Role of DAX-1 (NROB1) and Steroidogenic Factor-1 (NR5A1) in Human Adrenal Function

The nuclear receptor transcription factors DAX-1 (NROB1) and SF-1 (NR5A1) regulate many aspects of adrenal and reproductive development and function. Disruption of the genes encoding these factors can be associated with pediatric adrenal disease. DAX-1 mutations are classically associated with X-linked adrenal hypoplasia congenita, hypogonadotropic hypogonadism and impaired spermatogenesis. However, other phenotypes are also being reported, such as isolated mineralocorticoid insufficiency, premature sexual development, primary adrenal insufficiency in a 46,XX patient and late-onset X-linked adrenal hypoplasia congenita and/or hypogonadotropic hypogonadism. SF-1 mutations have also been associated with primary adrenal insufficiency, together with 46,XY disorders of sex development. However it is emerging that SF-1 changes are a relatively rare cause of primary adrenal failure in humans, and most individuals with SF-1 mutations have a spectrum of 46,XY disorders of sex development phenotypes. These conditions range from 46,XY females with streak gonads and miillerian structures, through children with ambiguous genitalia and inguinal testes, to severe penoscrotal hypospadias with undescended testes. Therefore, the human gonad appears to be more sensitive than the adrenal gland to loss of SF-1 function. This review will focus on the expanding range of phenotypes associated with DAX-1 and SF-1 mutations

Large Mitochondrial DNA Deletion in an Infant with Addison Disease

Abstract Background: Mitochondrial diseases are a group of disorders caused by mutations in nuclear DNA or mitochondrial DNA, usually involving multiple organ systems. Primary adrenal insufficiency due to mitochondrial disease is extremely infrequent and has been reported in association with mitochondrial DNA deletion syndromes such as Kearns-Sayre syndrome. Aim: To report a 3-year-old boy with Addison disease, congenital glaucoma, chronic pancreatitis, and mitochondrial myopathy due to large mitochondrial DNA deletion. Method: Molecular analysis of mitochondrial DNA samples obtained from peripheral blood, oral mucosa, and muscle tissue. Results: A novel large mitochondrial DNA deletion of 7,372 bp was identified involving almost all genes on the big arch of mtDNA. Conclusions: This case reaffirms the association of adrenal insufficiency and mitochondrial DNA deletions and presents new evidence that glaucoma is another manifestation of mitochondrial diseases. Due to the genetic and clinical heterogeneity of mitochondrial disorders, molecular analysis is crucial to confirm diagnosis and to allow accurate genetic counseling

The AMS-02 RICH Imager Prototype - In-Beam Tests with 20 GeV/c per Nucleon Ions -

A prototype of the AMS Cherenkov imager (RICH) has been tested at CERN by means of a low intensity 20 GeV/c per nucleon ion beam obtained by fragmentation of a primary beam of Pb ions. Data have been collected with a single beam setting, over the range of nuclear charges 2<Z<~45 in various beam conditions and using different radiators. The charge Z and velocity beta resolutions have been measured.Comment: 4 pages, contribution to the ICRC 200

In-beam tests of the AMS RICH prototype with 20 A GeV/c secondary ions

Abstract A prototype of the AMS Cherenkov imager (RICH) has been tested by means of a low intensity 20 GeV /c per nucleon ion beam coming from the fragmentation of a primary beam of Pb ions. Data have been collected for charges

Catch-Up Growth Following Fetal Growth Restriction Promotes Rapid Restoration of Fat Mass but Without Metabolic Consequences at One Year of Age

BACKGROUND: Fetal growth restriction (FGR) followed by rapid weight gain during early life has been suggested to be the initial sequence promoting central adiposity and insulin resistance. However, the link between fetal and early postnatal growth and the associated anthropometric and metabolic changes have been poorly studied. METHODOLOGY/PRINCIPAL FINDINGS: Over the first year of post-natal life, changes in body mass index, skinfold thickness and hormonal concentrations were prospectively monitored in 94 infants in whom the fetal growth velocity had previously been measured using a repeated standardized procedure of ultrasound fetal measurements. 45 infants, thinner at birth, had experienced previous FGR (FGR+) regardless of birth weight. Growth pattern in the first four months of life was characterized by greater change in BMI z-score in FGR+ (+1.26+/-1.2 vs +0.58 +/-1.17 SD in FGR-) resulting in the restoration of BMI and of fat mass to values similar to FGR-, independently of caloric intakes. Growth velocity after 4 months was similar and BMI z-score and fat mass remained similar at 12 months of age. At both time-points, fetal growth velocity was an independent predictor of fat mass in FGR+. At one year, fasting insulin levels were not different but leptin was significantly higher in the FGR+ (4.43+/-1.41 vs 2.63+/-1 ng/ml in FGR-). CONCLUSION: Early catch-up growth is related to the fetal growth pattern itself, irrespective of birth weight, and is associated with higher insulin sensitivity and lower leptin levels after birth. Catch-up growth promotes the restoration of body size and fat stores without detrimental consequences at one year of age on body composition or metabolic profile. The higher leptin concentration at one year may reflect a positive energy balance in children who previously faced fetal growth restriction

Using enhanced number and brightness to measure protein oligomerization dynamics in live cells

Protein dimerization and oligomerization are essential to most cellular functions, yet measurement of the size of these oligomers in live cells, especially when their size changes over time and space, remains a challenge. A commonly used approach for studying protein aggregates in cells is number and brightness (N&B), a fluorescence microscopy method that is capable of measuring the apparent average number of molecules and their oligomerization (brightness) in each pixel from a series of fluorescence microscopy images. We have recently expanded this approach in order to allow resampling of the raw data to resolve the statistical weighting of coexisting species within each pixel. This feature makes enhanced N&B (eN&B) optimal for capturing the temporal aspects of protein oligomerization when a distribution of oligomers shifts toward a larger central size over time. In this protocol, we demonstrate the application of eN&B by quantifying receptor clustering dynamics using electron-multiplying charge-coupled device (EMCCD)-based total internal reflection microscopy (TIRF) imaging. TIRF provides a superior signal-to-noise ratio, but we also provide guidelines for implementing eN&B in confocal microscopes. For each time point, eN&B requires the acquisition of 200 frames, and it takes a few seconds up to 2 min to complete a single time point. We provide an eN&B (and standard N&B) MATLAB software package amenable to any standard confocal or TIRF microscope. The software requires a high-RAM computer (64 Gb) to run and includes a photobleaching detrending algorithm, which allows extension of the live imaging for more than an hour

Differential Kinetics of Immune Responses Elicited by Covid-19 Vaccines

To the Editor: Previous studies have shown that the BNT162b2 (Pfizer–BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & Johnson–Janssen) vaccines provide robust protective efficacy against coronavirus disease 2019 (Covid-19). Here, we report comparative kinetics of humoral and cellular immune responses elicited by the two-dose BNT162b2 vaccine (in 31 participants), the two-dose mRNA-1273 vaccine (in 22 participants), and the one-dose Ad26.COV2.S vaccine (in 8 participants). We evaluated antibody and T-cell responses from peak immunity at 2 to 4 weeks after the second immunization in recipients of the messenger RNA (mRNA) vaccines or after the first immunization in recipients of the Ad26.COV2.S vaccine to 8 months (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org)

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic