percentile data for ages 2 to maturity, and smoothed with cubic splines. Selected pecentiles for weight and height from birth to maturity were then re-calculated using LMS values. Charts were designed in two formats: birth to maturity and birth to 6.0 years. Now, users can calculate “z” scores automatically at the new site provided bythe Department of Growth and Development, Hospital Garrahan, which enables the use of the LMS growth programme. We have also incorporated into the new charts, percentiles of the age of attaining menarche and Tanner´s stage II of breast, genitalia and pubic hair for Argentine children. We think thenew references represent an improvement in the assessment of growth in our country.

Early biomarkers and potential mediators of ventilation-induced lung injury in very preterm lambs.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is closely associated with ventilator-induced lung injury (VILI) in very preterm infants. The greatest risk of VILI may be in the immediate period after birth, when the lungs are surfactant deficient, still partially filled with liquid and not uniformly aerated. However, there have been very few studies that have examined this immediate post-birth period and identified the initial injury-related pathways that are activated. We aimed to determine if the early response genes; connective tissue growth factor (CTGF), cysteine rich-61 (CYR61) and early growth response 1 (EGR1), were rapidly induced by VILI in preterm lambs and whether ventilation with different tidal volumes caused different inflammatory cytokine and early response gene expression. METHODS: To identify early markers of VILI, preterm lambs (132 d gestational age; GA, term approximately 147 d) were resuscitated with an injurious ventilation strategy (V(T) 20 mL/kg for 15 min) then gently ventilated (5 mL/kg) for 15, 30, 60 or 120 min (n = 4 in each). To determine if early response genes and inflammatory cytokines were differentially regulated by different ventilation strategies, separate groups of preterm lambs (125 d GA; n = 5 in each) were ventilated from birth with a V(T) of 5 (VG5) or 10 mL/kg (VG10) for 135 minutes. Lung gene expression levels were compared to levels prior to ventilation in age-matched control fetuses. RESULTS: CTGF, CYR61 and EGR1 lung mRNA levels were increased approximately 25, 50 and 120-fold respectively (p < 0.05), within 30 minutes of injurious ventilation. VG5 and VG10 caused significant increases in CTGF, CYR61, EGR1, IL1- , IL-6 and IL-8 mRNA levels compared to control levels. CTGF, CYR61, IL-6 and IL-8 expression levels were higher in VG10 than VG5 lambs; although only the IL-6 and CYR61 mRNA levels reached significance. CONCLUSION: CTGF, CYR61 and EGR1 may be novel early markers of lung injury and mechanical ventilation from birth using relatively low tidal volumes may be less injurious than using higher tidal volumes.

Glucocorticoids antagonize estrogens by glucocorticoid receptor-mediated activation of estrogen sulfotransferase.

Glucocorticoids and estrogens are two classes of steroid hormones that have essential but distinct physiologic functions. Estrogens also represent a risk factor for breast cancer. It has been suggested that glucocorticoids can attenuate estrogen responses, but the mechanism by which glucocorticoids inhibit estrogenic activity is unknown. In this study, we show that activation of glucocorticoid receptor (GR) by dexamethasone (DEX) induced the expression and activity of estrogen sulfotransferase (SULT1E1 or EST), an enzyme important for the metabolic deactivation of estrogens, because sulfonated estrogens fail to activate the estrogen receptor. Treatment with DEX lowered circulating estrogens, compromised uterine estrogen responses, and inhibited estrogen-dependent breast cancer growth in vitro and in a xenograft model. We further showed that the mouse and human SULT1E1 genes are transcriptional targets of GR and deletion of Sult1e1/Est in mice abolished the DEX effect on estrogen responses. These findings have revealed a novel nuclear receptor-mediated and metabolism-based mechanism of estrogen deprivation, which may have implications in therapeutic development for breast cancers. Because glucocorticoids and estrogens are widely prescribed drugs, our results also urge caution in avoiding glucocorticoid-estrogen interactions in patients.

Early undernutrition leads to long-lasting reductions in body weight and adiposity whereas increased intake increases cardiac fibrosis in male rats.

Previous studies suggest that both overfeeding and undernutrition during development increase the risk of obesity and hypertension in adulthood. In this study, we examined both short- (24 d) and long- (16 wk) term effects of early postnatal over- and underfeeding in rats on body weight, body composition, plasma hormones, adiposity markers, and hypothalamic neuropeptide Y content. Cardiovascular changes were also examined by measuring blood pressure and cardiac fibrosis. Rats raised in litters of 3, 12, or 18 pups per mother were used to model early onset overfeeding, control, and underfeeding, respectively. At 24 d of age, pups raised in small litters (SL) were 10% heavier than pups from normal litters, accompanied by increased organ mass and fat mass, elevated plasma leptin, corticosterone, and uncoupling protein-1 mRNA in brown adipose tissue. On the other hand, pups raised in large litters were 17% lighter with no significant changes in plasma leptin. Overfeeding during the first 3 wk of life led to increased plasma leptin concentration in adulthood, whereas underfed rats remained significantly lighter throughout the study, with no evidence of catch-up growth. Rats raised in SL were more susceptible to developing cardiac fibrosis with a 22% increase in collagen deposition compared with control rats at 16 wk of age (P < 0.05). This was independent of any changes in blood pressure. This study demonstrates that nutritional changes early in postnatal development can have long-lasting effects on body weight, adiposity, and some mediators involved in energy homeostasis and can also lead to structural changes in the heart in adulthood. This highlights the importance of identifying potential early life risk factors involved in the modulation of childhood nutrition.