Publications

After i.v. oCRH, plasma immunoreactive ACTH (ACTH-IR) is significantly greater in blacks than in whites; however, there is no corresponding increase in cortisol secretion. To test the hypothesis that there are black-white differences in adrenal responsiveness to ACTH that underlie this phenomenon, weight-, age-, and education-matched black (n = 10) and white (n = 10) women were i.v. infused with 5 differing doses of ACTH1-24 (0, 0.003, 0.01, 0.1, and 1 microgram/kg) with measured plasma cortisol and DHEA. To test the alternative hypothesis that greater post-CRH plasma ACTH-IR in blacks is caused by qualitative differences in circulating ACTH-immunoreactive peptides, we collected pre- and post-CRH plasma from 5 black and 5 white women and measured ACTH-IR after sample fractionation, using high-pressure liquid chromatography. There were no racial differences in adrenal responsiveness to differing doses of ACTH1-24 and no differences in the distribution of the forms of ACTH-IR before CRH. After CRH, whites had predominant ACTH-IR peaks at the retention times of ACTH1-39 and ACTH1-39-sulfoxide, whereas blacks had prominent peaks at several additional retention times. The post-CRH ratio of intact to total ACTH was significantly lower in blacks than in whites (0.27 +/- 0.17 vs. 0.71 +/- 0.17, P < 0.003). We conclude that there are qualitative differences in post-CRH circulating ACTH-IR in blacks and whites, leading to a greater immunoreactive to bioactive ACTH ratio in blacks. Such differences in the circulating forms of ACTH can account for greater CRH-stimulated ACTH-IR in blacks.

Breast milk is the ideal food for infants and undoubtedly has immediate and long‑term benefits. Breast milk contains extracellular vesicles (EVs) i.e., exosomes secreted by maternal breast cells. Exosomes carry genetic material, such as long non‑coding RNAs (lncRNAs), which possibly participate in cell‑to‑cell communications, as they are known to regulate critical gene pathways. The aim of the present study was to screen human breastmilk exosomes for their lncRNA cargo and to examine exosomal lncRNA levels associated with milk obtained from mothers that gave birth at term or prematurely (<37 weeks of gestation). Samples were collected at 3 weeks postpartum from 20 healthy, breastfeeding mothers; 10 mothers had given birth at full‑term and 10 mothers preterm. Exosomal RNA was extracted from all samples and the expression of 88 distinct lncRNAs was determined using reverse transcription‑quantitative PCR. A total of 13 lncRNAs were detected in ≥85% of the samples, while 31 were detected in ≥50% of the samples. Differential expression analysis of the lncRNAs between the two groups revealed ≥2‑fold differences, with generally higher lncRNA concentrations found in the milk of the mothers that gave birth at term compared with those that gave birth preterm. Among these, the non‑coding RNA activated at DNA damage (NORAD) was prominently detected in both groups, and its expression was significantly downregulated in the breast milk exosomes of mothers who delivered preterm. On the whole, the present study demonstrates that breast milk lncRNAs may be important factors of normal early human development. Collectively, the presence of lncRNAs in human breast milk may explain the consistent inability of researchers to fully 'humanize' animal milk.

Congenital adrenal hypoplasia is a rare cause of primary adrenocortical failure, which was first described in 1948. During the last two decades, the genetic basis for several forms of familial adrenal insufficiency syndromes has been elucidated. The molecular mechanisms for these disorders involve a broad spectrum of cellular and physiologic processes, including metabolism, nuclear protein import, oxidative stress defense-mechanisms, and regulation of cell cycle. Adrenal hypoplasia can occur: 1) secondary to defects in transcription factors involved in pituitary development or 2) defects in ACTH synthesis and secretion; 3) as a primary defect in the development of the adrenal gland; 4) as part of rare syndromes associated with adrenal hypoplasia/aplasia, which are inherited in an autosomal recessive or autosomal dominant manner; and 5) in the context of chromosomal abnormalities. Early diagnosis and management are crucial because of the life-threatening nature of the condition. Depending on the etiology, adrenal crisis may occur in early infancy or could insidiously develop over the course of childhood or adolescence. Moreover, some of these conditions previously thought to occur only in childhood, may also be diagnosed later in adulthood and present with variable phenotypes, including isolated infertility or disorders of sex differentiation. The clinical manifestations of primary adrenal insufficiency (PAI) result from deficiency of all adrenocortical hormones (aldosterone, cortisol, androgens). The acute presentation can be precipitated by physiologic stress, such as surgery, trauma, or an intercurrent infection. Patients may present with signs and symptoms of complete adrenal insufficiency, usually early in life, including hypoglycemic convulsions, hyponatremia, hyperkalemia, metabolic acidosis or later with hyperpigmentation, vomiting and poor weight gain. It should be remembered, that the most common cause of PAI in children is congenital adrenal hyperplasia due to 21-hydroxylase deficiency and can be excluded by measuring baseline or ACTH-stimulated 17-hydroxyprogesterone levels in serum. Screening for autoimmune Addison disease includes detection of 21-hydroxylase antibodies. Males with negative 21-hydroxylase antibodies should be tested for adrenoleukodystrophy measuring very–long-chain fatty acids concentrations in plasma. The presence of alacrima in patients with PAI should raise suspicion for Triple A syndrome, whereas the combination of PAI and hypogonadotropic hypogonadism in a male patient point towards X-linked adrenal hypoplasia congenita. To date, molecular genetic testing is commercially available for the identification of several genes involved in adrenal hypoplasia syndromes. The early identification of these diseases can have important prognostic and therapeutic implications for patients with respect to surveillance for associated conditions, initiation of early treatment or screening of family members who are at risk. Adrenal insufficiency is potentially life threatening, thus treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in adrenal crisis. Therapy consists of life-long replacement therapy with glucocorticoids and mineralocorticoids. Hypogonadism or other associated disorders should be treated appropriately. Screening of family members for the disease or carrier status may also be indicated and can be critical for family planning. When a monogenic cause of adrenal failure is identified, genetic counseling is indicated. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

Background: Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these risks differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. Methods and Findings: We conducted an individual participant data meta-analysis of data from 162,129 mothers and children from 37 pregnancy and birth cohort studies from Europe, North-America and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges with the risks of overweight/obesity in early- (2.0-5.0 years), mid- (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal socio-demographic and life style related characteristics. We observed that a higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (Odds Ratios (OR) for overweight/obesity in early-, mid- and late childhood, respectively: 1.66 (95% Confidence Interval (CI): 1.56, 1.78), OR 1.91 (95% CI: 1.85, 1.98), and OR 2.28 (95% CI: 2.08, 2.50) for maternal overweight, OR 2.43 (95% CI: 2.24, 2.64), OR 3.12 (95% CI: 2.98, 3.27), and OR 4.47 (95% CI: 3.99, 5.23) for maternal obesity, and OR 1.39 (95% CI: 1.30, 1.49), OR 1.55 (95% CI: 1.49, 1.60), and 1.72 (95% CI: 1.56, 1.91) for excessive gestational weight gain. The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity and excessive gestational weight gain ranged from 10.2 to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (P-values for interactions of maternal BMI with gestational weight gain: p=0.038, p<0.001 and p=0.637, in early-, mid- and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North-America and Australia, results need to be interpreted with caution with respect to other populations. Conclusions: In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.

Le diabete de type 1 (DT1) est une maladie metabolique qui exige une therapie de remplacement de l'insuline pendant toute la vie[1][1]. L'incidence du diabete apparaissant durant l'enfance augmente dans de nombreux pays du monde[2][2]. En 2002, elle se situait a 14,9/100 000 personnes chaque

Vgontzas, Alexandros N.; Legro, Richard S.; Bixler, Edward O.; Grayev, Allison; Kales, Anthony; Chrousos, George P.

To evaluate the impact of a stress management program on weight loss, depression, anxiety and stress as well as on the adoption of healthy lifestyle in adults with obesity.Adults with obesity who sought help for weight loss at a medical obesity clinic were consecutively enrolled in the study and were randomly assigned to the intervention or control group. All participants received standard instructions for a healthy lifestyle. The intervention group attended an 8-week stress management program that comprised diaphragmatic breathing, progressive muscle relaxation, guided visualization and instructions about healthy nutrition/dietary habits. Anthropometric parameters were assessed and several questionnaires were completed by all participants, at the beginning and at the end of the study.A total of 45 adults (mean age±SD 45.7±10.55 years) with obesity were enrolled in the study; 22 in the intervention group and 23 in the control group. Participants in the two groups were matched for age and BMI. Participants in the intervention group achieved a significantly larger reduction in BMI compared to the control group (ΔBMI -3.1 vs. -1.74 kg/m2 respectively, P<0.001). In addition, they displayed ameliorated depression and anxiety scores and a reduction in the health locus of control based on chance.

A virtual mid-size oil refinery, located in a high-seismicity region of Greece, is offered as a testbed for developing and testing system-level assessment methods due to direct impact from seismic shaking and without considering geohazards, such as liquefaction and surface faulting. Its characterization is offered in a dedicated repository ( https://doi.org/10.5281/zenodo.11419659 ) and it comprises (a) a comprehensive probabilistic treatment of seismic hazard tied to an open-source seismological model; (b) a hazard-consistent set of ground motion records; (c) a full geolocated exposure model with all pertinent critical assets, namely tanks, pressure vessels, process towers, chimneys, equipment-supporting buildings, and a flare; (d) the corresponding record-wise asset demands and summarized fragilities derived via nonlinear dynamic analyses on reduced-order numerical models. Background information is provided on all refinery assets to delineate their role in the refining process. Furthermore, an explicit homogenization of the damage states is proposed, translating them from the asset level to the refinery system level considering the importance of each asset on the overall operational and structural integrity of the refinery. The results can form the basis of any follow-up study that seeks to characterize the effects of cascading failures (fires, explosions), mitigation measures, seismic sequences, and operational constraints on the functionality, risk, and resilience of refining facilities.

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-β in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2.